HODGKIN'S LYMPHOMA
HODGKIN'S LYMPHOMA
Epidemiology
( US incidence = 7,500 cases/yr
3 per 100,000 people
< 1% of all cancers
( 15% of all lymphomas
( 1.3 male : 1 female
1.8 white : 1 black
( age: rare in those < 10 yr
median age = 26 yr
bimodal peak – 20’s (large peak) & > 50 yr (smaller peak)
Risk Factors
( no well defined risk factors
Relative Risk
( same-sex sibling with Hodgkin's disease 9.0
opposite-sex sibling with Hodgkin's disease 3.0
( h/o mononucleosis (EBV) 2.5
possible association with EBV infection, especially with mixed cellularity subtype -- can see high anti-EBV titers
( possible association with immunosuppression:
HIV - associated with advanced stage at presentation, systemic symptoms, & unusual pattern of involvement
transplant recipients
( increased educational level / socioeconomic status ?
( s/p tonsillectomy or appendectomy ?
Pathology
( Reed-Sternberg cell
- binucleate, prominent nucleolus, well-demarcated nuclear membrane, eosinophilic cytoplasm, perinuclear halo
- arise from germinal center or post-germinal center B-cells
- CD30+, CD15+, CD45(LCA)-, CD20-
o CD45 may be most important b/c usually + in NHL and – in HD (7% may be + in HD)
- has NF(B DNA binding activity - NF(B induces anti-apoptotic effects
( RYE Classification:
Nodular Sclerosis 65%
Mixed Cellularity 20%
Lymphocyte Predominant 10%
nodular subtype (majority)
diffuse subtype
Lymphocyte Depleted 5%
( REAL Classification:
Classic Hodgkin's Disease (95%):
Classic Lymphocyte Predominant
classic Reed-Sternberg cells – CD45-, CD20-
Nodular Sclerosis
Mixed Cellularity
Lymphocyte Depletion
Nodular Lymphocyte Predominant (5%)
scarce Reed-Sternberg cells – CD45+, CD20+ (( Rituxin may be useful)
frequent "popcorn cell" variants
background of B-lymphocytes
( Lymphocyte Predominance Hodgkin's Disease (LPHD):
Nodular Subtype:
- abundant normal-appearing lymphocytes
- scarce atypical mononuclear cells
- absence of classic Reed-Sternberg cells
- "popcorn cells": CD20+, CD45+, CD15-, CD30-
- nodular growth pattern +/- diffuse areas
- +/- progressive transformation of germinal centers (PTGCs) = enlarged follicles than contain numerous small
B cells of mantle zone type (may precede the development of this form of Hodgkin's disease)
- Incidence is evenly distributed among all ages
- 75% are early stage I an II
- Much less involvement of the mediastinum
- Rare to be Lap+ if Stage 1 Disease involving cervical, axillary, femoral LN
Diffuse Subtype:
- abundant normal-appearing lymphocytes
- classic Reed-Sternberg cells
- Acts more like HD than nodular subtype
( Nodular Sclerosis Hodgkin's Disease (NSHD):
- most common type in US
- broad bands of birefringent collagen (fibrotic nodes) surrounding macroscopic nodules consisting of
lymphocytes, eosinophils, plasma cells, histiocytes, atypical mononuclear cells, & Reed-Sternberg cells
- lacunar-type Reed-Sternberg cells (clear spaces are 2(/2 formalin fixation artifact)
- necrosis is commonly seen
- Usually involves the mediastinum/lower cervical LN
- Can be divided into
1. NSLP
2. NS Mixed Cell
3. NS Lymph depleted
• But all act with same outcomes
( Mixed Cellularity Hodgkin's Disease (MCHD):
- diffuse effacement of lymph nodes by lymphocytes, neutrophils, histiocytes, eosinophils, plasma cells, &
abundant atypical mononuclear and Reed-Sternberg cells
- Usually older pts with B symptoms
- Often have abdominal involvement
( Lymphocyte Depletion Hodgkin's Disease (LDHD):
- least common type is US
- paucity of normal-appearing lymphocytes
- abundance of abnormal mononuclear cells, Reed-Sternberg cells, & Reed-Sternberg cell variants
- diffuse fibrosis and necrosis
- With most modern techniques, most of these cases are really found to be NHL
- Most frequently found in ederly pt with advanced disease
Staging
( Ann Arbor Staging System:
stage I involvement of a single lymph node region
IE involvement of a single extralymphatic organ or site
stage II involvement of a two or more lymph node regions on the same side of the diaphragm
IIE involvement of a single extralymphatic organ or site and its regional nodes +/- other lymph node
regions on the same side of the diaphragm
stage III involvement of lymph node regions on both sides of the diaphragm
IIIE involvement of a single extralymphatic organ or site and lymph node regions on both sides of the
diaphragm
IIIS involvement of the spleen and lymph node regions on both sides of the diaphragm
IIIE+S involvement of a single extralymphatic organ or site, the spleen, and lymph node regions on both
sides of the diaphragm
stage IV involvement of multiple extralymphatic organs +/- associated lymph
node involvement or involvement of a single extralymphatic organ
with distant / nonregional lymph node involvement
( A no B symptoms
B unexplained weight loss > 10% in the 6 mo preceding diagnosis
unexplained fever > 38(C for 3 consecutive days
drenching night sweats
limitations of Ann Arbor staging system: bulky disease is not taken into account
no distinction between minimal (< 5 nodules) or extensive splenic dz
( Lymphoid Structures not considered as E-lesions:
Waldeyer's ring
thymus
spleen
appendix
Peyer's patches (ileum)
( Lymphoid Regions Defined by the Ann Arbor Staging System:
Waldeyer's ring (palatine tonsil, base of tongue / lingual tonsil, nasopharynx / adenoids)
Neck = Cervical, Supraclavicular, Occipital, & Pre-auricular
Infraclavicular
Mediastinal
Hilar
Axillary
Epitrochlear / Brachial
Paraaortic
Spleen
Mesenteric
Iliac
Inguinal / Femoral
Popliteal
( Cotswold's Modification of the Ann Arbor Staging System:
stage I involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer's ring)
IE involvement of a single extralymphatic organ or site
stage II involvement of a two or more lymph node regions on the same side of the diaphragm
IIE involvement of a single extralymphatic organ or site and its regional nodes +/- other lymph node
regions on the same side of the diaphragm
stage III involvement of lymph node regions on both sides of the diaphragm
III1 with or without involvement of splenic, hilar, celiac, or portal nodes (above renal vein)
III2 with involvement of paraaortic, iliac, and mesenteric nodes (below renal vein)
IIIE involvement of a single extralymphatic organ or site and lymph node regions on both sides of the
diaphragm
IIIS involvement of the spleen and lymph node regions on both sides of the diaphragm
IIISE involvement of a single extralymphatic organ or site, the spleen, and lymph node regions on both
sides of the diaphragm
stage IV diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without
associated lymph node involvement
( A no B symptoms
B unexplained weight loss > 10% in the 6 mo preceding diagnosis
unexplained fever > 38(C for 3 consecutive days
drenching night sweats
E involvement of a single extranodal site that is contiguous or proximal to the known nodal site
X bulky disease -- nodal mass > 10 cm in maximal dimension (many consider > 5 cm peripheral mass)
mediastinal widening > 1/3 thoracic width at T5/6 on PA up-right CxR
CS clinical stage
PS pathological stage
PS III1 = limited to the upper abdomen (splenic, hilar, celiac, & portahepatic nodes)
PS III2 = involvement of paraaortic, mesenteric, or pelvic nodes
PS IIIS + minimal = < 5 visible nodules in the spleen
PS IIIS + extensive = > 5 visible nodules in the spleen
• Note Mediastinum considered one site
• Hilar LN Considered Lateralized site
• Liver involvement includes
1. Either enlargement of liver and at least an abnl Alk Phos and 2 different LFTs abnl
2. Abnl Liver on imaging and one abnl liver LFT
Presentation
( symptoms/signs:
- painless lymphadenopathy (80%): firm or rubbery, mobile, non-tender nodes
- systemic symptoms: 15-20% of stage I-II cases
B-symptoms = unexplained fever > 38( x 3 d (classic waxing & waning Pel-Ebstein pattern)
drenching night sweats
weight loss > 10% in preceding 6 mo
generalized pruritus
alcohol-induced pain in tissues involved by Hodgkin's disease (~ 10% ??)
- mediastinal mass on CxR +/- cough, wheezing, dyspnea, SVC syndrome(rare)
- complex deficiency in cellular immunity:
- Paraneoplastic effects include
o Increased Eosinophils
o Increased Platelets (may herald relapse if present prior to therapy)
o Autoimmune anemia
o Nephrotic Syndrome
( DDx of adenopathy:
infectious – usually soft, tender, < 2 cm
located in areas that drain common infections (anterior or posterior cervical nodes)
ex. common communicable diseases, mono (EBV), CMV, HIV/AIDS, syphilis, TB
hypersensitivity reactions – serum sickness, drug pseudolymphoma
connective tissue disease – SLE, RA
primary lymphoproliferative diseases – HD, NHL, leukemia (CLL, ALL, blast crisis of CML),
Waldenstrom’s macroglobinemia
metastatic carcinomas – breast, lung, GI, H&N, skin, …
endocrine disorders – hyperthyroidism, hypoadrenocorticism, hypopituitarism
lipidoses
dermatopathic lymphadenitis
granulomatous disease – sarcoidosis
drugs – phenytoin, isoniazid, antithyroid, anti-leprosy drugs
( location:
- > 80% present with cervical lymph node involvement
- > 50% have mediastinal disease (young adults > elderly)
- 25% of elderly have isolated subdiaphragmatic disease at diagnosis (only ~ 10% overall)
- isolated extralymphatic involvement is rare
- #1 extranodal site = spleen
- 5% have BM involvement – almost always associated with extensive disease & B symptoms
- 2-6% have liver involvement – almost always occurs with concomitant splenic involvement
- rarely involves GALT, MALT, CNS, or skin
- rarely involves Waldeyer’s ring
supradiaphragmatic 90%
|nodal region | |prevalence (%) |
|mediastinum | |59% |
|neck | |70% |
| |left |58% |
| |right |55% |
|axilla | |27% |
| |left |14% |
| |right |13% |
|hilum | |23% |
| |left |12% |
| |right |11% |
|upper neck | |5% |
|infraclavicular | |3% |
|epitrochlear | |2% |
|cardiac | |1% |
subdiaphragmatic 25%
|nodal region |prevalence (%) |
|spleen |25% |
|liver |3% |
|paraaortic | |
|iliac | |
|inguinofemoral | |
|popliteal | |
|mesenteric | |
|Peyer's patches | |
|appendix | |
( PM Mauch, et al. Cancer. 71:2062-2071, 1993. - Joint Center
analyzed pattern of nodal involvement in 719 pt with HD who underwent staging lap between '69-'86
positive associations: mediastinum ( hilum and neck
ipsilateral neck ( ipsilateral axilla (75 / 398)
axilla ( upper abdomen
hilum ( upper abdomen (Also shown by the German HD group)
spleen ( upper abdomen and lower abdomen
| |LPHD |NSHD |MCHD |LDHD |
|distribution |5% |78% |16% |1% |
|median age |30 yr |26 yr |30 yr |38 yr |
|Male:female ratio |5.3:1 |1.1:1 |3.9:1 |2:1 |
|Stage: I |45% |6% |13% |0% |
| II |37% |53% |28% |13% |
| III |16% |29% |44% |33% |
| IV |1% |12% |15% |53% |
|B symptoms |2% |30% |31% |60% |
Stanford Experience with 2,116 pt treated between '68-'96
Work-up
( history:
adenopathy, B symptoms (30% to 40%), alcohol intolerance, pruritus, energy loss, respiratory problems
( physical exam:
nodal chains, size of liver & spleen, Waldeyer's ring, bony tenderness
( laboratory studies:
CBC (often see a mild pancytopenia 2(/2 paraneoplastic effect) Anemia also possible
lytes, BUN/Cr
LFTs (alk phos = nonspecific marker of tumor activity or hepatic, BM, or bone involvement)
LDH (may reflect tumor burden)
ESR & serum copper (may correlate with disease activity)
(2-microglobulin
( radiographic studies:
CxR (60% will have evidence of intrathoracic involvement)
CT chest / abd / pelvis (info on chest CT alters the RT plan in ~ 15%)
- 70% sensitivity for paraaortic nodes & 30% for pelvic nodes
- 92% specificity for paraaortic nodes
- 58% accuracy for spleen
PET scan
- 18F-FDG (18F-fluorodeoxyglucose)
- may be more sensitive than Gallium scan
- especially important for NSHD
- useful in assessing residual masses on CT scan after chemo ( if (+), 60-90% relapse with observation
- Up to 20% of adults with – PET and residual mass will eventually have a relapse
Weihrauch, et al. Blood. 98:2930-2934, 2001. – Germany
prospective study
29 pt with HD and residual mediastinal mass > 2 cm after chemo underwent 18FDG-PET between 1994-2000
minimum f/u = 1 yr
median f/u = 28 mo
all (+)PET scans showed only uptake in the mediastinum
|PET scan result |relapse rate |1-yr DFS rate |
|negative (n=19) |16% |95% |
|positive (n=10) |60% |40% |
PPV = 60%
NPV = 95%
all relapsing pt with (+)PET scan relapsed in the mediastinum only
conclusions = pt with a residual mass after chemo but (-)PET are unlikely to relapse & can be observed
Mikhaeel, et al. Ann Oncol. 1:147-150, 2000. – UK
32 pt with residual mediastinal mass > 2 cm after chemo (15 HD, 17 NHL) underwent 18FDG-PET
median f/u = 38 mo
|PET scan result | |relapse rate |
|negative (n=23) |HD (n=11) |0% |
| |NHL (n=12) |17% |
|positive (n=9) |HD (n=4) |75% |
| |NHL (n=5) |100% |
Naumann, et al. Br J Haematol. 115:793-800, 2001. – Germany
58 pt with residual mediastinal mass > 1 cm after chemo (43 HD, 15 NHL) underwent 18FDG-PET
median f/u = 36 mo
HD – all (+)PET scans showed only uptake in the mediastinum
|PET scan result | |relapse rate |
|negative – SUV < 3 (n=50) |HD (n=39) |0% |
| |NHL (n=11) |18% |
|positive – SUV > 3 (n=8) |HD (n=4) |25% |
| |NHL (n=4) |100% |
N Maisey, et al. Eur J Cancer. 36:200-206, 2000. – Royal Marsden
prospective study
24 pt with residual mass after treatment (33 HD, 25 NHL) underwent 18FDG-PET between 1990-96
median f/u = 29 mo
|PET scan result | |relapse rate |relapse pattern |
|negative (n=15) |HD (n=9) |44% |75% at site of residual mass |
| | | |25% at other sites |
| |NHL (n=6) |33%% | |
|positive (n=9) |HD (n=3) |0% |5 of 6 at sites of residual mass |
| | | |1 of 6 at other sites |
| |NHL (n=6) |67% | |
K Spaepen, et al. Br J Haematol. 115:272-278, 2001. – Belgium
60 pt with HD treated with chemo + RT & underwent 18FDG-PET after chemo and again after RT
median f/u = 955 days
PET post-chemo & pre-RT – 49 negative, 11 positive
| | |2-yr PFS rate |
|PET post-chemo + RT |negative (n=55) |91% |
| |positive (n=5) |0% |
Gallium-67 scan
- 10 mCi Ga67 given IV and binds to transferrin
- 85% sensitivity for NSHD
- especially important for NSHD
- especially useful in detection of residual disease after treatment (NSHD often leaves scar) & recurrent disease
- normal uptake occurs in the spleen, liver, and bowel ( therefore, not as good for infradiaphragmatic dz
- useful to distinguish residual mass vs necrosis/fibrosis
King, et al. J Clin Onc. 12:306-311, 1994. –
Bipedal Lymphangiogram (LAG)
- indications: CS I-II subdiaphragmatic dz
equivocal abdominal CT
CS I-II supradiaphragmatic dz, no staging lap, intend RT only
- can not evaluate obturator, hypogastric, splenic, or mesenteric nodes
- lymphatic vessels between 1st and 2nd toes on each foot are cannulated with 27G needle
- filling phase films taken 1 hr after dye injection
- nodal phase films taken 24 hr after dye injection
- 85% sensitivity for pelvic and paraaortic nodes
- 95% specificity
- contraindications 2(/2 pulmonary microemboli = poor pulmonary function, ASD, VSD
( special studies:
cytologic examination of effusions, if present
+/- bone marrow bx
- indications = stage III-IV
B symptoms
(WBC, (RBC, (plt
consider for:
bulky dz
- needle aspirate and biopsy via posterior iliac crest
- not performed if clinical stage IA or IIA supradiaphragmatic non-bulky disease
+/- percutaneous liver biopsy
+/- staging laparotomy
- thorough exploration of abdominal cavity + sample LNs from splenic, porta hepatis, celiac, & PA regions
+ splenectomy + wedge bx of right lobe of liver + needle biopsy of both lobes of liver + bilateral BM
biopsy +/- oophoropexy
- indicated only if it alters stage in a way that alters therapy (ie. if considering RT alone for stage I-IIA)
- 30% of clinical stage I-II are up-staged (#1 location = spleen)
- 25% of clinical stage III are down-staged
- appropriate in patients with > 10% risk of subdiaphragmatic disease
- low yield (6-9%) -- female with clinical stage IA supradiaphragmatic disease
clinical stage IA supradiaphragmatic disease located in peripheral site (ex. high neck)
clinical stage IA LPHD, nodular subtype
- high yield (25-35%) -- clinical stage IIA
clinical stage IB & IIB
- immunization prior to splenectomy (Pneumovax for pneumococcal pneumonia, …)
( fertility issues:
if pelvic RT is contemplated in men, consider sperm banking
if pelvic RT is contemplated in women, perform oophoropexy (move ovaries to midline low pelvis behind uterus & clipped)
( tissue diagnosis:
FNA of enlarged lymph node is inadequate
excisional / incisional biopsy of enlarged lymph node allows examination of architecture
steroid administration can obscure diagnosis
( P Mauch, et al. J Clin Onc. 8:257-265, 1990. - Joint Center
retrospective review
552 pt with clinical stage I-II Hodgkin's disease underwent staging lap from
|group |# pt |upstaged |
|female |256 |18% |
|male |296 |29% |
|no B symptoms |444 |21% |
|B symptoms |108 |34% |
|1 site |171 |17% |
|> 2 sites |381 |27% |
|IA, female |65 |6% |
|IA, male |90 |18% |
|IA, 1 site (peripheral) |18 |6% |
( M Leiberhaut, et al. J Clin Onc. 7:81-91, 1989. - Stanford University
retrospective review
915 pt with supradiaphragmatic clinical stage I-II Hodgkin's disease undergoing staging lap from 1968-86
|clinical stage | |# pt |upstaged |extensive splenic involvement |
|I |no B symptoms |126 |21% |6% |
| |B symptoms |11 |9% |9% |
| |LPHD |19 |10% |0% |
| |NSHD |67 |16% |4% |
| |MCHD |39 |31% |13% |
| |female |33 |6% |0% |
| |male |104 |24% |9% |
|II |no B symptoms |615 |31% |13% |
| |B symptoms |163 |28% |16% |
| |LPHD |18 |22% |0% |
| |NSHD |655 |27% |11% |
| |MCHD |89 |52% |34% |
| |female |363 |22% |9% |
| |male |415 |36% |17% |
|All |1 site | |20% | |
| |2 sites | |29% | |
| |3 sites | |26% | |
| |> 4 sites | |33% | |
Natural History
( Nodular Sclerosis Hodgkin's Disease (65%)
- adolescents and young adults typically age 20-40 yr
- 1 male : 1 female
- usually involves lower cervical nodes &/or mediastinum
- frequent thymic involvement
- 60% are stage I-II
- 30% are stage III
- 30% have B-symptoms
- less favorable prognosis than LPHD
( Mixed Cellularity Hodgkin's Disease (20%)
- seen at any age & lacks the early adult peak of NSHD (usually > 40 yr)
- male > female
- less commonly involves the mediastinum
- more commonly presents with abdominal lymph node and splenic involvement
- 60% are stage III-IV
- 30% have B symptoms
- less favorable prognosis than NSHD
( Lymphocyte Predominance Hodgkin's Disease (10%)
- typically age < 16 or > 40 yr
- 3 male : 1 female
- usually involves peripheral LNs and spares the mediastinum
- 85% are stage I-II
- 5% have B-symptoms
- 10-yr overall survival = 90%
- Nodular Subtype:
- long natural history with late relapses are more common than with other types of Hodgkin's disease
- higher risk of developing NHL than with other types of Hodgkin's disease
- many consider it a form of low grade B-cell lymphoma
- 2-6% transform into large cell lymphoma (usually B-cell)
( Lymphocyte Depletion Hodgkin's Disease (5%)
- commonly seen in elderly people, HIV+ patients, & non-industrialized countries
- commonly presents with abdominal adenopathy, with spleen, liver, and bone marrow involvement
& without peripheral lymphadenopathy (ie. advanced stage at diagnosis)
- 85% are stage III-IV
- 60% have B-symptoms
- worst prognosis
( risk of occult subdiaphragmatic disease on staging laparotomy:
|clinical stage |upstaging rate |
|I, LP |10% |
|I, NS |15% |
|I, MC |30% |
|IA, female |6% |
|IA, male |18% |
|IB |25% |
|IIA or IIB |30% |
Essentially all IIA, IB, MC- 30% risk of upstaging
( relapse pattern:
| |median time to relapse |
|lymphocyte predominant |5 yr |
|stage I-IIA |2.5 yr |
|bulky dz |1.5 yr |
80% of relapses occur within 5yr
|initial treatment |relapse pattern |
|RT |outside RT field |
|Chemo |original site of disease |
• Nodal Recurrence is 50-60% after CT alone with bulky disease
( spread pattern:
- spreads to contiguous lymph node groups (SC nodes & upper PA nodes-celiac axis-spleen are contiguous via the thoracic duct)
- visceral involvement 2(/2 extension from adjacent lymph node regions
- direct correlation between extent of disease in the spleen and the likelihood of hematogenous dissemination
- nearly all pt with hepatic or bone marrow involvement have extensive splenic involvement
Prognostic Factors
( age > 40 yr do worse
- Worse OS rate, but not higher RR compared to younger patients
- Only older age has been consistently found to be a significant adverse factor for survival with combined therapy
( stage
( B-symptoms: pt with both wt loss and fever have a particularly poor prognosis
MJ Crunkovich, RT Hoppe, et al. J Clin Onc. 4:472, 1986. & 5:1041, 1987. -
( bulk of disease: pt with > 10 cm bulk or large mediastinal adenopathy (LMA) do worse
Bradley, et al. J Clin Onc. 2493-2498, 1999.
