The Oncologist, Vol. 2, No. 3, 181-a–183,
June 1997
© 1997 AlphaMed Press
SPECIAL FEATURE
BRIEF REPORT |
Lymphoma Update: 1997
George P. Canellos, M.D.
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115-6084
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THE ROLE OF SALVAGE THERAPY IN MALIGNANT LYMPHOMAS
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Three modalities are available for second line therapy of the malignant lymphomas and Hodgkin’s disease. They include: A) chemotherapy at increased or conventional doses; B) high-dose therapy with autologous stem cell support, and C) biologic therapy with immunotoxins or adoptive immunotherapy. Biologic therapy is still in the developmental phase and has not had a wide application. The first two approaches have had extensive testing.
In non-Hodgkin’s lymphomas, as well as in Hodgkin’s disease, the benefits of salvage therapy are determined by a variety of clinical factors, including: A) the tumor burden at the time of presentation for second-line treatment; B) the extent of prior response to conventional-dose therapy; C) the duration of first complete remission (if achieved)—this is especially true in Hodgkin’s disease; D) response to second-line therapy, especially prior to consideration of high-dose therapy with stem cell support, i.e., sensitive relapse, and E) possibly the nature of second-line therapy, i.e., high-dose versus standard-dose treatment. Since dose-response is an important component of first-line induction chemotherapy, it would be reasonable to assume that it would also apply to second-line therapy. Relapse of drug-sensitive lymphoma, especially after long remission detected early, clearly represents a favorable circumstance for second-line therapy, whereas primary refractory or incomplete responses represent an order of tumor cell resistance that is unlikely to be impacted upon by standard-dose second-line chemotherapy and, possibly, high-dose therapy if there is drug resistant relapse or primary refractory lymphoma. There remains to be explored a group of patients who achieve a good but definite partial response to initial therapy. They may represent a subgroup in whom sensitive imaging techniques can detect incomplete response and for whom a change in treatment to high-dose induction therapy would be appropriate for investigational treatment. Similarly, a clear-cut definition of presenting prognostic factors which predict for an unsatisfactory long-term disease-free remission would justify the application of high-dose therapy early in the treatment plan. These principles would apply to both non-Hodgkin’s lymphoma and Hodgkin’s disease.
Second-line chemotherapy regimens given at standard dose have been less extensively applied. It would appear that no more than 20%-30% of patients with Hodgkin’s disease in relapse achieve long-term benefit from second-line chemotherapy when all patients are considered. However, the circumstances are more favorable the longer the first remission, so that a first remission lasting over 12 months has a very high likelihood to respond completely to a second-line or even the same first-line chemotherapy regimen, resulting in long-lasting second remission with 
50% progression-free survival at five years (Milan series). The Cancer and Leukemia Group B has advanced a Hodgkin’s disease trial comparing MOPP to ABVD up front with a crossover to the alternate regimen at relapse or initial incomplete remission provided a database to examine prospective salvage chemotherapy. The failure-free survival is similar (25% and 34%) at three years. In the lymphomas, especially the large cell non-Hodgkin’s lymphomas, relapse usually occurs in the first two years, if it is to occur. It is unclear whether very long second remissions can be achieved with standard-dose chemotherapy, although some trials suggest that no more than 20%-25% of previous complete responders may be relapse-free at two to three years after second-line therapy. It is unclear whether any relapsing large cell lymphomas can be cured by second-line standard-dose chemotherapy, especially if they have been primarily treated intensively with a third generation regimen. The role of high-dose therapy is still being defined. In Hodgkin’s disease, the complete response rate in 240 patients (published in 1989) was 46%, with 35% continuously free of disease at three years. The criteria which predicted a good result include 0 performance status, sensitive relapse and failure of no more than two prior regimens. In non-Hodgkin’s lymphoma the accumulated results are similar, with a clear message that the remission status and presence of a sensitive relapse correlate with the final results. It is unclear whether the results are affected by the type of induction high-dose regimen or by marrow purging. Most series represent clear-cut patient selection. One trial in a patient with large cell lymphoma in relapse from a complete remission suggests that the benefits of high-dose therapy with stem cell support will result in two- to three-year progression-free benefit in about 25% of eligible patients. Newer programs, including multiple high-dose regimens supported by hematopoietic growth factors, may offer an effective approach to cancer cell reduction.
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SYSTEMIC THERAPY FOR ADVANCED HODGKIN’s DISEASE
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The introduction of combination chemotherapy, especially the MOPP (nitrogen mustard, oncovin, procarbazine, and prednisone), was a pivotal event in the treatment of Hodgkin’s disease presenting in a disseminated stage or in relapse from primary radiation therapy. This regimen and its analogues are still used, but a series of randomized trials has shown that MOPP alternating with ABVD (doxorubicin-Adriamycin, bleomycin, vinblastine, DTIC) or a hybrid of MOPP-ABV was superior to MOPP in progression-free survival. A number of randomized trials has shown no difference between the "hybrid" and MOPP alternating with ABVD.
The choice of primary combination chemotherapy should be based on efficacy and toxicity. When ABVD (with or without radiation therapy) is compared to MOPP alone, there is a superiority in progression-free survival for the non-alkylating agent containing-regimen, ABVD. The absence of male/female sterilization and secondary myelodysplasia/acute myeloblastic leukemia, both known to occur with MOPP, has led to a wider use of ABVD, especially in earlier stage disease with radiation therapy. It is unknown (and under investigation) whether hybrid is superior to ABVD alone. Another factor which complicates the use of MOPP is the particularly toxic effect of this regimen on bone marrow stem cells, which limits the doses of drugs that can be given in subsequent cycles.
At the present time, ABVD or hybrid are the most commonly used regimens in North America. A number of variants for MOPP and ABVD exist which attempt to reduce some of the acute toxicities. The British developed a regimen, ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone), which reduced the hair loss, neuropathy and nausea/vomiting of MOPP with equal efficacy. Modifications of the ABVD regimen tend to omit the bleomycin to reduce pulmonary toxicity, but have not been widely tested.
The expected benefits of chemotherapy are based on clinical prognostic factors. They include age, stage, number of extranodal sites, B symptoms when in stage IV, and performance status. Age is the most significant factor in most series. About 50%-60% of patients in stage III/IV will be cured of Hodgkin’s disease after first-line therapy. In the poor prognostic subgroups, such as those >50 years of age or Stage IV with more than one extranodal site, the outcome is poorer, in the range of 30%. Other series have used elevated serum alkaline phosphatase with elevated sedimentation rate to predict a poor outcome in Stage III/IV.
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