Radiation Oncology/Hodgkin/Overview

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

Epidemiology[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

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


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[edit]

(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[edit]

  • 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[edit]

  • 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[edit]

  • 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
  • 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[edit]

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[edit]

Need to add these[edit]

  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[edit]

  • 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[edit]

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% thryoid 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[edit]

  • 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[edit]

  • 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[edit]