- Approx 50% RR with bulky mediastinal disease treated with RT alone
( histologic type: (best) LPHD ( NSHD ( MCHD ( LDHD (worst)
stage-for-stage they all do about the same
( ESR > 40 do worse (ESR prognostically for HD & LDH for NHL)
( E-lesions do worse
Outcomes
( Stanford Experience with 2,116 pt treated between '68-'96:
|histology |survival |relapse-free survival |
| |5-yr |10-yr |15-yr |5-yr |10-yr |15-yr |
|LPHD |95% |84% |76% |94% |87% |84% |
|NSHD |89% |82% |75% |75% |72% |71% |
|MCHD |83% |72% |60% |75% |72% |70% |
|LDHD |67% |44% |33% |45% |38% |19% |
( Stanford Experience with 1,678 pt treated between '74-'95:
|stage |survival |freedom from relapse |
| |5-yr |10-yr |20-yr |5-yr |10-yr |20-yr |
|I-II (n=978) |93% |88% |79% |85% |81% |80% |
|IIIA (n=330) |92% |83% |69% |77% |75% |72% |
|IIIB (n=168) |81% |72% |55% |75% |73% |71% |
|IV (n=202) |78% |67% |47% |59% |57% |54% |
( Stanford Experience between 1980-94:
|stage |# pt |5-yr OS |10-yr OS |5-yr DFS |10-yr DFS |
|I-II, RT alone |367 |95% |90% |83% |78% |
|I-II, Chemo + RT |231 |95% |92% |89% |89% |
|IIIA |188 |92% |86% |83% |79% |
|IIIB-IV |215 |80% |71% |69% |69% |
| |# pt |5-yr OS |10-yr OS |5-yr DFS |10-yr DFS |
|laparotomy staging (PS I-IIA) |233 |96% |92% |85% |80% |
|clinical staging (CS I-IIA) |92 |91% |91% |86% |86% |
( outcome by stage: ??
|Stage |10-yr OS rate |10-yr DFS rate |
|IA |95% |90% |
|IB |90% |85% |
|IIA |90% |85% |
|IIB |85% |80% |
|IIIA |85% |80% |
|IIIB |75% |70% |
|IV |65% |60% |
cure rate: stage I-II 80%
stage III-IV 60%
( after 12 yr, death from other causes dominates the causes of death
Early Stage Patients
# Pt Stage F/u Therapy 5 yr OS 5 yr DFS
Full dose IR alone (IR or EF)
Stanford (Donaldson JCO 8: 128, 1990) 48 PS I/II 10 yrs EF RT 86% 82%
Intergroup (Gehan 65: 1429, 1990) 39 PS I/II 5 yrs IF RT 95% 41%
58 PS I/II 5 yrs EF RT 96% 67%
Full Dose RT + CT
Intergroup (Gehan 65: 1429, 1990) 97 PS I/II 5 yrs IF RT 90% 95%
MOPP x 6
Low Dose RT + CT
Stanford (Hunger JCO 12: 2160, 1994) 27 PS I/II 10 yrs MOPP x 6 100% 96%
(Donaldson Pediatr Clin No Am 38: 457, 1991) 44 CS/PS I-III MOPPx3/ABVDx3 100% 100%
St Judes’ (Hudson JCO 11: 100, 1993) 28 CS I-IIB 5 yrs IF RT + COP(P)x4-5 96% 96%
Or IF RT + ABVDx3-4
CT Alone
Uganda (Olweny Cancer 42: 787, 1978) 38 CS I/II 5 yrs MOPP x 6 100% 100%
Advanced Stage Patients
# Pt Stage F/u Therapy 5 yr OS 5 yr DFS
Stanford (Hunger JCO 12: 2160, 1994) 28 III-IV 7.5 yrs IF 15-25 Gy 78% 84%
MOPP x 6
(Donaldson Pediatr Clin No Am) 13 IV 10 yrs IF 15-25 Gy 85% 69%
MOPPx3/ABVDx3
French (SFOP) 69 I/IIB, III-IV 2.5 yrs IF + PA 20 Gy 95% 93%
(Dionet IJROBP 15: 341, 1988) MOPPx3/ABVDx3
CCG 521 111 III-IV 3 yrs no RT 90% 77%
(Hutchinson Med Pediatr Onc 21: 61, 1993) MOPPx 6/ABVDx6
III-IV 3 yrs IF 21 Gy
ABVD x 6 90% 84%
POG (Weiner JCO 9: 1591, 1991) 62 IIB-IV 3-5 yrs TNI 21 Gy 91% 77%
MOPPx4/ABVDx4
(Weiner JCO 15: 2769, 1997) 81 IIB, IIIA2 no RT 96% 79%
MOPPx4/ABVDx4
80 IIIB, IV IF 21 Gy 87% 80%
MOPPx4/ABVDx4
SIOP 65 IV 8 yrs IF 20 Gy
(Schellong Baillieres Clin Haem 9: 619,1996) OPPAx2/COPPx4 93% 78%
St. Jude 57 III-IV ?? IF 20 Gy 93% 93%
(Hudson JCO 11: 100, 1993) COP(P)x4-5/ABVDx3-4
Treatment
Chemotherapy
( MOPP:
- first successful drug combination
- Mechlorethamine (Nitrogen Mustard) 6 mg/m2 IV on days 1 and 8
- Vincristine (Oncovin) 2 mg/m2 IV on days 1 and 8
- Procarbazine 100 mg/m2 PO on days 1-14
- Prednisone 40 mg/m2 PO on days 1-14
- q4wk cycle
- acute toxicity = N/V, peripheral neuropathy, constipation, leukopenia, thrombocytopenia
- late toxicity = sterility (80%), AML (5% with latency period of 3-7 yr)
- Less sterility with 3 cycles of MOPP
COPP
- Same as above but substitute cyclophasphamide for mechlorethamine
( ABVD:
- Adriamycin 25 mg/m2 IV on days 1 and 15 ( maximum cumulative dose = 450 mg/m2
- Bleomycin 10 mg/m2 IV on days 1 and 15
- Vinblastine 6 mg/m2 IV on days 1 and 15
- Dacarbazine 375 mg/m2 IV on days 1 and 15
- q4wk cycle
- acute toxicity = N/V, hair loss, myelosuppression (less than with MOPP)
- late toxicity = cardiac, pulmonary
o In comparison to MOPP, ABVD showed higher FFP but no significant difference in OS
• EBVP II
- Epirubicin
- Bleomycin
- Vinblastine
- Prednisone
( MOPP/ABVD:
- MOPP on days 1-14
- ABVD on days 29 and 43
- q8wk cycle
- non-cross-resistant drugs are used to prevent emergence of resistant clones
( MOPP-ABV hybrid:
- MOPP on days 1-7
- Adriamycin 35 mg/m2 IV on day 8
- Bleomycin 10 mg/m2 IV on day 8
- Vinblastine 6 mg/m2 IV on day 8
- Prednisone 40 mg/m2 PO on days 8-14
- q4wk cycle
( PAVe: Procarbazine, Alkeran, Vinblastine
( VBM: Vinblastine, Bleomycin, Methotrexate
( BCVPP: BCNU, Cytoxan, Vinblastine, Procarbazine, Prednisone
( ChlVPP: Chlorambucil, Vinblastine, Procarbazine, Prednisone
( MVPP: Mechlorethamine, Vinblastine, Procarbazine, Prednisone
( EBVP: Epirubicin, Bleomycin, Vinblastine, Prednisone
( Stanford V: Adriamycin, Vinblastine, Mechlorethamine, Vincristine, Bleomycin, Etoposide, Prednisone
aka. ABV/MO Prednisone Etoposide
( BEAM: BCNU, Etoposide, Ara-C, Melphalan (preparation for BMT
• Number of cycles
- Some data suggest that 4 cycles may be as effective as 6 cycles in controlling occult abdominal disease
- But uncertain on the number of cycles needed to control microscopic disease
- Current German study is randomizing pt to 2-4 cycles of ABVD and IF RT
Radiation Therapy
- RT considerations
o Never more than 150 cGy/d when entire heart or lungs are in field
o Dose inhomogeneity can be improved with extended SSD
o Rec 6 mV Mantle and 6-18 mV Para-aortic
- IF considerations
o Treat a region, not an individual LN
o Usually use involved pre-chemotherapy sites and volume with the exception of the transverse diameter of the mediastinal and para-aortic LN for which post-chemo volumes used
o Supraclavicular LN are considered as part of cervical region and if involved alone or with other cervical LN, the whole unilateral neck is treated. If the supraclav is an extension of mediastinal disease and other neck areas are not involved (CT and PET) the upper neck (above larynx) is spared
Unilateral Cervical/Supraclavicular Field:
Indications: Involvement of any cervical level with or without involvement of supraclav
Simulation
Arms akimbo or at sides
Borders
Superior= 1-2 cm above the tip of mastoid process and midpoint through the chin
Lower = 2 cm below the bottom of the clavicle
Lateral = Medial 2/3 of the clavicle
Medial = Supraclav LN not involved, place border at ipsilateral transverse process (unless original LN
on staging CT lies close to vertebral bodies and then the entire vertebral body is included)
Supraclav LN + -- Then Border placed at the contralateral transverse process
For Stage 1 pts the larynx and vertebral bodies above larynx can be blocked
Blocking:
Posterior cervical block is required only if cord dose >40 Gy. (mid neck calcs should be done)
Block Larynx unless LN in field. If treat Larynx, add block at 1980 cGy
[pic]
Bilateral Cervical/Supraclavicular Field:
Simulation
Arms akimbo or at sides
Borders
Superior= 1-2 cm above the tip of mastoid process and midpoint of chin
Lower= 2 cm below the bottom of the clavicle
Lateral= Medial 2/3 of the clavicle
Blocking
Posterior cervical block is required only if cord dose > 40 Gy (mid neck calcs should be done)
Block larynx unless LN In field in which case add block at 1980 cGy
Axillary Region:
Indications: Axilla involvement
Target volume: ipsilateral axillary, infraclavicular and supraclavicular
Simulation
Arms should be up or akimbo
Borders
Superior = C5-C6 interspace
Inferior border = The lower of either
a. Tip of the scapula
b. 2 cm below the lowest axillary LN
Medial = Ipsilateral cervical transverse process. Include vertebral bodies only if the SCL are involved
Lateral = Flash axilla
[pic]
( Mantle Field:
dental exam & fluoride tx before RT
General Reference points: Sternal notch T2-T3, carina T5, Xyphoid T10,
target volume:
- all major lymph node regions above the diaphragm (submandibular, cervical, supraclavicular, infraclavicular, axillary,
mediastinal, & hilar nodes)
- excludes pre-auricular nodes and Waldeyer's ring
- post-chemo volumes) for lateral extent only, use pre-chemo volumes for craniocaudal extent
- approx 8 cm wide
simulation:
- supine with (-cradle immobilization
- may have to treat PA field prone if gantry can't rotate 180( with extended SSD (110-130 cm)
- neck hyperextended; tape chin & forehead – allows tx of submandibular nodes yet moving the oral cavity out of the field
- arms above head (adults) – pulls axillary nodes laterally & allows more lung to be shielded
can’t block humeral heads b/c lower axillary nodes move up toward it
- hands on hips / akimbo (prepubertal kids) – allows blocking of the humeral epiphysis, but treats more lung
- Hands on hips used unless treating axillary LN
- BB on thyroid notch
- BB on dose-calculation points – axilla, SCF, …
- wire around enlarged nodes or on scar if node excised
- Recommend placing wire around the breast in females
Set-up Considerations
- 7 point set up technique is used for positioning
CAX (central axis), Right and left points
- 2 points along horizontal axis spaced 10 cm from CAX to facilitate shoulder alignment
- 1 point at the inferior border
- 1 point at the superior border
AP/PA with 6 MV photons prescribed at MPD (C-spine runs at ~ 110%; higher energy would underdose superficial nodes)
perform an irregular field point calculation for each important nodal group & isocenter:
central axis isocenter at MPD
neck midway from upper border to base of neck at anterior border of SCM muscle
SCF 1-2 cm medial to mid-clavicular line & just superior to the clavicle
axillae apex of axilla at MPD
mid-mediastinum mid-point of sternum at MPD
lower-mediastinum 3 cm above the lower border of the field at MPD
borders:
superior = (AP) BB just above mentum (dip between lip & chin) to split mandible but spare teeth
(PA) lower 1/3 of mastoid process / tragus
inferior = T9/10 interspace (covers diaphragm insertion)
possibly T8/9 to avoid spleen if treating paraaortic field – watch breathing under fluoro and place
border above cephalad excursion of diaphragm
lateral = lateral edge of humeral head / surgical neck of humerus to include axilla
Borders: For LN – disease in neck suggested ASTRO 2002
Superior = C5-C6 interspace. If supraclavicular LN involved, top should be at top of larynx
Inferior = 5 cm below carina OR 2 cm below pre-chemotherapy volume
Lateral = 1.5 cm margin on post-chemotherapy volumes
Hilar = 1.0 cm margin on hila unless involved and then 1.5 cm
Borders for LN + disease in neck
Mantle without the axilla if both necks involved
If only one neck involved, then contralateral upper neck and larynx can be blocked as per neck guidelines.
Neck above larynx should be shielded at 3060 cGy
If Para cardiac LN are involved, the whole heart should be treated to 14.4 Gy and initially involved LN
treated to 3060
blocking:
(1) lung blocks
superior = (AP) 2 cm below clavicle to include IC nodes
(PA) may be closer to clavicle b/c nodes & clavicle are anterior (?along posterior 4th rib)
lateral = 1 cm margin on chest wall to insure adequate coverage of axillary nodes
extend straight laterally @ 6th rib junction with CW below axilla (~ tip of scapula)
medial = 1 cm margin on superior mediastinum
1.5 cm margin on hilum (ie. bifurcation of mainstem bronchus)
if no bulky mediastinal dz or pericardial LAD, block at transverse processes (8 cm wide)
below hilum to treat mediastinum but maximally shield heart ( add subcarinal block
at 30 Gy (horizontal line 5 cm below carina)
if bulky mediastinal dz with subcarinal extension, pericardial LAD, or pericardial effusion,
initial medial border of left lung block is 1 cm along the cardiac border to treat entire
cardiac silhouette ( add apex block (at transverse processes to include mediastinum only – 8 cm
wide) at 15 Gy ( may add subcarinal block at 25-30 Gy if not blocking disease
if bulky mediastinal dz, consider using shrinking-field technique after each 15 Gy
(re-sim after 10-14 d break ( widen lung block as tumor shrinks)
(2) subcarinal heart block
add at 30 Gy (consider adding at 25 Gy if prior adriamycin)
horizontal line 5 cm below the carina
omit if subcarinal LAD
(3) for pulmonary involvement,
if RT alone, use 37% partial transmission lung blocks to deliver ~ 15 Gy to whole lung
if Chemo + IF RT, treat only residual pulmonary disease ??
(4) trapezoid larynx block in AP field
add at 20 Gy unless involved LN near larynx
~ 2 cm long (thyroid notch to cricoid cartilage) x 2 cm wide (between pedicles)
omit if anterior cervical LAD
clinically ( set-up of block on machine to ensure not blocking cervical nodes
(5) humeral heads in AP & PA fields if akimbo position (esp. children)
along inferior edge of humerus, around humeral head, 1 cm medial & above AC-joint, then lateral
(6) occipital block in PA field
blocks divergence thru oral cavity
borders: superior = field edge
inferior = block lips & commissure, stay just above lower teeth so not to block level I nodes
lateral = 2 cm mandible margin so not to block level II nodes
(7) C-spine cord block in PA field
add at beginning or at 30 Gy
2 cm wide with inferior extent @ bottom of C7
prevents overdosing of the C-spine & Lhermitte's syndrome
important if needs BMT in future b/c TBI is ~ 10 Gy
remember, C-spine gets ~ 110% of daily dose (ex. 36 Gy in 1.8 Gy fx ( C-cord sees 40 Gy in 2 Gy fx)
(8) 2 x 2 cm long midline cheater block at inferior border of PA field
avoids spinal cord overlap between mantle and paraaortic fields
OK b/c lymphatics are sparse here
prescription:
RT alone: field1 = mantle + entire cardiac silhouette
dose1 = 1500 cGy in 150 cGy x 10 fx
field2 = add cardiac apex block
dose2 = 1440 cGy in 180 cGy x 8 fx (total = 2940 cGy)
field3 = add subcarinal block
dose3 = 720 cGy in 180 cGy x 4 fx (total = 3660 cGy)
field4 = bulky dz
dose4 = 360-900 cGy in 180 cGy x 2-5 fx (total = 4020-4500 cGy)
field1 = mantle
dose1 = 3060 cGy in 180 cGy x 17 fx
field2 = add subcarinal block
dose2 = 540 cGy in 180 cGy x 3 fx (total = 3600 cGy)
field3 = bulky dz
dose3 = 360-900 cGy in 180 cGy x 2-5 fx (total = 3960-4500 cGy)
Chemo + RT: field1 = involved nodal regions
dose1 = (non-bulky dz) 3060 (CR) – 3600 (PR)
(bulky dz) 3600 (CR or PR)
( Mini-Mantle Field:
sim as above
includes bilateral necks + bilateral axilla + upper mediastinum to level of the carina
[pic]
( High-Mantle Field:
indications:
unilateral cervical nodal involvement above hyoid bone or preauricular involvement
additional target volume:
ipsilateral preauricular & postauricular nodes
borders:
superior border is extended to top of pinna of ear
blocking:
oral cavity and contralateral parotid gland
put wire on mentum
medial – ipsilateral commissure of lips
lateral – mid-mandible
( Preauricular Field:
indications:
clinical involvement of the preauricular nodes
prophylactically when cervical nodes above thyroid notch are clinically involved
target volume:
preauricular nodes
unilateral field with 8-9 MeV e- (spares opposite parotid)
borders:
superior = bisects sphenoid sinus / top of zygomatic arch / 2 cm above tragus / just below superior edge of helix
inferior = matched on skin to the mantle field
posterior = just anterior to the external auditory canal
anterior = posterior to last molar / anterior edge of masseter muscle
dose:
RT alone = (prophylactic) 3000 cGy
(gross dz) 3600 cGy
Chemo + RT = (gross dz) 3060 cGy
( Waldeyer Field:
Waldeyer's ring = palatine tonsil, base of tongue (lingual tonsil), nasopharynx (adenoids)
indications:
involvement of tonsils, nasopharynx, or bilateral preauricular nodes
bulky upper cervical nodes, not adequately covered by a mantle field
target volume:
submandibular, preauricular, occipital, and upper cervical nodes
bilateral opposed fields
6 MV photons
wires on lateral bony canthi during sim
borders:
superior = bisects sphenoid sinus / inferior pituitary fossa
inferior = matched to mantle field below gross dz (thyroid notch if possible; otherwise low neck) – ? HBB both fields
posterior = cover spinous processes
anterior = flash mandible
blocking:
bisect mandible to block portion of oral cavity
posterior ¼ of orbits, posterior 1/3 of nasal cavity
( Extended Mantle Field:
includes paraaortics and spleen, thus avoiding matching problems
requires extended SSDs and limited to short pt
not used much anymore b/c of increased morbidity
( Epitrochlear Field::
nodes located in medial half of arm if rotated outward
( Subdiaphragmatic Fields:
2 wk break between mantle and paraaortic field b/c of fatigue and to allow bone marrow to recover
If you know you will be treating spleen/PNI at time of mantle, need to consider where to match and watch
breathing under flouro
matching techniques:
(1) at MPD*
set up mantle field
calculate gap (typically ~ 1-2 cm)
G1 = ½L1 ( field size at MPD* _G1 = ½L1 ( field size on skin with ruler
MPD SAD d SSD
potential cold spot in front of vertebral bodies where paraaortic nodes are located
typically not a problem b/c lymphatics are sparse around level of the diaphragm where match is
could use asymmetric jaws on mantle field so divergence is the same as the paraaortic field
2) Skin Gap
S1 = L1/2 * d/SSD1 where L is field width and e is depth at which 2 field edges cross
Total gap = S1 + S2
(d)S = S1 – S2
Give 4-6 week treatment break between mantle and paraaortic fields
Use asymmetric jaws to maintain same angle of divergence between inf mantle and sup PA
Alternatively, a 2 x 2 cm cord block can be placed at border of PA field
(2) at anterior edge of vertebral body ???
