Radiation Oncology/Hodgkin/Overview

Epidemiology About 14% of lymphomas; 1% of all cancers. Adult HD has bimodal age distribution: peaks at age 20-29 and again in the 50+ range Pediatric HD typically occurs 4-14 years old; marked male predominance 4:1 90% have disease in contiguous nodes (assuming para-aortics are contiguous to SCV via thoracic duct) Visceral involvement may be local extension or hematogenous; rare to GI lymphatics (Waldayer's ring or Peyer's patch) Work-Up History: look for B symptoms. Also fatigue, alcohol-induced pain, pruritus. PE: Palpable nodes, palpable viscera Labs: CBC, blood chemistry, albumin, ESR Radiology: CXR, CT, PET Biopsy: LN excision; bone marrow Bx if B-symptoms, subdiaphragmatic disease or Stage III-IV disease Staging laparotomy no longer used Classification Rye classification (1966) By Lukes and Butler. Presented at a conference in Rye, New York. Found that different subtypes have different prognoses: Lymphocyte predominant (most favorable) Nodular sclerosis (favorable) Mixed cellularity (guarded) Lymphocyte depleted (least favorable) World Health Organization (WHO) classification Classic Hodgkin lymphoma: CD 15+, CD 30+ Nodular lymphocyte predominant CD 15-, CD 30-, CD 20+ Pathology Classic HL Presence of classic Hodgkin/Reed-Sternberg (HRS) cells Do not exhibit phenotypes typical of any normal cell CD15+; marker is expressed on granulocytes Somatic hypermutation of immunoglobulin genes, with VDJ rearrangement. This is typically seen only in germinal B cells and post-germinal B cells Study of patients with both HL and NHL shows they are clonally related, suggesting that initial transformation occurred in a germinal B cell. Subsequently, there are two distinct sets of molecular lesions, which lead to divergent phenotypes of HL and NHL HRS cells appear to lose their germinal B cell characteristics, and become unable to transcribe RNA for immunoglobulin due to impaired activation of Ig promoters There is also activation of NF-kB pathway, which leads to c-REL increase and promotion of lymphocyte transformation and prevention of apoptotic deletion There is a widespread genomic instability, which contributes to the strange nuclear appearance Nodular lymphocyte predominant HL Prevalent tumor cell is "lymphocytic and histiocytic" (L&H) subtype of HRS cells Pathologically looks like popped corn Express B-cell markers Have multiple features that resemble normal germinal B-cells Classic HRS rare or absent; appears with multiple nuclear lobes and large nucleoli Prognostic Factors and Treatment Groups Definitions Prognostic Risk Factors GHSG — Bulky disease (mediastinal mass >1/3 intrathoracic diameter); Extranodal disease; ESR >50 w/o B Sx's or >30 w/ B sx's; 3+ LN regions EORTC/GELA — Mediastinal mass > 0.35 intrathoracic diameter at T5/6; Age >=50, ESR >50 w/o B Sx's or >30 w/ B sx's; 4+ LN regions NCCN — Bulky disease (mediastinal mass on CXR > 1/3 intrathoracic diameter or any mass > 10 cm on CT); Age >=40; ESR >50 or B sx's; 4+ LN regions or 2+ extranodal sites Note: The GHSG nodal areas include: left and right cervical (cervical, supra- and infraclavicular), left and right axillar, mediastinal (including bilateral hila), higher abdomen (portal, celiac and splenic), lower abdomen (para-aortic and mesenteric), left and right iliac and left and right inguinal. The EORTC only considers 5 supradiaphragmatic regions: left and right cervical (including supraclavicular), left and right axillar (including infraclavicular) and mediastinal (including bilateral hila). EORTC Prognostic Score (Stage I-II) Feature 0 Points 1 Point 9 Points Age <40 40-49 >=50 Gender Female Male   Stage I II2-3 II4-5 Mediastinum M/T ratio <0.35   MT ratio >0.35 B Symptoms / ESR No B symptoms ESR <50 B Symptoms ESR <30 B Symptoms + ESR >=30 or ESR >50 Histology LP-NS MC-LD Score 0: Very low risk Score 1-5: Favorable risk Score >=9: Unfavorable risk Treatment groups Lymphocyte Predominant Early-stage favorable GHSG — stage I-II with no risk factors EORTC/GELA — stage I-II supradiaphragmatic with no risk factors NCCN — stage I-IIA, no risk factors Early-stage unfavorable GHSG — stage I, stage IIA with 1+ risk factors, or stage IIB w/ elevated ESR or 3+ LN regions (not bulky or extranodal disease) EORTC/GELA — stage I-II supradiaphragmatic with 1+ risk factors NCCN — Stage I-II, any risk factors Advanced stage GHSG — stage III-IV, or IIb w/ bulky or extranodal disease EORTC/GELA — stage III-IV NCCN — stage III-IV Comparison of Definitions of Risk for Early Stage Disease Study Risk GroupingGerman Hodgkin