National Oncology Forum: perspectives for the year 2000.

Despite advances in treatment, long-term outcome of patients with diffuse large B cell lymphoma (DLBCL) is no better today than reported in 1975. A recent study applying DNA microarray technology revealed that patients whose cancer related to patterns of genes expressed in germinal center lymphocytes responded more favorably to chemotherapy than patients whose cancer related to patterns of genes expressed in activated lymphocytes. cDNA and oligonucleotide microarrays are described, and their applications in cancer research are reviewed. In addition to DLBCL, microarray technology has been used to study several types of cancer. The applications of microarray technology are numerous and include profiling gene expression patterns in order to facilitate diagnosis and predict response to therapy; correlating patterns of gene expression with prognosis; and identifying genes and gene products that are associated with tumorigenic phenotype or with drug resistance, among other applications. Microarraytechnology has also been used in cell lines to correlate gene expression and chemotherapy response. Furthermore, microarray technology may provide a useful tool to examine the development of drug resistance in cancer and has recently been used to study changes in gene expression caused by activated c-Myc in primary human fibroblasts. Tissue microarrays are described. In addition to the amplification of limited tissue re sources, tissue microarrays have the advantages of limiting the variability associated with tissue processing and limiting the necessary amount of reagent. Tissue microarrays have been used to determine the frequencies of amplication of 3 major breast cancer genes and identify overexpression of ERBB2 mRNA; assess and compare gene amplification in benign prostatic hyperplasia, primary prostate carcinoma, recurrent prostate tumors, and metastatic tumors; compare aggressiveness of prostate carcinoma in 2 patient populations; and study gene amplification across various tumor types. Furthermore, DNA microarray and tissue microarray techniques can be combined to provide convergent evidence of findings and to examine different aspects of gene expression. DNA array technology may also be used to identify critical molecular targets or to identify the critical rate-limiting step in a cascade of genes under the influence of a mutated gene. The historical progression of goals of the National Cancer Institute is reviewed, as well as the economic impact of reduction in cancer-associated mortality. Future efforts should continue the investment in basic research and more effectively integrate it with clinical trials and with approaches to prevention and treatment.

A phase I study of the antimetabolite (E)-2'-fluoromethylene-2'-deoxycytidine (MDL 101,731) administered as a twice-weekly infusion.

PURPOSE: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule. PATIENTS AND METHODS: The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients. RESULTS: Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred. DISCUSSION: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.

The lymphomas.

The history of therapeutic advances in the lymphomas is reviewed. The initial studies that led to the cure of Hodgkin's disease and diffuse large B-cell lymphomas set a paradigm of cancer treatment broadly applicable to a number of malignancies. In recent times our knowledge of the biology of the Immune system has clarified the origin of subsets of lymphomas and provided specific targets of future therapeutic approaches.

Hodgkin's disease and transplantation: a room with a (nontransplanter's) view.

Hodgkin's disease is a malignancy curable by combination chemotherapy in newly diagnosed patients. Management of refractory disease or relapse has been unsatisfactory with salvage chemotherapy alone, although some patients with long initial remission can be cured with this approach. Because correlations between dose intensity and response to treatment in animal models and in clinical studies have been positive, high-dose chemotherapy (HDT) with bone marrow (BM) or peripheral blood stem-cell (PBSC) transplantation support has been used in an attempt to improve disease-free and overall survival in patients with refractory disease or relapse. Controversy exists over who and when to transplant. Results are difficult to interpret because of the heterogeneous nature of the patients under study and short follow-up times. In general, patient disease-free and overall survival appear to be improved with HDT and PBSC support when compared with historical controls. Allografting has also been tried in Hodgkin's disease as well, but is not recommended due to high associated mortality. Improvements in supportive care for transplantation in general, and antiviral and graft-versus-host disease prophylaxis in particular, have decreased early mortality associated with allografting in other malignancies, but not yet in Hodgkin's disease. The fact that allografted patients who survive the initial transplant procedure have an impressively lower relapse rate makes Hodgkin's disease patients potential candidates for future studies of allografting under more modern circumstances. Some suggestions are made about the introduction of new approaches to treatment.

Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease.

PURPOSE: To evaluate the efficacy and toxicity of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy plus mantle-field radiation therapy in the treatment of patients with massive mediastinal Hodgkin's disease of any stage. PATIENTS AND METHODS: Eighty patients presented with Hodgkin's disease and a mediastinal mass greater than one third the greatest chest diameter on chest radiograph. Patients were staged and treated with MOPP alternated with ABVD chemotherapy for a total of six cycles. Patients then received 10 Gy mantle-field radiation therapy delivered to the original extent of disease followed by 25 to 35 Gy to the residual abnormalities. RESULTS: The complete response (CR) rate was 89%. With a median follow-up duration of 10 years, disease-free survival of the complete responders is 78% at 15 years and overall survival is 75% at 15 years. For patients with stage I or II disease, disease-free survival was 76% at 15 years and overall survival was 79%; for those with stage III or IV disease, disease-free survival was 82% at 15 years and overall survival was 64%. Age, stage, sex, B symptoms, number of extranodal sites, lactate dehydrogenase (LDH) levels, erythrocyte sedimentation rate, and platelet count did not influence treatment outcome. Treatment-related pneumonitis was noted in 16% of patients (fatal in one), mainly in those older than age 35 years who received total doses of radiation therapy greater than 42 Gy. Fertility is more often preserved with MOPP/ABVD therapy than with MOPP chemotherapy and there appears to be less pulmonary and cardiac disease than with ABVD chemotherapy. Two patients have developed second solid tumors within radiation ports and one relapsed patient developed acute leukemia after MOPP salvage therapy. CONCLUSION: MOPP/ABVD followed by mantle-field radiation therapy is an effective treatment for all stages of Hodgkin's disease that present with a large mediastinal mass. Our data suggest that the large mediastinal mass is a more dominant determinant of prognosis than Ann Arbor stage or other clinical prognostic factors.

