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 Grouping
German 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 ESR
NCI-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 PMID 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 PMID 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: PMID 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). PMID 7537796.

Standard of care is ABVD, which is superior or equivalent to MOPP, MOPP/ABVD, or MOPP-ABV

Comparison of gonadal toxicity:

• PMID 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 - PMID 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: PMID 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: PMID 23790512Full 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 - PMID 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

1. 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
2. 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
3. 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 PMID 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 PMID 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) - PMID 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) - PMID 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) - PMID 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) - PMID 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 PMID 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 PMID 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