Radiation Oncology/Pediatric Hodgkin's

Epidemiology

 * Childhood HD occurs at age 4-14 years
 * Male predominance 4:1
 * Associated with decreasing socio-economic status and increasing family size
 * Young adult HD occurs at age 15-30 years
 * Equal male/female incidence
 * Associated with increasing socio-economic status and decreasing family size

Pathology

 * Clonal expansion of a single transformed B-cell
 * Two separate phenotypes:
 * Classical HD : has Hodgkin and Reed-Sternberg (HRS) cells; CD30+, J chain-
 * Lymphocyte predominant : has Lymphocytic and Histiocytic (L&H) cells; CD30-, J chain+, CD20+, CD15-
 * Strong association with EBV, particularly in young children and developing countries
 * Association with congenital (AT) and acquired (HIV) immunodeficiency

Staging

 * Uses standard Ann Arbor system
 * Location
 * 80% cervical lymphadenopathy
 * 75% mediastinal involvement in >10 year olds but 33% mediastinal involvement in <10 year olds
 * Isolated infradiaphragmatic disease is rare (<5%)
 * Stage I-II 60%, Stage III-IV 40%
 * B-symptoms: <10 year olds 20%, >10 year olds ~30%

Treatment

 * Goal of risk-adapted therapy is to define least amount of therapy with the fewest long-term complications; controversy remains about the minimal required therapy:
 * Prevent impairment of skeletal and soft tissue growth after high dose EFRT
 * Decrease risk of AML and infertility after high doses of alkylating agents (MOPP)
 * Decrease risk of CAD after treatment after thoracic RT and anthracyclines
 * Decrease risk of pulmonary fibrosis after thoracic RT and bleomycin
 * Eliminate life-threatening consequences of splenectomy from surgical staging
 * Decrease risk of breast cancer and secondary solid tumors after IFRT
 * Initial treatment in 1960's was high-dose RT alone to 40 Gy EFRT modeled after adult treatment; 5-year DFS was 60-80% in pathologically staged children with early-stage disease
 * Concerns about skeletal and soft tissue dysfunction, and resulting growth impairment, led to evaluation of multiple cycles of chemotherapy replacing a portion of RT. Addition of MOPP allowed Stanford investigators to lower RT dose to 15-25 Gy in 1970's, with OS and EFS at 10 years ~90% for the entire cohort
 * ABVD was tried to mitigate some of MOPP toxicity, particularly reducing risk of sterility and second malignancy.
 * Reports showed that MOPP + ABVD and ABVD + RT were better than MOPP alone or MOPP + RT
 * As a result, CCG 521 was undertaken, and demonstrated that ABVD x 6 cycles + low-dose 21 Gy EFRT is comparable to ABVD/MOPP x12 cycles. MOPP (and its toxicity) could be eliminated from first line therapy
 * Meanwhile, another Stanford series demonstrated good outcomes in patients with bulky disease with dose intensified MOPP/ABVE (Stanford V) and 36 Gy RT. However, there are concerns about combining alkylating agents and high-dose RT for delayed toxicity of treatment
 * Pediatric Oncology Group developed a series of trials around ABVD. In POG 9425, patients with advanced disease were treated on risk-adapted ABVE-PC protocol with IFRT 21 Gy. In POG 9426, patients were treated on DBVE with IFRT. Both studies are maturing.
 * POG and CCG also performed trials attempting to eliminate RT altogether. POG 8725 compared MOPP/ABVD x8 cycles with and without low dose TNI/sub-TNI in advanced patients. There was no benefit for RT. However, the chemo regimen used included significant doses, and which are concerning for long-term toxicity (gonadal, cardiac, secondary leukemias)
 * CCG 5942 attempted to eliminate RT in patients who had complete response to 4 cycles of COPP/ABV. The study was closed early, after demonstrating benefit of RT in all patients subgroups. However, the benefit is likely to be smaller compared to toxicity in low risk patients, and higher compared to toxicity in high risk patients
 * Similarly, a European trial GPOH-HD 95 showed that elimination of RT is not advisable for intermediate and advanced stages, but is possible in patients with early stage and good response to chemotherapy.
 * The conclusions thus far appear to be 1) low-dose RT may be omitted, but appears to require excessive chemotherapy to compensate, and 2) patient subgroups for whom RT may be safely omitted with reasonable chemotherapy have not yet been well defined. Low disease burden and early response to treatment may be prognostic factors, which may allow elimination of RT
 * to be continued ...