set up PA mantle field and mark inferior border on skin with wire
match PA paraaortic field exactly
Paraaortic / Splenic Pedicle Field
sim with CT or IVP for kidney position
target volume:
paraaortic, celiac, splenic, hepatic nodes
spleen or splenic pedicle
AP/PA with 18 MV photons
borders:
superior = matched to the mantle field (T8/9) with calculated gap
inferior = L4/5 interspace (aorta bifurcates at L3-4)
left = outer rib cage
right = transverse processes
splenic pedicle + 2.5-3 cm margin on clips if s/p splenectomy
spleen + 1.5 cm margin (post-chemo vol), if present (only 1 cm margin in region of kidney)
2 x 2 cm cheater block in superior edge of PA field (OK b/c lymphatics are sparse here)
Para-aortic Field
Superior = Top of T11 and at least 2 cm on pre-chemo volumes
Lower = Bottom of L4 and at least 2 cm of pre-chemo volumes
Spade Field:
sim with CT or IVP for kidney position
target volume:
paraaortic, celiac, splenic, hepatic nodes
spleen or splenic pedicle
common iliac nodes
borders:
superior = matched to the mantle field (T8/9) with calculated gap
inferior = below aortic bifurcation at S1/2 (~ L5/S1 & no lower than top of SI joints if female with no oophoropexy)
lateral = splenic pedicle + 2.5-3 cm margin on clips if s/p splenectomy
entire spleen + 2 cm margin, if present (only 1 cm margin in region of kidney)
transverse processes down to L4
oblique line from lateral tip of transverse process of L4 to point 1.5-2 cm beyond pelvic inlet
Inguinal/Femoral/External Iliac Region:
Groups are treated together if any are involved
Borders
Superior – Middle of SI joint
Inferior – 5 cm below lesser trochanter
Lateral – greater trochanter and 2 cm lateral to initially involved LN
Medial- medial border of the obturator foramen with 2 cm medial to involved LN
Note if common iliac LN are involved, the field should be extended to L4-L5 interspace
Inverted Y Field:
target volume:
paraaortic, celiac, splenic, hepatic nodes
spleen or splenic pedicle
pelvic nodes
simulation:
supine
fluoroscopy – watch spleen motion with breathing & include entire hemidiaphragm with upper border
CT planning:
depth of inguinal nodes for calculation point
determines position of spleen & kidneys
AP/PA with 18 MV photons
borders:
superior = matched to the mantle field (T8/9) with calculated gap
if no prior mantle field, watch spleen move under fluoro and include entire hemidiaphragm
inferior = bottom of obturator foramen (female) or ischial tuberosities (male)
left = outer rib cage
right = transverse processes
splenic pedicle + 2.5-3 cm margin on clips if s/p splenectomy
entire spleen + 2 cm margin, if present (only 1 cm margin in region of kidney)
diverge at L4/5, 1.5-2 cm lateral to pelvic inlet, & spare femoral head
blocking for pelvic field:
iliac wing blocks to spare bone marrow
midline block for bladder & rectum – superior = top of femoral heads vs symphysis pubis ???
lateral = medial edge of obturator foramina
if s/p oophoropexy, use 10 HVL thick block & ensure ovaries under block by at least 2 cm
testicular shield – ~ 1 cm thick lead shield
not designed to block 6 MV photons (~ 5 cm lead), just scattered lower energy photons
used if can position it under the MLB; otherwise, leave it out
dose: RT alone: subclinical dz = 3060 cGy
gross dz = 3600 cGy
bulky dz = 3960 cGy
post-chemo RT: (non-bulky dz) 3060 cGy (CR) – 3600 cGy (PR)
(bulky dz) 3600 cGy (CR or PR)
Inverted Y Including Inguinal Nodes
see above
6 MV photons to adequately dose groin nodes – if pt separation > 25 cm may need ( energy + 1 cm bolus
borders:
superior = watch spleen move under fluoro and include entire hemidiaphragm
inferior = 8 cm below inguinal ligament or straight line 2.5 cm below ischial tuberosity
lateral = right transverse processes
splenic pedicle + 2.5-3 cm margin on clips if s/p splenectomy
entire spleen + 2 cm margin (1 cm margin near kidney), if present
diverge at L4/5, 2 cm lateral to pelvic inlet
cover medial 2/3 of inguinal ligament (ant sup iliac spine ( pubis) or lateral edge of femoral head
Whole Lung Field:
May give chemo with pulmonary parenchymal involvement and then RT to post-chemo volumes which may
mean no lung RT
Typically treat Mantle field with infereior border at diaphragmatic crura (T12)
Lungs are treated through a partial (50%) transmission blocks
Dose is 10 – 15 Gy in 0.9 Gy fractions
STAGE IA, IB, & IIA SUPRADIAPHRAGMATIC HODGKIN'S DISEASE
Age > 16 yr
( initial therapy is determined by prognostic factors such as number of nodal regions involved, size of nodal
involvement, pt age, & presence of B-symptoms
Clinical Stage IA & IIA with “favorable” features defined by the EORTC studies (~ 60% of stage I-II pt)
1-3 nodal sites involved
no bulky disease (LMA (> 1/3 thoracic diameter at T5/6) or > 5 cm for peripheral nodes)
no B-symptoms (EORTC uses no B-sx + ESR < 50 or B-sx + ESR < 30)
age < 50 yr
ESR < 50 (PMH uses ESR < 40)
LP or NS histology (even stage I MC has a 30% risk of subdiaphragmatic dz & 15% risk of extensive splenic involvement – Stanford)
( Mantle RT alone without prior staging lap
not off protocol
may consider for stage IA LP HD in peripheral nodal site (ie. above thyroid notch or epitrochlear), female, age < 40, ESR < 50
EORTC H7VF group may be adequately treated with mantle alone (long-term results not available)
( Staging Lap & if (-), then Mantle RT alone
field1 = mantle
dose1 = 3060 cGy
field2 = add subcarinal block
dose2 = 540 cGy
total dose = 3600 cGy
( Extended-Field RT without Staging Lap
consider getting a lag 1st to better assess pelvic and PA nodes (esp. with CS II or MC/LD histology)
field1 = mantle
dose1 = 3060 cGy in 180 cGy x17 fx
field2 = add subcarinal block
dose2 = 540 cGy in 180 cGy x 3 fx (total = 3600 cGy)
2 wk break to allow return of energy and recovery of blood counts
field3 = paraaortics + spleen
dose3 = 3060 cGy in 180 cGy x17 fx
pelvic relapse rate = 5% for LP/NS vs 11% for MC
( ABVD x 4
Involved Field RT (30-36 Gy per NCCN guidelines)
field1 = involved nodal sites (excluding uninvolved axilla significantly reduces volume of breast irradiated)
minimum of 2 cm margin on pre-chemo disease (except bulky mediastinum dz pushing into lung)
typically more than just Ann Arbor site ( mini-mantle; bilateral necks + upper mediastinum, …
Stanford – always include SC & hila if treating mediastinum; may ( upper border to thyroid notch
dose1 = (CR) 3060 cGy (Dr Dawson at U of M – 30 Gy + CD to pre-chemo dz to 36 Gy)
(PR) 3600 cGy
( Note: optimal RT dose with chemo is unknown
no consensus on definition of IF RT
unclear how much chemo is needed with RT
chemo + RT ( DFS without ( OS compared to STLI
no randomized trials for adults comparing chemo alone vs chemo + RT
ongoing EORTC H9F – closed chemo alone arm b/c relapse
proposed CALGB/SWOG trial
PEDS trials closed early b/c of ( relapse rate in chemo alone arm
NCCN recommendations for favorable CS IA-IIA = ABVD x 4 + IF RT (30-36 Gy)
Stage I Nodular LPHD in Upper Neck
( Mini-Mantle RT Alone
no chemo
rarely involves the mediastinum
36 – 40 Gy alone
- Note ASTRO 2003 rec were to AVOID mediastinal RT and CHEMO
Clinical Stage I-II with “unfavorable” features defined by the EORTC studies that benefit from addition of chemo (~ 40% of stage I-II pt)
> 4 nodal sites involved
bulky disease (LMA (> 1/3 thoracic diameter at T5/6) or > 5 cm for peripheral nodes (some say > 10 cm))
B-symptoms (esp. fever and wt loss) (EORTC uses no B-sx + ESR > 50 or B-sx + ESR > 30)
age > 50 yr
ESR > 50 (PMH uses ESR > 40)
MC/LD histology
( ABVD x 4-6 cycles (2 cycles beyond CR)
typically 4 cycles without bulky dz & 6 cycles with bulky dz
giving chemo first allows assessment of chemo response
maximization of the amount of drug needed
smaller radiation fields
re-staging CT and PET vs. Gallium scans after every 2 cycles
if (+)PET after 4 cycles of ABVD:
if LMA is shrinking & only slightly (+), then give 2 more cycles of chemo & re-stage
if not shrinking & strongly (+), then biopsy & give high dose chemo with stem cell rescue
Involved Field RT (30-36 Gy per NCCN guidelines)
field1 = involved nodal sites (excluding uninvolved axilla significantly reduces volume of breast irradiated)
minimum of 2 cm margin on pre-chemo disease (except bulky mediastinum dz pushing into lung)
typically more than just Ann Arbor site ( mini-mantle; bilateral necks + upper mediastinum, …
Stanford – always include SC & hila if treating mediastinum; may ( upper border to thyroid notch
dose1 = (CR) 3060 cGy (Dr Dawson at U of M – 30 Gy + CD to pre-chemo dz to 36 Gy)
(PR) 3600 cGy
field2 = bulky dz + 2 cm
total dose = (CR or PR) 3600 (ASTRO 2001 refresher course recommends 36-40 Gy for bulky dz)
( Note: EF RT = IF RT if give 4-6 cycles of chemo
ABVD is superior to MOPP
hybrid regimens are more toxic & don’t add to survival
4 cycles of chemo is likely sufficient
NCCN recommendations for unfavorable CS I-II = ABVD x 4-6 (CR+2) + IF RT (30-36 Gy)
PMH Recommendations:
CS IA or IIA with LP/NS histology, no bulky dz, age < 50 yr, ESR < 40
Extended-field RT alone to mantle (35 Gy) + PA (25 Gy)
CS IA or IIA with MC histology, age > 50 yr, ESR > 40
ABVD x 2 cycles ( RT to mantle (35 Gy) + PA (25 Gy)
CS IB or IIB &/or bulky mediastinal mass
ABVD to CR + 2 cycles ( RT to upper mantle (35 Gy)
1991 Patterns of Care Recommendations:
RT dose without chemo: uninvolved sites 30-40 Gy
involved sites 36-44 Gy
RT dose with chemo: no consensus on dose, but did recommend a minimum of 25 Gy
S/P Chemo Involved-Field Design (Ann Arbor nodal region):
neck
ipsilateral neck + SC/IC
many recommend bilateral necks + SC/IC + upper mediastinum to 30 Gy with CD to 36 Gy
may need to cross midline to ensure 2 cm on original disease extent
AP/PA
6 MV
superior = (AP) BB just above mentum (dip between lip & chin) to split mandible but spare teeth
(PA) lower 1/3 of mastoid process / tragus
+/- pre-auricular field if disease is above the thyroid notch
inferior = bottom of clavicular head / ensure 2 cm on original disease extent
lateral = medial aspect of acromion to encompass SC and low neck nodes / flash lateral neck skin ??
medial = ipsilateral vertebral pedicles (provided that this ensures 2 cm on original disease extent)
mediastinal disease
T1-T7 with 2 cm margin superiorly & inferiorly
superior = thyroid notch
inferior = 2 cm below disease (spares heart) vs. entire mediastinum with subcarinal block at 30 Gy
lateral = medial 2/3 of clavicle, excluding the axilla
SC + mediastinum
superior = thyroid notch, sparing upper necks and parotids
inferior = 2 cm below disease (spares heart) vs. entire mediastinum with subcarinal block at 30 Gy
lateral = medial 2/3 of clavicle, excluding the axilla
cervical + mediastinum
modify mantle by moving lateral border to cover medial 2/3 of clavicles (be sure to cover SC dz) excluding the axilla
paraaortic disease
AP/PA
18 MV
axilla
ipsilateral axilla + SC/IC
AP/PA
6 MV
J Clin Onc. 16:830, 1998.
J Clin Onc. 8:257, 1990.
J Clin Onc. 7:81, 1989.
Cancer. 65:1155, 1990.
( STLI = mantle + PA
TLI = mantle + inverted-Y
RT Alone Dose-Response Data
( HS Kaplan. Hodgkin’s Disease. Cambridge: Harvard University Press. 1980:689.
|bulk of disease |RT dose (without chemo) required for 95% control rate |
|Subclinical disease |25-30 Gy |
|< 5 cm |30-35 Gy |
|> 5 cm |35-45 Gy |
H Kaplan et al. Cancer Res 26:1221-4; 1966 - Stanford University
landmark article
|dose (rads) |recurrence rate |
|< 1000 rads |78% |
|1000 rads |60% |
|1500 rads |48% |
|2000 rads |35% |
|2500 rads |26% |
|3500 rads |11.5 % |
|4000 rads |4.4% |
comments: included some patients treated with orthovoltage
did not account for tumor bulk
lack of imaging and concern for geographic miss
( E Duehmke, et al. IJROBP. 32:213, 1995. - GHSG (German Hodgkin’s Study Group) HD4-trial
updated in IJROBP. 36:305-310, 1996. & J Clin Onc. 19:2905-2914, 2001.
