Hodgkin's Disease

Natural History

  • Peak incidence in 2nd and 5th decades.
  • 7900 new cases a year.
  • Maybe no relationship with EBV (often have Reed Sternberg cells) and HD.
  • The spread of disease is contiguous.
  • Splenic involvement is more likely with subdiagphragmatic LN involvement, B symptoms, unfavorable histology (MC and LD) and liver/BM involvement.
  • Relapse occurs within 5 years (LP closer to 5 years but LD much earlier). If treated with RT failure is outside the treatment field and next group of adjacent nodes and if with chemotherapy fail at the primary site (50%).
  • HL in economically developed counties have association with
    • higher maternal education
    • decreased # of playmates/siblings
    • eaarly birth order
    • residence in single-family dwelings in childhood

Clinical Presentation

  • Present with painless lymphadenopathy.
  • The younger patients present with 80% cervical nodes, 50% mediastinal disease and 10% below the diaphragm.
  • The elderly will present 25% in the abdomen, <25% in the mediastinum.
  • 1/3 present with one of the B symptoms including waxing and waning of fever (38), drenching night sweats, and >10% weight loss over 6 months. Very uncommon for early stage.
  • Also, they can have alcohol-induced pain, and generalized pruritis.

Risk of radiographically occult infradiaphragmatic disease at laparotomy
q Summary Chart , ,

Clinical Stage (CS) Risk of infradiaphragmatic disease
CS I
-- Overall 20%
-- Women or mediastinal disease only 5-8%
-- Men with high-neck or LP histology 5-8%
CSII
-- Overall 30%
-- Women < 27 y.o. with 2 or 3 sites 9%
  • Occult adenopathy in patient with negative radiographic staging ranges from 6-35%.
  • The spleen is involved more frequently in patients with adenopathy below the diaphragm, systemic symptoms, and MC histology.
  • Involvement of the liver in an untreated patient is rare and almost always occurs with concomitant splenic involvement. (ie. If liver is involved spleen is ~ 90% likely to be involved).

Diagnostic Workup

History of B Symptoms

  • Fevers > 101.4 F (38 C)
  • Drenching sweats
  • Chills

Physical Examination of Lymph

  • Waldeyer’s ring: palatine tonsil, lingual tonsil, nasopharyngeal tonsil
  • Neck, SC, Axilla, Inguina, para-aortic, spleen

Imaging

  • PET/CT: sensitive and specific (65% and 92%) for retroperitoneal disease
    • PET after therapy has a negative predictive value (NPV) and positive predictive value (PPV) of around 90% with NPV being better than PPV.
  • Gallium scan (67Ga): 76%–100% sensitivity and 75%–96% specificity for differentiating necrosis vs mass vs. tumor.
    • Weakness includes: less sensitivity and specific for disease below the diaphragm
    • Inconvience: Ga to be injected 2–3 d before the patient is imaged
  • Advantages of PET: detect abdominal involvement better than CT or 67Ga.
  • Advantages of PET: 1 day test.

Labs

  • CBC
  • ESR
  • LDH
  • LFT
  • creatinine.

Biopsy

  • Core needle biopsy may be adequate for diagnosis, but the NCCN recommends excisional lymph node biopsy.
  • Bone marrow biopsy in stage IB, IIB, III, and IV patients
  • BM biopsy in early favorable stage patient have a yield of < 1%.

Pathology

WHO Histologic Classification of HD

Classic Hodgkin's Lymphoma
Lymphocyte rich classical HD 5% resembles NLPHD histologically. Male predominance. Older population. Lack mediastinal presenation.
Nodular sclerosing classical HD (NSHL) (60-70%) most common subtype, positive mediastinal involvement, 1/3 with B symptoms, younger, equally affects men or women. There are collagenous bands dividing the lymph nodes into circumscribed nodules and these nodules carry a variant of RS cells called lacunar cell.
Mixed cellularity classical HD (25%) Strongest EBV association; more advanced stage, older, combined with inflammatory cells with RS cells.
Lymphocyte depleted classical HD (<5%): older, advanced disease and B symptoms, more RS and pleomorphic cells seen.
Non-classic Hodgkin's Lymphoma
Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHD) 5% of cases. Male predominance, older age at diagnosis; an indolent clinical course (rarely fatal); the main causes of death are treatment-related; Early stage NLPHD may be treated with IFRT or Surgery alone (Europe) - Treat more line low-grade B-cell Lymphoma
  • Other non-classic histology: Hodgkin’s Not otherwise specified

