Heterogeneity of drug resistance in human breast and ovarian cancers.
Oncotech, Inc., Irvine, CA 92714, USA.
PURPOSE: This study quantitates the extent of heterogeneity of drug resistance in breast and ovarian cancers. Identification of drug-specific resistance in tumors from multiple sites provides information necessary to understand the unique biology of a patient's disease. MATERIALS AND METHODS: Drug resistance to cisplatin, paclitaxel, and doxorubicin was measured in multiple synchronous or metachronous tumors using the extreme drug resistance (EDR) assay. The degree of resistance for each tumor was classified into one of three categories: low drug resistance (LDR), EDR, or intermediate drug resistance (IDR). RESULTS: When tested against cisplatin, 66% of primary ovarian cancers and their paired synchronous distant metastases (N = 88) shared the same resistance category, while 4% of the results were discordant (one site had EDR and the other site had LDR). Of the paired results for paclitaxel (N = 68), 54% were in the same resistance category, while 13% of the comparisons were discordant. Heterogeneity of drug response to cisplatin was also measured in primary ovarian cancers and paired recurrent tumors from 108 women. Median time to recurrence was 9.6 months. Only 55% of the paired results fell into the same resistance category, while 19% of the results were discordant. Drug resistance to doxorubicin was measured in primary breast cancers and paired synchronous metastases from 23 women: 74% of the paired results fell into the same resistance category, while 13% of the results were discordant. Metastatic sites had a slightly higher incidence of EDR than primary sites (26% and 17%, respectively). Heterogeneity of drug response to doxorubicin was then determined in primary breast cancers and paired recurrent tumors from 26 women with a median time to recurrence of 14.3 months. Only 52% of the paired results fell into the same resistance category, while 24% of the results were discordant. DISCUSSION: Heterogeneity of drug resistance for ovarian and breast cancer is a serious clinical problem encountered in administering chemotherapy for overt metastatic or recurrent cancers. The first step in managing this problem is to recognize that heterogeneity of drug resistance exists. Drug resistance tests may then help the physician avoid administering certain chemotherapeutic agents when a patient's metastatic or recurrent tumor is found to be resistant to those agents.
Comparable safety and antiemetic efficacy of a brief (30-second bolus) intravenous granisetron infusion and a standard (15-minute) intravenous ondansetron infusion in breast cancer patients receiving moderately emetogenic chemotherapy.
Perez EA. Lembersky B. Kaywin P. Kalman L. Yocom K. Friedman C.
Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL 32224, USA.
PURPOSE: For patients receiving chemotherapy, optimization of antiemetic therapy in terms of safety of administration, efficacy, cost, and convenience remains a subject of intense clinical research. In this study, we evaluated and compared the safety and antiemetic efficacy of a single 30-second intravenous bolus infusion of granisetron which those of a standard 15-minute intravenous infusion of ondansetron in chemotherapy-naive breast cancer patients receiving moderately emetogenic chemotherapy. PATIENTS AND MATERIALS: This was a randomized, double-blind, double-dummy, multicenter crossover study of 623 chemotherapy-naive patients (two male, 621 female) receiving moderately emetogenic chemotherapy (cyclophosphamide plus doxorubicin, with or without 5-fluorouracil) for breast cancer. Patients were assigned randomly to receive either granisetron or ondansetron in cycle 1 and the other agent in cycle 2. Granisetron (10 micrograms/kg) was administered as a 30-second intravenous bolus infusion within 5 minutes before the start of chemotherapy, and ondansetron (32 mg) was administered as a 15-minute intravenous infusion beginning 30 minutes before the start of chemotherapy. A total of 573 patients received the two planned chemotherapy cycles. Safety assessment was based on the type and frequency of adverse experiences reported by the patient at 24 and 48 hours after chemotherapy began. Efficacy assessments included the occurrence of nausea or emesis and the proportion of patients who achieved total emetic control at 24 and 48 hours after chemotherapy. RESULTS: Similar proportions of patients in both treatment groups remained free of emesis at the 24-hour assessment period (58.6% and 62.7% of granisetron- and ondansetron-treated patients, respectively) and at 48 hours (42.2% and 45.0% for granisetron vs ondansetron) in both cycles. The proportions of granisetron- and ondansetron-treated patients who remained nausea-free for the first 24 hours after treatment in both cycles were 44.0% and 48.5%, respectively, and at 48 hours were 26.7% and 31.0%, respectively. Statistical analysis demonstrated no significant treatment-by-cycle interaction. The 30-second granisetron infusion and the 15-minute ondansetron infusion were well tolerated. However, administration of ondansetron as a 15-minute intravenous infusion produced abnormal vision (6.28%) in significantly more patients than granisetron (0.35%). DISCUSSION: These two intravenous 5-hydroxytryptamine3-receptor antagonist antiemetics were similarly effective in controlling acute nausea and emesis during two cycles of moderately emetogenic chemotherapy. Granisetron (30 seconds) and the longer infusion of ondansetron (15 minutes) were well tolerated; however, ondansetron was associated with a greater proportion of patients reporting abnormal vision. Granisetron administered as a 30-second bolus infusion allows a considerably shorter waiting time between the end of the antiemetic infusion and the initiation of chemotherapy. This shorter administration time may enhance patient convenience and provider efficiency.
