Vitamin A intoxication during taxol therapy for refractory ovarian cancer.
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Alkaloids↗
Biomedical subjects
F M Muggia
Publications and source records attributed to F M Muggia.
Managing breast cancer in an outpatient setting.
The treatment of advanced breast cancer has undergone relatively little change in the past decade. Reasons for such a static situation are the sobering realization that even effective chemotherapeutic regimens have had a minor impact on survival, and the paucity of new effective agents that have been introduced since initial combination treatments. Based in part on this lack of progress, in recent years dose-intensification in search of a curative strategy has been widely adopted. Its role remains to be defined, but ultimately it is likely to be relegated to situations where tumor burdens have been effectively reduced. This reduction in burden may not currently be feasible in many advanced presentations. Outpatient efforts will therefore focus on the following: 1) employing single agents optimally (e.g. infusion 5-fluorouracil), 2) using regimens which integrate new drugs with activity (e.g. taxol), and 3) testing measures which may improve the quality of life (e.g. bisphosphonates in the presence of bone metastases). Although one cannot approach the treatment of advanced breast cancer with the (misplaced) optimism of two decades ago, the expanded armamentarium currently available should lead to a more rational application of chemotherapy. Treatments will increasingly be based on the biology of the cancer, and on the therapeutic index and action of the drugs.
Algorithms↗
Intraperitoneal therapy for ovarian cancer: analysis of fluid distribution by computerized tomography.
Nineteen patients with ovarian cancer and minimal residual or persistent disease who were treated with cisplatin or carboplatin-based intraperitoneal (IP) regimens had distribution studies of IP contrast and computerized tomography prior to and during treatment. The distribution pattern was assessed retrospectively and scored for the presence of contrast in each of eight regions: the under surface of right and left diaphragms, the right and left paracolic gutters, the lesser omental sac, the intramesenteric region and the true and false pelvis. Assigning a point to each region with adequate distribution, we classified 10 patients to an excellent pattern (greater than or equal to 7 of 8 regions), 6 to a good pattern (5 to less than 7 regions), and 3 to an inadequate distribution pattern (less than 5 regions). Serial studies were performed in 8 patients after more than 4 cycles of IP therapy. In these patients, all of whom were tolerating treatment without progression, the distribution remained virtually unchanged for those with excellent distribution. One of three with good distribution manifested inadequate distribution on repeat study, and one of two with inadequate distribution improved to show a good pattern. In this small study there was no correlation of distribution patterns with plasma CA-125 at onset of IP treatment and prior surgical procedures or placement of the catheter tip. However, three patients with unsatisfactory patterns had procedures consisting of catheter placement only rather than formal reassessment laparotomies for ovarian cancer. Since satisfactory IP distribution may be required for obtaining a therapeutic advantage from IP therapy, methods for its assessment must be developed.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Combined Chemotherapy Protocols↗
Randomized trial: another opinion.
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Ethics, Medical↗
High incidence of coagualopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers.
This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program.
PURPOSE: A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. METHODS AND MATERIALS: Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. RESULTS: Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. CONCLUSION: This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.
Adenocarcinoma↗
No evidence of acute cardiovascular complications of chemotherapy for testicular cancer: an analysis of the Testicular Cancer Intergroup Study.
PURPOSE: The purpose of this study is to evaluate the risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer. PATIENTS AND METHODS: A questionnaire assessing cardiovascular toxicity was distributed to all participants in the Testicular Cancer Intergroup study and details of toxicity from the chemotherapy flow sheets were reviewed. Patients with pathologic stage I testicular cancer were registered on to the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receive two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who had disease recurrence after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy. RESULTS: Review treatment-related toxicity for those patients receiving adjuvant chemotherapy (n = 97) or chemotherapy for recurrent disease (n = 83) showed no cases of acute cardiovascular toxicity. The median follow-up period after study enrollment was 5.1 years; 459 questionnaires were mailed and 270 were returned. The percent return was equal among the observed adjuvant and recurrent groups (59%, 54%, and 64%). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in two patients in the observation group and one nonfatal infarction was reported in the adjuvant treatment group. No patient in any group reported an incidence of stroke. Three patients in the observation group and one patient in the recurrent group experienced a thromboembolic event. CONCLUSION: Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.