Comparisons

Classic NLPHD
Malignant Cells R-S L/H
CD 30 + -
CD 15 +* -
CD 45 - +
CD 20 -* +
CD 79a -* +
  • * In most cases
  • R-S: Reed Sternberg cell (RS) is binucleated
  • RS are CD15/CD30 (+).
  • L/H: Lymphocytic/histiocytic (also known as "popcorn" cells), CD20/CD45(+).

Prognostic Factors for Stage I/II HD

EORTC GHSG
No LMA and No LMA and
ESR < 50 for (A) ESR < 50 for (A)
ESR < 30 for (B) ESR < 30 for (B)
1-3 LN Sites 1-2 LN Sites
Age ≤ 50
No Extra lymphatics
  • Gender: W>M
  • Age: Children>elderly
  • Histological type: LP>NS>MC>LD
  • Stage: most important
  • Bulky disease: more than 1/3 of the diameter of the mediastinum or greater than 6cm.
  • Number of sites involved: 4 or greater
  • B symptoms: fever alone is not poor prognosis
  • SED Rate (> 30 or >50 or >70 is poor prognosis)

Staging and Outcome

== Lymphoma Staging ==

Stage OS DFS
I/II 80-85% 70-75%
III 65-70% 30-45%
IV 40% 20%

Treatment

Typical Standard Treatment Strategy:

CS I-II, Favorable

  • ABVD x 4 + IF 30 Gy. Per Control arm of GHSG HD 10 trial.
    • 4 arm study of ABVD x 2 vs 4 and 20 Gy vs 30 Gy.
  • Complete restaging takes place at completion of chemotherapy
  • 36 Gy for > 5 cm tumor or PET positive after chemotherapy

CS IA-IIA, Unfavorable

  • ABVD x 4 + IF 30 Gy.
  • Complete restaging takes place at completion of chemotherapy
  • If patient has achieve CR or PR, 2 additional cycles of chemotherapy for a maximum of 6 cycles
  • 36 Gy for > 5 cm tumor or PET positive after chemotherapy

CS IB-IIB non-bulky and Stage III-IV(bulky and non-bulky)

  • ABVD x 4
  • Complete restaging takes place at completion of chemotherapy
  • If patient has achieve CR or PR, 2 additional cycles of chemotherapy for a maximum of 6 cycles
  • 36 Gy for > 5 cm tumor or PET positive after chemotherapy

E2496 (only trial of large mediastinal mass)

  • Eligibility Stage I-IV with MMR > 0.33
  • Treatment: ABVD x 6-8 + RT

Surgery

Generally useful for biopsy only.
Oophoropexy (move the ovary out of RT field)

  • right of midline
  • dose to overy 1%

Chemotherapy:

  • Standard is ABVD (adriamycin, bleomycin, vincristine, darcarbazine). No very much sterility or seoncdary leukemia, but have cardiac and pulmonary toxicity from doxorubicine and bleomycine, respectively.
  • MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) long term side-effects include sterility (80% of men; in women it is directly linked to age) and secondary acute nonlymphocytic leukemia (usual latent period, 3-7 years; actuarial risk 3-5% at 7-10 years) MOPP is sometimes preferred for LP histology
  • Standford V:
    • Mechlorethamine
    • Doxorubicin
    • Vinblastine
    • Vincristine
    • Bleomycin
    • Etoposide
    • Prednisone

Mantle RT alone for Early Stages, favorable

Stage IA and IIA (Don't dot this)

  • The EORTC H1 in early clinically staged patients I and II were treated with mantle alone versus mantle + velban and found that more recurrences with MC histology below the diaphragm suggesting that mantle alone is not sufficient.

