John H. Saiki

Paraplegia following intrathecal chemotherapy

A case report and review of the literature of paraplegia following intrathecal chemotherapy with methotrexate and cytosine arabinoside is presented. Autopsy identified damage to the spinal nerve roots within the subarachnoid space, which accounted for the neurologic deficit. The only substances common to both chemotherapeutic agents were their preservatives, methylhydroxybenzoate and benzyl alcohol, which were used, in the diluent. Prolonged exposure to these preservatives is known to cause severe neurotoxicity. Though the specific agent responsible for paraplegia following intrathecal chemotherapy is unknown, there is evidence to suggest that the preservatives rather than the therapeutic agents themselves are responsible.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

5‐azacytidine in acute leukemia

101 patients with acute leukemia in relapse were treated with 5‐azacytidine according to three schedules: Regimen A—300 mg/m2(day divided intravenously at 8 hour intervals for 5 days; Regimen B—750 mg/m2 as a single iv pulse dose administered at 2 to 3 weeks intervals; and Regimen C—300 mg/m2/day by continuous infusion daily for 5 days. Twelve patients achieved a complete remission (CR) and six achieved a partial remission (PR) for an overall 18% response rate. Of 78 patients receiving an adequate trial the response rate was 23%. An average of 1.5 courses and a median of 5 weeks were necessary to achieve a response. The median duration of CR patients was 21 weeks and for PR patients it was 5 weeks. Response rates were 24% for Regimen A, 0 for Regimen B, and 1 of 8 for Regimen C. The CR rate for AML and AMML was 13%. Two of eight AMOL patients achieved a CR. Only 2 of 23 ALL patients responded, one of whom achieved a CR. Toxicity included moderate to severe nausea and vomiting, diarrhea, stomatitis, skin rash, and prolonged myelosuppression. 5‐azacytidine has significant activity in the acute nonlymphoblastic leukemias. Cancer 42:2111–2114, 1978.

Peripheral blood T- and B-lymphocytes in patients with lymphoma and acute leukemia☆

Abstract Peripheral blood lymphocytes from 38 patients with malignant lymphoma and 14 subjects with acute lymphatic leukemia were studied for relative distribution of thymus-derived (T-cells) and bone-marrow derived (B-cells). B-cells were identified using direct immunofluorescent enumeration of lymphocytes showing surface Ig, and T-cells were counted using indirect immunofluorescence and rabbit antihuman fetal thymocyte antisera. When absorbed with B-cells from patients with chronic lymphatic leukemia, the latter antisera appeared to show θ-like or T-cell specificity. Patients with lymphoma showed a significant increase (P By contrast acute lymphatic leukemia was characterized by a significant increase in peripheral blood T-cells (P

Effect of schedule on activity and toxicity of 5‐azacytidine in acute leukemia: A southwest oncology group study

One‐hundred‐fifty‐four patients with acute leukemia and extensive prior chemotherapy were treated with 5‐Azacytidine and evaluated according to five different schedules. One‐hundred‐twenty patients received adquate trials; 34 patients died within 14 days of onset of treatment. Nine patients achieved a complete remission (CR) and two achieved a partial remission. Although two of the treatments have a higher remission rate, the data were not statistically significant. The median time to CR was 48 days (range 21–173). The median duration of CR was 65 days (range 39–369). There was no difference in responders. Proportionately there were more women among responders (5M/6F) and more men (70M/39F) among nonresponders. At onset of therapy the median leukocyte counts were similar between responding (5.4 × 103) and nonresponding (5.7 × 103) patients, but the proportion of leukemic cells was significantly higher among nonresponding patients (46% vs. 7%). Toxicities included nausea, vomiting, diarrhea, skin rash, myalgias, prolonged myelosuppression, hypotension, and central nervous system stupor and/or coma. Lower dose continous infusion schedules of five‐, seven‐, and ten‐days duration appear effective and were associated with less toxicity.

Combination chemotherapy, radiotherapy, and BCG immunotherapy in limited small‐cell carcinoma of the lung: A Southwest Oncology group study

From November 1976 to March 1979 the Southwest Oncology Group treated 298 patients with limited (disease confined to the chest and encompassed by one radiotherapy port) small‐cell carcinoma of the lung with combination chemotherapy and radiotherapy with or without BCG immunotherapy. Two induction chemotherapy programs were utilized: (1) cyclophosphamide, vincristine, methotrexate, fluorouracil; or (2) cyclophosphamide, doxorubicin, and vincristine. Patients received 4500 rads of radiation therapy to the bulk primary tumor and 3000 rads to whole brain followed by maintenance chemotherapy. One‐half of all the patients were randomized to receive one vial (5 × 108) of high viability Pasteur BCG by scarification technique given on days 8 and 15 of each 21–28 day treatment cycle. Increased granulocytopenia accompanied the addition of BCG immunotherapy. Patients receiving BCG achieved a response rate of 49% vs. those patients not receiving BCG of 44% (P = 0.579). Median response duration was 40 weeks for the BCG arms and 38 weeks for the arms without BCG; survival was no different, 42 weeks for the BCG arms vs. 50 weeks for the arms without BCG. In patients who responded to therapy and survived longer than one year, those who continued to receive BCG therapy demonstrated a slight, yet significant, survival benefit over those patients not receiving BCG (93 weeks vs. 81 weeks, P = 0.03). It appears that BCG immunotherapy has no beneficial effect on response rate, duration of response, or survival in programs using chemotherapy and radiotherapy for control of limited small‐cell carcinoma of the lung except in this small group of long‐term survivors.