prospective randomized trial
376 pt with pathologic stage IA-IIB non-bulky HD treated between 1988-93
pt char: only 5% had B-symptoms
all pt underwent staging lap
exclusion criteria: large mediastinal mass, > 5 splenic nodules, extranodal disease, > 3 involved nodal areas,
ESR > 30 (CS B) or 50 (CS A)
stratification: location of disease (supradiaphragmatic vs infradiaphragmatic) & treating institution
randomization: (1) 40 Gy EF-RT @ 1.8-2 Gy fx
(2) 30 Gy EF-RT with boost to 40 Gy to involved nodal regions
RT: EF definition: supradiaphragmatic disease mantle (+ Waldeyer’s ring if high cervical nodes) + PA/splenic pedicle
PA field was excluded if disease was confined to the upper cervical nodes
infradiaphragmatic disease inverted-Y including groin nodes + T-field for mediastinum/SC nodes
T-field was excluded if disease was confined to the inguinofemoral nodes
3-4 wk break between supra- and infradiaphragmatic fields
central review of sim films
median f/u = 86 mo
end-points = freedom-from relapse (FFR), overall survival (OS)
prognostic factors well balanced between treatment groups
protocol violations = majority 2(/2 inadequate margins ( 6 cm disease
prior analysis (with primarily kilovoltage data in 1960s) looked at 1040 sites at risk & suggested a 98% in-field control rate with 44 Gy
re-analysis (including modern megavoltage data) looked at 4117 sites at risk shows similar in-field control rates with ≤ 37.5 Gy
|extent of disease |dose required for 98% in-field control rate |
|subclinical disease |32.4 Gy |
|disease < 6 cm |36.9 Gy |
|disease > 6 cm |37.4 Gy |
K Schewe et al. IJROBP 15: 25-28; 1988 - MCW
retrospective
evaluation of dose-response data between 30-45 Gy from 1970-1982
112 pts with stage I/II disease
58% were pathologically staged
RT: 1970-72 300 cGy on M/W/F alternating AP and PA fields
82. 150-180 cGy, 5 days/wk
split-course = mantle 18 Gy ( PA/spleen 18 Gy ( mantle boost ( PA/spleen boost ( 2-4 wk break ( pelvis
continuous = mantle ( 2-4 wk bread ( inverted-Y field encompassing PA/spleen/pelvis
median f/u 89 months (range 29-183 months)
|dose (Gy) |in-field recurrence (per # nodal groups treated) |
|≤ 30 Gy |10.7% (3/28) |
|30.1-36 Gy |1.7 % (6/344) |
|36.1-39 |2.6% (12/456) |
|> 39 |1.6% (4/252) |
outcome vs. nodal size for doses > 30 Gy:
| |in-field & marginal recurrence (per # nodal groups treated) |
|nodal size | |
|subclinical |1.8% (12/685) |
|0.5-3 cm |4.3% (10/233) |
|> 3 cm |5.2% (7/134) |
** trend toward higher recurrence rates with increasing nodal size but did not reach significance
conclusions: no dose-response relationship for Hodgkin’s disease above 30 Gy
use of doses > 40 Gy for larger nodal volumes does not appear to improve local control
RT Hoppe, et al. Cancer. 74:3198-3203, 1994. - Patterns of Care Study
P Mauch, et al. J Clin Onc. 13:957-952, 1995. - Joint Center
MJ Crnkovich, et al. J Clin Oncol. 5:1041-1049, 1987. - Stanford and Joint Center
RT s/p Chemo Dose Response Data
( M Loeffler, et al. J Clin Onc. 15:2275-2287, 1997. – GHSG (German Hodgkin’s Study Group) HD1 & HD5
prospective randomized trial
260 pt with CS/PS I-IIIA HD with ‘high-risk’ features treated on 2 trials between 1984-92
pt char: 5% stage I, 60% stage II, 36% stage III
eligibility criteria: > 1 of the following (bulky mediastinal dz, massive spleen involvement, extranodal involvement), age 15-60
bulky dz = mediastinal mass > 1/3 thoracic diameter
> 7.5 cm diameter
central path review
HD1 (1984-88):
147 pt
all pt got 4 cycles of chemo: COPP ( ABVD ( COPP ( ABVD
randomization: (1) 40 Gy EF RT
(2) 20 Gy EF RT with 40 Gy to bulky dz
EF RT: upper cervical only Waldeyer’s ring + Mantle
supradiaphragmatic Mantle + Paraaortic + Spleen
supradiaphragmatic + paraaortic Mantle + Inverted-Y + Spleen
infradiaphragmatic
median f/u = 6.5 yr
HD5 (1988-92):
111 pt in arm 1
randomization: (1) COPP ( ABVD ( COPP ( ABVD
(2) IMEP (rapidly alternating COPP/ABV/Ifosfamide, Methotrexate, Etoposide, and Prednisone)
all pt got 30 Gy EF RT with 40 Gy to bulky dz
median f/u = 3 yr
| |RT dose to clinically(-) or non-bulky dz sites | |
| |20 Gy (n=71) |30 Gy (n=111) |40 Gy (n=76) |p-value |
|CR rate |92% |94% |92% |NS |
|4-yr freedom from treatment failure rate |79% |86% |80% |NS |
|4-yr survival rate |94% |93% |88% |NS |
more acute and late radiation complications in the 40 Gy arm
22 of 26 (85%) relapsing pt did so in initial bulky sites, extranodal sites, or outside the RT field
conclusions = (1) following 4 cycles of chemo, LC in clinically (-) sites & non-bulky dz was similar for 20 Gy, 30 Gy, or 40 Gy
(2) 10% failure rate at initial bulky sites after 40 Gy
criticisms = not too useful to know subclinical dz dose b/c only need to treat involved-field
GHSG HD10 Trial
on-going
randomization: (1) ABVD x 2 + IF RT 30 Gy
(2) ABVD x 2 + IF RT 20 Gy
(3) ABVD x 4 + IF RT 30 Gy
(4) ABVD x 4 + IF RT 20 Gy
GHSG HD11 Trial
on-going
randomization: (1) ABVD x 4 + IF RT 30 Gy
(2) ABVD x 4 + IF RT 20 Gy
Mantle RT alone without a Staging Lap
M Tubiana, et al. Blood. 73:47-56, 1989. – EORTC H1
prospective randomized trial
288 pt with supradiaphragmatic clinical stage I-II HD treated between 1964-71
no staging LAP
randomization: (1) mantle RT (n=152)
(2) mantle RT + vinblastine IV q1wk x 2 yr (n=136)
| |mantle RT |mantle RT + vinblastine |p-value |
|15-yr DFS rate |38% |60% |0.001 |
|15-yr OS rate |58% |65% |NS |
high relapse rate in the unirradiated paraaortic region
conclusions = paraaortic region should either be explored or treated
( EM Noordijk, et al. Ann Oncol. 5:S107-S112, 1994. – EORTC H7VF
605 pt with supradiaphragmatic clinical stage I-II HD treated between 1988-
6 prognostic factors to form treatment groups
very favorable group (H7VF): 35 pt
CS IA, NS or LP histology, no bulky dz, age < 40 yr, female, ESR < 50
all pt treated with mantle RT alone
| |mantle RT |
|3-yr RFS rate |82% |
|3-yr OS rate |100% |
conclusions = very favorable HD (CS IA, NS/LP, no bulky dz, age 70 (4) MC/LD histology
favorable group (H5F): 237 pt (9% B-symptoms)
no unfavorable prognostic factors (CS I or II without mediastinal dz, NS/LP histology, age < 40 yr, ESR < 70)
all pt underwent staging lap-splenectomy (39 pt with (+)lap pt were treated on H5U arm)
198 pt with (-)lap, randomized: (1) mantle RT (n=100)
(2) mantle/PA RT (n=98)
field1 = mantle
dose1 = 40 Gy
field2 = PA from T11-L4
dose2 = 40 Gy
| |mantle RT (n=100) |mantle/PA RT (n=98) |p-value |
|CR rate |99% |99% |NS |
|6-yr FFP rate |73% |71% |NS |
|6-yr OS rate |96% |90% |NS |
mean f/u = 5.3 yr
conclusions = favorable stage IA-IIA pt (I or II without mediastinal dz, NS/LP, age 6 cycles (2 cycles beyond maximal response)
(2) RT: dose = 45 Gy
field = IA high neck or axilla only mini-mantle +/- Waldeyer’s
IA inguinal inverted-Y
non-bulky dz limited to mediastinum mantle
IA or IIA supradiaphragmatic dz mantle + paraaortic-spleen
B-symptoms total nodal irradiation
median f/u = 7.5 yr
| |RT (randomized pt) |MOPP |p-value |
|CR rate |96% |96% |NS |
|10-yr OS rate |81% (76%) |92% |0.05 |
|10-yr DFS rate |74% (60%) |86% |0.01 |
all 13% of MOPP pt relapsed in previously involved sites
subgroup analysis: only subgroups with a significant advantage with MOPP are pt with bulky mediastinal dz or IIIA
conclusions = MOPP is at least as effective as RT for treatment of early-stage HD
GP Biti, et al. J Clin Onc. 10:378-382, 1992. - Italy
prospective randomized study
89 pt with stage I-IIA HD treated between '79-'82
all pt underwent staging laparotomy
randomization: (1) RT (n=45)
(2) Chemo (n=44)
RT: mantle and paraaortic irradiation (3 wk rest period between fields)
36 Gy to uninvolved sites & 40-44 Gy to involved sites @ 2 Gy fx
chemo: MOPP x 6 cycles
definition of bulky disease = > 5 cm node or mediastinal mass:thorax ratio > 1/3
end-points = pattern of relapse -- true relapse = within previously involved areas or radiation volume
lymph node extension = in previously uninvolved areas or adjacent to irradiated volume
dissemination = parenchymal involvement
overall survival
relapse-free survival
variables analyzed for prognostic significance = age, sex, histology, stage, mediastinum, bulky dz, ESR, treatment, response
median f/u = 96 mo
patient characteristics were well balanced
| |MOPP chemotherapy |mantle/periaortic RT |p-value |
|complete response rate |91% (40/44) |100% (45/45) | |
|8-yr RFS rate |71% |64% |NS |
|8-yr OS rate |56% |93% |0.001 |
|disease specific mortality |18% (8/44) |4% (2/45) | |
relapse pattern correlated with treatment group:
| |MOPP chemotherapy |mantle/periaortic RT |p-value |
|relapse rate |27% (12/44) |27% (12/45) |NS |
| true relapses |67% (8/12) |8% (1/12) |< 0.01 |
| nodal extension or dissemination |33% (4/12) |92% (11/12) |< 0.01 |
|complete response to salvage therapy |50% |92% | |
outcome with salvage therapy correlated with treatment group:
| |MOPP chemotherapy |mantle/periaortic RT |p-value |
|6.75-yr survival rate |15% |85% |0.02 |
MVA -- treatment, stage, and histology correlated with survival
conclusions = (1) relapse rate was similar for stage I-IIA HD patients treated with MOPP x 6 or mantle/periaortic RT;
however, patients relapsing after MOPP are more resistant to salvage therapy
(2) 8-yr survival rate was significantly better for the RT group
NCI Canada CTG HD6 Study
on-going trial
CS I-II HD with favorable prognostic factors
eligibility criteria: age < 40 yr, NS/LP histology, 1-3 nodal sites, ESR < 50
randomization: (1) ABVD x 4
(2) STLI
EF RT vs IF RT
• Meta-analysis showed increased FFP for EF vs IF RT, but no OS advantage
( Specht L et al. Journal of Clinical Oncology 16:830-843; 1998 – International Hodgkin’s Disease Collaborative Group
meta-analysis of 1,974 pt in 8 trials evaluating RT vs. more extensive RT (larger fields) (1962-1982)
most trials compared extended-field or STLI vs. involved-field RT
some trials included chemo in both arms (always identical)
|Group |Arm |#pt |10-yr failure rate |10-yr OS rate |
|stage IA |more RT | 348 |24% | |
| |less RT | 300 |36% | |
|stage IB |more RT | 22 |18% | |
| |less RT | 19 |47% | |
|stage IIA |more RT | 449 |34% | |
| |less RT | 460 |44% | |
|stage IIB |more RT | 130 |45% | |
| |less RT | 120 |53% | |
|stage IIIA |more RT | 22 |14% | |
| |less RT | 30 |33% | |
|age < 40 |more RT | 772 |30% | |
| |less RT | 757 |40% | |
|age ( 40 |more RT | 221 |35% | |
| |less RT | 205 |49% | |
|all patients |more RT |1005 |31% |77% |
| |less RT | 969 |43% |77% |
Death Due to Other Causes (Not Hodgkin’s)
|Arm |Solid Tumors |Non-Hodgkin’s Lymphoma |Leukemia |All Deaths from Other Causes |
|more RT |2.8% |0.5% |0% |10% |
|less RT |1.3% |0.2% |0.1% | 6% |
conclusions = EF RT ( relapse rate by ~ 10-15% compared to IF RT alone
EF RT does not ( OS compared to IF RT due to excellent salvage therapy
Chemo + EF RT vs EF RT
• Meta-analysis has shown improved DFS in all patients with chemo/EF RT vs EF RT alone, but b/c salvage, no OS has been noted
- Also shown in early results of German trial and SWOG trial
( Specht L et al. Journal of Clinical Oncology 16:830-843; 1998 – International Hodgkin’s Disease Collaborative Group
meta-analysis of 1,688 pt in 13 trials evaluating chemo + RT vs. RT (1967-1988)
included 476 patients in trials evaluating chemo + RT vs. same RT (unconfounded)
included 1219 patients in trials evaluating chemo + less RT vs. more RT (confounded)
most trials used MOPP or variants of MOPP
|Group |Arm |# pt |10-yr failure rate |10-yr OS rate |10-yr CSS rate |
|stage IA |chemo + RT |191 |11% | | |
| |RT |186 |20% | | |
|stage IB |chemo + RT |25 |4% | | |
| |RT |30 |37% | | |
|stage IIA |chemo + RT |336 |15% | | |
| |RT |326 |28% | | |
|stage IIB |chemo + RT |112 |24% | | |
| |RT |118 |38% | | |
|stage IIIA |chemo + RT |105 |20% | | |
| |RT |122 |42% | | |
|stage IIIB |chemo + RT |24 |46% | | |
| |RT |25 |80% | | |
|age < 40 |chemo + RT |647 |15% | | |
| |RT |650 |31% | | |
|age ( 40 |chemo + RT |179 |19% | | |
| |RT |194 |31% | | |
|all patients |chemo + RT |839 |16% |79% |88% |
| |RT |856 |33% |77% |85% |
Death Due to Other Causes (Not Hodgkin’s):
|Arm |Solid Tumors |Non-Hodgkin’s Lymphoma |Leukemia |All Deaths from Other Causes |
|chemo + RT |3.5% |0.4% |1.1% |13% |
|RT |2.6% |0% |0.5% |11% |
conclusions = chemo + RT ( relapse rate by ~ ½ (30% ( 15%) for all stages of HD compared to RT alone
chemo + RT does not improve OS or CSS compared to RT alone due to excellent salvage therapy
preliminary data from ASTRO 2001 refresher course – GHSG HD7
1994-98
643 pt with CS IA-IIB HD & favorable prognostic factors
randomization: (1) ABVD x 2 + STLI
(2) STLI
| |ABVD x 2 + STLI |STLI |p-value |
|RFS rate |96% |87% |0.05 |
Press, et al. J Clin Onc. 2001. – SWOG 9133 / CALGB 9391
prospective randomized trial
randomization: (1) AV x 3 + STLI
(2) STLI 36-40 Gy
( recurrence rate with chemo + STLI but no difference in OS
Chemo + Mantle RT vs. EF RT
M Tubiana, et al. Blood. 73:47-56, 1989. – EORTC H1
prospective randomized trial
288 pt with supradiaphragmatic clinical stage I-II HD treated between 1964-71
no staging LAP
randomization: (1) mantle RT (n=152)
(2) mantle RT + vinblastine IV q1wk x 2 yr (n=136)
| |mantle RT |mantle RT + vinblastine |p-value |
|15-yr DFS rate |38% |60% |0.001 |
|15-yr OS rate |58% |65% |NS |
high relapse rate in the unirradiated paraaortic region
conclusions = paraaortic region should either be explored or treated
( P Carde, et al. J Clin Onc. 6:239-252, 1988. – EORTC H5U
prospective randomized trial
494 pt with supradiaphragmatic clinical stage I-II HD treated between 1977-82
eligibility criteria: age 15-70 yr, normal LAG
4 unfavorable prognostic factors: (1) CS II with mediastinal dz (2) age > 40 yr (3) ESR > 70 (4) MC/LD histology
mean f/u = 5.3 yr
unfavorable group (H5U): 257 pt (24% B-symptoms) & 30 pt with +lap from H5F group
any of 4 unfavorable prognostic factors
no staging lap
randomization: (1) TNI or STNI (n=132)
(2) MOPP x 3 + mantle RT + MOPP x 3 (“3M protocol”) (n=135)
TNI: field1 = mantle
dose1 = 40 Gy
field2 = PA + spleen + iliac + inguinal regions (optional in young women)
dose2 = 40 Gy
3M: field = mantle
dose = 35 Gy
| | |TNI (n=132) |MOPP + mantle RT + MOPP (n=135) |p-value |
|CR rate |H5U group |95% |98% |NS |
| |(+)lap pt |90% |89% |NS |
|6-yr FFP rate |H5U group |73% |89% |0.01 |
| |(+)lap pt |47% |89% |0.008 |
|6-yr OS rate |H5U group |82% |89% |0.05 |
| |(+)lap pt |95% |88% |NS |
*for H5U group pt < 40 yr old, there was no difference in OS between treatment arms
conclusions = unfavorable stage I-II pt (II with mediastinal dz, MC/LD, age>40, ESR>70) should receive chemo + mantle RT
instead of TNI or STNI
Chemo + IF RT vs EF RT
( EM Noordijk, et al. Ann Oncol. 5:S107-S112, 1994. – EORTC H7F
605 pt with supradiaphragmatic clinical stage I-II HD treated between 1988-
6 prognostic factors to form treatment groups
favorable group (H7F): 354 pt
CS I (other than above)
CS II, < 3 Ann Arbor sites, age < 50 yr, ESR < 50
randomization: (1) mantle/PA/spleen RT
(2) EBVP x 6 + involved-field RT
| |mantle + PA/spleen RT |EBVP x 6 + IF RT |p-value |
|3-yr RFS rate |81% |71% |NS |
|3-yr OS rate |99% |100% |NS |
EBVP: Epirubicin
Bleomycin
Vinblastine
Prednisone
conclusions = favorable HD (all other CS I, CS II with 2-3 involved nodal sites, age 5 cm
STLI: mantle RT + PA/spleen RT
40-44 Gy to involved regions
30-40 Gy to uninvolved regions
> 40 Gy to involved extranodal sites
VBM: q4wk cycles
vinblastine 6 mg/m2 IV on d 1 & 8
bleomycin 10 U/m2 IV on d 1 & 8 ( 2.5 U/m2 for 4 cycles after RT
methotrexate 30 mg/m2 IV on d 1 & 8
IF RT: started 2 wk after VBM
mediastinal mantle field
neck or axilla bilateral neck + axilla + upper mediastinum to 2 cm below head of clavicles
35-36 Gy to involved regions
30-35 Gy to uninvolved regions
median f/u > 4 yr
| |STLI (n=43) |VBM x 2 + IF RT + VBM x 4 (n=35) |p-value |
|5-yr DFS rate |92% |87% |NS |
|5-yr OS rate |98% |94% |NS |
conclusions = for pt with favorable clinical stage IA-IIA HD, VBM x 6 + IF RT is equivalent to STLI
N Nissen, et al. Cancer Treat Rep. 66:799-803, 1982. – Danish LYGRA II
prospective randomized trial
327 pt with HD
randomization: (1) MOPP + IF RT
(2) STLI
RJ Klasa, et al. Proc Am Soc Clin Oncol. 13:372, 1994. – Vancouver
120 pt with stage IA-IIA HD
ABVD x 2
EF RT
40 mo f/u
RFS = 100%
OS = 96%
V Bonfante, et al. Proc Am Soc Clin Oncol. 13:373, 1994. –
Chemo + IF RT vs Chemo + EF RT
( for CS I-II Hodgkin’s dz, IF RT appears sufficient after 6 cycles of chemo
for CS I-II Hodgkin’s dz, IF RT may be sufficient after 4 cycles of chemo, but longer follow-up is needed
Overall randomized trials have shown that reduction in field size does not compromise outcome
( Engert et al. JCO 2003. HD8
Lymphoma Articles\HD\HD rand trial of EFRT vs IFRT JCO 2003.pdf
German HD group
1204 pts randomized trial
Eligibiltiy: Stage I-II with one or more risk factors. Stage IIIA with no risk factors
Risk factors:
1. LMA
2. Extranodal disease
3. Splenic Involvment
4. ESR > 50 and – B sympt
5. ESR > 30 and + B symptoms
6. > 3 LN areas involved
IIB allowed if only increase in ESR or > 3 LN involved with no other risk factors
Randomized to
1. COPP/ABVD x 2 (total 4) ( EFRT (30 Gy then boost of 10 Gy to bulky disease)
2. COPP/ABVD x 2 (total 4) ( IFRT (30 Gy then boost of 10 Gy to bulky disease)
IF defined as the involved regions at diagnosis
EFRT defined as IF fields at dx + adjacent non-involved sites
Median f/u was 55 months
| |EFRT (40 Gy) |IFRT (40 Gy) |
|CR |98% |97% |
|DFS |86% |84% |
|OS |91% |92% |
Acute SE much higher with the EFRT
Secondary Malignancies on short f/u not different between the 2 arms
Conclusion: Recommend following 4 cycles of chemotherapy, IFRT
( L Viviani, et al. Proc of ASCO. 20: 281a (#1120), 2001, - ? Milan trial
prospective randomized trial
136 pt with clinical stage IB, I bulky, IIA, IIA bulky, or IIEA HD treated between 1990-96
randomization: (1) ABVD x 4 + STNI
(2) ABVD x 4 + IF RT
RT: 30 Gy to uninvolved sites
36 Gy to involved sites
median f/u = 87 mo
| |ABVD + STNI |ABVD + IF RT |p-value |
|CR rate |100% |97% | |
|FFP rate |97% |94% | |
|OS rate |93% |94% | |
conclusions = ABVD x 4 + IF RT can achieve results comparable to ABVD x 4 + STNI
Zanini, et al. Proc 37th ASTRO. #281, 1995. – Milan Trial
prospective randomized trial
114 pt with stage IA-IIA HD
randomization: (1) ABVD x 4 + EF RT
(2) ABVD x 4 + IF RT
38 mo f/u
RFS = 94%
OS = 100%
French Cooperative Trial
on-going
MOPP x 3 ( RT ( MOPP x 3
randomization: (1) EF RT
(2) IF RT
Chemo + IF RT – choice of chemo regimen
( ABVD is at least as efficacious as MOPP or MOPP-like regimens & has markedly reduced risk of leukemia
( P Carde, et al. J Clin Onc. 11:2258-2272, 1993. – EORTC H6U
prospective randomized trial
578 pt with supradiaphragmatic clinical stage I-II HD treated between 1982-88
eligibility criteria: age 15-60 yr, WHO PS 0-2
staging: ESR, CxR, LAG, BM biopsy, CT chest/abd
unfavorable group (H6U): > 3 nodal sites, bulky mediastinum, B-symptoms + ESR > 30 or no B-symptoms + ESR > 50
no staging lap
(1) MOPP x 3 + mantle RT 35 Gy + MOPP x 3
(2) ABVD x 3 + mantle RT 35 Gy + ABVD x 3
| |MOPP |ABVD |p-value |
|6-yr DFS rate |76% |88% |0.01 |
|5-yr OS rate |88% |89% |NS |
|pulmonary toxicity |2% |12% | |
|hematologic toxicity requiring discontinuation of chemo |15% |7% | |
|gonadal toxicity | | | |
central path review
end-points: OS, RFS, CSS
median f/u = 5.3 yr
CR rate = 98%
| | |6-yr RFS rate |6-yr OS rate |6-yr CSS rate |p-value |
|Overall | |81% |89% |92% | |
|initial CR patients | |83% | | | |
|Stage |CS IA |87% |93% | | |
| |CS IB |81% |91% | | |
| |CS IIA |81% |89% | | |
| |CS IIB |74% |84% | | |
conclusions = for unfavorable CS I-II HD (>3 nodal sites, bulky dz, B-sx, ESR > 50), ABVD x 6 + mantle RT produces superior
outcome compared to MOPP x 3 + mantle RT, and staging lap is not necessary
( EM Noordijk, et al. Ann Oncol. 5:S107-S112, 1994. – EORTC H7U
605 pt with supradiaphragmatic clinical stage I-II HD treated between 1988-
6 prognostic factors to form treatment groups
unfavorable group (H7U): 316 pt
> 1 of the following: age > 50, >4 nodal sites, bulky med dz, no B-sx + ESR > 50, B-sx + ESR > 30
randomization: (1) EBVP x 6 + involved-field RT
(2) MOPP/ABV x 6 + involved-field RT
| |EBVP x 6 + IF RT |MOPP/ABV x 6 + IF RT |p-value |
|3-yr RFS rate |72% |88% |0.001 |
|3-yr OS rate |92% |92% |NS |
EBVP: Epirubicin
Bleomycin
Vinblastine
Prednisone
conclusions = unfavorable group (>4 involved nodal sites, bulky mediastinal dz, age>50, no B-sx + ESR>50, B-sx + ESR>30) should
receive MOPP/ABV x 6 cycles + IF RT
ECOG HD11
on-going
randomization: (1) ABVD x 6 + IF RT
(2) Stanford V x 12 wk + IF RT
GHSG HD11
on-going
randomization: (1) ABVD x 4
(2) BEACOPP x 4
2nd randomization: (1) IF RT 20 Gy
(2) IF RT 30 Gy
bulky sites will not receive a boost dose
Chemo + IF RT – how much chemo?