Results

  • 20% infradiaphramatic recurrences

Conclusion

  • Relapse rate not acceptable

Clinically Staged, Very Favorable (Don't do this)

Patients who have all of the following:

  • stage IA
  • female
  • <40 years old
  • ESR < 50 mm/h
  • NLPHD or NSHL
  • no bulky mediastinal disease

Trials

  • EORTC H7VF adn H8VF treated these patients with mantle RT alone;

Results

  • complete remission was reached in 95%.
  • 23% relapsed with 6-EFS of 66%
  • 96% 6-DSS and 6-OS

Conclusion

  • Relapse rate not acceptable

Laparotomy-staged IA and IIA (OK to do this)

Patients who have all of the following:

  • stage I or II
  • female
  • <40 years old
  • ESR < 70 mm/h
  • NLPHD or NSHL
  • no bulky mediastinal disease

Trial

  • The EORTC H5F had stage I and II patients with favorable factors (NS or LP, 40 years or younger, ESR <70) underwent laporatomies which were negative and compared mantle versus STNI and found that there was no difference in DFS and OS although there was higher rate of subdiaphragmatic failures in the mantle alone group suggesting closer follow-up in that group.

Results

  • No difference in DFS or OS

Conclusion

  • Ok to do this

Lymphocyte-predominant

General

  • because of its rarity, no clear standard therapy had been established.
  • recommendations include
  • radiation with or without chemotherapy
  • watch and wait
  • surgery alone

NCCN Guidlines (7/7/2007)

Stage IA • Involved-field or regional RT
• Observation (if patient cannot tolerate RT)
Stage IIA • Involved-field or regional RT
• Chemotherapy + involved-field RT (category 2B)
• Observation (if patient cannot tolerate RT)
  • Rituximab
    • not proven to have durable response despite CD 20 positivity
    • no proven role in primary therapy

Special Case

  • LP s/p excision of stage IA tumor
    • still recommend IFRT

Results

  • relapses occur in 20% to 25%
  • but patients tend to remain responsive to further therapy despite multiple relapses

Radiation Alone
1. Field Size:

  • Two trials in early stage have shown advantage of STLI over IF radiation in DFS and FFP which are the Stanford and Collaborative Clinical Trial.
  • Specht in meta-analysis with 8 trials showed that the risk of recurrence is higher in less extensive RT but the survival is the same suggesting good salvage with chemotherapy.
  • Recommendation: 35Gy to gross disease and 30Gy to adjacent subclinical disease and 25Gy to non-adjacent disease, 1000 to the lung and 25Gy to the part of the cardiac shadow. If use chemotherapy then reduce by 500cGy if 3 cycles and 1000cGy for 6 cycles but never going under 20Gy. If pediatric also reduce 5-10Gy due to age and chemotherapy.
  • Dumhke (German): compared 30Gy versus 40Gy for areas of subclinical disease for RT alone and found no difference in two arms but did show that quality of RT did impact FFR.

Chemotherapy alone
Italian study (Biti): In patients with stage IA or IIA, STLI versus 6 cycles of MOPP with relapses and salvage worse for the chemotherapy group (85% versus 15%), which was refractory to salvage. The recommendation was no chemotherapy alone for early stage.
NCI: RT versus MOPP but included more unfavorable groups
including IIB and IIIA as well as excluded IA. Found no
difference between the 2 groups
Combined Modality (CMT)

  • There have been 22 randomized trials comparing RT versus CMT RFS favoring CMT but no difference in OS, which has been confirmed with a meta-analysis.
  • Horning 1988: Patients with I,II or IIIA were given chemotherapy (VBM) for 6 cycles and then involved field irradiation compared to STNI /TNI with 5 year PFR was 70% as opposed to 95%.
  • Stanford in IA and IIA compared IF + MOPP versus STNI/TLI and FFR was better for CMT but OS was nearly the same.

Intermediate Risk

Stage I-II with non-favorable factors >50 years, no B symptoms but ESR >50 or B symptoms and ESR > 30, 4 or more sites of involvement, bulky mediastinal disease. Also includes stage IIIA. Treatment involves RT + chemotherapy. If adjuvant regimen then 2-3 cycles first and then RT with STNI or TNI. If consolidate then 4-6 cycles and then add 20-40Gy with IF to the area involved.
Chemotherapy alone versus RT alone

  • NCI (see above) mixed IIIA and IIB with better group and there appeared no difference. The Italian study also had a mixed group with RT doing better. Conclusion was chemotherapy alone is not good

Chemotherapy alone versus CMT

  • Pavlovsky randomized patients with unfavorable factors to CVPP alone versus CVPP + IF and DFS and OS was better with CMT. Again no chemotherapy alone.