Study Group High Low mediastinal mass (>1/3 thoracic diameter) extranodal disease ≥ 3 nodal areas ESR >50 (if asymptomatic) or >30 (if symptomatic) no large mediastinal mass no extranodal disease < 3 nodal areas low ESRNCI-Canada / ECOG Very High High Low Very Low any mass > 10 cm mediastinal mass (≥1/3 thoracic diameter) intraabdominal disease age ≥ 40 yr ESR ≥ 50 mixed cellularity or lymphocyte depleted ≥ 4 sites of disease age < 40 ESR < 50 no mixed cellularity or lymphocyte depleted < 4 sites of disease single node <3 cm in upper neck or epitrochlear region lymphocyte predominant or nodular sclerosis ESR < 50 EORTC High Low Very Low ≥ 9 points 1-5 points 0 points NTI-Milan High Low nodal mass > 10 cm mediastinal mass (>1/3 thoracic diameter) pulmonary hilar involvement contiguous extranodal extension stage I with systemic symptoms no large nodal or mediastinal mass no systemic symptoms Dana-Farber Cancer Institute High Low any mass > 10 cm mediastinal mass (>1/3 thoracic diameter) no large nodal or mediastinal mass International Prognostic Score High Low ≥ 3 points 0-2 points adapted 20818856 Full text -- "Early-Stage Hodgkin's Lymphoma" (Armitage JO, N Engl J Med 2010 Aug 12;363:653-662) Survival (from the NCI, 2003) Stage I - up to 90% Stage II - 78 - 90% Stage IIIA - 60 - 78% Stage IIIB - 50 - 60% Stage IV - 40 - 50% Advanced / Bulky - cure rate 60-80% with combination chemotherapy Prognostic factors British Columbia/University of Nebraska; 2010 20220182 -- "Tumor-associated macrophages and survival in classic Hodgkin's lymphoma." (Steidl C, N Engl J Med. 2010 Mar 11;362(10):875-85.) Retrospective. 130 frozen samples, classic HL. Gene expression profiling Outcome: Gene signature of tumor-associated macrophages (CD68+) associated with primary treatment failure (SS). In validation cohort, CD68+ macrophages correlated with shorter PFS (SS) and DSS (SS). In MVA, it outperformed IPS score. Patients with limited-stage disease without CD68+ macrophages had 100% DSS Conclusion: Increased number of tumor-associated macrophages associated with shortened survival in classic HL Prognostic score for advanced Hodgkin disease: 9819449 Full text — "A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease." Hasenclever D et al. N Engl J Med. 1998 Nov 19;339(21):1506-14. Stage III-IV pts, treated 1983-92. Included a few with Stage I-II with high-risk features. 1 point for each. 7 prognostic factors, mnemonic "HAL SWAM": Hemoglobin < 10.5, Age 45 years or older, Lymphocytes < 600, Stage IV, WBC > 15,000, Albumin <4, Male sex. None: 84% FFP at 5 yrs; 1: 77%; 2: 67%; 3: 60%; 4: 51%; 5+: 42% Other definitions of bulky disease: Many studies use 5cm or 6cm. (e.g., SWOG) Chemotherapy regimens ABVD - Adriamycin, bleomycin, vinblastine, dacarbazine COPP - Cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone EBVP - Epirubicin, bleomycin, vinblastine, and prednisone. Used in EORTC H7. MOPP - Mechlorethamine, vincristine (Oncovin), procarbazine, prednisone Stanford V (1989-) - essentially MOP/ABV + etoposide - uses mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (uses decreased doxo, bleo, and mustard cumulative doses and is a shorter course over 12 wks. Originally used RT). 7537796. Standard of care is ABVD, which is superior or equivalent to MOPP, MOPP/ABVD, or MOPP-ABV Comparison of gonadal toxicity: 2408897 - ABVD vs MOPP. Complete recovery of sperm count in all male pts with ABVD. Radiation fields Mantle field - suggestions per Fletcher's textbook, 3rd edition. Place isocenter midway between superior and inferior edges. Usually is near or slightly below the suprasternal notch. Borders: Superior - Midpoint of chin, along mandible, 2-3 cm above tip of mastoid. Inferior - near diaphragm, ~4 cm above xiphoid. Inferior axillary - 4th costochondral junction. Include ~1 cm of lung in lower axilla and 2-4 cm of lung in upper axilla. Lateral axillary - junction of lateral margin of pectoralis with deltoid. Exclude humeral heads. Mediastinum / hilum - Shield: larynx - thyroid notch to cricoid. Superior border of the PA field can be lowered to avoid irradiation of the oral cavity and cerebellum. Place border at thyroid notch. Modified mantle / mini-mantle - includes mediastinum, bilateral hila, supraclavicular. Excluded axilla and neck/occipital unless bulky disease present. From larynx to T10-12 used in Stanford V protocol - 7537796 Waldeyer's ring (typically for NHL) - Lateral fields matched to lower neck field. Borders: Inferior - thyroid notch. Superior - 1 cm above zygomatic arch. Posterior - tragus, then posterior