Jane Myers

Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin's disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy.

The initial promising results with alternating chemotherapy regimens (mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine [MOPP/ABVD]; lomustine, melphalan, and vindesine [CAD] plus MOPP plus ABV) combined with intermediate-dose radiation therapy (RT) have been sustained with further follow-up; 82.2% of patients (152 of 185) achieved a complete remission (CR), and overall survival is 71.7% +/- 4.4% at 8 years (median follow-up is 55 months among the survivors). No statistically significant differences were found in CR percentage, CR duration, or survival between stages IIB, IIIB, and IV patients. For that reason, stepwise Cox regression analyses to identify the important prognostic factors were performed on overall survival, tumor mortality, freedom from disease progression, and survival following disease progression. Pretreatment characteristics were also tested for association with the probability of achieving CR, CR duration, and death due to other causes. Characteristics that were consistently associated with an independently unfavorable prognosis were low hematocrit, high serum lactic acid dehydrogenase (LDH), age more than 45 years, inguinal node involvement, mediastinal mass greater than .45 of the thoracic diameter, and bone marrow involvement. Patients with two or more unfavorable characteristics were much more likely to fail treatment (median survival, 62.4 months) than those with none or only one unfavorable factor (greater than 95% survival). This striking difference between the low- and high-risk groups remained even if the comparison was restricted to patients less than or equal to 45 years of age. These results provide a basis for selecting the young patients at high risk of failure for more intensive initial treatment with either autologous bone marrow rescue or hematopoietic growth factors.

Impact of adjuvant radiation on the patterns and rate of relapse in advanced-stage Hodgkin's disease treated with alternating chemotherapy combinations.

The role of adjuvant radiation therapy (RT) in the management of advanced-stage Hodgkins disease (HD) was analyzed in 222 patients who attained a complete remission (CR) with alternating chemotherapy combinations. Mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) or MOPP/ABV alternating with the lomustine, melphalan, and vindesine combination (MOPP/ABV/CAD) were similarly effective in inducing a CR in 222 of 270 (83%) patients. These patients were scheduled to receive consolidative RT to bulky disease or other critical sites of initial nodal involvement to a total dose of 2,000 cGy, with an optional additional boost of 1,000 cGy. However, only 125 (56%) patients received radiation to all initial nodal sites of disease. In 69 (31%) patients, only selected nodal sites were included in the radiation fields, and 28 (13%) did not receive any RT. Of the 222 CR patients, 42 (19%) relapsed during a median follow-up period of 6.5 years (range, 2 to 15 years). Of these, 26 (62%) patients relapsed exclusively in unirradiated nodal sites, six (14%) within irradiated sites, and 10 (24%) both within and outside irradiated fields. The actuarial 10-year relapse-free survival (RFS) and overall survival (OS) for patients receiving radiation to all initially involved nodal sites were 89% and 94%, respectively, compared with 68% and 71% (P less than .0001) for patients who had only partial or no RT. Cox proportional hazards regression analysis showed that RT to all sites of initial disease was the most significant independent covariate (P less than .005) affecting RFS and OS. These data demonstrate that residual microscopic disease is relatively frequent in patients with apparent CR after alternating combination chemotherapy, and that irradiation of all sites of initial nodal involvement decreases relapse and improves survival in advanced-stage HD.

Phase I dose-escalation trial of iodine 131-labeled monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma.

PURPOSE Eighteen patients with recurrent or refractory CD21-positive, non-Hodgkins lymphoma (NHL) were treated in a phase IA dose-escalation therapeutic trial of iodine 131 labeled to a fixed dose of OKB7. METHODS Individual doses of 30 to 50 mCi of 131I on 25 mg OKB7 were administered 2 to 3 days apart to achieve four total 131I-OKB7 dose levels of 90, 120, 160, and 200 mCi. Pharmacology, dosimetry, therapeutic effects, toxicity, human anti-mouse antibody (HAMA) response, and maximum-tolerated dose (MTD) were determined. Patients were evaluated by imaging studies (including whole-body gamma camera or single-photon emission computed tomography [SPECT] scans), flow cytometric analysis, bone marrow biopsy, and serial blood sampling. RESULTS Median plasma and whole-body half-lives (T1/2) were 16 hours and 14 hours, respectively. Plasma and whole-body radiation doses were 0.0081 Gy/mCi and 0.0022 Gy/mCi, respectively. Specific tumor visualization was noted in eight of 18 patients. HAMA was detected in 12 of 16 patients. Nonhematologic toxicity was limited to asymptomatic elevations of thyroid-stimulating hormone (TSH) in five of 15 patients. Hematologic toxicity was observed in six of 18 patients, but was severe in only two patients. MTD in patients with diffuse lymphomatous bone marrow involvement was determined to be 200 mCi in four divided doses of 50 mCi 131I/25 mg OKB7. Antitumor activity was observed in 13 of 18 patients (one partial response [PR] and 12 mixed responses) and was dependent on the 131I-OKB7 dose administered. In general, palpable peripheral lymphadenopathy, enlarged spleens, skin lesions, and circulating OKB7-positive peripheral lymphocytes responded most readily to treatment. 131I-OKB7 was safely administered to a patient in leukemic phase of NHL with prompt subsequent loss of approximately 1 kg of tumor cells from the peripheral blood without associated tumor lysis syndrome. CONCLUSION Because antitumor activity with tolerable toxicity was observed in the majority of this group of heavily pretreated patients, phase II investigation of mAb OKB7 radioconjugates in the therapy of NHL is warranted.

