More Questions About Hodgkin's Lymphoma

The article by Dr. Hagemeister nicely reviews the complicated evolution in the care of patients with Hodgkin's lymphoma (HL) and some of the evidence that has brought us to 2007 with very different questions than we had 10 to 20 years ago. The wealth of data from numerous randomized trials following the inception of MOPP (mechlorethamine [Mustargen], vincristine [Oncovin], procarbazine [Matulane], prednisone) combination chemotherapy demonstrates how, in a relatively short time, the focus of treating a curable lymphoma has shifted from "cure" to "curing with the minimum of both early and late toxicities."

With such a wealth of information from so many large randomized trials, one might superficially feel lulled into a sense that we have a complete understanding of the best therapy for this illness, but nothing could be further from the truth. There are probably more questions about the management of HL today than there were 20 years ago, and they are questions that are much more difficult to answer. I will summarize a few of these difficult ongoing questions here.

What are the most appropriate endpoints in trials for HL patients?

Classical endpoints such as response rates, event-free survival, and overall survival seem nearly irrelevant for today's trials in Hodgkin's lymphoma because virtually all initial therapies are associated with very high remission rates and long-term event-free survival, particularly in good-risk patients. To measure the benefit of overall survival differences in studies of HL has become nearly impossible since patients that fail primary therapy are very commonly salvaged with second-line therapy.

The most appropriate question in HL trials today perhaps then is: What is the incidence of late toxicity? Since late toxicity endpoints are not "reached" by all patients, and since they take years to develop, the size and duration of follow-up in future trials will need to be almost prohibitive for statistically significant differences in late toxicities to be measurable. However these are the endpoints that will be required to truly define new standards of care in the coming decades beyond individual and group biases, and this puts into perspective the size of trials and level of commitment and cooperation that will be required to answer such questions.

What is the best treatment for early-stage Hodgkin's disease?

Recognizing that it may be possible to achieve nearly identical results with less therapy, the pendulum is clearly swinging back toward less intensive initial therapy for good-risk patients. The German Hodgkin's Lymphoma Study Group (GHSG) HD10 study used a 2⋅2 factorial design to randomize patients to two vs four cycles of ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) and to 20 vs 30 Gy of involved-field radiotherapy (IFRT).[1] Although not yet sufficiently mature, early results from this large randomized trial suggest the possibility that the minimum therapy offered in this trial may be equivalent to the maximum therapy with respect to the primary endpoint—freedom from treatment failure.

Not surprisingly, toxicity has been higher in the arms receiving four cycles of ABVD. As significant and occasionally fatal pulmonary toxicity is not unheard of with ABVD, particularly in conjunction with the use of radiotherapy, the other obvious question would be: What is the need for bleomycin in patients with early-stage disease? The HD13 study compares two cycles of ABVD with two cycles of ABV, two cycles of AVD, and two cycles of AV followed by 30 Gy of IFRT, and this could help define the minimum chemotherapy regimen associated with the best combined-modality outcome. The Cancer and Leukemia Group B has just completed accrual to a phase II study of AVG (doxorubicin, vinblastine, gemcitabine [Gemzar]) × 6 cycles without the use of radiation therapy for patients with nonbulky stage I/II HL. The addition of gemcitabine essentially replaces the use of bleomycin and dacarbazine and may offer similar efficacy with less toxicity.

What are the advantages of using chemotherapy alone?

Collectively, we have been slow to recognize the significance of the late effects of radiotherapy in young patients. Breast cancer is the most common second malignancy in women treated for Hodgkin's lymphoma, and the largest excess of cases seems to occur in women 30 years of age or younger at diagnosis. The risk appears to be dose-related, appears to persist for 25 years or more, and in one study, was associated with a relative risk of 8.5 for patients who received doses of 20 to 40 Gy without alkylating agents.[2] The absolute risk of breast cancer in this subgroup aged 30 years at diagnosis was 34% 30 years later. However taking into consideration improvements in staging, reductions in radiation dose and field size (eg, involved-field vs extended-field), and the use of more modern delivery (eg, intensity-modulated radiotherapy), it is difficult to project these types of absolute risks onto a woman treated in 2007. Full discussion of these types of uncertainties is required before therapy can be selected.