( there is data suggesting that 4-6 cycles of chemo are sufficient to control occult abdominal dz in most pt with CS I-II
however, the optimal extent of RT fields with less than 4 cycles of chemo is uncertain
EORTC H8U
on-going trial
unfavorable group (H8U):
randomization: (1) ABVD x 4 cycles + IF RT
(2) ABVD x 6 cycles + IF RT
GHSG HD10
on-going trial (1998-present)
assessing optimal # of cycles of chemo with IF RT & RT dose
randomization: (1) ABVD x 2 + IF RT
(2) ABVD x 4 + IF RT
2nd randomization for pt in a cCR after chemo: (1) 20 Gy IF RT
(2) 30 Gy IF RT
Chemo + IF RT vs Chemo
• Tried in European study and in POG study
• Both Closed early b/c increased relapses without the RT
EORTC H9F
on-going
CS I-II HD with favorable prognostic factors
all pt receive EBVP II x 6 cycles
randomization for pt in a cCR after chemo: (1) IF RT 36 Gy
(2) IF RT 20 Gy
(3) no RT
- Note Study Closed with no RT arm b/c increased number of relapses
CALGB/SWOG
on-going
randomization: (1) ABVD x 6
(2) ABVD x 4 + IF RT
MSK
on-going trial
CS I-IIIA
all pt receive ABVD x 6
randomization of pt in a cCR after chemo: (1) mantle RT 36 Gy
(2) no RT
STAGE IA, IB, IIA, & IIB SUPRADIAPHRAGMATIC HODGKIN'S DISESASE
Age > 16 yr
Bulky Disease &/or Extensive Pericardial Disease
( Bulky Mediastinal Disease:
combined modality therapy
unacceptably high rate of relapse with radiation therapy or chemotherapy alone
ABVD x 6 cycles (CR + 2 cycles)
IF RT to 36 Gy (modified mantle field)
- reduced RT dose is under study, esp. for pt with CR after chemo (Duke, U of M)
RT Alone
RT Hoppe, et al. Blood. 59:455-465, 1982. - Stanford University
PJ Schomberg, et al. Cancer. 53:324-328, 1984.
GA Gomez, et al. Am J Clin Oncol. 7:65-73, 1984.
( MJ Crnkovich and RT Hoppe, et al. J Clin Onc. 4:472-479, 1986. - Stanford University
Chemotherapy Alone
G Bonadonna, et al. Cancer Surv. 4:439-458, 1985.
S Pavlovsky, et al. J Natl Cancer Inst. 80:1466-1473, 1988.
Chemotherapy + RT
NT Leslie, et al. Cancer. 55:2072-2078, 1985.
( DL Longo, et al. J Clin Oncol. 9:227-235, 1991. - NCI
retrospective study
188 pt with HD treated with MOPP chemotherapy between '64-'76
49 pt with bulky mediastinal disease (mediastinal mass ratio > 1/3)
staging evaluation = LAG; Gallium scan; CxR; radionuclide scans of liver, spleen, and bone; bone marrow biopsy
no staging lap
90% were stage III or IV
10 pt (20%) received mantle RT after chemo -- ?dose
end-points = DFS and OS
factors analyzed for prognostic significance = treatment, stage, B symptoms, sex, age, histology
median f/u = 20 yr
| |bulky mediastinal disease (n=49) |no bulky disease (n=139) |
| |MOPP alone (n=39) |MOPP + RT (n=10) |p-value |MOPP alone |
|complete response rate |67% |90% | | |
|relapse rate for CR pt |50% |11% | | |
|20-yr DFS rate |50% |90% |0.053 | |
|20-yr tumor mortality |54% |20% |0.055 |40% |
conclusions = disease-free survival and tumor mortality is significantly improved with combined modality therapy over
chemotherapy alone for bulky mediastinal dz
( RA Behar, et al. IJROBP. 25:771-776, 1993. - Stanford University
retrospective study
48 pt with clinical stage IA-IIIA HD + bulky mediastinal disease treated with combined modality therapy between '80-'88
staging evaluation = CBC, ESR, serum Cu++, LFTs, CxR, CT chest/abdomen/pelvis, LAG, bone marrow biopsy
10 pt underwent staging lap
mean mediastinal mass ratio = 0.46 (range 0.35-0.85)
stage = I-IIA in 18 pt; IIB in 15 pt; IIIA in 15 pt
treatment = chemotherapy -- MOPP in 15 pts, ABVD in 14 pts, PAVe in 19 pts
radiation therapy -- mantle +/- infradiaphragmatic field (after completion of chemo)
shrinking field technique -- 15-20 Gy ( re-evaluation +/- field change ( mean total 44 Gy
partial transmission lung blocks to deliver 15-18 Gy used in 46% (22 pt)
infradiaphragmatic RT in 37% (18 pt)
88% sandwich technique = 2-4 cycles chemo ( 2-4 wk break ( mantle RT ( chemo (total of 6 cycles)
median f/u = 52 mo
end-points = freedom from relapse, survival
90% complete response rate
9-yr actuarial FFR rate = 84%
9-yr actuarial OS rate = 88%
no significant difference in outcome among different chemo regimens or whether staging lap was performed
complications = 25% hypothyroid; 17% herpes zoster; 15% mild radiation pneumonitis; 4% pericarditis
conclusions = with 9-yr freedom from relapse rates of 85-90%, combined modality therapy without staging laparotomy and
RT limited to involved areas should be considered standard
Longo, et al. J Clin Onc. 15:3338, 1997.
( L Hughes-Davies, et al. IJROBP. 39:361-369, 1997. - Joint Center University
retrospective study
172 pt with CS IA-IIB HD + bulky mediastinal disease treated between '69-'92
definition of bulky mediastinal disease = > 1/3 width of max thoracic diameter on upright PA CxR
> 10 cm cephalocaudad diameter on chest CT
staging evaluation = bone marrow biopsy, CxR, LAG or abdominal CT, lung tomography or chest CT
57% (98 pt) had staging lap ( 17% (16 pt) of these had abdominal involvement
treatment groups = group 1 (staging lap and treatment with RT alone)
group 2 (staging lap and treatment with chemo/RT)
group 3 (no staging lap and treatment with chemo/RT)
pt characteristics = group 1 had significantly less B symptoms, more extranodal extension, & more infradiaphragmatic dz
RT = group 1 & 2: mantle field ( paraaortic/splenic pedicle field
group 3: mantle field only in 95%
dose = 30 Gy + boost to 40 Gy in areas of gross disease
15-16 Gy lung dose if parenchymal lesions or extensive hilar adenopathy
15-16 Gy heart dose if extensive pericardial disease or apical cardiac adenopathy
chemo = MOPP x 6 cycles in 82%
ABVD or ChlVPP in the remainder
sequencing was variable = group 1 & 2: > 2 cycles chemo ( RT ( chemo
group 3: > 90% had 6 cycles chemo ( RT
end-points = freedom-from relapse (FFR) and overall survival (OS)
| |RT alone |Chemo/RT |p-value |clinically staged |pathologically staged |p-value |
|10-yr actuarial FFR rate |54% |88% |0.001 |84% |74% |NS |
|10-yr actuarial OS rate |84% |89% |NS |87% |87% |NS |
|pneumonitis rate |11% |17% |NS | | | |
pattern of failure = 54% in mediastinum
median time to relapse = 1.5 yr
pneumonitis rate was higher when any part of chemo was given after RT vs all chemo given before RT (29% vs 13%, p=0.1)
conclusions = patients with clinical stage I-II supradiaphragmatic Hodgkin's disease with bulky mediastinal involvement do
not require staging lap and combined chemoradiotherapy significantly decreases local recurrence risk.
JE Elconia, LR Prosnitz, et al. IJROBP 45 (suppl): abstr 135, 1999 - Duke and Yale
retrospective
71 with HD and bulky (> 1/3 thoracic diameter) mediastinal disease treated with combined modality therapy (1983-1997)
work-up: PE, CXR, CT chest/abd, LAG, blood chemistries (staging lap performed in 4 pt; Gallium scan in 44 pt)
staging: IA-3, IB-1, IIA-22, IIB-26, IIIA-3, IIIB-6, IVA-2, IVB-8
treatment: induction chemo (various regimens used) x 6 cycles ( re-staged
- 66 pt had a CR: no residual radiologic abnormality or negative Gallium in face of abnormal x-ray / CT
- 5 pt had induction failure
RT: all sites of initial involvement in CR pt to 18.6-43 Gy (AP/PA, 6 MV, 150-180 cGy/fx)
median f/u = 6.4 yr
| |# pt |5 yr OS |5 yr FFS |10 yr OS |10 yr FFS |
|all pt with CR |66 | |78.8% | | |
|RT = 30 Gy |9 | |66.7% | | |
|all pt |71 |93% |76% |76% |74% |
no significant difference in failure rate between dose groupings
of 14 CR pt who had a recurrence: 7 were in field only, 3 were out of field only, and 4 with in and out of field
conclusion = low dose RT following CR to induction chemo may be as effective as high doses in patients with bulky mediastinal dz
STAGE IA, IB, IIA, & IIB INFRADIAPHRAGMATIC HODGKIN'S DISEASE
- 10% of cases
- male predominance
Stage IA-IIA Inguinofemoral +/- Pelvic Disease, Non-Bulky
( ( LAG
( abd/pelvic CT to evaluation liver, spleen, celiac, mesenteric nodes
( BM biopsy
( ABVD x 4
IF RT
field = IF RT
dose = (CR) 3060 cGy
(PR) 3600 cGy
( Staging Lap if considering RT alone (40% splenic involvement)?? ( if (-), then …
EF RT alone
field1 = inverted-Y field + spleen
dose1 = 3600 cGy in 180 cGy fx
2 wk break
field2 = mantle
dose2 = 3060 cGy in 180 cGy fx
( Stage IA LP histology with non-bulky inguinofemoral disease only may be adequately treated with RT alone
(but don’t do it on the boards)
( LAG
( abd/pelvic CT to evaluation liver, spleen, celiac, mesenteric nodes
no staging lap
no BM biopsy
RT alone
field = inverted-Y field +/- spleen
dose = 3600 cGy in 180 cGy fx
Stage IA or IIA Para-aortic Node Disease, Non-Bulky
( ( BM biopsy
if (-)BM, treat like stage III b/c 40% risk of splenic dz
( can’t do extended-field RT alone b/c this would be total nodal RT
( ABVD x 4
IF RT
field = IF RT
dose = (CR) 3060 cGy
(PR) 3600 cGy
Stage IB or IIB or Bulky Disease
( ( LAG
( abd/pelvic CT to evaluation liver, spleen, celiac, mesenteric nodes
( BM biopsy
no staging lap
( ABVD x 4-6
IF RT
field1 = inverted-Y
dose1 = (CR) 3060 cGy
(PR) 3600 cGy
field2 = bulky disease
dose2 = (CR or PR) 3600 cGy
Z Liao, et al. IJROBP. 41:1047-1056, 1998. – MD Anderson
retrospective study
87 pt with stage I-II infradiaphragmatic HD treated between 1962-95
path reviewed
staging evaluation: CxR, BM biopsy, LAG, LAP, CT abd/pelvis
definition of bulky dz = > 7 cm
treatment: RT alone 60 pt
chemo alone 4 pt
chemo x 2-3 cycles + RT (bulky dz, B-symptoms) 23 pt
chemo regimen: MOPP
NOVP
ABVD
RT: field: IF (initial anatomic location of the adenopathy) 14 pt
pelvic (iliac and inguinofemoral nodes) 7 pt
inverted-Y (paraaortic, iliac, and inguinofemoral nodes) 12 pt
inverted-Y + spleen 7 pt
total abdomen (upper 2/3 abdomen, iliac, and inguinofemoral nodes) 34 pt
central lymphatic irradiation (mantle + total abdomen) 6 pt
paraaortic + spleen 1 pt
dose: median = 30 Gy
range = 25-45 Gy
CR rate = 98%
median time to relapse = 15.5 mo
median f/u = 15 yr
| | |relapse rate* |10-yr OS rate |10-yr DFS rate |
|overall | | |75% |72% |
|stage |IA |10% | | |
| |IIA |29% | | |
| |IIB |46% | | |
|treatment |RT alone |22% | | |
| |chemo alone |25% | | |
| |chemo + RT |44% | | |
*16 of 24 relapses occurred above the diaphragm
3 relapses occurred in the RT field
factors analyzed: age, gender, stage, B-symptoms, histology, bulky dz, # sites, Hb, albumin, LDH, treatment
UVA: predictors of ( OS = age > 40 yr, B-symptoms, MC or NS histology (compared to LP), Hb < 12, albumin < 3.5
predictors of ( DFS = # involved sites > 3, stage II, B-symptoms, albumin < 3.5, treatment
MVA: predictors of ( OS = age > 40 yr RR 5
Hb < 12 RR 3.4
NS or MC RR 5 vs LP
predictors of ( DFS = albumin < 3.5 RR 12.8
chemo + RT RR 3.6
M Hull, N Mendenhall, et al. IJROBP. 52:161-166, 2002. – U of Florida
retrospective study
21 pt with stage I-II subdiaphragmatic HD treated with curative intent between 1966-98
median f/u = 12.3 yr
10-yr OS rate = 70%
10-yr PFS rate = 80%
recommendations:
cIA inverted-Y + spleen
cIIA, NS/LP inverted-Y + spleen
pIA inverted-Y
pIIA inverted-Y
cI-II, > 3 nodal sites, B-symptoms, bulky dz (> 6 cm), central (para-aortic) presentation, splenic involvement chemo + RT
STAGE III HODGKIN'S DISEASE
Age > 16 yr
( 5-yr OS rate = 75%
5-yr RFS rate = 70%
80% for stage IIIA with minimal (< 5 nodules) or no splenic involvement
- Prognostic Factors for stage III and IV
stage IV
male sex
age ( 45 yr
leukocytosis (WBC count > 15,000)
lymphocytopenia (lymphocyte < 600)
Hb < 10.5 g/dl
serum albumin level < 4 g/dl
( NEJM. 339:1506, 1998. –
MVA of prognostic factors for stage III-IV HD
7 factors identified: stage IV, male gender, age > 45 yr, WBC > 15,000/cc, ANC < 600/cc, Hb < 10.5 g/dl, albumin < 4 g/dl
|# of adverse factors |5-yr OS rate |
|0-3 |83% |
|4-7 |59% |
Clinical Stage IIIA or IIIB, Non-Bulky or Bulky
( chemotherapy is standard and consolidation RT is controversial
rational approach b/c most relapses occur in sites of initial disease
realize that BMT is more difficult after prior thoracic RT – ( bone marrow reserve & ( pulmonary toxicity
Up to 20% of pts with advanced stage HD fail to CR to chemotherapy
( ABVD x 6-8 cycles (CR + 2 cycles) +/- Consolidation RT
or BEACOPP high dose X 8 cycles
re-stage after 4 cycles & 6 cycles with CT of initially involved areas and gallium scan or PET scan
if give more than 6 cycles, bone marrow reserve is reduced, thus hindering chance for BMT if necessary
6 cycles ( non-bulky ( cCR ( +/- 2 additional cycles of chemo
cSD/PD (+PET)( BMT
cPR ( IF RT (30 – 36 Gy) vs BMT
bulky ( cCR ( +/- 2 additional cycles of chemo
cSD/PD (+PET) ( BMT
cPR ( IF RT (30 – 36 Gy) vs BMT
consolidation RT is controversial
indications: PR after chemotherapy (vs BMT?) 30 – 36 Gy
or not treated to 2 cycles past CR?? – personal indication
field = initially involved nodal sites – (off protocol consider only sites of initial bulky dz)
dose = 20 Gy in 1.8 Gy fx
• Pt refuses Chemo
Per PC- if bulky Mediastinal disease would treat whole lung with transmission blocks (37%) would allow for 40 Gy to mantle and 1500 cGy to lungs
( Peripheral Stem Cell Transplant
clear indications: refractory to standard chemo
early relapse < 1 yr
( NCCN Guidelines:
ABVD x 4 cycles ( re-stage with CT of all initially (+)sites
CR/PR ( ABVD x 2 cycles (6 total) +/- IF RT 20-36 Gy
stable/minimal response ( Gallium scan ( (-) ( ABVD x 2 cycles (6 total) + IF RT
(+) ( biopsy ( high-dose chemo +/- IFRT + peripheral stem cell
transplant
progression ( biopsy ( high-dose chemo +/- IF RT + peripheral stem cell transplant
Pathologic Stage III (CS I-II with (+)staging lap)
( ABVD x 6-8 cycles +/- IF RT
STAGE IV HODGKIN'S DISEASE
( BEACOPP high dose X 8
ABVD x 6-8 cycles
+/- IF RT for complete responders (see NCCN guidelines for stage III)
if Gallium scan is still (+), then chemo resistant disease and RT is unlikely to convert pt to CR ( needs BMT
( Pediatric Patients:
- chemotherapy alone vs combined therapy with low dose radiation (15-25 Gy) to limit growth retardation
- whole lung RT for pulmonary mets ??
mantle field with partial transmission blocks for lungs (inferiorly to T12 to cover all lung volume)
dose = ~ 10 Gy for kids (ie. 50% transmission blocks b/c total mantle dose = 21 Gy)
~ 12 Gy for adults (ie. 33% transmission blocks b/c total mantle dose = 36 Gy)
Choice of Chemo Regimen
• High dose BEACOPP current standard of care based of randomized trial comparing COPP/ABVD vs BEACOPP vs High dose BEACOPP
• Stanford 5
12 week dose-intensive regimen
Cumulative dose of alkylating agents is only 25% that of MOPP
Adriamycin dose 50% of ABVD and bleo is 25% of ABVD
- Note, I believe all trials with Stanford 5 have included 36 Gy IF RT to sites >5 cm
( GP Canellos, et al. NEJM. 327:1478-1487, 1992. - CALGB Trial
prospective randomized trial by CALGB
361 pt with stage III-IV HD and those with relapse after RT alone randomized to MOPP vs ABVD vs MOPP/ABVD.
eligibility criteria = age > 16 yr, adequate renal function and bone marrow reserves
24% had staging lap
stratification by age, stage, histology, previous RT, performance status, presence of mediastinal mass
randomization: (1) MOPP -- q28days until CR, then 2 additional cycles (minimum = 6 cycles; maximum = 8 cycles)
(2) ABVD -- q28days until CR, then 2 additional cycles (minimum = 6 cycles; maximum = 8 cycles)
(3) MOPP/ABVD -- MOPP alternating with ABVD for 12 cycles
for MOPP and ABVD groups, if stable or progressive disease after 2 cycles or < CR after 6 cycles ( alternative regimen
no adjuvant RT
response evaluated after every 2 cycles with CxR, bone scan, liver and spleen scans, abdominal x-ray
follow-up = q3mo x yr 1-2, then q6mo thereafter with CxR, bone scan, liver and spleen scan, abdominal x-ray
end-points = failure-free survival (FFS), disease-free survival (DFS), overall survival (OS)
median f/u = 6 yr
| |MOPP (n=123) |ABVD (n=115) |MOPP/ABVD (n=123) |p-value |
|complete response rate |67% |82% |83% |0.006 (MOPP vs others) |
|5-yr failure-free survival |50% |61% |65% |0.02 (MOPP vs others) |
|5-yr overall survival |66% |73% |75% |NS |
MVA: factors significantly affecting CR rate = age (67% for age > 50 yr; 80% for age < 50 yr)
performance status (52% for PS 2; 80% for PS 0-1)
B symptoms (73% vs 84%)
liver involvement (65% vs 79%)
factors significantly affecting FFS rate = age, chemo regimen, stage, > 1 extranodal site involved
prognostic groups: low risk group = age < 50 yr, stage III or IV with one extranodal site involved ( 5-yr FFS = 70%
high risk group = age > 50 yr, stage IV with > 2 extranodal sites involved ( 5-yr FFS = 45%
toxicity: MOPP -- severe neutropenia in 50% and life-threatening in 25%
ABVD -- severe neutropenia in 18% and life-threatening in 3%; severe pulmonary toxicity in 6%
salvage after failure: CR rate = 35% for those who failed MOPP and 61% for those who failed ABVD
conclusions = ABVD and MOPP/ABVD are superior to MOPP in achieving complete remission and failure-free survival
in those with stage III-IV Hodgkin's disease
Duggan et al. JCO 2003
Phase III trial of pts with adv HD disease 856 pts included
Eligibility: IIIA, IIIB, or IV or pts with relapse s/p RT alone
Randomized to
1. ABVD
2. MOPP/ABV
|Treatment |CR |FFS |OS |2nd Malig |
|ABVD |76% |63% |82% |18 total |
|MOPP/ABV |80% |66% |81% |28 total |
ABVD associated with equivalent OS with less 2nd malignancies
( Diehl et al. NEJM 2003
Phase III trial with 1201 pts included
Eligibility: IIB or IIIA with Large Mediastinal Mass
IIIA with ESR > 50 or ESR > 30 with B symptoms, or > 3 LN areas involved
IIIB or IV
- essentially high risk III and IIIB any, IV any
Randomized pts to
1. ABVD/COPP (8 total cycles) – stopped early at interim analysis b/c poor results
2. BEACOPP (Standard dose)
3. BEACOPP Dose increased with Neuopen support
- Bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, Procarbazine, Prednisone
Pts were restaged s/p 4 cycles
RT given to sites > 5 cm (30 Gy) or residual masses (active) 40 Gy
| |COPP/ABVD (260 pts) |Standard BEACOPP |High dose BEACOPP |P value |
|Progression on chemo |10% |8% |2% |Sig for high dose BEACOPP|
|CR |85% |88% |96% | |
|5 yr FFF |69% |76% |87% |Sig for high dose BEACOPP|
|5 yr OS |83% |88% |91% |0.002 vs ABVD COPP |
| | | | |0.06 vs Stand BEACOPP |
Conclusion: High dose BEACOPP had improved FFF and almost significantly improved OS compared to standard BEACOPP.
