Margaret N. Wesley

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.

High-Dose Cisplatin in Hypertonic Saline

To overcome the dose limiting toxicity of cisplatin we have administered high-dose cisplatin (200 mg/m2 body surface area in five divided daily doses with each dose administered in 250 mL of 3% saline) together with extensive hydration (250 mL/h normal saline with 20 meq KCI/L). In 17 previously untreated patients with poor prognosis nonseminomatous testicular cancer, 8 with tumor-associated obstructive uropathy, there was no statistically significant decrease in creatinine clearance or elevation of serum creatinine after three to four cycles of a high-dose cisplatin in combination chemotherapy regimen. High-dose cisplatin in combination with vinblastine, bleomycin, and VP-16 produced an 88% complete response rate in these high-risk patients who are characterized primarily by the presence of advanced bulky lung and abdominal disease. Six patients with ovarian cancer who had a relapse after treatment with standard dose cisplatin regimens were treated with high-dose cisplatin and three partial responses were seen. Four patients had no adverse effects on renal function whereas 2 patients had transient elevations in serum creatinine (4 to 5 mg/dL). Hypertonic saline did not provide protection against the nonrenal toxicities of cisplatin.

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.

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.

Survival Following Aggressive Resection of Pulmonary Metastases from Osteogenic Sarcoma: Analysis of Prognostic Factors

Between 1975 and 1982, 80 patients with osteogenic sarcoma were entered into prospective trials in the Surgery Branch of the National Cancer Institute. In 43 of these patients, pulmonary metastases developed as the initial site of recurrence, and 39 underwent one or more thoracotomies for resection of the disease. The actuarial five-year survival for the group of 43 patients with pulmonary metastases was 40%. Various prognostic factors were analyzed for their influence on survival after thoracotomy. Age, sex, location of primary tumor, tumor doubling time, and involvement of one or both lungs (bilaterality) were not significant in predicting survival. Prognostic factors that influenced survival, calculated by regression analysis, included the number of nodules on preoperative lung tomograms (negative correlation, p = 0.0004), disease-free interval (positive correlation, p = 0.0136), resectability (positive correlation, p = 0.002), and the number of metastases resected at thoracotomy (negative correlation, p = 0.0032). The presence of 3 nodules or less on preoperative full-lung linear tomography was found to be the single most useful preoperative prognostic factor. The application of these prognostic factors preoperatively may identify patients who will benefit optimally from thoracotomy.

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.

Comparison of Median Sternotomy and Thoracotomy for Resection of Pulmonary Metastases in Patients with Adult Soft-Tissue Sarcomas

Thoracotomy and median sternotomy have both been advocated for resection of pulmonary metastases, and the advantages of each approach remain disputed. Patients with adult soft-tissue sarcomas undergoing resection of pulmonary metastases at the National Cancer Institute were studied retrospectively to assess the results of each surgical approach. Between 1981 and 1984, 65 patients underwent 78 sternotomies (7 lobectomies, 71 wedge resections); a mean of 9.5 nodules were resected per patient (range, 1 to 61). Resection of all nodules was accomplished in 60 of 71 explorations (84%) in patients with documented metastases. Benign lesions were found during 7 explorations (9%). Thirteen of 30 patients (43%) with unilateral metastases on linear tomography (LT), 45% (9 of 20) of patients with unilateral metastases on computed tomography (CT), and 38% (5 of 13) of patients with unilateral metastases on both CT and LT had bilateral metastases at sternotomy. Survival by type of incision was compared for 84 patients who underwent complete resection of their metastases (42 by sternotomy and 42 by thoracotomy); the minimum follow-up was two years. The groups did not differ significantly with respect to prognostic variables (tumor doubling time, disease-free interval, or number of nodules resected). There was no significant difference in actuarial survival between the two groups. The complication rate was 15% for the sternotomy group and 10% for the thoracotomy group (difference not significant). There were no operative deaths. Median sternotomy results in detection of unsuspected bilateral metastases and avoidance of a second operative procedure, but it does not increase operative morbidity or mortality or compromise overall patient survival.

Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients

A study was performed to determine if prognostic factors could be used preoperatively to predict outcome following resection of metastases. Sixty‐seven soft tissue sarcoma (STS) patients (median follow‐up, 36 months) and 39 osteogenic sarcoma patients (OGS) (median follow‐up, 29 months) underwent thoracic exploration at the first indication of pulmonary metastases, and the results for each group were reviewed. The number of metastatic nodules, disease‐free interval (DFI), and tumor doubling time (TDT) significantly correlated with postoperative survival for STS patients. Patients with four or fewer nodules on preoperative linear tomograms survived longer (median, 23 months) than patients with more than four nodules (median, 6 months; P < 0.005). Patients with a DFI > 12 months had a longer survival (median, 30 months) than patients with a DFI > 12 months (median, 10 months; P < 0.005). Patients with a TDT > 20 days had a longer survival (median, 22 months) than patients with a TDT < 20 days (median, 6 months; P < 0.005). The only significant predictor of survival for OGS patients was the number of nodules on preoperative linear tomograms (⩽4, 37 months median survival;>4, 10 months median survival; P < 0.05). This was due to significant differences noted for the DFI and TDT distributions between OGS and STS patients, with most OGS patients having a short DFI (⩽12 months) and a rapid TDT (⩽20 days) whereas STS patients had a more heterogeneous distribution (P < 0.01). Thus, the number of metastases visible on the preoperative tomogram was the best predictor of survival for both OGS and STS patients. However, the applicability of other prognostic factors could not be generalized for these two closely related groups of patients. Cancer 55:1361‐1366, 1985.

Adjuvant chemotherapy in males with cancer of the breast

Analysis of recurrence rates in male breast cancer (MBC) has suggested that tumor size and degree of axillary lymph node involvement carry the same prognostic implications as for breast cancer in women. A similar spectrum of antineoplastic agents appears active in both females and males. Based on reports of active adjuvant chemotherapy of women with breast cancer, we initiated a trial of adjuvant chemotherapy of MBC in July 1974. Twenty-four patients have been treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). All patients had nodal involvement (median three nodes positive; seven patients had a single positive lymph node). All patients began adjuvant therapy within 4 weeks of either a radical or modified radical mastectomy. No postoperative radiotherapy was given. Median potential follow-up is 46 months. Four patients have recurred, one each at 15, 45, 61, and 65 months following mastectomy; two are dead of metastatic disease. The five-year survival rate projected by actuarial means is in excess of 80% (95% confidence interval: 74–100%). Based on these data, this treatment is highly encouraging when compared to other forms of treatment reported in the literature in which 5-year disease-free survival rates are less than 30%. We conclude that adjuvant therapy of MBC with a CMF regimen is feasible and may be associated with substantial improvement in disease-free survival and overall survival.

A randomized attempt to increase the efficacy of cytotoxic chemotherapy in metastatic breast cancer by hormonal synchronization.

Human breast cancer cells in tissue culture can be growth inhibited by tamoxifen, an inhibition that can be reversed by estrogen. The question of whether tamoxifen inhibition of breast cancer followed by estradiol reversal would increase the efficacy of chemotherapy was asked. One hundred ten patients were prospectively randomized to chemotherapy consisting of cytoxan (750 mg/m2) and Adriamycin (30 mg/m2) on day 1 plus 5-fluorouracil (5-FU) (500 mg/m2) and methotrexate (MTX, 40 mg/m2) on day 8 versus the same chemotherapy plus tamoxifen (20 mg/m2) on days 2-6 and premarin (0.625 mg every 12 hours for three days) on day 7. Chemotherapy was given in 21-day cycles. The first 55 patients were randomized to a regimen in which 5-FU preceded MTX by 24 hours; thereafter, all patients received MTX followed in one hour by 5-FU. No difference in any response parameter was seen between these two 5-FU/MTX schedules. A limited number of patients with inflammatory breast cancer had a significantly higher response rate (93% versus 61%; p = 0.03) than patients with recurrent metastatic disease. Time to progression (13 versus 17 months) and survival (17 versus 23 months) of responders significantly favored the treatment arm including tamoxifen and premarin. Whereas an additive effect of hormones plus chemotherapy cannot be entirely excluded as the explanation for the improved results with the addition of tamoxifen for four days plus one day of premarin, results suggest that further efforts to increase the efficacy of chemotherapy by perturbing tumor growth rates may be worthwhile.