Biomedical subjects
Publications and source records attributed to H B Muss.
Four patients with acute nonlymphocytic leukemia developed one or more components of the "ara-C syndrome" including fever, peritonitis, pericarditis, and a maculopapular rash during therapy with continuous infusions of low-dose (20 mg/m2/d) cytosine arabinoside (ara-C). These complications, described with standard and high doses of ara-C, have not been previously noted with low-dose regimens.
Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m2 (1mg = 2.4 X 10(7) international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance status of 0-2 (Karnofsky greater than or equal to 50). Thirteen patients had two or three sites of metastatic disease and seven were estrogen receptor positive. No complete or partial responses were noted. Although some patients had brief periods of stable disease, almost all patients progressed after one or two courses. Only one patient was able to receive six courses of induction therapy and a brief course of maintenance. Flu-like symptoms and nausea were seen in all patients; vomiting and anorexia were frequent. Hepatic toxicity manifested by enzyme elevation was common and was most severe in patients with liver metastases. In this study a highly purified biologically active gamma interferon was not associated with anti-tumor activity in previously treated women with metastatic breast cancer.
In a murine model system, pyridoxine has demonstrated protective properties during administration of lethal doses of vincristine (VCR). Subsequently, pyridoxine has been evaluated in patients receiving VCR during an adjuvant chemotherapy program for stage II carcinoma of the breast. The toxicities, cumulative VCR dosage, and percentage of ideal dosage observed in 24 patients receiving pyridoxine have been compared to those observed in 88 patients who previously received VCR without pyridoxine in the same chemotherapy program. All patients ideally were to receive VCR 1.0 mg/m2 weekly for 6-weeks with dose modification for neurotoxicity. Treatment patients received pyridoxine 1.5 grams p.o. daily in three divided doses during the 6-week course. The degree of neurotoxic manifestations of VCR was similar in the treatment and comparison patients. Absent to mild neurotoxicity was observed in approximately 70% of patients in both groups; moderate or greater neurotoxicity occurred in about 30% of patients in both groups. Full dosage (6.0 mg/m2) was attained in 8 (33%) treatment patients and 18 (24%) comparison patients (p = 0.28). The mean percentage of ideal dosage of VCR was 84.6 +/- 10.8 in patients receiving pyridoxine and 81.9 +/- 21.6 in those given only VCR (p = 0.59). Gastrointestinal and hematologic toxicities were similar in both groups. Pyridoxine in this dose and schedule afforded no protection from the neurotoxic side effects of VCR.
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Prolonged intravenous infusion of vincristine was evaluated in 26 patients with advanced, refractory gynecologic malignancies. Most patients (88%) had progressive disease following treatment with one or more chemotherapeutic agents. Treatment consisted of a 0.5 mg intravenous bolus injection followed immediately by continuous infusion of 0.25-0.50 mg/m2 vincristine given daily for 5 days. There were no objective responses observed among 14 patients with carcinoma of the cervix, 7 patients with carcinoma of the ovary, or 5 patients with carcinoma of the endometrium. Toxicity was mild when present and consisted of paresthesias and myalgias. Vincristine infusion appears to be a well-tolerated but ineffective treatment for refractory gynecologic malignancies.
Twenty-four patients with limited disease small cell lung cancer (SCLC) were treated with sequential hemibody irradiation (SHB) integrated into a conventional chemotherapy-local radiotherapy (LRT) program. Among 23 evaluable patients, 12 (52%) attained a complete response (CR) and 8 (35%) attained a partial response for an overall major response rate of 87%. The median time since study entry is 29 months. Durations of response are 9.9 months for all patients and 16.5 months for patients who achieved a CR. The primary site was the predominant area of recurrence. The median survival is 13.2 months for all patients and 23.2 months for the 12 patients who attained a CR. Myelosuppression, especially thrombocytopenia, was the major toxicity. Acute radiation toxicities and subacute pneumonitis previously associated with hemibody radiotherapy were well controlled or prevented using the current dose, premedication, and shielding techniques. This integrated program of systemic therapies with SHB and combination chemotherapy plus LRT is feasible for limited disease SCLC; it may prolong survival in patients who attain a CR but compared to similar programs without hemibody irradiation, there was no improvement in overall response rate, response duration, or survival.
The purpose of this study was to assess the efficacy and side effects of morphine sulfate controlled-release (MSCR) in patients with cancer pain who had previously required narcotic analgesia. The study design included an attempt at conversion of 30 patients from the previously required narcotic analgesic to around the clock (ATC) 4-h dosing of morphine sulfate immediate-release (MSIR) that would provide satisfactory analgesia. All patients controlled on MSIR at 4-h ATC were then successfully converted to MSCR and had an appropriate dosage regimen established. The patients were subsequently maintained for 4 weeks on MSCR, with the majority of patients adhering to a 12-h schedule at two-thirds the total daily morphine dose of the q 4 h regimen. Twenty-four patients completed this dosage range study. Five dropouts were not related to use of MSCR, while one patient was discontinued because of nausea following administration of both MSIR and MSCR. Patients preferred the analgesic relief of MSCR over their previous narcotic regimen. Half the patients manifested fewer side-effects compared with their prestudy narcotics. No patients had greater side-effects with MSCR. These findings support the efficacy and safety of MSCR at appropriate dosage for the prolonged relief of cancer pain.