Consider BEACOPP high dose for this patient population
Federico et al ASCO 2004 – Italy
Randomized trial of 355 pts comparing 3 different chemotherapy regimens
Eligibility: Stage IIB – IV Hodgkins
Randomized to
1. ABVD x 6 cycles
2. MOPP-EBV-CAD
3. Stanford 5
RT: Delivered to residual masses or to the sites of previous bulky disease
Results
| |ABVD |MOPP/EBV/CAD |Stanford 5 |Pvalue |
|CR |88% |94% |72% |0.01 |
|5 yr PFS |83% |85% |67% |>0.01 |
|5 yr OS |90% |90% |83% |NS |
Conclusion: Show an advantage of ABVD and MEC over Stanford V
Chemo + RT vs Chemo
• Indications for RT in Stage III-IV disease
1. PR s/p all chemo
2. ? Did not give 2 cycles past CR?
for stage III-IV HD who achieve a CR after chemo, would not recommend RT if 2 cycles past CR given
- Previously, RT shown to improve EFS. However, several randomized trials have not shown a beneficial role for RT s/p chemotherapy
o Studies have taken 2 approaches
1. Same chemo with observation vs consolidation RT
Usually shows improved EFS with consolidation RT
OS usually equal
2. Different chemo with essentially RT instead of chemotherapy
Usually shows equivalent DFS and OS
- If RT used, recommend 20 Gy to IF for CR pts and 36 Gy for PR
• Relapses occur in about half of the advanced stage pts who achieve CR with chemo alone
• Meta-analysis done showing no benefit and what many quote
- only 6 of the 14 trials were included
- 2 different “designs” seen
• Largest trial done in US is SWOG trial
- Poorly done in that not all randomized to RT actually received it, but was improvement in DFS – as treated
• German study 2nd largest study and was a design where chemo given and then CR randomized to further chemo or RT IF. No benefit seen for RT arm
• Argentine trial done with II/IV HD but all were randomized, not just those in CR, and therefore, the CMT group has improved FFS compared to CT alone pts
• Pediatric study randomized IIB, III, and IV HD to 8 cycles of ABVD +/- IF RT and found no benefit with intent to treat, but the as-treated analysis showed superior outcome for the RT group
• CCG trial compared 12 cycles of MOPP/ABVD to 6 cycles of ABVD + EF RT and a non significant improvement in OS and FFS in CMT group
• Recent CCG trial randomized pts with COPP/ABV and CR randomized to RT vs no RT
- trial close early b/c increased FFS without the RT
• Largest trial was EORTC which gave 4 cycles of chemotherapy and then restaged. IF CR then 2 more cycles. If PR 2 more cycles then restage at 6. Needed to treat 2 cycles past CR and then randomized to IF RT. No benefit for the RT
( Nachman, et al. – CCG 5942 Rand trial of IFRT vs no RT for HD with CR to chemo. JCO 20: 3765-3771 2002Lymphoma Articles\HD\Peds HD Rand trial of CR to RT vs no RT.pdf
closed early due to excessive failures in chemo alone arm. Open from ’95 to ’98
829 pts with Pediatric HD (/=4 LN regions, Mediastinal dz > 1/3 thorax, >10 cm peripheral mass
Group 1 pts: Stage I without adverse features and IIA without adverse features
Group 2 pts: Stage I with adverse features and Stage II with adverse features or B symptoms, and Stage III pts
Group 3 pts: IV pts
chemo: Group 1--stage I, IIA non-bulky, < 4 sites, no hilar dz (alternating 2 COPP & 2 ABV)
Group II--stage I, IIA bulky or IIB-III (alternating 3 COPP & 3 ABV)
Group III--stage IV (Ara-C/VP-16, COPP/ABV, CHOP x 2)
if CR, randomized to (1) IF RT – 2100 cGy in 175 cGy fx
(2) no RT
if PR, then IF RT to 3500 cGy in 175 cGy fx
Note if IV disease with pulmonary involvement, pts received 10.5 Gy to lungs in 12 fractions
if < PR, then off study
CR- If incomplete radiologic response in mediastinum, could still have CR if >70% reduction and gallium – if prev +
PR- defined as 50-70% reduction in TV
Overall 650 pts had CR and eligible for randomization. Only 501 pts were randomized, most off protocol were observed
| |COPP/ABV x 4 (n=245) |COPP/ABV x 4 + IF RT (n=249) |p-value |Group 1 |Group 2 |Group 3 |
|3-yr EFS rate (for |87% |92% |0.57 |95% |82% |83% |
|CR) | | | | | | |
|3 yr EFS as treated |85% |93% |.0024 | | | |
|3-yr OS rate |98% |99% |NS | | | |
Median time to relapse for chemotherapy with observation was 6 months, and most 29/34 were in sites of known disease. Median time for relapse in IFRT was 14 mo with 7/12 occurred within in field only. Post relapse survival was better for rand pts who relapsed after chemo alone compared with those who relapsed after combined therapy (94% vs 84%). This improvement in EFS was seen in all stages treated. In addition, when analyzed by treatment actually received, those with RT did even better. Therefore, combination treatment has remained the standard of care
( J Raemaekers, et al. Ann Oncol. 8:S111-S114, 1997. – EORTC 20884 Trial
update in B Aleman, et al. Proc of ASTRO. 51(suppl 1): 2, 2001.
Update NEJM 2003
prospective randomized trial
Eligibility: III-IV HD (but not IIIAs)
736 pt with CS III-IV HD s/p 6-8 cycles of MOPP/ABV (CR + 2 cycles, 6 if CR after 4, 8 if CR after 6)
pt char: 35% bulky dz
42% stage IV
pt with CR (60%) were randomized: (1) no further therapy
(2) IFRT
RT: 24 Gy to all initially involved nodal areas
16-24 Gy to all initially involved extranodal areas
Note- lower CR rate than normally noted
pt with PR (35%) after 6 cycles - RT to all initially involved nodal (30 Gy) & extranodal (18-24 Gy +/- 4-10 Gy boost) sites
5% failed to respond
median f/u = 79 mo
| |CR – no RT (n=161) |CR – RT (n=172) |p-value |PR – RT (n=243) |
|5-yr RFS rate |84% |85% |NS | |
|5-yr EFS rate |84% |79% |NS |79% |
|5-yr OS rate |91% |85% |0.07 |87% |
|Death 2nd Malig |25% |39% | | |
|Death from |6% |18% | | |
|intercurrent | | | | |
|disease | | | | |
|5 yr cumulative |4% |7.8% |0.05 | |
|2nd malign rate | | | | |
|Liquid tumor |17% |53% | | |
Conclusions: IF RT did not improve outcome in pts with Stage III-IV HD after CR to 6-8 cycles of MOPP/ABV chemotherapy.
RT may benefit those pts with PR
( CJ Fabian, et al. Ann Intern Med. 120:903-912, 1994. - SWOG 7808
prospective randomized trial – total 530 pts entered, 322 achieved CR, 278 randomized
278 pt with clinical stage III-IV HD
- only 104/135 pts randomized to RT actually received it
all had CR after MOP/BAP chemo
randomization: (1) chemo + IF RT (23% did not receive RT)
(2) chemo
RT: field = involved nodal sites
dose = 2000 cGy
field = involved extranodal sites
dose = 1000-1500 cGy
actual treatment received analysis:
| |Chemo + RT |chemo |p-value |
|5-yr DFS rate |85% |67% | |
Pts who had PR all received RT without randomization and FFS and OS was identical to those getting chemo/RT
conclusions = RT in addition to chemotherapy improved the DFS but not the OS
( V Diehl, et al. Proc Am Soc Clin Oncol. 1057:273, 1990. - German HD-3 Trial
prospective randomized trial
274 pt with stage IIIB-IV HD
induction chemo = COPP/ABVD x 6 mo
pt with CR were randomized: (1) COPP/ABVD x 2 mo
(2) IF RT to 20 Gy
| |COPP/AVBD x 6 + IF RT 20 Gy |COPP/ABVD x 8 |p-value |
|5-yr OS rate |93% |80% | |
|5-yr RFS rate |80% |79% | |
conclusions = for stage IIIB-IV HD after achieving a CR with 6 cycles of chemo, addition of IF RT to 20 Gy improves survival
compared to 2 additional months of chemo
( Ferme, et al. Blood. 95:2246, 2000. – GELA H89
prospective randomized trial
559 pt with advanced HD
1st randomization: (1) MOPP/ABV x 6 cycles
(2) ABVPP
pt in cCR or good cPR, randomized to (1) chemo x 2
(2) SNTI
median f/u = 48 mo
| |MOPP/ABV x 8 |MOPP/ABV x 6 + STNI |ABVPP x 8 |ABVPP x 6 + STNI |p-value |
|5-yr DFS rate |80% |82% |68% |75% |0.01 |
|5-yr OS rate |85% |88% |94% |78% |NS (MOPP/ABV) |
| | | | | |0.002 (ABVPP) |
( NL Bartlett, et al. J Clin Onc. 13:1080, 1995. & Horning, et al. J Clin Onc. 20:630-637, 2002. – Stanford University
142 pt with stage II with bulky mediastinal involvement (n=__) or stage III-IV (n=__) HD treated between 1989-
Stanford V + RT to areas of PR or initial bulk > 5 cm
Stanford V: q1wk x 12 wk
Adriamycin
Vinblastine
Mechlorethamine
Vincristine
Bleomycin
Etoposide
Prednisone
initial 25 pt received RT to initial bulky disease or residual radiographic abnormalities after chemo
final 117 pt received RT only to bulky disease (> 5 cm or macroscopic splenic nodules on CT)
RT: field = IF
dose = 36 Gy
median f/u = 5.4 yr
| |overall |stage II with LMA |stage III-IV |p-value |IPI score 0-2 |IPI score > 3 |p-value |
|3-yr OS rate |96% | | | | | | |
|5-yr OS rate |96% | | | | | | |
|3-yr FFS rate |87% |100% |82% | | | | |
|5-yr FFS rate |89% | | | |94% |75% |< 0.0001 |
no pt progressed during treatment
no treatment-related deaths
female and male fertility appears to be preserved
no secondary leukemia was observed
Horning, et al. J Clin Onc. 18:972-980, 2000. – ECOG 1492
multi-institutional phase II pilot study
47 pt with bulky mediastinal stage I-II or stage III-IV HD
Stanford V x 12 wk ( RT 36 Gy to initial bulky nodes (> 5 cm) or macroscopic splenic disease
median f/u = 4.8 yr
5-yr PFS rate = 85%
5-yr OS rate = 96%
ECOG 2496 / Intergroup
on-going
comparing Stanford V to ABVD
J Yahalom, et al. J Clin Onc. 9:2193-2201, 1991. – MSK
retrospective (review of pt treated on 2 protocols)
| | |RT to all initial dz sites |RT to only some of initial dz sites / no RT |p-value |
|10-yr RFS rate |all pt |89% |68% |0.001 |
| |stage II |90% |80% |0.09 |
| |stage III-IV |87% |66% |0.009 |
| |< 5 involved sites |93% |77% |0.005 |
| |> 5 involved sites |73% |59% |0.045 |
|10-yr OS rate |all pt |94% |71% |0.001 |
| |stage II |96% |64% |0.0002 |
| |stage III-IV |92% |72% |0.042 |
| |< 5 involved sites |91% |84% |NS |
| |> 5 involved sites |91% |60% |0.036 |
Loefler, et al. J Clin Onc. 16:818-829, 1998. – Meta-Analysis
meta-analysis of 1,740 pt from 14 prospective randomized trials from 1968-88 (8% I-IIA, 27% IIB-IIIA, 65% IIIB-IVA)
7 trials with 918 pt compared chemo vs. identical chemo + RT
7 trials with 837 pt compared chemo + RT vs. chemo + additional chemo
median f/u = 8.5 yr
| |chemo + RT |chemo |p-value |chemo + RT |chemo + additional chemo |p-value |
|10-yr OS rate |61% |65% | |61% |68% | |
|10-yr DFS rate |62% |51% | |58% |59% | |
KC Marcus, et al. J Clin Oncol. 12:2567-2572, 1994.
J Clin Onc. 18:972, 2000. – Stanford University
Proznit, et al. 1988.
Prizel, et al. 1990. - Intergroup Trial
on-going
ABVD x 6-8 + RT for LMA
GHDSH HD12
on-going
Brizel, et al. IJROBP. 19:535-542, 1991. – Duke University
retrospective study
177 pt with advanced HD
all had chemo
154 pt had cCR ( 87 pt had no RT
67 pt had RT
23 pt had < cCR
|complete responders |chemo + RT |chemo |p-value |
|10-yr OS rate |92% |59% | |
|10-yr DFS rate |87% |56% | |
RECURRENT HODGKIN'S DISEASE
adverse prognostic factors:
initial treatment included chemo vs RT alone
disease free interval < 1 yr
|DFI |salvage rate (without BMT) |
|> 1 yr |50% vs 65% ? |
|< 1 yr |25% |
location of relapse
|location |salvage rate (without BMT) |
|nodal only |50% |
|nodal + extranodal |30% |
Relapse After Chemotherapy:
limited nodal relapse
( RT
- 5 yr DFS approx 30% and OS of 55 - 70%
• Combined non-cross resistant chemotherapy and RT
diffuse relapse > 1 yr after initial therapy
( chemo with non-cross resistant drugs
+/- RT
diffuse relapse < 1 yr after initial therapy
• Several studies including small randomized trials have shown an advantage in DFS and OS for those pts who receive BMT as part of regimen compared to chemotherapy alone
( high-dose chemotherapy and autologous stem-cell support +/- IF RT
20- 30% salvaged after standard dose chemo
55% salvaged after high dose chemo + PSCT
80-100% of failures s/p PSCT are at sites of initial disease ?
- 30-65% OS with Children and BMT
- Some data shows that those with history of atopy and asthma at higher risk of pulmonary problems
- RT is used for IF RT before transplant and reduces risk of relapse at RT sites, also may be used for those who fail to CR to pre-transplant chemotherapy
- Retrospective series have shown improved FFR in pts who received IFRT
- RT doses to IF range from 20 to 36 Gy
M Uematsu, et al. Cancer. 72:207-212, 1993. - Joint Center
retrospective study
28 pt with relapse of HD after combination chemotherapy alone were treated between 1971-90
eligibility criteria = nodal relapse only
75% stage III-IV initially
75% initially treated with MOPP & remainder with ABVD or MOPP/ABVD ( 61% initial CR rate
restaging evaluation = CxR, abd CT or LAG, bone marrow bx
recurrence in a single node in 12 pt (43%)
recurrence in multiple nodes in 16 pt (57%)
treatment = (1) chemo/RT (14 pt): 50% ABVD; 50% MOPP
57% mantle RT; 28% mantle & paraaortic RT; 14% total nodal RT
(2) RT alone (14 pt): 21% mantle RT; 57% mantle & paraaortic-splenic pedicle RT; 21% total nodal RT
**RT dose = 35-44 Gy
end-points = survival & disease-free survival
median f/u = 80 mo
| |RT alone (n=14) |Chemo / RT (n=14) |p-value |
|7-yr actuarial DFS rate |36% |93% |0.002 |
|7-yr actuarial OS rate |36% |85% |0.03 |
conclusions = combination of extended-field RT and chemotherapy is significantly more effective than RT alone for
treatment of nodal only relapse after initial treatment with chemotherapy alone
Lancet. 341:1051, 1993. –
MSK 94-68
re-induction with ICE chemotherapy ( if responding, then IF RT to sites > 5 cm ( PSCT
Relapse After RT Alone
( salvage rate after combination chemo: 10-yr DFS rate = 57-80%
10-yr OS rate = 57-81%
relapse stage I-IIA
( ABVD to CR + 2 cycles (max 6)
( +/- RT
15-25 Gy to previously irradiated sites
30-40 Gy to nonirradiated regions
relapse stage I-IIB, III-IV
( ABVD to CT + 2 cycles (min 6)
( +/- RT
15-25 Gy to previously irradiated sites
30-40 Gy to nonirradiated regions
EA Healey, et al. Cancer. 71:2613-2620, 1993. - Joint Center
retrospective study
127 pt with PS IA-IIIB HD treated between '69-'85 who developed relapse and underwent salvage therapy
initial staging included LAG, CT, CxR, staging lap
initial treatment = RT alone (total nodal RT or extended field RT) in 110 pt (group 1)
Chemo/RT (MOPP) in 17 pt (group 2)
pt characteristics were similar except for initial stage (PS III - 37% vs 76%) and B symptoms (13% vs 76%)
staging at relapse = bone marrow biopsy, CxR, CT chest/abdomen
pattern of relapse by initial treatment group: group I -- nodal sites only in 59%
group II -- nodal sites only in 53%
therapy for relapse:
| |Chemo alone |Chemo/RT |RT alone |
|group 1 |99 pt (90%) |8 pt |3 pt |
|group 2 |13 pt (76%) |3 pt |1 pt |
factors analyzed for prognostic significance:
sex, age (< 40 vs > 40), initial PS (I-II vs III), relapse stage (I-II vs III-IV), histology (NS/LP vs MC/LD),
time to relapse (< 12 mo vs > 12 mo), prior pelvic RT, nodal only vs extranodal +/- nodal relapse,
relapse inside vs outside of RT field
median f/u after relapse = 92 mo
end-points = second CR rate, freedom from second relapse (FSR) rate, overall survival (OS), cause-specific survival (CSS)
| |all pts |group I |group II |p-value |
|second CR rate |79% |82% |59% |0.05 |
|10-yr actuarial FSR rate |53% |58% |13% | |
| - with second CR | |71% |22% |0.04 |
|10-yr actuarial OS rate |57% |59% | | |
| - with second CR | |75% |40% |NS |
|10-yr actuarial CSS rate | |62% |24% | |
UVA: factors favoring a second CR = NS/LP histology, nodal relapse only, no initial pelvic RT, low relapse stage (I-II)
Pediatric Population (age < 16 yr)
Epidemiology
( 6% of childhood malignancies
40% of childhood lymphomas
( male : female predominance
age 3-7 yr 4:1
age 7-9 yr 3:1
age 9-16 yr 1.3:1 (similar to adults)
( peak age = adolescence
rare < 5 yr
Bimodal peak peaking in the 20’s and then after 50 yo
Risk Factors
( h/o infectious mononucleosis ( see ( EBV-Ab titers prior to diagnosis, esp. in MCHD
( affected sibling 2-9 RR for sibling and 99X increased risk for monozygotic twins
Presentation
( painless adenopathy 90%
|nodal region |frequency of involvement |
|cervical |80% |
|mediastinum |75% (adolescents) vs 33% (age 1-10 yr) |
|infradiaphragmatic |5% |
( B-symptoms 33%
Work-up
( H&P
( blood work: CBC, lytes, BUN/Cr, LFTs, Alk phos, ESR, LDH
( CxR
CT chest/abd/pelvis
Gallium (Ga67) scan – rebound thymic hyperplasia can cause abnormal uptake in kids (false +)
( bone marrow biopsy – only if clinical stage III-IV or B-symptoms
( excisional LN biopsy
Natural History
( histology
|histologic subtype |age < 10 yr |age 10-16 yr |age > 17 yr |
|NSHD |44% |77% |72% |
|MCHD |33% |11% |17% |
|LPHD |13% |8% |5% |
|LDHD |0% |1% |1% |
S Cleary, et al. IJROBP. 28:77-84, 1994. - Stanford University
( 60% stage I-II
40% stage III-IV
Prognostic Factors
R Smith, et al. Proc of ASTRO. 119, 2001. – multi-institutional
analysis of pre-tx factors in 320 pt to develop a prognostic index in children with clinical stage I-IV HD between 1990-2000
tx = chemo + low-dose IFRT
median f/u = 53 mo
MVA – 4 factors predicting for ( DFS = male gender; stage IIB, IIIB, or IV; WBC > 11,500, Hb < 11
(insignificant factors = age, histology, B-symptoms, ESR, extranodal dz, bulky dz)
|# prognostic factors |5-yr DFS rate |5-yr OS rate |
|0-1 |94% |96% |
|2 |78% |95% |
|3-4 |63% |77% |
( stage
( bulk of disease
large mediastinal mass
> 4 sites involved
> 5 splenic nodules
stage IV with multiple extranodal organs involved
( B-symptoms
( ( LDH, ESR, ferritin
( age
|Age |5-yr OS rate |10-yr OS rate |
|< 10 yr |94% |92% |
|11-16 yr |93% |86% |
|> 16 yr |84% |73% |
S Cleary, et al. IJROBP. 28:77-84, 1994. - Stanford University
Outcome
( 80% overall survival
|Stage |10-yr OS rate |10-yr DFS rate |
|I-IIA(non-bulky) |~ 97% |~ 93% |
|IIA(bulky), IIB-IIIA |~ 90% |~ 87% |
|IIIB-IV |~ 75% | |
Treatment (p214-216 of peds book)
Stage IA-IIA (non-bulky) – current standard per ASTRO 2001 refresher course is combined modality therapy
( COPP alternating with ABV x 4 cycles
OR
ABVD x 4 cycles
for peds pt, chemo is always involved in tx regimen
chemo + low dose IF RT will result in less late toxicity than with RT alone (bone & muscle hypoplasia)
OR
ABVE-PE x 4 cycles
RT: field = involved nodal areas
Ann Arbor site
Neck: Treat ipsilateral neck and include entire width of vertebral bodies (to prevent any future growth abnormalities)
mediastinal mass – initial CC dimension + 2 cm; post-chemo lateral extent + 1.5 cm; include SCF; exclude axilla is not involved
iliac nodes – perform oophoropexy in females to preserve fertility
pulmonary nodules – may require whole lung RT
