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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 Hodgkins disease relapsing from a chemotherapy-induced complete remission. PATIENTS AND METHODS Study population comprised 107 patients with Hodgkins 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.

Nonlymphomatous malignant tumors complicating Hodgkin's disease. Possible association with intensive therapy.

Abstract Case records of 425 patients with Hodgkins disease treated at the NIH were reviewed. Note of all biopsy-proved malignant tumors other than Hodgkins disease was made. Cases were divided into subgroups on the basis of treatment received, and expected incidences of malignant tumors were calculated for each subgroup on the basis of age, sex, and mean follow-up period from the time of diagnosis of Hodgkins disease. Significantly increased risks of development of second malignant tumors were found in the entire 425 patients (ratio of observed to expected, 3.5) and in the subgroups treated with both radiotherapy and chemotherapy (ratio, 3.3) and with intensive radiotherapy without intensive chemotherapy (ratio, 3.8). The greatest increase in risk was observed in 35 patients who received both intensive radiotherapy and intensive chemotherapy (ratio, 29).

Superiority of ProMACE-CytaBOM Over ProMACE-MOPP in the Treatment of Advanced Diffuse Aggressive Lymphoma Results of a Prospective Randomized Trial

One hundred ninety-three patients with stage II, III, or IV follicular large-cell, diffuse large-cell, diffuse mixed, immunoblastic, or diffuse small noncleaved-cell (non-Burkitts) lymphoma were randomized to receive either cyclophosphamide 650 mg/m2 intravenously (IV), doxorubicin 25 mg/m2 IV, etoposide 120 mg/m2 IV on day 1, mechlorethamine 6 mg/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV on day 8, prednisone 60 mg/m2 orally daily days 1 through 14, procarbazine 100 mg/m2 orally daily days 8 through 14, and methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate with cycles repeated every 28 days (ProMACE-MOPP) or same day-1 treatment as ProMACE-MOPP plus cytarabine 300 mg/m2 IV, bleomycin 5 U/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV, and methotrexate 120 mg/m2 IV on day 8, leucovorin 25 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate, and prednisone 60 mg/m2 orally daily days 1 through 14 with cycles repeated every 21 days (ProMACE-CytaBOM). Co-trimoxazole two double-strength tablets orally twice daily throughout the period of treatment was added to the ProMACE-CytaBOM regimen when an increased risk of Pneumocystis carinii pneumonia was found in the first 35 patients receiving this combination. Median follow-up is 5 years. Among the 99 patients treated with ProMACE-MOPP, 73 achieved a complete remission (CR) (74%), 30 complete responders have relapsed (41%), and 45 patients have died (45%), including two (2%) of treatment-related causes. Among the 94 patients treated with ProMACE-CytaBOM, 81 achieved a CR (86%), 22 complete responders have relapsed (27%), and 31 patients have died (33%). The complete response rate (P2 = .048) and survival (P2 = .046) were significantly higher for patients treated with ProMACE-CytaBOM. The mortality of ProMACE-CytaBOM treatment overall was six of 94 patients (6.4%). There was no treatment-related mortality among patients treated with prophylactic co-trimoxazole (n = 59). ProMACE-CytaBOM combination chemotherapy with co-trimoxazole prophylaxis is a safe and effective treatment for patients with aggressive histology malignant lymphoma and is superior to ProMACE-MOPP.

Residual abdominal masses in aggressive non-Hodgkin's lymphoma after combination chemotherapy: significance and management.

When patients with aggressive lymphoma present with intraabdominal disease, a stable residual mass is frequently detected radiographically at the time of the clinical complete remission. To discern the optimal management for this clinical problem, we reviewed 241 patients with aggressive lymphoma treated at the National Cancer Institute (NCI) from 1977 to 1986. Seventy-two/241 patients (30%) had an abdominal mass at diagnosis and 29/72 (40%) were left with a radiographically detectable residual mass at clinical complete remission. The likelihood of a residual mass was much higher for patients with bulky disease (P2 less than .0003) (two-tailed test [P2]). Twenty-nine patients had radiologically stable residual masses after therapy, and of 22 (76%) with pathologic evaluations, 21 had negative specimens (95%) and one was positive (5%). None of the patients with negative pathologic evaluation has relapsed in the abdominal site (median follow-up, 31 months). Seven patients were observed clinically without laparotomy: five are alive, without evidence of disease, at 2 to 9 years; two relapsed with disseminated disease within 2 months of chemotherapy. Initial tumor size and size of the residual mass did not correlate with residual disease, since residual masses identified by radiographic examination did not usually harbor viable lymphoma cells. Aspiration cytology was negative for residual tumor in 15/16 cases. One negative result was not confirmed at laparotomy, presumably due to sampling error. The one positive aspiration was followed by a negative laparotomy, possibly due to subsequent tumor necrosis. Restaging laparotomy has a low yield. In most patients with aggressive lymphoma who have otherwise completely responded to carefully administered full-dose combination chemotherapy, stable residual abdominal masses can be closely followed clinically without surgical exploration.

Risk of new cancers in patients with Hodgkin's disease.