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One-hundred thirty eligible patients with advanced colorectal carcinoma who had received no prior chemotherapy were randomized to either methyl-CCNU, 70 mg/m2 orally every 6 weeks on day 1, mitomycin C, 10 mg/m2 intravenously every 6 weeks on day 1, and 5-fluorouracil (5-FU), 400 mg/m2 intravenously weekly--(MMF)--or 5-FU, 600 mg/m2 intravenously weekly (5-FU). One hundred twenty-six patients are evaluable for response. Of 62 patients treated with MMF, one (2%) achieved complete remission, and three (5%) attained partial remission. Of 64 patients treated with 5-FU, two (3%) achieved complete remission, and eight (13%) attained partial remission. The median survival for patients receiving MMF was 9.5 months compared with 10.3 months for patients receiving 5-FU. The survival distributions for the two regimens were not significantly different, either unadjusted or adjusted for pretreatment characteristics. Performance status and lactic dehydrogenase (LDH) were both significantly associated with survival. Patients with liver metastases only and normal liver function tests had a median survival of 19.8 months and a 40% response rate. This randomized phase III trial did not show any therapeutic advantage for MMF compared to 5-FU therapy alone in advanced colorectal cancer. In addition, hematologic toxicity was significantly greater with the combination (MMF) regimen.
Myelography was performed on 78 patients with breast cancer who had signs or symptoms compatible with spinal cord compression. Of 42 patients (54%) with extradural defects, 21 (50%) had a complete block. All patients with positive myelograms (M+) had a positive bone scan and 41 of 42 (97%) had positive skeletal x-rays. Except for paraplegia, paraparesis, or a sensory level abnormality, signs and symptoms were usually not precise enough to accurately predict patients with cord lesions; however, back pain, paresthesias, and bladder or bowel dysfunction were significantly more common in M+ patients. Cerebrospinal fluid (CSF) protein was elevated in almost all M+ patients but also in approximately half of the M- group. Cytology and glucose analysis of CSF were not of value in predicting cord involvement. Response to treatment was better for patients with fewer sites of metastatic disease and a shorter time from diagnosis to treatment. There was no notable difference in survival between M+ and M- patients. Myelography remains the most precise tool for diagnosing spinal cord lesions. Unfortunately, the prognosis of patients with metastatic breast cancer is poor regardless of whether spinal cord compression is present.
Recurrent or metastatic uterine sarcoma represents an ominous and aggressive form of malignant disease. In an attempt to define a beneficial treatment program, we compared treatment with doxorubicin (A) 60 mg/m2 versus a combination of doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m (CA), each regimen given every 3 weeks. Of 132 patients entered on study, 104 were eligible; 50 received A and 54 CA. Pretreatment characteristics were similar, and no patient had received prior chemotherapy. The proportion of complete responses (CR) + partial responses (PR) for measurable disease patients was 5 of 26 (19%) for both A and CA. Multivariate analysis done on progression-free interval (PFI) and survival (S) showed CA to be of no benefit over A (PFI, P = 0.22; S, P = 0.55). For both A and CA patients, measurable disease (PFI, P = 0.002; S, P = 0.02, respectively), performance status (PFI, P = 0.004; S, P = 0.0002; respectively), and sites of residual disease (PFI, P = 0.008; S, P = 0.003, respectively) were detected as prognostic variables. Conversely, histologic type, age, and recurrence status (primary versus recurrent at entry) were not prognostic indicators. These data indicate no significant benefit of CA versus A alone in patients with uterine sarcoma.
Seventy patients with Stage I and II malignant melanoma were randomized to treatment with either intravenous dacarbazine alone or intravenous dacarbazine plus intradermal injection of the methanol-extracted residue of bacillus Calmette-Guerin (BCG). Analysis of treatment failed to reveal a statistically significant difference between these two forms of treatment in Stage I and II patients. It is possible that chemoimmunotherapy may increase survival in Stage II patients, but this possibility should be interpreted with caution.