5-fluorouracil, methyl-CCNU, and radiotherapy with or without testolactone for localized adenocarcinoma of the exocrine pancreas. A southwest oncology group study

Since August 1975, 69 patients with localized pancreatic carcinoma (extent of tumor confined to a 15 cm × 15 cm radiotherapy port) have received either Regimen A, comprising radiotherapy (6,000 rad) to the tumor area with simultaneous combination chemotherapy utilizing methyl‐CCNU, 125 mg/m2 orally, every six weeks, and 5‐fluorouracil, 400 mg/m2 intravenously, weekly; or Regimen B, comprising Regimen A with the addition of testolactone, 200 mg, orally every day. Thirty‐eight patients on Regimen A and 30 patients on Regimen B are currently evaluable. Median survival, which appeared not to be affected by the addition of testolactone, was 38 weeks for those on Regimen A and 30 weeks for those on Regimen B (P = 0.677). The median survival time for all patients was 38 weeks. Good performance status did correlate with improved survival vs. poor performance status (46 weeks vs. 20 weeks, P = .008). Fifteen patients have survived for more than 52 weeks, with the longest survival time being 160 + weeks, and in 3 cases all therapy has been discontinued. However, most patients experienced moderate to severe hematologic toxic reactions. There was one treatment‐related death and significant gastrointestinal bleeding developed in 6. Because of the toxic reactions of this program, it should not be considered in favor of similar less aggressive programs.

Methyl CCNU and adriamycin for patients with metastatic sarcomas a southwest oncology group study

This protocol study (SWOG‐7431) combining adriamycin and methyl CCNU (MAD) for metastatic sarcomas was initially used on patients who were refractory to cytoxan, vincristine, and/or actinomycin‐D. After the initial good results, the study was expanded to include any untreated patients with metastatic sarcoma. The initial starting dose of adriamycin was 60 mg/M2 on day 1 and 45 mg/M2 on day 22. Methyl CCNU was given once every six weeks at an initial dose of 150 mg/M2 orally. Fifty‐five patients received therapy and 53 were evaluable for response. The complete remission rate was 9.4%. The partial remission rate was 35.9%, with a total complete and partial remission rate of 45.3%. The median survival time was ten months. When the combination of cytoxan, DIC, vincristine and adriamycin was used, the response rate was similar and the median survival time in eligible patients was 10 months. The methyl CCNU and adriamycin combination is more convenient for the patient because it necessitates fewer clinic visits and significantly fewer injections than other combinations. These data suggest that treatment with methyl CCNU, when combined with adriamycin, increases the response rate and survival time over adriamycin alone, but that the response is similar to that seen with the combination of cytoxan, DIC, vincristine, and adriamycin. Cancer 46:446–451, 1980.

Chemotherapy trial with comp-F regimen in advanced adenocarcinoma of prostate

Multiple agent combination chemotherapy was used to treat 16 patients with Stage D adenocarcinoma of the prostate in relapse. Agents employed were cyclophosphamide (Cytoxan), methotrexate, 5-fluorouracil, vincristine, and prednisone. Results were encouraging. Six of 16 patients achieved an objective response (2 complete, 3 partial, 1 stabilization) for a 37.5 per cent response rate. Eleven of 16 patients achieved a subjective response for a 69% response rate. Soft tissue metastases may be more responsive than bony lesions. Employment of vincristine made no obvious difference in response rate in those patients in whom it was used. Toxicity was only moderate. Further studies are warranted.

A useful high-dose intermittent schedule of Adriamycin and DTIC in the treatment of advanced sarcomas

One‐hundred‐fourteen evaluable patients with metastatic soft tissue or bony sarcoma with measurable disease were treated with Adriamycin (doxorubicin) administered intravenously at a dose of 60 mg/M2on day 1, followed by DTIC (dacarbazine) at a dose of 750 mg/M2; courses were administered at 3‐week intervals. Ten complete remissions and 17 partial remissions were observed. The most responsive cell type was malignant fibrous histiocytoma with a response rate of 54%. This treatment schedule was very well tolerated, with only moderate myelosuppression and moderate nausea and vomiting. Cardiac toxicity was identified in three patients, with two patients demonstrating electrocardiogram (EKG) changes and arrhythmias and only one patient developing heart failure. The 24% overall response rate suggests no compromise in activity on this schedule, with a significant reduction in toxicity.