Late sequelae of treatment of Hodgkin's disease.

Twenty-three years after it was observed that successful treatment of Hodgkin's disease was associated with risk of a second malignancy related to treatment, the literature is maturing. Early reports of leukemia risk rising and falling between 5 and 10 years after treatment continue to be supported. The real problem is the steady emergence of solid tumors in radiation treatment fields, particularly breast cancer and in females treated between the ages of 10 and 25. Several reports this year again emphasize this point. One avenue to pursue to avoid this complication is to use combination chemotherapy alone, especially in young women. The other relates to one observation made this year that low doses of radiation may not be as carcinogenic as full doses. These data suggest that chemotherapy and low-dose radiotherapy in early stage Hodgkin's disease need our attention in rigorously designed clinical trials.

The cell cycle: Probing new molecular determinants of resistance and sensitivity to cytotoxic agents.

The introduction of chemotherapy in the fifth and sixth decades of this century has resulted in the development of curative therapeutic interventions for patients with several types of solid tumors and hematopoietic neoplasms. The important obstacles encountered in the use of chemotherapy have been toxicity on the normal tissues of the body and the presence of mutations that confer resistance to these chemotherapeutic agents. During the past 5 years, the application of molecular analysis to the DNA of normal and neoplastic cells has uncovered some of the mechanisms through which chemotherapy induces cell death, and the changes within these cells that can confer either sensitivity or resistance to these cells. This new level of understanding of the mechanisms through which chemotherapy works, and by which genetic change can result in resistance to this therapy, has opened the door to totally new paradigms of treatment. These paradigms use molecular, genetic, and biologic therapies together to increase the sensitivity of abnormal cells to treatment, and to protect the normal tissues of the body from therapy-induced side effects. The implementation of these new strategies, which is already well under way, promises to dramatically change the way in which therapy is delivered over the next few years, and to improve the outcome especially in patients with neoplasms that currently are resistant to conventional dose therapy.

Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy.

PURPOSE: To review the efficacy of cyclophosphamide, doxorubicin, etoposide, methotrexate with leucovorin, and prednisone (ProMACE)-based combination chemotherapy programs in the treatment of patients with diffuse small noncleaved-cell non-Burkitt's lymphoma. PATIENTS AND METHODS: Thirty-three patients with diffuse small noncleaved-cell non-Burkitt's lymphoma were accrued: eight with localized disease were treated with modified ProMACE-mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) plus involved-field radiation therapy, and 25 with advanced-stage disease were treated with ProMACE/MOPP flexitherapy (n = 8), ProMACE-MOPP (n = 9), or ProMACE-cytarabine, bleomycin, vincristine, and methotrexate with leucovorin (CytaBOM) (n = 8). The median follow-up duration is 10 years. RESULTS: All eight patients with localized disease achieved a complete response, none have relapsed, and one died of intercurrent illness. Among patients with advanced-stage disease, five of eight (63%) flexitherapy-treated patients, six of nine (67%) ProMACE-MOPP-treated patients, and eight of eight (100%) ProMACE-CytaBOM-treated patients achieved a complete response. If the two ProMACE-MOPP-based groups are considered together, disease-free and overall survival rates at 15 years are projected at 61% and 35%, respectively. In contrast, only one patient has relapsed from a ProMACE-CytaBOM-induced complete remission, and overall survival of ProMACE-CytaBOM-treated patients (88%) is significantly higher than that for flexitherapy and ProMACE-MOPP (P2 = .04). CONCLUSION: Adult patients with diffuse small non-cleaved-cell non-Burkitt's lymphoma may be effectively treated with regimens that are effective in other aggressive lymphomas (eg, diffuse large-cell lymphoma).

Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure.

PURPOSE: The study was undertaken to evaluate clinical prognostic factors, probability of response to therapy, duration of response, and overall survival of patients with Hodgkin's disease relapsing from a chemotherapy-induced complete remission. PATIENTS AND METHODS: Study population comprised 107 patients with Hodgkin's disease treated with combination chemotherapy at the National Cancer Institute who relapsed after achieving a complete remission. RESULTS: Half of the relapses occurred within the first year of achieving complete remission; among patients in remission 5 years or longer, only 4% relapsed. The overall survival of the relapsed patients is projected to be 17% at 20 years, calculated from the date of relapse. Primary treatment regimen, presence of B symptoms, stage, sex, liver involvement, pleural involvement, marrow involvement, and histologic subtype did not affect the survival of relapsed patients. Only age at diagnosis (older or younger than 30 years) and length of initial remission (shorter or longer than 1 year) made a significant impact on survival. Patients whose initial remission was longer than 1 year had significantly higher complete response rates to salvage therapy, significantly more durable second remissions, and significantly longer survival than patients whose initial remission was shorter than 1 year. Survival beyond 11 years from relapse of patients with long initial remissions was 24%; for those with short initial remissions, 11% (P2 = .027). Despite the fact that with salvage therapy, patients with long initial remission had an 85% complete response rate to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) with a disease-free survival of 45% at 20 years, acute leukemia and other treatment-related complications combined to lower the survival rate of this more favorable subset. CONCLUSIONS: These data with conventional-dose salvage therapy provide results for comparison with novel salvage approaches including myeloablative therapy with autologous marrow or peripheral-blood stem-cell support.