Radiotherapy alone versus CMT

  • There have been 22 randomized trials comparing RT versus CMT RFS favoring CMT but no difference in OS, which has been confirmed with a meta-analysis.
  • Stanford with patients IB and IIB compared MOPP +TNI versus TNI and found similar FRR and OS.
  • EORTC H5 had those patients with poor prognostic signs were randomized without laporatomy to either TNI versus sandwich MOPP and RT. The RFS was better for CMT but little difference in OS.
  • EORTC recommends CMT for all I and II with unfavorable factors.

CMT

  • Best Chemotherapy: MOPP is problematic for leukemia (Nitrogen Mustard)and sterility. ABVD is better with less toxicity but there are cardiac (Adria) and pulmonary (Bleo) risks. There is the option of either alternating two regimens or creating a hybrid. The EORTC H6 has randomized patients with unfavorable characteristics to either RT + MOPP versus ABVD + RT (difference sandwich for both) and found that DFS was better at 5 years for ABVD but not in OS. EORTC H7 is accruing and comparing EBVP II versus ABV/MOPP hybrid with IF for poor risk.
  • Best number of cycles of chemotherapy: EORTC H8 is addressing this with early stage poor factored patients comparing 4 versus 6 cycles of MOPP/ABV + IF.
  • Best timing of chemotherapy: to be decided. Currently give upfront rather than sandwich style.
  • Radiotherapy Dose: If one looks at pediatric data from Stanford with CMT, doses of 15-20Gy are adequate. Duke data using doses 15-25Gy showed infield failure of <5%. Loeffler (German) HD1 compared patients I-IIIA with poor factors given COPP/ABVD chemotherapy 4 cycles to either 20Gy versus 40Gy and showed no difference between the groups of patients in RFS and OS.

Advanced Risk

Stage IIIB and IV. These patients typically fail in previous presenting sites.

Chemotherapy Alone

  • The regimens used include ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) alone or ABVD/ MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and the MOPP-ABV hybrid uses all except the dacarbazine.
  • MOPP alone: the CR rates are 60-80% with 20-50% relapsing and dying of disease. The overall survival with MOPP alone is 40-60% at 10 years.
  • ABVD or ABVD/MOPP: the CR is better 70-90% with relapses of 10-40% and 5 year survival at 70-90%.
  • CALGB: randomized 361 patients to MOPP, ABVD, and ABVD/MOPP and CR rates were 67%, 83% and 84%. The FFR at 5 years was 50%, 60% and 65%. The OS was 66%, 73% and 75%. CR and FFR were significant but OS was not.
  • Milan study: 88 patients with stage IV disease compared MOPP and MOPP/ABVD and FFR at 8 years was 36% and 64% and OS was 62% and 64% with no significant difference.
  • British National Lymphoma Investigation: MOPP versus LOPP (leukeran) in 290 patients with FFR and OS was the same between the 2 groups.
  • There appears to be room for improvement regarding chemotherapy alone. It appears that combined regimens are better than MOPP alone especially in FFR but not significantly different regarding OS.

