Michael A. Burgess

Chemoimmunotherapy of disseminated malignant melanoma with dimethyl triazeno imidazole carboxamide and bacillus calmette--guérin.

Abstract Eighty-nine patients with disseminated malignant melanoma were treated with a combination of dimethyl triazeno imidazole carboxamide (DTIC) administered intravenously and bacillus Calmette–Guerin (BCG) administered by scarification. The results were compared to those in a comparable retrospective group of 111 patients treated with DTIC alone. Metastatic areas regional to BCG immunization showed an augmented response to chemotherapy. Thus, chemoimmunotherapy-treated patients with lymph-node metastasis had a remission rate of 55 per cent compared to one of 18 per cent for patients treated with chemotherapy alone (p = 0.025). The duration of remissions and survival was significantly longer for patients (both nonvisceral and visceral metastases) treated with chemoimmunotherapy than for those treated with chemotherapy alone (p = 0.05, 0.001, respectively). A good prognosis was associated with immunocompetence before treatment or an increase in immunocompetence during treatment. Chemoimmunotherapy was ...

Metastatic patterns of choroidal melanoma

Twenty‐five patients with choroidal melanoma are presented who subsequently developed disseminated disease. Fifteen of 25 patients developed hepatic metastases as the sole initial manifestation of metastatic disease. The median time from enucleation to hepatic metastases was 43 months and the survival from onset of metastatic spread was 7 months.

Angiosarcoma of the breast: Angiosarcoma of the Breast

Angiosarcoma of the breast is a rare entity. The objectives of this study were to evaluate prognostic factors and determine outcomes in a large contemporary series of patients.

Management of fever of unknown origin in patients with neoplasms and neutropenia.

During 81 febrile episodes, 76 cancer patients with neutropenia were randomly allocated to continue or discontinue antibiotics 4 days after initiation of carbenicillin and cephalothin therapy, if no infection had been demonstrated. During 56 episodes, the patients became afebrile, after initiation of antibiotics. Infection as a cause of fever was identified in 21% of the episodes. The cause of fever could not be identified in 72% of the episodes. Three of 30 patients randomized to discontinue antibiotics developed infection which ultimately caused their death. During 25 episodes, the patients remained febrile. Infection was the ultimate cause of fever in 40% of the episodes. The cause of fever could not be identified in 48%. The majority of infections documented in this group responded when gentamicin was added. Antibiotic therapy with carbenicillin and cephalothin is effective initial therapy for fever due to presumptive infection. If, after 4 days of therapy, no infection is documented and the patient is responding, the antibiotics should be continued for an additional 3 to 5 days. However, for patients not responding after the initial 4 days of therapy, the addition of gentamicin is indicated.

Chemoimmunotherapy of advanced breast cancer: prolongation of remission and survival with BCG.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.

Sequential chemotherapy and late intensification for malignant lymphomas of aggressive histologic type

Fifty-six patients with malignant lymphoma of aggressive histologic type (51 large cell, three diffuse undifferentiated, and two nodular mixed) were treated with three non-cross-resistant combination chemotherapy regimens that were introduced sequentially according to the response to therapy. The objective was to increase the complete remission rate by changing the chemotherapy regimen early if the patient did not attain a complete remission after three courses of treatment. Late intensification was also used with the aim of prolonging the duration of complete remission. The overall complete remission rate obtained with this approach was 82 percent (100 percent in stages I to III and 66 percent in stage IV). The projected survival at four years is 71 percent (93 percent for stages I to III and 55 percent for stage IV). Eighty percent of patients with complete remission are projected to have continued remission at four years. Compared with previous experience with Adriamycin-based combination regimens, these results represent an improvement in remission and survival parameters. The most significant gains occurred in the prolongation of survival of patients with stages I to III disease and in the improved duration of complete remission of patients with stage IV disease. Toxicity included 15 documented infections among 320 courses of therapy, four cases of congestive heart failure, one case of bleomycin lung toxicity, and two cases of liver dysfunction. This multiple combination regimen represents an improvement over previous results utilizing Adriamycin-based combination chemotherapy.

Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.

PURPOSEnTo evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression.nnnPATIENTS AND METHODSnPIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321.nnnRESULTSnTreatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P < .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days < 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P < .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P < .02), with the peak effect observed at 750 micrograms/m2/d.nnnCONCLUSIONnThese results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.