Low Risk

 * Typically Stage I-IIA, non-bulky, no extranodal disease, <3 sites
 * 10-year EFS ~90%, OS 96%


 * COG AHOD-0431 (Ongoing) - "A Phase III Study for the Treatment of Children and Adolescents With Newly Diagnosed Low Risk Hodgkin Disease"
 * Prospective single arm. Children with low risk disease (IA-IIA, nonbulky, non-B). Treated with response directed therapy. Initially AVPC x 3 cycles. If CR, then no RT and salvage as per protocol. If PR, then IFRT 21/14 to disease involved at presentation. For mediastinum, modified mantle.


 * POG 9426 (Completed 10/2004)
 * Prospective. Children with low risk disease (IA, IIA, IIIA1 (spleen, celiac, portal nodes), nonbulky, non-B). Treated with DBVE x2 cycles. If CR, then IFRT 25.5/17. If PR, then DBVE x2 more courses, followed by IFRT 25.5/17. RT to disease involved at presentation.


 * Stanford, 2007 PMID 17235049 -- "Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease." (Donaldson SS, J Clin Oncol. 2007 Jan 20;25(3):332-7.)
 * Prospective. 110 children, low risk (Stage I-II, mediastinal mass <1/3 diameter, no extranodal disease, peripheral LN <6cm). Treated with VAMP x4 cycles and low-dose IFRT (15 Gy if CR, 25.5 Gy if PR). Median F/U 9.6 years
 * 10-year outcome: OS 96%, EFS 89%; Favorable factors: early CR, absence of B-symptoms, lymphocyte predominant, <3 initial sites of disease
 * Toxicity: correctable hypothyroidism 42%, 1 patient cardiac dysfunction, 2 malignant tumors (1 thyroid CA within RT field, 1 Ewings outside RT field). 17 healthy babies born to 106 survivors
 * Conclusion: Risk-adapted strategy effective and well tolerated, without alkylating agents, bleomycin, etoposide, or high-dose EFRT. Children expected to retain normal fertility, organ function, and low risk of second tumors

Unfavorable

 * Typically:
 * Stage I-II with bulky disease, or extranodal, or with B-symptoms
 * Stage III-IV disease
 * 5-year EFS 70-90%, OS ~85%


 * COG AHOD0031 (Ongoing)
 * Intermediate disease (I-II bulky or extranodal or B-symptoms, all III, IVA, IVAE). ABVE-PC x2 cycles, followed by response evaluation. Early responders with CR randomized to +/- IFRT, if PR receive IFRT. Late responders randomized to ABVE-PC x2 cycles + IFRT 21/14 (standard arm) vs. DECA + ABVE x2 cycles + IFRT 21/14 (augmented arm). Goal of the study is to see if some patient (early CR) may not need IFRT, and if some patients (late CR) may benefit from additional chemo dose escalation and IRFT.


 * POG 9425
 * 216 patients. Intermediate (IIA/IIIA, bulky) or high stage (IIB, IIIB, IV). DBVE-PC and using early response to limit cumulative therapy. Everyone IFRT 21/14 (Stage II: mantle only, Stage III-IV subtotal/total NI). Randomized to +/- dexrazoxane for cardiopulmonary protection
 * 2002 ASCO Abstract - "POG 9425: response-based, intensively timed therapy for intermediate/high stage (IS/HS) pediatric Hodgkin's disease" (Schwartz CL, Proc Am Soc Clin Oncol 21: 2002 (abstr 1555)
 * 2-year outcomes: EFS 88% (IS 86%, HS 89%)
 * Conclusion: Thus far, 63% required only 9 weeks of chemo, followed by RT. This may reduce long-term toxicity
 * Dexrazoxane, 2007 PMID 17290056 -- "Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease." (Tebbi CK, J Clin Oncol. 2007 Feb 10;25(5):493-500.)
 * Studies POG 9425 and POG 9426 randomized patients to DRZ (n=239) or no DRZ (n=239) concomitant with chemo as a cardiopulmonary protectant
 * 4-year second malignancies: DRZ 3.4% vs. no DRZ 0.8% (p=0.06)
 * Conclusion: DRZ is a Topo-II inhibitor; adding it may have increased incidence of 2nd malignancy and AML/myelodysplasia


