Susan M. Hubbard

Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkins disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkins disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkins disease appears to be curable by chemotherapy.

Twenty years of MOPP therapy for Hodgkin's disease.

The results of treatment of 198 patients with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) for Hodgkins disease were analyzed after a median of 14 years of follow-up. Throughout the period of follow-up, 103 patients have remained continuously free of disease. Review of biopsy specimens of 43 patients originally classified as Hodgkins disease, lymphocyte-depleted type, revealed that ten of these patients actually had diffuse immunoblastic or large cell non-Hodgkins lymphomas. Of the 188 patients with Hodgkins disease, 157 achieved a complete response (CR) (84%), and 66% of them (101 patients) have remained disease-free more than 10 years from the end of treatment. Absence of B symptoms and receiving higher doses of vincristine were factors associated with a higher CR rate and longer survival. Patients entering complete remission in five cycles or less had significantly longer remissions than those requiring six or more cycles. Forty-eight percent of the Hodgkins disease patients have survived between 9 and 21 years (median, 14 years) from the end of treatment. Nineteen percent of the CRs have died of intercurrent illnesses, free of Hodgkins disease.

Diffuse Aggressive Lymphomas: Increased Survival After Alternating Flexible Sequences of ProMACE and MOPP Chemotherapy

A new treatment program was developed in an attempt to increase the complete remission rate and survival of previously untreated patients with advanced stages of diffuse aggressive lymphomas. A flexible number of cycles of ProMACE chemotherapy (prednisone, methotrexate, doxorubicin, cyclophosphamide, and epipodophyllotoxin VP-16) was alternated with a flexible number of cycles of MOPP chemotherapy (mechlorethamine, vincristine sulfate, procarbazine, and prednisone), and finally late intensification with ProMACE therapy was given. The duration of each phase of treatment was determined by the patients rate of tumor response. Complete remissions were achieved in 55 of 74 patients (74%) with a median duration of follow-up exceeding 2 1/2 years. Only ten of the complete responders (18%) have had relapse. The dose-limiting toxicity is myelosuppression, and eight patients (10%) died from sepsis. Median survival for all patients has not been reached but is predicted to exceed 4 years with 65% of patients alive at 4 years. Previously we achieved a 46% complete remission rate with 38% of all patients alive at 4 years; relapse-free survival beyond 2 years was tantamount to cure. Therefore, ProMACE-MOPP chemotherapy represents a substantial improvement in treating patients with diffuse aggressive lymphomas.

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.

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.

Decreasing Risk of Leukemia with Prolonged Follow-up after Chemotherapy and Radiotherapy for Hodgkin's Disease

Acute nonlymphocytic leukemia is a recognized complication of combined chemotherapy and radiation treatment of patients with Hodgkins disease. Previous studies have suggested that the risk of leukemia in these patients increases with time after treatment. We analyzed the occurrence of second neoplasms among 192 patients with Hodgkins disease who were followed for a median of over 15 years. We originally planned to identify prospectively the morphologic changes in bone marrow that precede the development of acute leukemia. All 63 patients consenting to bone marrow aspiration had normal marrow morphology, and no case of acute leukemia occurred more than 11 years after treatment. Actuarial analysis revealed that the peak onset of leukemia-related complications was between three and nine years after first treatment. We conclude that there appears to be a period of increased risk in patients treated with chemotherapy and radiation, after which the risk of secondary leukemia decreases. Patients surviving for more than 11 years after treatment appear to be at no increased risk of acute leukemia.

Long-term follow-up of ovarian function in women treated with MOPP chemotherapy for Hodgkin's disease

Twenty-seven women previously treated with MOPP (mechlorethamine, vincristine, procarbazine, prednisone) chemotherapy were evaluated to determine the status of ovarian function. All patients had completed therapy a median of nine years earlier and had a median age of 30 years at the time of evaluation. Persistent amenorrhea has occurred in 11 of 24 patients (46 percent) treated with MOPP alone or MOPP plus radiation excluding the pelvis. Of patients with amenorrhea, 89 percent were older than age 25 at the time of treatment. In contrast, 80 percent of patients younger than age 25 at treatment continue to menstruate regularly. The time from diagnosis to amenorrhea was significantly shorter in the older patients (p = 0.001). Evaluation of serum gonadotropin and estradiol levels confirms ovarian failure as the cause of amenorrhea in all patients. Overall, these 27 patients have borne 13 normal children subsequent to chemotherapy. This long-term follow-up study demonstrates that chemotherapy-induced ovarian failure is age-related, that ovarian failure is often gradual in onset following the completion of chemotherapy and that, to date, the children born of women treated with this chemotherapy regimen appear to be entirely normal.

Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial.

The study population included 136 patients with stage IA, IB, IIA, IIB, or IIIA1 Hodgkins disease. The median follow-up is 7.5 years. Among the 30 patients with peripheral IA disease, all patients achieved a complete response (CR) with radiation therapy, and no patient has relapsed. Patients of other stages were randomized to receive radiation therapy or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Among the 51 patients randomized to receive radiation therapy, 49 (96%) achieved complete remission, 17 (35%) have relapsed, and 10 (20%) have died. Fifty-two of the 54 (96%) assessable patients randomized to receive MOPP obtained CRs, seven (13%) have relapsed, and four (7%) have died. The projected 10-year disease-free survival of patients randomized to receive radiation therapy is 60%; for those randomized to receive MOPP, it is 86% (P2 = .009 in favor of MOPP). The projected 10-year overall survival for patients randomized to radiation therapy is 76%, and for MOPP-treated patients it is 92% (P2 = .051 in favor of MOPP). When the randomized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis, the disease-free (67% for radiation v 82% for MOPP) and overall survival (85% for radiation v 90% for MOPP) were not significantly different between the two arms. Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups: stage IIIA1 or massive mediastinal disease, no B symptoms, initial erythrocyte sedimentation rate greater than 20 mm, four or more sites of disease, and younger than age 40 years. Preliminary analysis of this ongoing study shows that MOPP chemotherapy is at least as effective as radiation therapy in the treatment of the specific groups of early-stage Hodgkins disease patients randomized. The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed.

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.

Patterns of relapse in advanced Hodgkin's disease treated with combination chemotherapy

One hundred sixty‐one patients with advanced Hodgkins disease achieved complete remission after combination chemotherapy. Of these, 52 (32%) have subsequently relapsed and the patterns of relapse have been studied. The probability of relapse increases with increasing stage and particularly with the presence of systemic symptoms. Patients with Nodular Sclerosis histology are more likely to relapse than those with other histologies. Patients relapse primarily (92%) in sites of previous disease and particularly in nodal sites (75%). Nodal sites most frequently involved at relapse are the central nodal areas and the left supraclavicular area. When patients relapse in new sites they tend to be either adjacent to sites of previous disease which relapse or to be contiguous with previously involved sites of disease. In the small number of patients who received prophylactic radiation therapy to sites of nodal disease after complete remission, the pattern of relapse was not significantly altered.