Consolidative RT after chemotherapy

  • Several studies (SWOG, NCI, and DUKE) have found that after MOPP chemotherapy the most common site of failure is the original site of disease. Yahalom also showed that even with MOPP/ABVD the initial site of disease is the region of most common failure.
  • Phase II trials:
  • Yale: 184 patients with different regimens + RT had FFR at 85% at 15 years with OS 54%
  • Duke: 154 patients had Chemotherapy alone versus CMT and 10 year FFR was 56% and 87% with survival 50% and 80%. All significant.
  • Phase III trials:
  • Duke (Brizel): 30 patients randomized to BCVPP alone versus CMT and 5 year actuarial survival were 67% and 100% with significance.
  • Stanford: PAVe/ABVD versus PAVe + RT in 22 patients with improvement in survival in CMT but not significant.
  • SWOG: 10 cycles of MOPP + bleomycin versus CMT for III disease with no difference in survival.
  • Christie Hospital: MVPP versus CMT in 56 patients with no difference.
  • Argentine Trial: 151 patients comparing CVPP versus CVPP + 3000 to initial sites of disease with significantly better FFR rates for CMT but OS was not significant again.
  • SWOG 1994: 530 patients where those with partial response to receive RT (32% did not). Pts with CR were randomized to further chemo or RT (10-20Gy) - 23% randomized to RT did not receive it. If they did receive RT, 18% had a major protocol violation (inadequate volume). There was no difference in overall survival or relapse rates based on intent to treat. If comparing those who got the planned treatment then those with CMT had better FFR at 5 years 85% versus 67% (p=0.002). For the partial responders, there was no difference if they received CMT.
  • If patient has residual disease after induction chemotherapy, a gallium scan can be done. DUKE showed that those with negative scans had a 4year FFR and OS of 75% and 100% after radiotherapy but if positive then 8% and 51%. So RT is unlikely to succeed with consolidative chemotherapy.
  • Sequence: 6 months of MOPP/ABVD or MOPP/ABV chemotherapy then RT with doses of 20-30Gy to involved field (bulky sites of areas with PR).

Radiation Techniques

  • Pattern of Care Study recommends doses of 35-44Gy to be tumorcidal at 1.5-1.8Gy a fraction to involved sites. Key component is to treat the contiguous uninvolved sites to 30Gy as per German study.
  • Mantle: AP and PA from the mandible to the insertion of the diaphragm. Use 4-6MV to avoid under dosing superficial nodes. Dose inhomogenity in mantle RT due to large field sizes and large differences in the patient separations. So to avoid this use extended SSD and higher energy. For example the cord does is 110% if at extended SSD as compared to 120%. Also can add a posterior cord block after 30Gy from the top of the field to C7. Typically block the occipital, lungs, humeral heads, larynx anteriorly. If significant mediastinal, subcarinal, or pericardial disease then need to treat the heart to 10-15Gy and then place block over apex and after 30GY need to shield more heart so bring field up 5cm below the carina. If there is hilar adenopathy and treating with RT alone need to treat whole lung to 15-16.5Gy. For whole lung and heart RT give at 1.5Gy/fraction. For children treat to 15-25Gy after chemotherapy.
  • Preauricular field: need to add if there is cervical node involvement above the hyoid bone with electrons.
  • Waldeyer fields: If high cervical nodal involvement consider adding Waldeyer’s field for adjacent nodes.
  • Para-aortic fields: AP and PA fields para-aortic with spleen to L4-5 intersperse. If splenectomy is done then treat the splenic hilum. If using RT alone, use doses of 30Gy if disease is above the diaphragm. If used chemotherapy, then can use doses of 25-30Gy. Be aware of the match technique.
  • Subtotal irradiation: mantle + RN/spleen but no pelvis.
  • Total nodal: mantle + RN + pelvic.
  • Oophoroplexy: done to avoid ammenorrhea by marking ovaries and placed medially behind the uterus body and blocked at midline with double thickness to reduce dose to <1%.

Follow-up

  • Laboratory studies:
    • TSH, CBC, platelets, ESR, chemistry profile
  • Imaging:
    • Chest x-ray or CT (category 2B for CT)
    • Annual mammographic screening: 5-8 y post-therapy, or at age 40, whichever comes first
    • PET is not encouraged due to risk for false positives. Management decisions should not be based on PET

scan alone, clinical or pathological correlation is needed
Monitoring for Late Effects after 5 Years
NLPHD

  • PET is not encouraged due to false positives.
  • CT may be helpful although, give its very indolent course need to follow patients long term.