 * US Multi-institutional (1993-2000)
 * Prospective. 4 institutions (St. Jude's, Stanford, DFCI, Maine). 159 children with unfavorable HD (52% Stage III-IV, or 48% Stage I-II with bulky disease or with B-symptoms). Treated with VAMP/COP x6 cycles, followed by IFRT (15/10 Gy if CR, 25.5/17 Gy if PR after 2 cycles). RT given to standardized treatment volumes.
 * Closed early after 5-year EFS was below expected
 * 2004 PMID 15542805 -- "Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease." (Hudson MM, J Clin Oncol. 2004 Nov 15;22(22):4541-50.) Median F/U 5.8 years
 * 5-year outcomes: EFS 76%, OS 93%
 * Conclusion: Risk-adapted VAMP/COP and response-based IFRT unsatisfactory


 * POG 8725 (1987-1992)
 * Randomized. 183 patients protocol, 161 in CR randomized. Stage IIB-IV. 77% NS, 50% bulky mediastinum, 37% Stage IV. MOPP/ABVD x8 cycles +/- 21 Gy in 1.5 Gy/fx.
 * RT 9/80 patients major protocol violation. If pelvic disease, TNI; if no disease below aortic bifurcation, sub-TNI (mantle, spleen, PA). Lymphoid tissue 21 Gy, nonlymphoid tissue 10.5 Gy
 * 1997 PMID 9256118 - "Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study." (Weiner MA, J Clin Oncol. 1997 Aug;15(8):2769-79.)
 * 5-year outcomes: EFS RT+ 79% vs. RT- 80% (NS), OS 87% vs. 96% (NS)
 * Conclusion: No advantage to RT
 * 2008 PMID 18406943 -- "Processes for quality improvements in radiation oncology clinical trials." (FitzGerald TJ, Int J Radiat Oncol Biol Phys. 2008;71(1 Suppl):S76-9.)
 * Quality assurance review
 * Outcome: 5-year RFS chemo alone 85% vs RT with deviations in volume 86% vs RT appropriate volume 96%
 * Conclusion: RT delivered according to protocol showed 10% relapse-free survival advantage, while RT delivered with deviations was no better than chemo alone


 * CCG 521 (1986-1990)
 * Randomized. 111 patients, Stage III-IV. Treated with MOPP/ABVD x12 cycles vs. ABVD x6 cycles + EFRT 21 Gy in 1.75 Gy/fx. If lung, used 10.5 Gy with 50% transmission blocks. If residual disease, boost 14 Gy for total 35 Gy
 * 1998 PMID 9508171 -- "MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial." (Hutchinson RJ, J Clin Oncol. 1998 Mar;16(3):897-906.)
 * 4-year outcomes: EFS: MOPP/ABVD 77% vs. ABVD/EFRT 87% (p=0.09), OS 84% vs. 90% (NS)
 * Outcomes by stage: Stage III 11% relapsed, Stage IV 27% relapsed
 * Toxicity: acute mostly hematopoietic, pulmonary/cardiac modest (8 patients Grade 3-4 pulmonary toxicity, all on chemo and likely due to bleomycin)
 * Conclusion: Equivalent, MOPP can be eliminated from front-line therapy


 * NCI, 1997 PMID 9363863 -- "Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease." (Longo DL, J Clin Oncol. 1997 Nov;15(11):3338-46.)
 * Prospective. 80 patients with bulky mediastinum. Treated with MOPP/ABVD x 6 cycles + 10 Gy mantle followed by 25-35 Gy to residual disease. Median F/U 10 years
 * 15-year outcomes: Overall CR 89%; DFS of CR 78%, OS of CR 75%
 * By Stage: I-II: DFS 76% OS 79%; III-IV DFS 82%, OS 64%
 * Toxicity: pneumonitis 16% (1 fatal). 2 patients solid tumors within RT fields. Fertility preserved more with MOPP/ABVD than MOPP alone; less cardiopulmonary toxicity than ABVD
 * Conclusion: MOPP/ABVD followed by mantle RT effective for bulky mediastinum


