Current Controversies in the Management of Hodgkin's Lymphoma

We read with interest the article by Dr. Hagemeister, particularly his comments related to the long-term toxicities after therapy for Hodgkin's lymphoma (HL). Clearly, minimizing the long-term toxicity of chemotherapy and radiotherapy is an important goal for improving outcomes, particularly among younger patients and those with limited-stage disease. Because several of the recently reported large retrospective studies of toxicity in long-term survivors of HL include patients who received treatment decades ago, we believe that interpretation of these toxicity data and extrapolation of the data to patients being treated today must be undertaken with caution.

What are the long-term risks?

Two of the largest retrospective reports of long-term toxicity in survivors of HL come from the Netherlands and the United States. The retrospective experience from the Netherlands involved 1,261 patients treated for HL before age 41. Follow-up exceeded 17 years, and 861 patients (68%) were treated from 1965 to 1979.[1] In this series, HL was the primary reason for excess mortality in the first 10 years after therapy, whereas causes other than HL constituted the primary reason for excess mortality after 10 years. Higher relative risks for excess mortality from solid tumors were significantly different based on the time of treatment, with a relative risk of 7.0 to 7.2 observed for patients treated from 1965 to 1979, and a lower relative risk of 4.4 observed for patients treated from 1980 to 1987. This trend likely reflects the emergence of modern radiotherapy techniques.

The US series from the Dana-Farber Cancer Institute included 1,319 patients treated from 1969 to 1997, with a median follow-up period of 12 years.[2] A total of 181 second malignancies and 18 third malignancies were observed; the relative risk of second malignancies was significantly higher with increased radiation field size (

P

= .03). By 5 years posttherapy, the relative risk of cardiovascular disease exceeded the risk in the general population. In the US series, the majority of patients treated with combined-modality therapy received wide-volume, extended-field radiotherapy (total nodal, mantle/para-aortic, or pelvic/para-aortic irradiation) rather than the involved field radiotherapy currently employed in HL trials.

Are the risks applicable to patients treated on contemporary protocols?

Results from these large retrospective series raise several issues regarding toxicity of HL therapy. There is no doubt that the toxicities resulting from treatment administered in the past are excessive. However, patients treated in this era typically received MOPP chemotherapy (mechlorethamine [Mustargen], vincristine [Oncovin], procarbazine [Matulane], prednisone), subtotal nodal irradiation (STNI), or some combination of the two. Current chemotherapy regimens such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) are clearly less leukemogenic than MOPP.

Long-term toxicity of radiotherapy is likely a function of radiation technique, field size, and dose. Historically, doses of radiotherapy were greater than 40 Gy, but doses ranging from 20 to 30 Gy are more typical in the era of combined-modality therapy. The use of large fields is extremely rare now that randomized clinical trials have convincingly demonstrated that involved-field radiotherapy can produce equivalent progression-free survival with less toxicity.[3,4] Emerging data suggest that reductions in field size and dose will result in fewer secondary malignancies.[5] In addition, investigation of further field reductions to "involved lymph node only" fields and tailoring of radiotherapy fields and doses based on the findings of positron-emission tomography (PET) imaging is likely to result in reduced normal tissue exposure and toxicity.[6]

Should radiation therapy be included in the treatment of limited-stage Hodgkin's lymphoma?

The literature is clear that consolidative radiotherapy improves relapse-free survival in HL patients. At least six clinical trials have attempted to answer the question of whether equivalent outcomes could be achieved with the elimination of radiotherapy.[7-12] One relatively small study from Memorial Sloan-Kettering Cancer Center demonstrated that radiotherapy could be safely omitted, but the remaining five trials indicated an increased risk of relapse when radiotherapy was not included. Two of these studies comparing chemotherapy alone with chemotherapy and consolidative radiotherapy (ie, European Organisation for Research and Treatment of Cancer [EORTC]/Group d'Etude des Lymphome d'Adulte [GELA] H9F, Children's Cancer Group [CCG] 5942) required premature closure of the chemotherapy-alone arms due to an unacceptably high number of relapses.[7,8]

Current trials (EORTC/GELA H10, Children's Oncology Group [COG] AHOD0431 and AHOD0031) are investigating whether radiation therapy can be eliminated in patients demonstrating an early radiographic response to chemotherapy. However, based upon the current evidence, our practice is to offer combined-modality therapy to all our patients with limited-stage HL. The optimal duration of chemotherapy and dose of radiotherapy is likely a function of individual patient prognostic factors and emerging data from the German Hodgkin's Lymphoma Study Group will help sort out these remaining issues.[13]

Should patients with advanced Hodgkin's lymphoma receive something other than ABVD?