Flow cytometry (FC), estrogen receptor (ER), and progesterone receptor (PR) analyses were performed on 226 breast cancers. The presence of steroid receptors was inversely proportional to proliferative index and percent aneuploidy. Within the two ER (+ and -) groups, the presence of PR did not add significantly to the comparison. The mean proliferative index for the diploid tumors was 17.5 +/- 6.8 compared to 27.8 +/- 9.8 for aneuploid tumors (p less than .001). The degree of aneuploidy, or DNA index, was not related to cell cycle kinetics or steroid receptor status. In 163 tissues analyzed for percent tumor present, a correlation between the relative number of aneuploid cells and percent tumor in the histologic review was observed. A study of the diploid tumors indicated greater than 75% had at least 10% tumor cells by histologic review. Since with FC one can observe at least 10% aneuploid cells in a tumor sample, it is our opinion that the percent aneuploidy in this study is not artifactually low due to sampling error. There was no significant relationship between nodal status or number of positive nodes and proliferative index, aneuploidy, or steroid receptor status. Metastatic tumors had a higher mean proliferative index, but this was not statistically significant. There was a relationship between age and proliferative index but not between age and ploidy status. In a small group of patients there was a trend for proliferative index and percent aneuploidy to be higher in the poorly differentiated and larger tumors when compared to the well differentiated and smaller tumors.
Seventeen patients with advanced, previously treated malignancies were entered into a phase I trial utilizing recombinant DNA produced alpha 2 leukocyte interferon (rIFN-alpha 2). Sixteen patients were evaluable. Patients were to receive rIFN-alpha 2 by either the I.V. or I.M. route for 35 consecutive days. The dosage was identical by both routes, and patients were escalated from 3 X 10(6) to 10 X 10(6) to 30 X 10(6) to 50 X 10(6) and to 100 X 10(6) I.U. every 7 days. No patient was able to tolerate the consecutive treatment protocol as planned. Dose-limiting toxicity was a flu-like syndrome in 10 patients and was usually associated with a fall in performance status. Confusion resulted in study withdrawal for five patients, four receiving rIFN-alpha 2 by the I.M. route. Hematologic and liver function abnormalities were common, usually transient, and not associated with clinical sequelae. One patient with non-Hodgkin's lymphoma showed substantial improvement; otherwise, all had stable or progressive disease. Pharmacologic studies indicated substantial serum levels at doses greater than or equal to 10 X 10(6) I.U. regardless of route. No consistent changes in NK activity, lymphocyte subpopulations, or immunoglobulin levels were noted, and no patient developed antibodies to rIFN-alpha 2. The dose and schedule used here indicate that high levels of serum rIFN-alpha 2 activity are obtainable by either the I.M. or I.V. route. Intermittent rather than daily dosage is more likely to be better tolerated and should be considered for phase II trials.
Twenty-six evaluable patients with advanced or recurrent squamous cell carcinoma of the uterine cervix were treated with mitoxantrone at a dosage of 12 mg/m2 every 3 weeks. Twenty-five of 26 patients had had prior irradiation and 24 prior chemotherapy. There were two partial responses, one in a patient with pelvic recurrence and another in a patient with a right upper quadrant mass. Progression-free intervals for these two patients were 5.1 and 4.6 months, respectively. Toxicity was moderate and consisted mainly of leukopenia. No septic or bleeding complications were observed. Mitoxantrone is minimally active in patients with advanced cervical cancer who have been previously treated.
Twenty-three patients with advanced prostatic cancer refractory to hormonal therapy were entered into a phase II study of cytotoxic chemotherapy combined with androgen priming. Patients received vincristine 0.5 mg on day 1; fluoxymesterone 10 mg p.o. TID, days 1-5; methotrexate 4 mg/m2 p.o., days 1-7; and cyclophosphamide 500 mg/m2 I.V., day 8. Patients entered had no prior chemotherapy, most were symptomatic but ambulatory (18/23), and almost all had bone metastases (22/23). There were two stable responses and 14 progressions in 16 patients evaluable for response. Hematologic and gastrointestinal toxicities were substantial. Androgen priming was an unsatisfactory method of improving response in this trial.
A patient whose initial hematologic evaluation suggested the diagnosis of a microangiopathic hemolytic anemia (MAHA) was further evaluated and found to have erythroleukemia (DiGuglielmo's syndrome). This prompted us to review retrospectively the peripheral blood morphology of 12 patients with erythroleukemia. Anisocytosis, poikilocytosis, macrocytosis, and nucleated red cells have been described in patients with erythroleukemia; however, changes characteristic of a microangiopathic hemolytic process (schistocytes) have not been previously described. Our patients with erythroleukemia had prominent helmet and fragmented red cells, as well as elliptocytosis. Six of our 12 patients with erythroleukemia did not have blasts on their peripheral smear, and platelets were decreased (platelet count ranged from 2 to 92 X 10(3)/microliter), resulting in changes similar to patients with MAHA due to thrombotic thrombocytopenic purpura (TTP), traumatic RBC lysis, and disseminated intravascular coagulation. Our data indicate the RBC changes characteristic of MAHA are commonly seen in erythroleukemia, and that as many as half of these patients may not have white cell changes suggestive of leukemia on the peripheral smear. Patients presenting with microangiopathic hemolytic anemia require a bone marrow examination to confirm or exclude a myelodysplastic syndrome.