 * Stanford, 1996 (1989-1995) PMID 8836420 -- "Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin's disease: an update." (Horning SJ, Ann Oncol. 1996;7 Suppl 4:105-8.)
 * Prospective. 94 patients. Bulky or Stage III/IV received Stanford V regimen x3 months +/- 36 Gy RT. Median F/U 3 years
 * Outcome: EFS 89%, OS 93%
 * Conclusion: Well tolerated and highly effective, with lower cumulative doses of alkylating agents and RT


 * Harvard, 1978 (1969-1974) PMID 698907 -- "The significance of mediastinal involvement in early stage Hodgkin's disease." (Mauch P, Cancer. 1978 Sep;42(3):1039-45.)
 * Retrospective. 111 consecutive surgically-staged IA/IIA patients. RT 36-44 Gy mantle + PA/splenic regions. Median F/U 4.7 years
 * Outcome: 14 patients (13%) relapsed, 3 (3%) died of treatment-related causes (MI x2, pneumonitis x1). Bulky mediastinum significant risk for relapse: 65% (9/18) vs. 5% (5/93) (SS)
 * Conclusion: recommend addition of MOPP to RT

All risk groups

 * GPOH-HD 95 Multi-national (1995-2001)
 * Prospective. 1018 children. Risk-adapted chemo OPPA/OEPA (Stage I-IIA 2 cycles, Stage IIEA, IIB, IIIA 4 cycles, Stage IIEB, IIIAE, IIIB, IV 6 cycles). If CR, no RT (22%); otherwise RT to involved sites if >75% PR received 20 Gy; if <75% PR received 30 Gy; if >50ml residual received 35 Gy)
 * 2004 ASTRO 2004 Abstract, Video:ASTRO Plenary Session &mdash; "The German Multinational GPOH-HD 95 trial: treatment results and analysis of failures in pediatric Hodgkin's Disease using combination chemotherapy with and without radiation." Ruhl et al.
 * 2003 PMID 12838937 -- "Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook." (Dorffel W, Klin Padiatr. 2003 May-Jun;215(3):139-45.)
 * Early (I-IIA): DFS 96%; no difference between RT and no RT
 * Intermediate (IIEA, IIB, IIIA): DFS better with RT 92% vs. 78%
 * Advanced (IIEA-IV): DFS better with RT 91% vs. 79%. No difference in OS
 * Conclusion: Reduction in RT to 20 Gy possible with good response. Omission of RT possible only for early stage (TG1); intermediate/advanced stage needs RT for better DFS


 * CCG 5942 (1995-1998)
 * 829 patients enrolled, 501 patients with CR randomized to +/- IFRT 21 Gy. Risk-adapted chemotherapy (26% Stage I-II low risk, 47% Stage I-II high risk/Stage III, 17% Stage IV). RT given 21 Gy in 12 fxs to IF, if pulmonary involvement 10.5 Gy in 12 fxs to whole lung
 * Study closed prematurely because of inferior EFS in no RT arm
 * 3-years, 2002 PMID 12228196 - "Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy." (Nachman JB, J Clin Oncol. 2002 Sep 15;20(18):3765-71.)
 * 3-year EFS: as-randomized RT 92% vs. no RT 87% (p=0.057), as-treated 93% vs. 85% (p=0.002). No survival difference
 * Group 1: 100% vs. 85% (survival 100%); Group 2: 88% vs. 83% (survival 95%-100%); Group 3: 91% vs. 79% (survival 100%-93%)
 * Patterns of failure: no RT - 85% in previously known disease; IFRT - 58% in-field, 25% in- and out-of-field
 * Conclusion: no RT worsened EFS even in low-risk (Group 1) patients after 4 cycles of chemo; study closed early


 * Stanford, 1987 PMID 3572464 -- "Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin's disease." (Donaldson SS, J Clin Oncol. 1987 May;5(5):742-9.)
 * Prospective. 55 children treated with MOPP x6 cycles and strict IFRT to 15 Gy / 20 Gy / 25 Gy depending on bone age, in order to decrease long-term toxicity. Boost if initially bulky disease or not CT after chemo. Median F/U 7.5 years
 * Outcomes: EFS 90%, OS 89% up to 15-years out. Relapse in bulky sites, despite RT 25-35 Gy
 * Toxicity: no growth alterations. 3 children with acute leukemia
 * Conclusion: Basis for ongoing chemo + low-dose IFRT protocols