Presently, we still consider ABVD to be the standard of care for advanced-stage HL. Certainly there are "issues" with this regimen including the questionable value of dacarbazine, the potential for bleomycin lung toxicity, and the mediocre cure rate in individuals with International Prognostic Scores (IPS) 4 to 7. Fortunately, severe bleomycin lung toxicity is a relatively infrequent event, and patients with IPS 4 to 7 disease comprise less than 25% of the population.[14] Because of the issues with ABVD, attempts to replace this regimen are ongoing.

For IPS low-risk patients, the regimen with the most promise is Stanford V (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone).[15] An intergroup trial (E2496) comparing Stanford V to ABVD recently completed accrual and will determine whether Stanford V represents a therapeutic improvement in advanced HL. For patients with IPS high-risk disease, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) deserves consideration, as it was associated with improved event-free and overall survival compared to COPP-ABVD in a large randomized clinical trial.[16] In a subsequent subset analysis, the overall survival advantage was limited to patients with an IPS 4 to 7.[17] A current EORTC trial is comparing four courses of escalated BEACOPP followed by four courses of baseline BEACOPP to eight courses of ABVD.

In summary, for low-risk patients, Stanford V is a very reasonable option, and for high-risk patients, escalated BEACOPP is a reasonable option. However, until the results of E2496 and the EORTC trial are available, we believe ABVD remains the standard.

—Julie Chang, MD
—Kristin Bradley, MD
—Brad Kahl, MD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Aleman BMP, van den Belt-Dusebout AW, Klokman WJ, et al: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21:3431-3429, 2003.

2. Ng AK, Bernardo MVP, Weller E, et al: Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood 100:1989-1996, 2002.

3. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal irradiation versus involved-field radiotherapy in early-stage Hodgkin's disease: Long-term results. J Clin Oncol 22:2835-2841, 2004.

4. Engert A, Schiller C, Josting A, et al: Involved field radiotherapy is equally effective and less toxic compared with extended filed radiotherapy after four cycles of chemotherapy in patiens with early stage unfavorable Hodgkin's lymphoma: Results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 23:3601-3608, 2003.

5. Koontz B, Kirkpatrick J, Clough R, et al: Combined modality therapy versus radiotherapy alone for treatment of early stage Hodgkin disease: Cure versus complications. J Clin Oncol 24:605-611, 2006.

6. Goodman KA, Toner S, Hunt M, et al: Intensity modulated radiation therapy in the treatment of lymphoma involving the mediastinum. Int J Radiat Oncol Biol Phys 62:198-106, 2005.

7. Nachman JB, Sposto R, Herzog P, et al: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20:3765-3761, 2002.

8. Noordijk E, Thomas J, Ferme C, et al: First results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL) (abstract 6505). J Clin Oncol 23(16S):561s, 2005.

9. Laskar S, Gupta T, Vimal S, et al: Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: Is there a need? J Clin Oncol 22:62-68, 2004.

10. Pavlovsky S, Maschio M, Santarelli MT, et al: Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin's disease. J Natl Cancer Inst 80:1466-1473, 1988.

11. Meyer R, Gospodarowicz M, Connors J, et al: A randomized phase III comparison of single-modality ABVD with a strategy that includes radiation therapy in patients with early-stage Hodgkin's disease: The HD-6 trial of the National Cancer Institute of Canada Clinical Trials Group (Eastern Cooperative Oncology Group Trial JHD06). J Clin Oncol 21:4634-4642, 2005.

12. Straus DJ, Portlock CS, Qin J, et al: Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) vs. ABVD alone for stages I, II, and IIIA non bulky Hodgkin's disease. Blood 104:3483-3489, 2004.

13. Diehl V, Brillant C, Engert A, et al: HD10: Investigating reduction of combined modality treatment intensity in early stage Hodgkin's lymphoma: Interim analysis of a randomized trial of the German Hodgkin Study Group (GHSG)(abstract 6506). J Clin Oncol 21(16S):561s, 2005.

14. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD adn MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an Intergroup trial. J Clin Oncol 21:607-614, 2003.

15. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locallly extensive and advanced Hodgkin's disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630-637, 2002.

16. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348:2386-2395, 2003.

17. Diehl V, Brillant C, Franklin J, et al: BEACOPP chemotherapy for advanced Hodgkin's disease: Results of further analyses of the HD9- and HD12- trials of the German Hodgkin Study Group (GHSG) (abstract 307). Blood 104:307, 2004.