Treatment of advanced hodgkin's disease with chemotherapy and irradiation: Controlled trial of two versus three alternating, potentially non-cross-resistant drug combinations

From January 1979 to June 1983, 71 evaluable, previously untreated patients with advanced Hodgkins disease completed a randomized trial of two or three potentially non-cross-resistant drug combinations and low-dose radiotherapy to initially involved nodal regions (2,000 to 3,000 rads). All patients received nine cycles of alternating chemotherapy regimens and radiotherapy between cycles 6 and 7. Thirty-four patients received three combinations: lomustine, melphalan, vindesine (CAD), MOPP, and doxorubicin, bleomycin, vinblastine (ABV). The complete remission rate was 82 percent, partial remission rate 12 percent, and progression rate 6 percent. There were two relapses from complete remission and three deaths. Thirty-seven patients received MOPP and ABV plus dacarbazine (D). The complete remission rate was 78 percent, partial remission rate 16 percent, and progression rate 6 percent, with three relapses from complete remission and five deaths. Myelosuppression was more frequent with CAD/MOPP/ABV/radiotherapy, and nausea and vomiting with MOPP/ABVD/radiotherapy. The results for both are among the best reported, and CAD/MOPP/ABV/radiotherapy was more acceptable to patients.

The eight-drug/radiation therapy program (MOPP/ABDV/RT) for advanced Hodgkin's disease. A follow-up report

Eighty‐four evaluable patients with advanced Hodgkins disease (Stages IIB, IIIA age > 35 or mixed cellularity or lymphocyte depletion histology, IIIB, IVA, and IVB) were treated with alternating monthly MOPP and Adriamycin, bleomycin, dacarbazine, and vinblastine (ABDV). Radiation therapy (RT), 2000 rads in two weeks, was given to areas of initial bulky disease in untreated patients. Complete remission (CR) rates were 80% for previously untreated, 65% for prior RT or minimal chemotherapy treated, and 50% for heavily pretreated patients. Among 49 previously untreated patients there were no primary treatment failures. The estimated two‐year relapse rate for the CR group was 9%. The therapeutic effectiveness of this program may have been due to either or both of the following elements: (1) two non‐cross‐resistant drug combinations, (2) low dose adjuvant RT to initial sites of bulky disease. These early results are among the best reported for the treatment of advanced Hodgkins disease.

Four cycles of chemotherapy and regional radiation therapy for clinical early-stage and intermediate-stage Hodgkin's disease

To achieve a high percentage of durable complete remissions (CR) and prolonged survivals and reduce toxicity in patients with early‐stage and intermediate‐stage Hodgkins disease, a randomized trial of four cycles of mech‐Iorethamine, vincristine, procarbazine, and prednisone (MOPP) versus four cycles of thiotepa, bleomycin, and vinblastine (TBV) combined with regional radiation therapy (RT) was conducted. For MOPP and RT, the CR percentage was 98% (60 of 61), and at 5 years, the percentage of patients in CR was 90%, with freedom from progression of 89% and overall survival of 91%. For TBV and RT, the CR percentage was 93% (55 of 59), with a 5‐year duration of CR of 83%, freedom from progression of 81%, and overall survival of 91% (P > 0.15). The median follow‐up was 65 months (range, 7 to 96 months). For 27 patients with clinical Stage IIIA, the CR percentage for MOPP and RT was 75% (12 of 16), with 1 relapse and 4 deaths. For TBV and RT, the CR percentage for clinical Stage IIIA was 73% (8 of 11) with 2 relapses and 2 deaths. Short‐term toxicity except for transient leukopenia was less for TBV and RT than for MOPP and RT. Good results are achievable with combined treatment without excessive toxicity. Cancer 1992; 69:1052–1060.