dose = (CR) 2100-2550 cGy
(< CR) 3500 cGy
ex. 2001 ASTRO case 1: 13 yo M with high left cervical node (4 cm), Gallium (+)left neck only, CT chest/abd/pelvis(-),
bx = NSHD, CS IA
prognosis – 10-yr DFS = > 90%
tx – ABVD x 4 + IF RT (2 cycles may be appropriate for early rapid responders on protocol)
field – left neck & SCF
if pre-pubertal, consider bilateral necks to ( hypoplasia (esp. if > 25 Gy)
if very high neck node, ( CT neck to r/o nasopharynx involvement
may be difficult to cover upper portion of very high neck dz with AP/PA ( may need lateral mixed
beam field matched to low neck field with common isocenter
if LPHD & completely excised, then tx with chemo + IF RT is still appropriate instead of IF RT alone
as in adults b/c dose required is high
RR of 2nd malignancy = ~ 20 for females & ~ 10 for males
< 10% infertility rate with ABVD
ex. 2001 ASTRO case 2: 9 yo F with left cervical, PA, bilateral iliac nodes (all < 3 cm), B-sx, bx = MCHD, CS IIIB
prognosis – 10-yr DFS = ~ 75%
ABVD + IF RT – while adult studies appear to be (-), CCG 5942 showed ( relapse rate with IF RT
RT field – inverted Y +/- spleen
ex. 2001 ASTRO case 3: 9 yo F with CS IIIB treated with ABVD x 6 but relapses 3 yr later in PA region
tx – high dose chemo + stem cell rescue (could consider RT alone in adult pt relapsing > 1 yr out)
TBI 12 Gy
also add IF RT after stem cell rescue
( Stanford data on transplants in relapsed kids
SS Donaldson, et al. J Clin Onc. 5:742-749, 1987. - Stanford University Ped HD 1 Study
retrospective study
55 pt < 14 yr old treated with MOPP x 6 cycles + low dose IF RT between 1970-83
staging lap in 96%
27 stage I-II & 28 stage III-IV
80% NSHD or MCHD
tx scheme: MOPP x 2 ( RT field#1 ( MOPP x 2 ( +/- RT field#2 ( MOPP x 2
RT: field: supramediastinal mantle (mini-mantle) field for dz limited to axilla, SC, IF, & cervical LNs
full mantle field to dz in thorax and cervical +/- axilla LNs
para-aortic or pelvic fields for infradiaphragmatic dz
dose: bone age (yr) dose (cGy)
< 5 yr 1500
6-10 yr 2000
11-14 yr 2500
? 10 Gy boost to those with < CR or bulky dz (> 6 cm node or LMA)
median f/u = 7.5 yr
| |overall |stage I-II |stage III-IV |
|10-yr actuarial OS rate |89% |100% |78% |
|10-yr actuarial FFR rate |90% |96% |84% |
|10 yr actuarial LC rate |97% | | |
low dose RT resulted in minimal inhibition of soft tissue and bone growth
secondary acute leukemia rate = 4% at 5-yr & 11% at 10-yr
conclusions = MOPP x 6 cycles + low-dose RT provides excellent dz control for pediatric HD
however, majority of males became sterile and secondary leukemia rate was significant
S Hunger, et al. J Clin Onc. 12:2160-2166, 1994. - Stanford University Ped HD 2 Study
57 pt < 16 yr old with HD (1 IA, 22 II, 21 III, 13 IV) treated with ABVD x 3 / MOPP x 3 + IF RT between 1982-90
ineligibility criteria: stage IA LPHD in high neck, treated with RT alone
staging lap in 70%
tx scheme: ABVD x 1 + MOPP x 1 ( RT field#1 ( ABVD x 1 + MOPP x 1 ( +/- RT field#2 ( ABVD x 1 + MOPP x 1
RT: field1 = involved field (most bulky area, usually mantle field)
dose1 = 1500 cGy
field2 = sites of bulky dz (LMA or > 6 cm nodal mass) OR < CR after 2 cycles of chemo
dose2 = 1000 cGy (total = 2500 cGy)
median f/u = 6.7 yr
all pt had CR after completing tx
| |overall |stage I-III |stage IV |p-value |
|10-yr actuarial OS rate |96% |100% |85% |0.02 |
|10-yr actuarial EFS rate |93% |100% |69% |0.0005 |
no second malignancies
no abnormal skeletal growth or pubertal development
no symptomatic cardiac, pulmonary, or thyroid dz
32% subclinical pulmonary dysfunction
16% chemical hypothyroidism
conclusions = alternating ABVD/MOPP x 6 cycles with involved field RT to 15 Gy [10 Gy boost to sites of bulky dz (LMA or
> 6 cm nodal mass) or < CR after 2 cycles of chemo] produces excellent results in pediatric HD stage I-III
O Oberlin, et al. J Clin Onc. 10:1062-1068, 1992. - French Society of Pediatric Oncology (SFOP)
prospective randomized trial
238 pt < 18 yr old with HD treated with chemo + RT between 1982-88
staging lap in 2%
randomization: clinical stage IA or IIA: (1) ABVD x 4
(2) MOPP x 2 + ABVD x 2
RT: started 1 mo after chemo
field = involved field
dose = (CR or good PR) 2000 cGy
(< good PR) 4000 cGy
clinical stage IB, IIB, III-IV: all pt got MOPP x 3 + ABVD x 3
RT: (IB or IIB) field1 = involved field
dose1 = see above
field2 = prophylactic paraaortic/splenic (after 2 wk break)
dose2 = 2000 cGy
(III-IV) field = involved field (excluding extralymphatic sites)
dose = see above
"good chemo response" (95%): CR = complete clinical &/or radiologic disappearance of dz OR
good PR = > 70% reduction in tumor size
"poor chemo response" = < 70% reduction in tumor size or early recurrence before starting RT
| |stage IA-IIA |stage IB-IIB-III |stage IV |
|CR rate |82% |63% |38% |
|PR (> 70%) rate |15.5% |34% |33% |
|good chemo response rate |97.5% |97% |71% |
median f/u = 6 yr
| |stage I-II |stage III |stage IV |"good responders" |"poor responders" |
| |(n=177) |(n=40) |(n=21) |(n=227) |(n=11) |
|6-yr actuarial DFS rate |89% |82% |62% |89% |18% |
no difference in the ABVD vs MOPP/ABVD arms
recommendations = (1) stage IA-IIA "responders" - ABVD x 4 + involved field RT to 20 Gy
(2) stage IB-IIB "responders" - MOPP x 3 / ABVD x 3 + involved field & paraaortic/splenic RT to 20 Gy
(3) BMT for "poor responders"
S Donaldson, et al. J Clin Onc. 8:1128-1137, 1990.
retrospective study
pediatric early-stage HD
compared results from Stanford (pathologic staging, EF RT or chemo/IF RT) with St Bartholomew’s (clinical staging, IF RT)
higher relapse rate for IF RT alone, but equivalent overall survival b/c salvage chemo
| |pathologic staging |clinical staging |p-value |
| |EF RT or chemo + IF RT |IF RT | |
|10-yr RFS rate | | | |
| - large mediastinal mass | |53% | |
| - small bulk disease | |86% | |
|10-yr OS rate |91% |91% | |
D Jenkin, et al. Med Pediatr Onc. 18:265-272, 1990. - University of Toronto
G Schellong, et al. Ann Onc. 7:567-572, 1996. - German
G Schellong, et al. J Clin Onc. 17:3736, 1999. – German-Australian Pediatric HD Study Group DAL-HD-90 Trial
Lymphoma Articles\HD\Ped HD 90 German JCO 1999.pdf
578 pt
chemo: OPPA (OEPA) / COPP
replaced etoposide for procarbazine in boys to preserve fertility
RT: field1 = IFRT95
dose1 = 25 Gy (20 Gy in high risk arm)
field2 = CD to residual dz
dose2 = 30-35 Gy total
low risk: CS I, IIA
OPPA (OEPA) x 2
intermediate risk: CS IIB, IIIA
OPPA (OEPA) x 2 + COPP x 2
high risk: CS IIIB, IV
OPPA (OEPA) x 2 + COPP x 4
no difference between OPPA and OEPA
5-yr EFS rate = 91%
5-yr OS rate = 98%
| |5 yr DFS |
|Low Risk |95% |
|Int Risk |93% |
|High risk |87% |
U Ruhl, et al. Proc of ASTRO. 48:178-179, 2000 (abstr #133). – GPOH-HD 95 trial, Germany
update in U Ruhl, et al. IJROBP. 51:1209-1218, 2001.
Lymphoma Articles\HD\German HD 95 IJROBP 2001.pdf
prospective trial
830 pt with HD treated between 1995-2000
gallium scans & PET scans were not routinely used for staging
initial therapy: low risk group, TG 1: CS I, IIA ( OPPA or OEPA x 2 cycles
intermediate risk group, TG 2: CS IIAE, IIB, IIIA ( OPPA or OEPA x 2 cycles + COPP x 2 cycles
high risk group, TG 3: CS IIBE, IIIAE, IIIB, IV ( OPPA or OEPA x 2 cycles + COPP x 4 cycles
additional therapy based on re-staging studies: if cCR, then no further therapy (23% of pt)
if good cPR (> 75% reduction), then 20 Gy IFRT (62% of pt)
if cPR with < 75% reduction, then 30 Gy IFRT
(any residual mass > 50 cc in volume received a boost to 35 Gy)
treatment: OEPA x 2-6 cycles
if CR (22%) ( no RT
if PR with > 75% tumor regression (61%) ( IF RT to 20 Gy
if PR with 50-75% tumor regression (12%) ( IF RT to 30 Gy
chemo: OPPA (girls) or OEPA (boys) q28d
Vincristine 1.5 mg/m2 IV on d 1, 8, 15
Procarbazine 100 mg/m2 PO on d 1-15 or Etoposide 125 mg/m2 IV on d 3-6
Prednisone 60 mg/m2 PO on d 1-15
Adriamycin 40 mg/m2 IV on d 1, 15
COPP q28d
Cytoxan 500 mg/m2 IV on d 1, 8
Vincristine 1.5 mg/m2 IV on d 1, 8
Procarbazine 100 mg/m2 PO on d 1-15
Prednisone 40 mg/m2 PO on d 1-15
median f/u = 38 mo
| | |overall |CS I, IIA |CS IIAE, IIB, IIIA |CS IIBE, IIIAE, IIIB, IV |
|5-yr EFS rate |overall |90% |94% |91% |84% |
| |RT |93% |97% |92% |
| |No RT |89% |92% |81% |
| | |p=0.09 |p=NS |p=0.01 |
|relapse rate |RT |6% | | | |
| |No RT |9% | | | |
|5-yr OS rate |overall |97% | | | |
100% of failure in those with no RT did fail in the initial site (as at least part of the failure), where as those with RT only
failed in the IF in 25%.
• German Studies tried different regimens
OPPA/COPP- Vincristine, procarbazine, prednisone and doxorubicin/cyclophosphamide, vincristine, procarbazie and pred
- This regimen had good DFS
Then the German group tried to eliminate procarbazine but had poorer disease free survival rates
VP-16 used next (OEPA) and had a good DFS with this regimen
Therefore, other groups tried to use etoposide in advanced disease but did not have a good outcome
- Felt that VP-16 May be used in early stage disease but not advanced disease
S Donaldson @ ASTRO 2001 - Tri-Center Protocols (Stanford, St. Jude, Dana-Farber)
1990-98
96 pt with clinical stage I-II non-bulky, age < 18 yr
VAMP x 2 ( IFRT ( VAMP x 2
chemo: velban, adriamycin, MTX, prednisone
RT: field = IFRT
dose = 15 Gy (CR) or 25 Gy (< CR)
4-yr EFS rate = 94%
4-yr OS rate = 99%
V Vecchi, et al. Cancer. 72:2049-2057, 1993. - Italian (AIEOP) Multicenter Study
prospective trial
215 pt < 15 yr old with HD treated between 1983-89
Group 1: stage IA-IIA (non-bulky)
ABVD x 3 cycles ( RT
RT: field =
dose = 20-25 Gy
Group 2: stage IA (bulky), IB, IIA (bulky), IIB, IIIA
alternating MOPP/ABVD x 6 cycles ( RT
Group 3: stage IIIB, IVA, IVB
alternating MOPP/ABVD x 6 cycles ( RT ( MOPP/ABVD x 4 cycles
re-staging performed after 2 cycles chemo, before RT, 1 mo after RT (group 1-2), before maintenance chemo (group 3)
| |stage IA-IIA (non-bulky) |stage IA-IIA (bulky), IB, IIB, IIIA |stage IIIB, IVA, IVB |
|7-yr DFS rate |95% | | |
|7-yr OS rate | | | |
Nachman, et al. – CCG 5942 Rand trial of IFRT vs no RT for HD with CR to chemo. JCO 20: 3765-3771 2002.
Lymphoma Articles\HD\Peds HD Rand trial of CR to RT vs no RT.pdf
closed early due to excessive failures in chemo alone arm. Open from ’95 to ’98
829 pts with Pediatric HD (/=4 LN regions, Mediastinal dz > 1/3 thorax, >10 cm peripheral mass
Group 1 pts: Stage I without adverse features and IIA without adverse features
Group 2 pts: Stage I with adverse features and Stage II with adverse features or B symptoms, and Stage III pts
Group 3 pts: IV pts
chemo: Group 1--stage I, IIA non-bulky, < 4 sites, no hilar dz (alternating 2 COPP & 2 ABV)
Group II--stage I, IIA bulky or IIB-III (alternating 3 COPP & 3 ABV)
Group III--stage IV (Ara-C/VP-16, COPP/ABV, CHOP x 2)
if CR, randomized to (1) IF RT – 2100 cGy in 175 cGy fx
(2) no RT
if PR, then IF RT to 3500 cGy in 175 cGy fx
Note if IV disease with pulmonary involvement, pts received 10.5 Gy to lungs in 12 fractions
if < PR, then off study
CR- If incomplete radiologic response in mediastinum, could still have CR if >70% reduction and gallium – if prev +
PR- defined as 50-70% reduction in TV
Overall 650 pts had CR and eligible for randomization. Only 501 pts were randomized, most off protocol were observed
| |COPP/ABV x 4 (n=245) |COPP/ABV x 4 + IF RT (n=249) |p-value |Group 1 |Group 2 |Group 3 |
|3-yr EFS rate (for |87% |92% |0.57 |95% |82% |83% |
|CR) | | | | | | |
|3 yr EFS as treated |85% |93% |.0024 | | | |
|3-yr OS rate |98% |99% |NS | | | |
Median time to relapse for chemotherapy with observation was 6 months, and most 29/34 were in sites of known disease. Median time for relapse in IFRT was 14 mo with 7/12 occurred within in field only. Post relapse survival was better for rand pts who relapsed after chemo alone compared with those who relapsed after combined therapy (94% vs 84%). This improvement in EFS was seen in all stages treated. In addition, when analyzed by treatment actually received, those with RT did even better. Therefore, combination treatment has remained the standard of care
POG 8625
prospective randomized trial
stage I-II
4 cycles of chemo (2 MOPP & 2 ABVD)
if CR, randomized to (1) 2 additional cycles of chemo (1 MOPP + 1 ABVD)
(2) IF RT
| |MOPP/ABVD x 6 |MOPP/ABVD x 4 + IF RT |p-value |
|5-yr OS rate |97% |86% | |
|5-yr EFS rate |97% |86% | |
|5-yr DFS rate |86% |89% | |
no fatal toxicities and no 2nd malignancies to date
POG 9426
on-going trial
eligibility criteria: CS or PS IA, IIA, & PS IIIAmiro (dz limited to spleen, splenic, celiac, or portal nodes), age < 21yr
exclusion criteria: B-symptoms, bulky mediastinal dz, extranodal dz
staging w/u: CxR, CT chest/abd/pelvis, Gallium scan, ESR, BM biopsy, biochem panel
+/- staging LAP
repeat initially (+)scans after 2nd and 4th cycle of chemo & 8 wk after RT
DBVE x 2 cycles ( if CR, no further chemo ( IF RT
if PR (non-mediastinal dz), DBVE x 2 cycles ( if stable or further regression, then IF RT
if progression & biopsy(+), then off study
if NR or PD (non-mediastinal dz), off study
if PR (> 50% reduction of mediastinal dz) & (-)Ga67 scan ( IF RT
if < PR (< 50% reduction of mediastinal dz) regardless of Ga67 scan, DBVE x 2 cycles (
if CR or further dz regression & (-)Ga67 scan, then IF RT
if dz progression or (+)Ga67 scan, then biopsy ( if (+), then off study
randomization: (1) Zinecar – topoisomerase II inhibitor
(2) no Zinecar
DBVE: q28d cycle
Doxorubicin 25 mg/m2/day IVP on d 1 & 15
Bleomycin 10 IU/m2/day IVP on d 1 & 15
Vincristine 1.5 mg/m2/day IVP (max 2 mg) on d 1 & 15
Etoposide 100 mg/m2/day IVPB on d 1-5
RT: start 28-40 days after beginning the last cycle of chemo
field = involved nodal sites + 2 cm around any residual dz in the mediastinum
1) to ensure a 2 cm margin on neck dz, a spine block may not be appropriate
2) some bulky axillary or SC/IC dz may overlie humeral head or medial clavicle & could be missed with standard axillary field
dose = 2550 cGy in 150 cGy x 17 fx
unilateral neck: superior = lower border of mandible, tips of the mastoid, mid tragus
inferior = below clavicle, 2 cm on original disease if lower neck involved
medial = cover medial head of SCM & clavicular head, exclude vertebral body if possible, if not possible to
exclude ipsilateral epiphysis of cervical vertebrae include both to assure symmetric neck growth
lateral = medial 2/3 of clavicle, 2 cm on disease
bilateral neck: see above for superior, inferior, and lateral borders
may treat bilateral neck for unilateral involvement to assure symmetric neck growth
when used with a mediastinal field, use a 2 cm wide C-spine block
axilla: superior = inferior edge of clavicle
medial = 1 cm margin on lateral surface of thoracic cage
lateral = 2 cm on disease
inferior = 2 cm on disease, at least as low as the bottom of the 4th rib
shield humeral head
unilateral neck + contralateral axilla: _____________
unilateral neck + ipsilateral axilla: connect unilateral neck field to unilateral axilla field
mediastinum: superior = ______________
inferior = if no subcarinal or pericardial nodes, then dome of diaphragm (T10/11)
if subcarinal, pericardial, or diaphragmatic nodes, then ____________
lateral = 2 cm margin on residual disease
1-2 cm margin on hilum
1.5 cm margin on vertebral bodies to include internal mammary and paraspinous nodes
mediastinum + neck: connect neck and mediastinum fields
2 cm wide posterior C-spine block
mediastinum + neck + axilla: connect neck, mediastinum, & axilla fields (mantle)
spleen: superior = 1 cm margin of lung above dome of diaphragm
inferior = 2 cm margin on spleen on CT
medial = 2 cm margin on spleen, 2 cm margin on contralateral side of vertebral bodies to include upper PA nodes
lateral = cover rib cage
femoral or inguinal: AP field prescribed at depth of femoral nodes on CT (8-12 MeV e-)
superior = 3 cm above palpable nodes and parallel to inguinal fold
inferior = 3 cm below palpable nodes, 1-2 cm on femoral triangle _________
medial = 1-2 cm on femoral triangle _____________
lateral = _____________
iliac + inguinofemoral: AP/PA thru pelvis portion
AP photon with e- boost for groin portion
superior = L5/S1
inferior = ___________
medial = ___________
lateral = ____________
inverted Y field: superior = dome of diaphragm
inferior =
lateral = transverse processes of vertebrae, 2 cm around nodes, 2 cm on spleen/splenic pedicle
remainder like iliac + inguinofemoral field
para-aortic nodes + splenic pedicle: for rare situation of isolated PA nodal involvement
superior = dome of diaphragm in an interspace
inferior = L4/5
lateral = transverse processes, 2 cm on residual dz, 1-2 cm on clips at splenic pedicle
supra + infra-diaphragmatic dz: 4 wk rest between fields
gap between fields or use an extended field
f/u protocol: TSH, T4 q1yr x 10 if chest RT
FSH, LH (if pubertal) q1yr x 10
CxR q6mo x yr 1-5 ( q1yr x yr 5-10
CT scan q6mo x yr 1 ( q1yr x yr 2-5
PFTs q1yr x 5
ECG/Echo q3yr
mammograms if chest RT
POG 9425
DBVE-PC x 3 cycles ( 25 Gy IFRT
2 more cycles ( 25 Gy IFRT
pt divided based on early rapid response
Stage IB-IIB or Bulky dz – current standard per ASTRO 2001 refresher course is combined modality therapy
( ABVD x 6 cycles
RT: field = involved field
dose = 2100 cGy
would follow CCG 5942
Link, et al. Proc of ASCO 1994. –
CS I-II bulky or CS III-IV
VEPA x 6 + IF RT (15-25 Gy)
chemo: velban, etoposide, prednisone, adriamycin
5-yr EFS rate = 68%
5-yr OS rate = 81%
closed early due to poor outcome
S Donaldson @ ASTRO 2001 - Tri-Center Protocols (Stanford, St. Jude, Dana-Farber)
1994-98
122 pt with CS I-II bulky or CS III-IV
VAMP/COPP x 2 ( IFRT ( VAMP x 2
chemo: velban, adriamycin, MTX, prednisone
cytoxan, vincristine, procarbazine, prednisone
RT: field = IFRT
dose = 15 Gy (CR) or 25 Gy (< CR)
| |2-yr EFS rate |
|CS I-II bulky |90% |
|CS III-IV |81% |
Stage III-IV – current standard per ASTRO 2001 refresher course is combined modality therapy
( ABVD x 6 cycles
OR
COPP/ABV X 6 total (3 of each)
RT: field = involved field
dose = 20 – 21 Gy
field = residual disease after PR
dose = 1000 cGy (total = 3500 cGy)
( MOPP/ABVD x 8 cycles without RT
controversial for children
do not recommend
R Hutchinson, et al. Med Pediatr Onc. 21:61, 1993. (abstract) - CCG 521
update in R Hutchinson, et al. J of Clin Onc. 16:897, 1998.