Acute Disease↗
Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.
We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)
Carboplatin↗
Role of carboplatin in endometrial and cervical carcinomas.
The role of carboplatin in cervical and endometrial cancers is being assessed through clinical trials. Preliminary results indicate some activity against both of these gynecologic tumors. Carboplatin is also being integrated into combination regimens with other active drugs. In the treatment of cervical cancer, it is used as part of combined-modality regimens prior to radiotherapy. Patients have shown better subjective tolerance to carboplatin than to cisplatin. This finding may facilitate the widespread implementation of carboplatin-based combinations.
Antineoplastic Combined Chemotherapy Protocols↗
Teniposide in adult solid tumors: a historical perspective.
Teniposide and etoposide are third-generation semi-synthetic derivatives of epipodophyllotoxin. Following the initial clinical introduction of teniposide in the 1970s, investigations focused almost exclusively on its analogue, etoposide, because of its formulation, which was felt to have advantages in addition to oral administration. Despite consistently inadequate dosing and scheduling, early phase I and II trial results with teniposide were promising, and current trends encourage a second look. The substantial antitumor activity of teniposide is comparable with that of etoposide, and clinical interest was rekindled when it was shown to have considerable activity against small cell lung cancer (SCLC). In view of the inadequacy of early trials and the premature cessation of clinical study, it is recommended that teniposide be reevaluated for its activity against malignant lymphomas, Hodgkin's disease, leukemias, and SCLC, against all of which its early results were encouraging. In addition, consideration should be given to its activity against brain tumors, neuroblastomas and other childhood solid tumors, and ovarian cancer; its potential value against gastric, hepatocellular, breast, and bladder cancers also should be investigated. Other areas that warrant further study include elucidation of the exact mechanism of action of teniposide, its role in both single- and multiple-agent chemotherapeutic regimens, and resolution of its optimal dose and schedule. Finally, it is suggested that with new routes of administration and improved formulations, teniposide may be expected to play a significant role in the treatment of malignant lymphomas, SCLC, and pediatric lymphocytic leukemia and neuroblastoma.
Adult↗
Treatment of colon cancer based on biochemical modulation of fluoropyrimidines by hydroxyurea.
Preclinical studies have indicated that hydroxyurea leads to enhancement of 5-fluorouracil (5-FU) activity when given after 5-FU. This is presumably due to hydroxyurea's actions resulting in maintaining low levels of deoxyuridine monophosphate pools. The combination of hydroxyurea and 5-FU has been tested in several inconclusive clinical trials in patients with advanced colorectal cancer. However, pharmacodynamic studies have been lacking, and the schedules tested have not usually tried to follow preclinical findings. With the current renewed interest in 5-FU, a role for hydroxyurea as part of its biochemical modulation is worthy of further study.
Animals↗
New chemotherapies for ovarian cancer. Systemic and intraperitoneal podophyllotoxins.
The epipodophyllotoxin derivatives etoposide and teniposide have been evaluated intermittently for possible use in the treatment of ovarian cancer. Conflicting studies suggest that variables such as dose and prior treatment have a major influence on outcome. Response rates ranged from 0% to 40% in five series with teniposide, and from less than a 10% overall response rate to greater than a 10% complete response rate in nine studies with etoposide. One study documented activity with oral etoposide. However, because all patients had received various prior chemotherapies, firm conclusions regarding the activity of etoposide could not be drawn. These results, and the expectation of synergy with etoposide and cisplatin, led to several studies that combined etoposide with platin compounds by the systemic and intraperitoneal (IP) routes. Various studies have used intravenous drug combinations of these agents in both previously treated and untreated patients. One study, which used carboplatin instead of cisplatin, reported only seven failures among 26 previously untreated patients. Conversely, the prominent toxicities reported by another study were discouraging, and responses did not exceed what might be expected from cisplatin alone. Studies of analogous combinations administered IP are ongoing. A favorable experience, which was initially reported by the University of California (San Diego group), is being confirmed by other investigators. This has prompted the incorporation of etoposide into first-line strategies. The pharmacologic advantage of etoposide by the IP route (related to its high protein binding) may provide appropriate dose intensity against IP disease while sparing systemic toxicities. Finally, systemic dose intensity with autologous bone marrow support indicates some promise for etoposide in combination with high-dose alkylating drugs.