 * Milan, 1987 PMID 2433409 -- "Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy." (Santoro A, J Clin Oncol. 1987 Jan;5(1):27-37.)
 * Randomized. 232 patients. Stage IIB, IIIA-B. Treated with MOPP + EFRT vs. ABVD + EFRT
 * 7-year outcomes: EFS ABVD 88% vs. MOPP 77% (p=0.06), OS 77% vs. 68% (SS)
 * Toxicity: gonadal dysfunction and acute leukemia with MOPP, no difference in cardiopulmonary toxicity
 * Conclusion: ABVD + EFRT valid alternative to MOPP + EFRT, with less toxicity


 * Milan, 1982 (Italy) PMID 6174865 -- "Alternating drug combinations in the treatment of advanced Hodgkin's disease." (Santoro A, N Engl J Med. 1982 Apr 1;306(13):770-5.)
 * Randomized. 75 patients with Stage IV HD, treated with MOPP vs. MOPP/ABVD
 * 5-year outcome: CR in 71% MOPP vs. 92% MOPP/ABVD (SS); EFS 54% vs. 84% (SS)
 * Conclusion: MOPP/ABVD better than MOPP alone


 * Stanford, 1976 (1962-1972) PMID 1260726 -- "Pediatric hodgkin's disease. II. Results of therapy." (Donaldson SS, Cancer. 1976 May;37(5):2436-47.)
 * Retrospective. 79 children. Aggressive treatment with RT and MOPP.
 * Conclusion: Combination effective, propose low-dose RT with MOPP

RT Technique

 * International Lymphoma Radiation Oncology Group
 * Practice Guideline; 2015 PMID 25413415 -- "Implementation of contemporary radiation therapy planning concepts for pediatric Hodgkin lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group." (Hodgson DC, Pract Radiat Oncol. 2015 Mar-Apr;5(2):85-92. doi: 10.1016/j.prro.2014.05.003. Epub 2014 Jul 9.)
 * 3D treatment volume definitions
 * Boost volume definitions
 * Organs at risk dose constraints


 * Justification for 21 Gy dose used in CCG-521
 * PMID 5947345 -- "Evidence for a tumoricidal dose level in the radiotherapy of Hodgkin's disease." (Kaplan HS, Cancer Res. 1966 Jun;26(6):1221-4.)
 * HD recurs in-field as a function of dose; approaches zero at ~40 Gy delivered at 10 Gy/week
 * PMID 4652410 -- "Theoretical considerations in combinations of localized and systemic therapy for neoplastic diseases." (Fischer JJ, J Theor Biol. 1972 Oct;37(1):105-14.)


 * Mantle field considerations
 * Arms up - pulls axillary LNs away from lungs toward humeral heads
 * Arms down (akimbo) - leaves axillary LNs near lungs, freeing up humeral heads
 * Choosing set-up position involves considerations of LNs to be treated, lung doses, and humeral head doses
 * Breast tissue should be excluded as much as possible, either out of the field or under blocks

Late Effects

 * Scandinavian second malignancy


 * Musculoskeletal: height reduction in prepubertal children after full dose
 * Cardiovascular: 45X excess mortality due to MI after full dose, concern about anthracyclines and low-dose
 * Pulmonary: pneumonitis concerns in conjuction with bleomycin (ABVD/ABVE)
 * Thyroid: hypothyroidism in 17% kids given <26 Gy vs. 78% given >26 Gy mantle
 * Gonads: pelvic radiation typically leads to infertility
 * Second malignancies: 15-year risk 8-15%


 * Stanford, 1975 PMID 813276 -- "The effects of radiation therapy on bone growth." (Probert JC, Radiology. 1975 Jan;114(1):155-62.)
 * Retrospective. 29 children treated with >35 Gy RT to spine, and 15 children treated with <25 Gy RT to spine, compared with 15,000 normal children. Standing and sitting heights
 * Growth retardation seen in children treated during active bone growth (<6 years and during puberty) in high-dose group, but not low-dose group