Sequalae

  • Pneumonitis: 10%; fibrosis (<1% due to RT and Bleomycin)
  • Radiation pericarditis < 5% with mantle RT
  • Constictricve Pericarditis: <1%;
  • Valvular problems (Doxorubicin)
  • Hypothyroidism: 25-50%
  • Musculoskeletal impairment
  • L’hermittes Syndrome:10-15% ( Electric sensation down the spine with bending of the neck )
  • Dental Caries
  • Herpes Zoster:10-15%
  • Postsplectomy sepsis with Streptococcus pneumonia, meningococcus, Haemophilus so immunize.
  • Azospermia: (<1%) due to RT or MOPP (alkylating agent and procarbizine).
  • Female sterility: (30%) due to RT or ABVD

Secondary malignancy:

  • leukemia, lymphoma, breast cancer, solid tumors and risk is RR = 6.4.
  • Increase of 0.4% of malignancy per year (RR = 2.3)
  • Total risk of 0.8% of malignancy per year including baseline risk
  • median survival for patient with secondary leukemia < 1 year.

Breast Cancer

  • For young women < 30 years old the excess risk 15 to 20 years and beyond 20 years after treatment, with an excess risk of 2.3% to 3.7% per person per year, respectively.
  • No excess breast cancer risk for women at age 40 or older. (Devita 7th ed. p 2577)
  • 25-year actuarial risk of breast cancer is ~16% (Devita 7th ed. p 2583)
  • At low dose of radiation breast cancer risk increase linearly with dose.
  • Acute non-lymphocytic leukemia (ANLL) is the most common leukemia following therapy
  • The risk of lung cancer following chemotherapy is high. Equivalent to or higher than risk after radiotherapy. (See appendix I).

SALVAGE

  • Recurrent disease after RT alone
  • The long-term freedom from additional relapses range from 55%-80%, which compares favorably with patients with newly diagnosed advanced-stage HD treated initially with chemotherapy. This suggests that prior exposure to RT does not lead to resistance to or compromise the ability to deliver effective doses of chemotherapy.
  • Recurrent disease after Chemotherapy alone
  • Two randomized trials compared high-dose therapy with rescue vs. conventional chemotherapy. British National Lymphoma Investigation group and GHSG. No significant survival differences in either of the two trials but event free surivival was improved to ~50% (53% and 55%) in the high-dose therapy group vs 10% and 34%.
  • Limited Relapse after Chemotherapy
  • A number of series showed that in selected patients with favorable features, a salvage rate of 48%-63% (high as 80%) can be achieved without exposing patients to high-dose therapy.

TABLE 41.5-19. Recommendations for Treatment of Relapsed and Primary Progressive Hodgkin's Lymphoma (Devita 7th ed.)

Relapse after first-line radiotherapy Conventional chemotherapy
Nodal relapse (CS I + II) Salvage radiotherapy
-- No B symptoms
-- No prior radiotherapy
Primary progressive disease HDCT + ASCT
Early relapse HDCT + ASCT
Late relapse HDCT + ASCT
  • ASCT, autologous stem cell transplantation;
  • CS, clinical stage;
  • HDCT, high-dose chemotherapy.

HISTORICAL

  • Standard specials: biopsy of node either excised or chamberlain procedure if mediastinal node not accessible by bronchoscope (ie AP window), BM biopsy (if B symptoms, III disease).
  • Optional specials: Extranodal site biopsy if suspicious, staging laporatomy (splenectomy, liver wedge and needle biopsy, BM biopsy, and nodal biopsies of paraaortic, mesenteric, portal, and splenic hilum).
  • Lymphangiogram is efficient in detecting subdiagphragmatic disease with sensitivity and specificity of 85% and 98% and the CT scan is less sensitive and specific (65% and 92%) in detection of retroperitoneal disease. Cannot do if large abdominal mass because can throw a fat emboli.
  • Gallium with SPECT (single photon emission CT scan) provides valuable images in detection of residual mediastinal disease after treatment so need one at initial diagnosis for baseline.
  • Laporatomy: EORTC H6F showed that in early stage I and II that it did impact on outcome. It is used to determine if a patient is a candidate for RT alone and is never done if chemotherapy will definitely be used such as in bulky mediastinal disease, stage III and IV, BM involvement, children, elderly, or medically unfit patients. Patients who are low risk (<10%) for subdiaphragmatic disease including those with very low risk disease (see below) also do not need LAG. Problems with laporatomy include cost, long hospital stay, complications, infection, and leukemia.

