# Radiation Oncology/Hodgkin/Overview

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| Hodgkin's lymphoma: Main Page | Overview | Early stage | Advanced stage | Pediatric | Randomized | |

## 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 | II$_{2-3}$ | II$_{4-5}$ |
| 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 | Risk Grouping | Risk Grouping | Risk Grouping |
| German Hodgkin Study Group | High | Low |
| German Hodgkin Study Group | 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 |
| NCI-Canada / ECOG | 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 |
| EORTC | ≥ 9 points | 1-5 points | 0 points |
| NTI-Milan | High | Low |
| NTI-Milan | 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 |
| Dana-Farber Cancer Institute | any mass > 10 cm mediastinal mass (>1/3 thoracic diameter) | no large nodal or mediastinal mass |
| International Prognostic Score | High | Low |
| International Prognostic Score | ≥ 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

* 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 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