to sternocleidomastoid muscle. Anterior - orbital rim posteroinferiorly to 2nd molar and then forward along the mandible. Lower neck field: Superior - matches inferior border of lateral fields. Midline larynx shielding from thyroid notch to 1-2 cm below cricoid. Laterally to junction of trapezius with clavicles. Inferiorly 1-2 cm below clavicles. Para-aortic - top of T11 to bottom of L4 Inverted Y - includes para-aortic + iliac + inguinal Total nodal irradiation (TNI) - Mantle followed by Inverted Y and spleen (usually after a break of 2-3 weeks between mantle and inverted Y). Sub-total nodal irradiation (STNI) - Mantle plus para-aortic + spleen. Excludes iliac + inguinal. Often used in females because of concern for fertility. Involved field: Involved field recommendations: Mediastinal disease - treat mediastinum + SCLV SCLV disease - treat ipsilateral neck Involved site radiotherapy Involved node radiotherapy Field design General: UK National Cancer Research Institute 2013: 22889569 Full text -- "Recommendations for the use of radiotherapy in nodal lymphoma." (Hoskin PJ, Clin Oncol (R Coll Radiol). 2013 Jan;25(1):49-58.) Treatment volumes: Wide field, Involved Field, Involved Site, Involved Node Dose Dose constraints International Lymphoma Radiation Oncology Group 2013: 23790512 Full text--"Modern Radiation Therapy Hodgkin Lymphoma: Field and Dose Guidelines from the International Lymphoma Radiation Oncology Group (ILROG)" (Specht L, IJROBP Jun 2013) Describes involved site radiation therapy for Hodgkins disease utilizing modern radiation techniques and intended to replace involved field radiation. Involved field: CALGB guidelines - 12078908 Full text (2002) — "The involved field is back: issues in delineating the radiation field in Hodgkin's disease." Yahalom J et al. Ann Oncol. 2002;13 Suppl 1:79-83. Boundaries of the involved fields. Treatment Need to add these Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252-259, 1975 Carde P, Hagenbeek A, Hayat M, et al: Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: The H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 11:2258-2272, 1993 Santoro A, Bonadonna G, Valagussa P, et al: Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: Superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 5:27-37, 1987 Response Criteria Lugano Classification 2014 25113753 -- "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification." (Cheson DB, J Clin Oncol. 2014 Sep 20;32(27):3059-68.) International Harmonization Project on Lymphoma; 2007 17242396 -- "Revised response criteria for malignant lymphoma." (Cheson BD, J Clin Oncol. 2007 Feb 10;25(5):579-86. Epub 2007 Jan 22.) Guidelines incorporating PET, IHC, and flow cytometry for definitions of response in NHL and HD. Standardized definitions of end points Treatment toxicity Radiation: JCRT, 1990 (1969-84) - 2105920 — "Thoracic irradiation in Hodgkin's disease: disease control and long-term complications." Tarbell NJ et al. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2): 275-81. Mantle irradiation. Pneumonitis 3% in those receiving RT alone. 2.2% pericarditis. 25% thyroid disorders. Second malignancies: See Second malignancies Chemotherapy: JNCI, 2002 (1965-1994) - 11830608 — "Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease." Travis LB et al. J Natl Cancer Inst. 2002 Feb 6;94(3):182-92. Risk of lung cancer after alkylating agents occurs soon after treatment and incidence increases with increasing dose of chemotherapy. JNCI, 2007 (1967-2000) - 17284715 — "Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study." Swerdlow AJ et al. J Natl Cancer Inst. 2007 Feb 7;99(3):206-14. Radiation and ABVD both independently increase the risk of MI mortality. Summary of trials Stanford trials, 1985 (1962-84) - 3881376 — "The evolution and summary results of the Stanford randomized clinical trials of the management of Hodgkin's disease: 1962-1984." Rosenberg SA et al. Int J Radiat Oncol Biol Phys. 1985 Jan;11(1):5-22. Reviews University of Pennsylvania; 2008 19028275 -- "Radiotherapy for early-stage Hodgkin's lymphoma: a 21st century perspective and review of multiple randomized clinical trials." (Bar AV, Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1472-9.) British Columbia; 2005 16155026 — "State-of-the-Art Therapeutics: Hodgkin's Lymphoma." Connors JM et al. Journal of Clinical Oncology, Vol 23, No 26 (September 10), 2005: pp. 6400-6408. Other Resources ASTRO/ARRO Journal Club Webinar 2011 - "“Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma” with Richard Hoppe, MD, FASTRO