Clinical pharmacology of 4-demethoxydaunorubicin (DMDR)

SummaryDMDR, a daunorubicin derivative with a higher therapeutic index and lower cardiotoxicity than either the parent drug or doxorubicin, is active when given PO in experimental animals. We studied its pharmacokinetics in ten patients receiving DMDR IV or PO or IV and PO sequentially at 10–12.5 mg/m2. DMDR and its metabolites were quantified by high-performance liquid chromatography and fluorometry. In nine patients who received DMDR IV the unchanged drug disappeared from the plasma biphasically with a mean terminal half-life of 27.0±5.5 h, an apparent volume of distribution of 63.9±12.61 kg-1, and a total clearance of 1.9±0.41 kg-1 h-1. In 24 h only 5.1%±1.1% of the dose was excreted in the urine. In comparison, in 19 studies the plasma half-life of DMDR given PO was 34.8±6.7 h, 2.3%±1.3% was excreted in the urine in 24 h, and the maximum plasma drug concentration was reached in about 1 h. The bioavailability of DMDR given PO was about 39% according to comparison of the areas under the plasma DMDR concentration versus time curves for the two routes, but 45% according to comparison of the 24-h cumulative urinary excretion rates. In one patient with severe liver dysfunction following oral administration, the plasma DMDR half-life was 56.8 h, more than twice the average length. By either route, the drug was quickly metabolized to one major metabolite, DMDR-ol. The plasma half-life of DMDR-ol was 72.5±24.7 h, or 35.7±7.4 when DMDR was administered IV or PO. In the plasma, DMDR-ol always exceeded DMDR in concentration. Moreover, the 24 h cumulative urinary excretion of DMDR-ol as a percentage of the dose of DMDR administered was 7.8 following IV and 7.4 following PO administration.

Alternating noncross‐resistant combination chemotherapy and active nonspecific immunotherapy with BCG or MER‐BCG for advanced breast carcinoma

One hundred fifty‐six evaluable patients with metastatic breast cancer were treated with vincristine, Adriamycin and cyclophosphamide alternating at fixed intervals with 5‐FU and methotrexate. Immunotherapy with BCG or MER‐BCG was administered to all patients in two consecutive treatment programs. Overall objective response rate and complete response rate were 67% and 20%, respectively. These were not significantly different between the two immunotherapeutic groups. The median time to progression was sixteen‐and‐a‐half months from initiation of therapy. The median survival of all patients was 21 months and that of responders was 26 months. Response rates, time to progression, and survival showed no significant advantage over a recent historical control group treated with FAC‐BCG. Toxicity related to the gastrointestinal tract and bone marrow was considerably higher in this protocol than in the FAC combinations. MER at the dose, route, and schedule administered in this protocol caused excessive local and systemic toxic reactions. The alternate use of these noncross‐resistant combinations in advanced breast cancer is not superior to combination chemotherapy used in the traditional manner. Cancer 45:742‐749, 1980.

Effects of intensive induction chemotherapy for extensive-disease small cell bronchogenic carcinoma in protected environment-prophylactic antibiotic units

Fifty-five patients with extensive-disease small cell bronchogenic carcinoma received three courses of intensive, inpatient, remission induction chemotherapy in (25 patients) or out (30 patients) of protected environment-prophylactic antibiotic (PEPA) units. Chemotherapy consisted of ECHO induction (E = epipodophyllotoxin VP-16-213; C = cyclophosphamide; H = hydroxydaunorubicin; O = Oncovin) and PRIME maintenance (PR = procarbazine; I = ifosfamide; ME = methotrexate). All evaluable patients (22 in the protected environment group and 26 in the control group) had a complete (50 percent in the protected environment group and 54 percent in the control group) or partial (50 percent in the protected environment group and 46 percent in the control group) remission. Median response and survival durations for both treatment groups were similar. The median survival duration of patients with a complete remission favored the protected environment group (16.5 versus 12.67 months; p = 0.20). Two patients (one from each group) are alive and disease-free for more than four years. Myelosuppression was intense and more pronounced in the protected environment group (p less than or equal to 0.01). Infectious complications were less common in patients receiving intravenous prophylactic antibiotics and in those treated with intravenous antibiotics in PEPA units (p less than or equal to 0.04). There were no treatment-related deaths, although treatment might have contributed to the death of three patients in the protected environment group and four in the control group. The administration of intensive ECHO induction chemotherapy to patients with extensive small cell bronchogenic carcinoma produced a high complete remission rate, although there was no significant long-term survival advantage over a program of less intensity. The administration of intravenous prophylactic antibiotics and the use of PEPA units significantly reduced the infectious morbidity of chemotherapy.