An assessment of the risk of new cancers in patients with Hodgkins disease (HD) requires consideration of potential intrinsic and extrinsic factors. Because series of untreated patients with HD do not exist, the true intrinsic risk of development of new cancers cannot be assessed, although the immunologic abnormalities associated with active HD are a potential contributory factor. In recent years, reports of new cancers occurring in patients with HD have considered the role of extrinsic factors in the form of therapeutic intervention. Exposure to ionizing radiation, a known carcinogen in humans, has been suggested as a possible explanation of increasing reports of cases of acute nonlymphocytic leukemia (ANLL) complicating HD. Studies from the National Cancer Institute have shown a highly significant increase in incidence of new cancers (including ANLL) in intensively treated HD patients, and suggested the possibility of a synergistic carcinogenic effect of combined exposure to ionizing radiation and cytotoxic drugs. While the mechanism of induction of second malignant tumors in patients with HD is not clear, it is probably complex, and may relate to interactions between immunosuppressive factors associated with the disease and further immunosuppression and direct cellular damage produced by radiation, cytotoxic drugs, or combinations of both. Further efforts to investigate long term complications of cancer therapy and to design therapeutic programs that will minimize these complications are most important, in view of the improved survival in a number of malignant diseases, which may be anticipated with modern multimodal anticancer therapy.

Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy.

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.

Cyclical combination chemotherapy for advanced breast carcinoma.

Twenty-five patients with advanced metastatic breast cancer were treated with the combination of methotrexate 60 mg/M2 and 5-fluorouracil 700 mg/M2 intravenously on the first and eighth days, and cyclophosphamide 100 mg/M2 and prednisone 40 mg/M2 by mouth daily for the first 14 days of a 28-day cycle. The patients had had no previous chemotherapy or extensive radiotherapy and all but two had not responded to hormonal therapy or endocrine ablation. The major metastatic lesions were: lung (12 patients), liver (four patients), bone (four patients), soft tissue (three patients), nodes (two patients). Seventeen of the 25 patients (68%) responded to treatment with seven complete remissions; these included patients suffering metastatic lesions in the lung, nodes, and soft tissue. The overall median duration of response was nine months (range 6-26 months). Toxicity was primarily haematological, but the group received an average of at least 75% of their calculated dose for each monthly cycle. Haematological toxicity was most pronounced in patients with liver dysfunction and bone marrow involvement. Out of eight nonresponders seven died, with a median survival of six months. Only six of 17 responders died, and the median survival in this group will exceed thirteen months. There was no correlation between the length of the metastasis-free interval after previous treatment and subsequent response to chemotherapy.

TREATMENT OF ADVANCED-STAGE MASSIVE MEDIASTINAL HODGKIN'S DISEASE : THE CASE FOR COMBINED MODALITY TREATMENT

In the initial series of 198 patients treated at the National Cancer Institute (NCI) with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy for Hodgkins disease, a review of presenting chest radiographs available on 192 of these patients showed 49 patients with mediastinal masses greater than one third the greatest posteroanterior chest diameter. Five patients had stage IIB disease, and 44 had stage III or IV disease. Thirty-five (71%) patients achieved a complete remission with MOPP chemotherapy. Fourteen (40%) of the complete responders relapsed, but four of these achieved durable remissions in response to subsequent therapy. Thirty (61%) patients have died (14 induction failures, nine relapsed patients, seven complete responders in remission). Thus, with a median follow-up of 20 years (range, 15 to 23), the overall survival for the group is 39%, and the disease-free survival for the complete responders is 60%. A subset of 10 patients received mantle radiation therapy after maximal response to MOPP. One of these patients failed to achieve complete remission, but among the nine complete responders only one has relapsed. In contrast, 13 of 26 (50%) patients achieving a complete response to MOPP alone have relapsed (P2 = .0536). Although MOPP alone was not prospectively compared with MOPP plus radiation therapy in the treatment of advanced-stage massive mediastinal Hodgkins disease in this series, the retrospective analysis shows a nearly significant difference in disease-free survival favoring combined modality treatment. The difference in tumor mortality between MOPP-treated (44%) and combined modality-treated patients (80%) was also nearly significant (P2 = .055). However, overall survival differences between patients treated with MOPP alone and those treated with combined modality therapy were not significantly different (P2 = 0.23) because of the mortality related to late complications of combined modality 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 Hodgkins disease of any stage. PATIENTS AND METHODS Eighty patients presented with Hodgkins 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 Hodgkins 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.

Treatment of advanced-stage Hodgkin's disease: alternating noncrossresistant MOPP/CABS is not superior to MOPP.

One hundred twenty-five assessable patients with advanced-stage Hodgkins disease were randomized to receive mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP alternating with lomustine (CCNU), doxorubicin, bleomycin, and streptozocin (CABS). The median follow-up is 7.7 years. The complete response rate was 60 of 66 MOPP-treated patients (91%) and 54 of 59 MOPP/CABS-treated patients (92%) (difference not significant). The level of the disease-free survival curve at longest follow-up is 65% for MOPP-treated patients and 72% for MOPP/CABS-treated patients (difference not significant). The overall survival at 12 years is projected at 68% for MOPP-treated patients and 54% for MOPP/CABS-treated patients (difference not significant). Thus, there were no significant differences in efficacy between MOPP and MOPP/CABS. However, MOPP/CABS was more emetogenic than MOPP, and four MOPP/CABS-treated patients went on to develop secondary acute leukemia. No MOPP-treated patients developed leukemia. High initial erythrocyte sedimentation rate (ESR) and high platelet counts adversely affected treatment outcome. MOPP-treated patients who received greater than 81% of the projected dose intensity of vincristine over the first three cycles had significantly improved disease-free survival rates over those receiving less than 81%. MOPP/CABS-treated patients who received greater than 82% of the projected dose intensity of vincristine had significantly better overall survival than those who received less than 82%. Disease-free survival on both arms was significantly better in patients who received greater than 84% of the projected dose intensity of all agents. The effect of dose intensity was particularly apparent in patients with poor prognostic factors where those who received greater than 84% of the projected dose intensity of all agents had significantly improved disease-free and overall survival.