Treatment of stages I and II hodgkin's disease with three different therapeutic modalities☆☆☆

Since 1969, 184 previously untreated and evaluable adult patients with Hodgkins disease, staged as I (43) or II (141), have been treated. Eighty patients were part of the National Hodgkins Disease Study, randomly assigned to receive radiotherapy to either an involved (39) or extended field (41). In a subsequent single-arm study, 104 patients were treated with involved-field radiotherapy preceded and followed by three cycles of MOPP chemotherapy. Median durations of follow-up have been 172, 172, and 92 months, for the involved-field radiotherapy, extended-field radiotherapy, and MOPP plus involved-field radiotherapy treatment groups, respectively. Although significant differences among the three treatment groups were observed with respect to disease-free survival (p less than 0.001), only the group of patients treated with involved-field radiotherapy had a statistically significant decline in overall survival as compared with the two other treatment groups (p less than 0.001). Moreover, patients who underwent clinical staging and were treated with MOPP plus involved-field radiotherapy had significantly prolonged disease-free survival compared with those who underwent surgical staging and were treated with extended-field radiotherapy (p less than 0.001). One of the patients who received MOPP plus involved-field radiotherapy had subsequent development of acute monocytic leukemia, and another had refractory anemia with excess blasts. One instance of diffuse poorly differentiated lymphocytic lymphoma was also observed. Acute monocytic leukemia developed in another patient treated with involved-field radiotherapy. The rates of amenorrhea in the group treated with MOPP plus involved-field radio-therapy were 9.6 percent and 78.5 percent for female patients younger and older than 30 years of age, respectively. Despite the universal azoospermia ensuing after MOPP plus involved-field radiotherapy, in three patients whose sperm counts were checked sequentially for 26 to 53 months after treatment, evidence of spermatogenesis was observed. Three patients with remission of Hodgkins disease after involved-field (two) and extended-field (one) radiotherapy died from cardiovascular disease that could only be attributed to the prior radiotherapy. Although further follow-up evaluation will be required to determine the impact of the three different treatment modalities on survival and long-term toxicity, MOPP plus involved-field radiotherapy appears to be superior to involved-field or extended-field radiotherapy alone in achieving prolonged disease-free survival without significant leukemogenic potential.

Combination chemotherapy for the treatment of Hodgkin's disease in relapse

SummaryVindesine (desacetyl vinblastine amide sulfate, DVA) was used in combination with CCNU (lomustine) and melphalan (Alkeran) (CAD) to treat 15 heavily pretreated patients with Hodgkins disease in relapse. The patients were treated with up to six cycles, depending upon their response. Two patients (13%) achieved a complete remission (CR) and five (33%) patients a partial remission (PR). The major toxicity was prolonged thrombocytopenia, which was decreased by a reduction in the initial drug doses for patients who had received extensive prior chemotherapy and radiotherapy (RT). The CAD regimen was then alternated with nitrogen mustard or cyclophosphamide, vincristine, procarbazine, and prednisone (MOPP, C-MOPP) and doxorubicin (Adriamycin), bleomycin, and vinblastine (ABV) for a total of nine cycles in 25 patients with Hodgkins disease in relapse with somewhat more favorable prognostic features. Two patients also received low-dose RT to areas of bulky nodal disease. Eleven patients (44%) achieved a CR and seven (28%) a PR. Of the 11 CR patients, six remain in remission. The serious toxicity was comparable to that seen with other combination chemotherapy regimens. These results indicated that the CAD/MOPP/ABVD regimen is as active as other so-called ‘salvage’ regimens for Hodgkins disease in relapse, and suggest that it might be useful for newly diagnosed Hodgkins disease.

Results and prognostic factors following optimal treatment of advanced Hodgkin's disease.

The introduction of the MOPP (mustine, oncovin, procarbazine, and prednisone) combination by DeVita and colleagues (Longo et al. 1986) represented a dramatic advance in the treatment of patients with advanced Hodgkin’s disease. The complete remission (CR) rate at Memorial Hospital was at the lower end of those reported in the literature, perhaps reflecting the inclusion of advanced Hodgkin’s disease patients with a worse prognosis than those seen in other centers.