Combined Modality Therapy↗
ICRF-187 (ADR-529) cardioprotection against anthracycline-induced cardiotoxicity: clinical and preclinical studies.
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Animals↗
Evaluation of fludarabine phosphate in malignant melanoma. A Southwest Oncology Group study.
Twenty-seven evaluable patients with advanced malignant melanoma received fludarabine phosphate in a daily x 5 injection. Initial dosing was based on the presence of previous radiation therapy. There was no response seen in these patients despite appropriate dose escalation. Myelosuppression occurred without significant sequelae.
Adult↗
Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A Southwest Oncology Group study.
Suggestions of a dose-response effect for cisplatin in non-small-cell lung cancer have contributed to the development of very high-dose cisplatin regimens (200 mg/m2 per cycle). We treated 53 eligible patients with metastatic or recurrent non-small-cell lung cancer with a combination of 100 mg/m2 cisplatin and 4 mg/m2 vinblastine, each given on days 1 and 8 of a 28-day cycle. We observed no complete response and 4 partial responses (8%). Median survival was 6 months. Toxicities of grade III or greater included leukopenia (11 cases), nausea/vomiting (6 cases), thrombocytopenia (2 cases), anemia (2 cases), and elevation of transaminase (1 case). Neurotoxicity has been reported to be a major problem in several other very high-dose cisplatin regimens. The low level of neurotoxicity observed in this study may be attributable to the median cumulative cisplatin dose of less than 600 mg/m2. This vinblastine/very high-dose cisplatin regimen showed minor activity against non-small-cell lung cancer. The level of activity did not surpass that of standard-dose (100 mg/m2 per cycle) cisplatin-containing regimens.
Antineoplastic Combined Chemotherapy Protocols↗
Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2'-deoxyuridine.
Intraperitoneal (i.p.) 5-fluoro-2'-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32-78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at greater than 3,000 mg x 3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg x 3 days and leukopenia and thrombocytopenia at 5,000 mg x 3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2-4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2-4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage. (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 1 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers.(ABSTRACT TRUNCATED AT 400 WORDS)
Ascitic Fluid↗
New anthracycline antitumor antibiotics.
Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.
Aclarubicin↗
Staging relationships and outcome in early stage testicular cancer: a report from the Testicular Cancer Intergroup Study.
The Testicular Cancer Center Intergroup Study entered surgically staged patients with nonseminomatous tumor and metastases limited to the regional lymph nodes into a previously reported cooperative trial of immediate versus delayed therapy for positive retroperitoneal node disease. Patients with negative nodes (stage I) were placed in an observation registry with specified treatment strategy upon relapse. Of 264 stage I cancer patients 27 (10.2%) had recurrence: 5 of these 27 patients died after recurrence of the testicular malignancies, while 4 other nontumor-related deaths have occurred. Pre-lymphadenectomy staging characteristics observed to predict significantly node positivity are the results of radiological examinations, presence of tumor invasion, vascular invasion and tumor histology. In a multiple logistic regression analysis with these variables, misclassification still occurs in more than a fourth of the patients. Future refinements in diagnosis may allow for better prediction of these patients at risk to have positive lymph nodes and ultimately recurrence. Presently, if assessment of nodal involvement is the objective, noninvasive procedures are not an adequate substitute for surgical staging with modified lymphadenectomy.
Adult↗