Appendix I From Devit 7th ed. p 2578.
TABLE 54.7-1. Relative Risks of Breast and Lung Cancer after Hodgkin's Disease, According to Radiation Dose to Affected Site in Breast or Lung and Number of Cycles of Chemotherapy

Radiation Dose to Affected Site in Lung (Gy) Lung Cancera Radiation Dose to Affected Site in Breast (Gy) Lung Cancerb

Cases/Controls Relative Risk 95% Confidence Interval Cases/Controls Relative Risk 95% Confidence Interval

0 43/87 1.0 (Referent) 0–3.9 15/76 1.0 (Referent)

5–14.9 14/18 4.2 0.7–21 7.0–23.1 16/30 4.1 1.4–12.3
15.0–29.9 14/22 2.7 0.2–15 23.2–27.9 9/30 2.0 0.7–5.9
30.0–39.9 60/102 8.5 3.3–24 28.0–37.1 20/31 6.8 2.3–22.3
≥40.0 31/45 6.3 2.2–19 37.2–40.4 12/31 4.0 1.3–13.4
40.5–61.3 17/29 8.0 2.6–26.4

No. of Cycles of Alkylating Agents No. of Cycles of Alkylating Agents

0 74/188 1.0 (Referent) 0 68/132 1.0 (Referent)
1–4 22/44 4.0 1.3–12.5 1–4 10/20 0.7 0.3–1.7
5–8 58/89 6.2 2.6–17.1 5–8 17/55 0.6 0.3–1.1
≥9 28/29 13.0 4.3–45 ≥9 4/29 0.2 0.1–0.7

Adapted from Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after treatment for Hodgkin'S disease: focus on radiation effects. Radiat Res 2003;159(2):161.
Adapted from Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003;290(4):465.

Bibliography
1. Liebenhaut et al (Stanford). JCO. Vol. 7(4): 81-91, 1989. Retrospective review of 915 CS I-II HD undergoing staging laparotomy. Results: 20% of CS I and 30% of CS II patients were pathologically upstaged. CS I women, CS I patients with mediastinal-only disease, and CS I men with LP histology were at low risk for having disease below the diaphragm (5%). CS II women < 27 y.o. with only 2 or 3 sites were also at low risk for upstaging (9%). MC histology and male gender were associated with increased risk for subdiaphragmatic disease.
2. Mauch et al. JCO. Vol 8(2):257-65, 1990. Retrospective review of 692 patients presenting with supradiaphragmatic HD undergoing staging laparotomy. Factors statistically significant for predicting disease below the diaphragm included B symptoms, MC or LD histology, number of supradiaphragmatic sites > 2, and age > 40. Three subgroups had low risk of infradiaphragmatic involvement Å CS IA females (6%), Ç CS IA males with LP histology (8%), and É CS IA males with high neck involvement (8%).
3. Johnson et al (Stanford). Cancer. Vol. 52(1): 8-13, 1983. Retrospective review of 1470 patients treated for HD, 44 had intrathoracic disease only. Of these 18 underwent laparotomy all negative. Patients were treated with multiple different regimens. Results: 10 year OS 89%. No patients relapsed below the diaphragm. Conclusions: Patients with intrathoracic disease alone have a low risk of systemic involvement and most can be treated with radiation alone. For those who do relapse chemotherapy provides good salvage.
4. Front D, Bar-Shalom R, Israel O. The continuing clinical role of gallium 67 scintigraphy in the age of receptor imaging. Semin Nucl Med. 1997;27:68–74.
5. Andrea K. Ng, M. V. Patricia Bernardo, Edie Weller, Kendall Backstrand, Barbara Silver, Karen C. Marcus, Nancy J. Tarbell, Mary Ann Stevenson, Jonathan W. Friedberg, and Peter M. Mauch ( Dana-Farber Cancer Institute. ). Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors . Blood, 15 September 2002, Vol. 100, No. 6, pp. 1989-1996
6. Dores GM, Metayer C, Curtis RE, Lynch CF, Clarke EA, Glimelius B, Storm H, Pukkala E, van Leeuwen FE, Holowaty EJ, Andersson M, Wiklund T, Joensuu T, van't Veer MB, Stovall M, Gospodarowicz M, Travis LB. Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol. 2002 Aug 15;20(16):3484-94
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