Similarly, the risk of cardiovascular events in patients receiving combined-modality therapy is historically high, with one study demonstrating a 14% risk at 12 years. This risk is also likely to decrease over time for the same reasons discussed above relevant to breast cancer risk. The use of chemotherapy alone has been associated with outcomes that are nearly equivalent to those of combined-modality therapy. A randomized comparison of ABVD vs ABVD/radiotherapy in unfavorable-risk patients showed a small difference in event-free survival in favor of combined-modality therapy (95% vs 88%,

P

= .004) but no difference in overall survival.[3] The National Comprehensive Cancer Network (NCCN) guidelines suggest chemotherapy alone as treatment for patients with early-stage disease only if radiotherapy is contraindicated.

Can we risk-adapt therapy during treatment?

The difficulty with minimizing therapy is that we do not have prognostic scoring systems that are sufficiently sensitive to allow the selection of patients who may be curable with chemotherapy alone vs those who require combined-modality therapy. Also, the strongest predictor of outcome may be early response to therapy rather than variables measured prior to the initiation of therapy. The addition of positron-emission tomography (PET) as a tool to measure early responses may identify a subgroup of patients who do not require radiotherapy for consolidation of their primary therapy. An example of the future possibility of this kind of risk stratification using PET was demonstrated by Hutchings et al,[4] who found that only 3 of 61 HL patients who were PET-negative after two cycles of chemotherapy showed disease progression. In this study, early PET results were an independent predictor of progression-free survival.

Is ABVD the best therapy for Hodgkin's disease?

The rationale behind the development of the Stanford V regimen (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone) was to develop an effective combination that produced less cumulative exposure to bleomycin and doxorubicin compared with ABVD, and to omit the use of nitrogen mustard and procarbazine included with MOPP or hybrid programs. Pilot data have been very encouraging, but a randomized trial by Gobbi et al[5] demonstrated inferiority to ABVD (although this trial did not deliver radiotherapy according to the original Stanford V criteria). A US intergroup randomized trial comparing ABVD to Stanford V has recently completed accrual, and the results of this study should represent an accurate comparison of the delivery of the two regimens as originally intended.

The use of the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) demonstrates that patients can have their therapy tailored to risk based on both their International Prognostic Score and on the subsequent response (by gallium Ga-67 scintigraphy or PET) to initial therapy with good results. Using a combination of baseline risk and interim restaging will probably be the best risk-stratification system available to clinicians in routine circumstances for years to come.

In summary, the best therapy for Hodgkin's lymphoma remains a moving target, especially with changes in technology allowing for dramatically smaller radiotherapy volumes then previously, improved staging techniques, sensitive interim restaging tests such as PET, and the possibility of newer chemotherapy regimens that could replace ABVD in both early- and late-stage disease. Concentrating on early and late toxicities as outcomes will require a degree of cooperation possibly never before seen in Hodgkin's trials. However, this will be an absolute requirement if we are to define new standards of care based on good science and sufficient data rather than by selecting our personal biases from the results of small trials.

—R. Gregory Bociek, MD

Disclosures:

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

References:

1. 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 23(16S):561s, 2005.

2. Travis LB, Hill D, Dores GM, et al: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97:1428-1437, 2005.

3. Meyer RM, Gospodarowicz MK, Connors JM, et al: Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited stage Hodgkin's lymphoma: National Cancer Institutie of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23:4634-4642, 2005.

4. Hutchings M. Loft A, Hansen M, et al: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin's lymphoma. Blood 107:52-59, 2006.

5. Gobbi PG, Levis A, Chisesi T, et al: ABVE versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate-and advanced stage Hodgkin's lymphoma: Final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 23:9198-9207, 2005.