prospective randomized trial
111 pt with stage III-IV
randomization: (1) alternating ABVD x 6 / MOPP x 6
(2) ABVD x 6 + IF RT
RT: field = involved field
dose = 2100 cGy
| |ABVD x 6 / MOPP x 6 |ABVD x 6 + RT |p-value |
|4-yr OS rate |84% |90% |NS |
|4-yr EFS rate |77% |87% |NS |
criticisms = not enough patients to show a difference
M Weiner, et al. J Clin Onc. 15:2769-2779, 1997. - POG 8725
prospective randomized trial
179 children with stage IIB, IIIA2, IIIB, & IV Hodgkin's Dz treated between 1987-92
staging lap in 36%
randomization: (1) alternating MOPP x 4 /ABVD x 4 cycles (n=89)
(2) alternating MOPP x 4 /ABVD x 4 cycles + EF RT (n=90)
RT: if no subdiaphragmatic dz ( STNI (mantle + paraaortic/spleen)
if subdiaphragmatic dz( TNI (mantle + paraaortic/spleen + pelvis)
dose = 2100 cGy in 150 cGy fx to nodes and spleen
1050 cGy in 150 cGy fx to nonlymphoid organs (liver, lung, pericardium, kidney, etc)
2 wk rest between fields
re-staging performed after 3, 6, & 8 cycles of chemo and after RT
if < CR after chemo ( biopsy suspicious site ( if confirmed residual dz, off protocol
90% CR rate after 8 cycles of MOPP/ABVD
10 of 80 RT patients did not receive it
| | |MOPP/ABVD x 8 (n=89) |MOPP/ABVD x 8 + RT (n=90) |p-value |
|5-yr actuarial OS rate | |96% |87% |NS |
|5-yr actuarial EFS rate |overall |79% |80% |NS |
| |CR after chemo (n=161) |82% |87% |NS |
if clinical CR after 3 cycles chemo, 5-yr EFS rate = 94%
if not clinical CR after 3 cycles chemo, 5-yr EFS rate = 78%
conclusions = (1) in children with stage clinical stage IIB-IV HD, 8 cycles of alternating MOPP/ABVD produces equivalent
outcome compared to chemo + RT
(2) clinical response after 3 cycles of chemo if a powerful predictor of outcome
Found no difference in 5 year EFS when analyzed by intent to treat, the 5 yr EFS of 80% was inferior to that of other trial
and when analyzed by treatment actually received, there was a benefit for radiation. Therefore, POG continued with RT
CCG-59704
eligibility criteria: stage II-III + bulky disease or B-symptoms, stage IV
BEACOPP x 2 ( re-evaluate ( BEACOPP x 2 ( re-evaluate (
if CR/PR-1(> 70% ( size & (-)Ga67 scan) ( if male, then ABVD x 2 + IF RT
if female, then COPP/ABV x 4
if PR-2(50-70% ( size) ( BEACOPP x 4 + IF RT
if PD, then off protocol
BEACOPP: Bleomycin
Etoposide
Adriamycin
Cytoxan
Vincristine
Procarbazine
Prednisone
Link, et al. Proc of ASCO 1994. –
CS I-II bulky or CS III-IV
VEPA x 6 + IF RT (15-25 Gy)
chemo: velban, etoposide, prednisone, adriamycin
5-yr EFS rate = 68%
5-yr OS rate = 81%
closed early due to poor outcome
S Donaldson @ ASTRO 2001 - Tri-Center Protocols (Stanford, St. Jude, Dana-Farber)
1994-98
122 pt with CS I-II bulky or CS III-IV
VAMP/COPP x 2 ( IFRT ( VAMP x 2
chemo: velban, adriamycin, MTX, prednisone
cytoxan, vincristine, procarbazine, prednisone
RT: field = IFRT
dose = 15 Gy (CR) or 25 Gy (< CR)
| |2-yr EFS rate |
|CS I-II bulky |90% |
|CS III-IV |81% |
G Schellong, et al. Baillieres Clin Haematol. 9:619-634, 1996. - German
P Mauch, et al. Cancer. 51:925-932, 1988. - Joint Center
Refractory/Relapsed Disease
• Divided into 3 groups
o Primary refractory disease
o Early relapse 1 year since remission
( relapse typically occurs within 4 yr
( prognostic factors:
site of relapse (nodal better than extranodal)
stage assigned to relapse (early better than advanced)
histology (LP & NS better than MC)
( things to consider when choosing appropriate salvage therapy:
did the pt ever achieve a CR or was the dz refractory to initial tx?
if a CR was achieved, was it durable (> 1 yr)?
was the relapse in nodal or extranodal sites?
was the stage at relapse early or advanced?
( Standard-Dose Chemotherapy
indications: initially treated with RT alone
DFS rate = 55-80%
Involved-Field RT
considered for areas of bulky dz if can be given safely
• Relapse at supradiaphragmatic nodal site alone without B symptoms may be able to be salvaged with RT alone
( High-Dose Chemotherapy + Stem-Cell Rescue
indications: initially treated with chemo
| |standard dose chemo |high dose chemo + BMT |
|DFS rate |10-50% | |
Involved-Field RT
considered for areas of bulky dz if can be given safely
( Palliative Therapy
J Yahalom, et al. Sem Radiat Oncol. 6:210-224, 1996. –
D Linch, et al. Lancet. 341:1051-1054, 1993. – BNLIG
prospective randomized trial
40 pts with recurrent HD
Study closed early due to better DFS with BMT arm
Randomized to
1. Standard-dose BEAM )mini beam
2. High dose BEAM with autologous BMT
DFS favored BMT with DFS of 53% for those with BMT vs 10% for those without BMT
A Yuen, et al. Blood. 89:814-822, 1997. – Stanford University
matched pair analysis
| |conventional dose chemo |high dose chemo + BMT |p-value |
|EFS rate |27% |53% | |
J Poen, R Hoppe, et al. IJROBP. 36:3-12, 1996. – Stanford University
retrospective study
pt with stage I-III HD at relapse
| |autologous BMT |autologous BMT + IFRT |p-value |
|3-yr RFS rate |67% |100% | |
|3-yr OS rate |60% |85% | |
Hodgkin’s Disease Diagnosed During Pregnancy
1st Trimester of Pregnancy
( Therapeutic Abortion
( Close Observation & Induce Delivery at 32-36 wk after Fetus Reaches Lung Maturity (by amniocentesis)
considered if stage I-IIA supradiaphragmatic and growing slowly
( Mantle Field RT
most of dose to fetus is via internal scatter
techniques to ( dose to fetus: raise lower border of field to T8/9
HBB lower border of field
lead shield over abdomen
Delivery by C-section after Fetus Reaches Lung Maturity and Simultaneous Staging Lap
if (-)lap, then PA RT
if (+)lap, then ABVD x 6
SY Woo, et al. IJROBP. 23:407-412, 1992. – MD Anderson
16 pt
mantle field with abdominal shielding
no congenital abnormalities
( Chemotherapy
not recommended during 1st trimester
1/3 of infants develop congenital abnormalities
Thomas, et al. Cancer. 38:1443-1451, 1976. –
2nd Half of Pregnancy
( Close Observation & Induce Delivery at 32-36 wk after Fetus Reaches Lung Maturity (by amniocentesis)
appropriate for most pt unless symptomatic advanced disease
C Jabobs, S Donaldson, et al. Annals of Int Med. 95:669-675, 1981. –
Nisce, et al. Am J Clin Onc. 9:146-151, 1986. –
( Vinblastine + Prednisone
used for symptomatic pt with advanced stage or rapidly progressing disease
vinblastine has never been associated with fetal abnormalities in the 2nd half of pregnancy
prednisone has an antitumor effect and hastens fetal pulmonary maturity
Follow-up
NCCN Guidelines:
( H&P – finds 70% of all the relapses
Note: Reactive hyperplasia of LN can occur in those just outside the prior RT port.
blood work (CBC, Plt, Lytes, LFTs, LDH, ESR)
q3mo x yr 1-2 ( q4mo x yr 3-4 ( q6mo x yr 5 ( q1yr
( TSH, T4
if neck RT given
q6mo
( CxR – Finds 25% of relapses
q6mo x yr 1-3 ( q1yr
( CT chest/abd/pelvis
if CS I-II, q1yr x 5 yr
if CS III-IV, q6mo x yr 1-3 ( q1yr x yr 4-5
(consider PET scan as an alternative ??)
( screening mammograms
if mantle RT given
q1yr
start 8-10 yr after RT or age 40 yr, whichever is earliest
( re-vaccinate for H. flu & pneumovax q6yr if splenectomy or spleen RT ??
Complications
RT Toxicity:
( Acute Side Effects:
Mantle Field
- occipital hair loss / epilation ( starts to regrow at 3 mo
- mild skin reaction in neck, shoulders, and axilla
- oral mucositis
- esophagitis
- thickening of saliva
- altered sense of taste
- fatigue
- nausea and occasional vomiting
- mild myelosuppression (50%)
Paraaortic Field
- nausea and vomiting
- fatigue
- mild myelosuppression (75%)
- transient ( liver enzymes (alk phos)
( Subacute Toxicity:
- Lhermitte Sign
- 10-15% incidence after mantle irradiation
- transient myelopathy with paresthesias down the dorsal portion of the extremities with neck flexion
- insidious onset 1-2 mo after RT and resolves over 2-6 mo
- caused by transient demyelination
- Temporary Xerostomia
- occurs after mantle irradiation & saliva returns to normal within 6 mo
- may be permanent after Waldeyer irradiation
- intensive fluoride treatment to minimize incidence of dental caries
- Radiation Pneumonitis
- 1-6 mo after completion with mild nonproductive cough, low-grade fever, & dyspnea on exertion
- may occur earlier with prior chemotherapy
- dose threshold =
- symptomatic incidence = 5% (2-3x ('d risk if large mediastinal LAD or MOPP chemo)
- treatment = NSAIDS
corticosteroids x 4-6 wk with slow taper
N Tarbell, et al. IJROBP. 18:275-281, 1990. - Joint Center
retrospective study
590 pt with stage IA-IIIB supradiaphragmatic HD received mantle field RT between 1969-84
RT doses: 3600-4000 cGy to uninvolved areas
4000-4400 cGy to involved areas
25% received MOPP chemo
median f/u = 104 mo
| | |symptomatic radiation pneumonitis rate |
|overall | |6% |
|small or no mediastinal dz | |4% |
|bulky mediastinal dz | |14% |
|RT alone |overall |3% |
| |whole lung to 1500 cGy |13% |
|chemo + RT |overall |11% |
| |whole lung to 1500 cGy |15% |
Hancock, et al. Semin Radiat Oncol. 6:225, 1996. –
- Acute Pericarditis
- 2-3% risk
- fever, chest pain, friction rub, pericardial effusion
- treatment = NSAIDS
- resolves over several weeks
- Acute Myocarditis
( Late Complications:
- Hypothyroidism
- 30% incidence after mantle irradiation
- subclinical with elevated TSH and normal T4
- treatment = L-thyroxine
N Tarbell, et al. IJROBP. 18:275-281, 1990. - Joint Center
retrospective study
590 pt with stage IA-IIIB supradiaphragmatic HD received mantle field RT between 1969-84
RT doses: 3600-4000 cGy to uninvolved areas
4000-4400 cGy to involved areas
25% received MOPP chemo
median f/u = 104 mo
| |overall |age < 16 yr |age > 16 yr |
|chemical hypothyroidism |25% |64% |29% |
|clinical hypothyroidism |3% (2(/2 early tx) | | |
|median time to onset |44 mo | | |
Sklar, et al. J Clin Endocrinol Metab. 85:4441, 2000. –
- Herpes Zoster
- occurs up to 1-2 yr after treatment in 10-15%
- treatment = acyclovir
- Cardiac Toxicity
- arrhythmias
- MI RR ~ 2.5
- CAD
- Second Primary Cancers
- RR 6.4
- 10-15% at 15 yr
- AML – 5% after MOPP x 4 (10% after 6 cycles)
seen after chemotherapy (alkylating agents or procarbazine) latent period of 3-7 yr
- lymphoma – diffuse large cell lymphoma after latent period of > 5 yr
- solid tumors – 8% @ 15-yr
after radiation therapy with latent period of 10-15 yr
breast > lung, GI tract cancers
- In a Stanford series one of the highest risks for 2nd malignancy was need for salvage therapy.
A Ng, et al. Proc of ASTRO. 51:67-68, 2001. – Harvard
Blood et al. 2002
retrospective study
1319 pts with stage IA-IVB Hodgkin’s dz treated between 1969-97
Included only 961 pts with > 10 yr f/u
66% had mantle and paraaortic with total dose near 40 Gy and median of 36 Gy
85% had chemo with 296 as MOPP
median f/u = 12 yr
181 2nd malignancies occurred (excluding epidermal skin ca)
3 most common solid tumors = breast, lung, GI tract
less common solid tumors = sarcoma, H&N, thyroid, melanoma
| |15 yr risk |20 yr risk |
|Risk of 2nd Malignancy |14% |23% |
|2nd malignancy type |median latent period |age at dx |RR breast cancer |yr from tx |RR of 2nd ca |
|Leukemia |4.8 yr |< 15 yr |111 |0-5 yr |2 |
|NHL |7.3 yr |15-19 yr |31 |5-10 yr |3 |
|solid tumor |12.7 yr |20-25 yr |16 |10-15 yr |4 |
| | |26-29 yr |8 |15-20 yr |7 |
| | |30-35 yr* |4 |> 20 yr |11 |
*no ( risk of breast ca if diagnosed after age 35 yr
no difference in 2nd malignancy risk between males and females
RR of 2nd malignancy was lower after RT alone vs chemo + RT (4 vs 6) aka higher rate of 2nd malig with combo Rx
Decreased risk of 2nd malignancy with decreasing field size
Risk of Breast cancer significantly increased with dx prior to age 30 vs not significant if after 35 yo
In 1st 10 yrs 50% are solid tumors and 2nd 10 yrs 85% are solid tumors
Overall 4.6 fold increase risk of 2nd cancer relative to general population. Increased risk after 10-15 yrs is mainly driven by
solid tumors, mostly breast
- Infertility
- for pelvic irradiation (ovaries overlie the iliac lymph nodes)
- 100% sterility and amenorrhea for doses of 30-35 Gy
- oophoropexy moves ovaries into midline low pelvis behind uterus to allow for shielding (keep dose < 4 Gy)
- Small Bowel Obstruction
- 1% after < 35 Gy
- Special Pediatric Issues
- Infertility
- 2nd Malignancy:
~ 15% risk at 10 yr
| |leukemia (2(/2 alkylating agent) |solid tumor* (2(/2 RT) |overall |
|5-yr rate |1% |0.4% |2% |
|10-yr rate |3% |2% |5% |
|15-yr rate |4% |6% |9% |
|median time delay |5 yr |12 yr | |
* basal cell ca, breast ca, thyroid ca, sarcoma
Bhatia, et al. NEJM. 334:12, 1996. – Late Effects Study Group (multi-institutional study)
1,380 pt
median f/u = 11.4 yr
L Constine, et al. Proc of ASTRO. 51:70, 2001. – multi-institutional
retrospective study
928 pt < 18 yr old treated for HD between 1960-90
median f/u = 14.5 yr
RR of 2nd malignancy = 17 (greater for females)
median latent period for breast ca = 15.3 yr
only 2 developed breast ca after doses < 25 Gy
Tucker, et al. NEJM. 318:76, 1988. – Stanford
15-yr risk: all cancers 18%
solid tumors 13%
leukemia 3%
lymphoma 2%
Wolden, et al. J Clin Onc. 16:536, 1998. – Stanford
694 pt < 21 yr old
tx: RT alone 46%
chemo + RT 51%
chemo alone 3%
mean RT dose = 38 Gy
mean f/u = 13 yr
56 pt developed a 2nd cancer: 27% breast, 22% sarcoma, 14% leukemia, 7% lung, 7% melanoma, 5% HNL,
5% thyroid, 5% salivary
- Bone and Soft Tissue Growth Impairment / Hypoplasia
short siting height, small neck circumference, shortened clavicles, small thorax
most significant in age < 13 yr & dose > 35 Gy
dose < 25 Gy results in no significant height abnormalities
Willman, et al. IJROBP. 28:85, 1994. –
SS Donaldson, et al. Pediatr Clin North Am. 38:457-473, 1991. - Stanford University
RJ Carmel, et al. Cancer. 37:2813-2725, 1976. -
SL Hancock, et al. NEJM. 325:599-605, 1991. -
M Henry-Amar, et al. Ann Oncol. 3:S117-128, 1992. –
FE Van Leeuwen, et al. J Clin Onc. 18:487-497, 2000. –
S Ghatia, et al. NEJM. 334:745-751, 1996. –
Chemotherapy Toxicity
( Acute Toxicity:
- alopecia
- nausea & vomiting
- diarrhea
- mucositis
- neuropathy -- paresthesias and weakness
- confusion
- myelosuppression
- procarbazine ( disulfiram reaction
( Chronic Toxicity:
- hypothyroidism
- pulmonary fibrosis
- MOPP ( 5% risk of AML at 10 yr
maximum risk at 5-9 yr
possibly increased with age > 40 yr or splenectomy
risk depends on the # of cycles given
male infertility (80%)
female infertility (50%)
25% for age < 25 yr
90% for age > 25 yr
- ABVD ( < 1% risk of AML at 10 yr
male infertility (20%)
female infertility (50%)
25% for age < 25 yr
90% for age > 25 yr
bleomycin lung toxicity (5%)
cardiomyopathy
Splenectomy Toxicity
( Bacterial Sepsis (3%)
all patients should be immunized for H. influenza b, Meningococcus, & S. pneumoniae at least 1 wk prior to therapy
re-immunization 2 yr after therapy & q6yr thereafter
( Leukemia
possibly slightly increased risk
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