Use of dexamethasone with 5-HT3-receptor antagonists for chemotherapy-induced nausea and vomiting.
Mayo Foundation, Jacksonville, Florida 32224, USA.
The use of 5-hydroxytryptamine (HT)3-receptor antagonists represents a major improvement in the management of chemotherapy-induced nausea and vomiting. Despite treatment with a 5-HT3-receptor antagonist, nausea and vomiting persist in approximately 40% to 60% of patients receiving highly emetogenic chemotherapy. To improve control of acute emetic episodes, dexamethasone is frequently added to enhance the antiemetic efficacy of a 5-HT3-receptor antagonist. Combination therapy with dexamethasone is rational given the different mechanisms of action, low incidence of adverse effects, and potential synergistic effect with 5-HT3-receptor antagonists. In > 1,600 cisplatin-treated patients evaluated in randomized clinical trials, complete response (no nausea and vomiting) was achieved in 58% to 92% of patients receiving a corticosteroid plus a 5-HT3-receptor antagonist, compared with 39% to 79% of patients receiving a 5-HT3-receptor antagonist alone. Combination antiemetic therapy also has demonstrated effectiveness in patients receiving repeat-cycle chemotherapy and in patients refractory to other antiemetics, including combinations of traditional antiemetics plus corticosteroids or 5-HT3-receptor antagonists alone. Intermittent use of high-dose corticosteroids is rarely associated with significant adverse effects. A corticosteroid plus a 5-HT3-receptor antagonist is a safe and effective combination to control chemotherapy-induced nausea and vomiting and should be considered in patients receiving moderately and highly emetogenic chemotherapy and in patients refractory to other antiemetics.
In situ radiotherapy with 111In-pentetreotide: initial observations and future directions.
McCarthy KE. Woltering EA. Espenan GD. Cronin M. Maloney TJ. Anthony LB.
Department of Radiology, LSUMC Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, USA.
PURPOSE: Somatostatin and its analogues, such as octreotide and lanreotide, are used to treat neuroendocrine malignancies. Somatostatin analogues bind to somatostatin receptors (sst 1-5), which are differentially expressed in a wide variety of neoplasms. Following ligand receptor binding, a fraction of these complexes internalize. Internalization of radiolabeled somatostatin analogues, especially those that emit Auger electrons, may allow treatment of somatostatin-receptor-positive tumors by delivering a radioactive isotope to the cancer cell in a targeted fashion. 111In-pentetreotide, an sst-2-preferring somatostatin analogue, has been used for scintigraphic evaluation and management of neuroendocrine cancer patients. We hypothesized that binding and internalization of 111In-pentetreotide, an Auger electron emitter, may induce receptor-specific cytotoxicity and could be a useful therapeutic agent in somatostatin-receptor-expressing malignancies. METHODS: To test this hypothesis, subjects who had failed conventional therapy and had somatostatin-receptor-positive malignancies, as determined by positive uptake on a 6.0 mCi 111In-pentetreotide scan, were treated with two monthly 180 mCi intravenous injections of 111In-pentetreotide. CT scans were obtained before therapy and within 30 days following the completion of the second 111In-pentetreotide dose. Toxicity was evaluated using standard criteria. RESULTS: Fourteen patients were studied from February 1997 to August 1997. Clinical benefit occurred in six of 10 gastroenteropancreatic tumor patients. Objective partial radiographic responses occurred in two of 14 patients, and significant tumor necrosis (defined by changes in Hounsfield units) developed in six of the 10 gastroenteropancreatic tumor patients. Possible treatment-related toxicity included two patients experiencing grade 3/4 myelosuppression, and two patients had no measurable toxicity. The most common toxicity was grade 1/2 hemoglobin (N = 6). CONCLUSION: One hundred eighty millicurie (180-mCi) doses of 111In-pentetreotide are well tolerated and are an effective therapy in some subjects with somatostatin receptor-expressing tumors. The maximal tolerated dose of 111In-pentetreotide and the optimal dosing schedules remain to be determined.
Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center.
Abrams RA. Pajak TF. Haulk TL. Flam M. Asbell SO.
Johns Hopkins Oncology Center, Baltimore, Maryland 21287-8922, USA.
PURPOSE: To analyze the observed therapeutic impact of the post-induction components of three treatment programs utilized sequentially between 1983 and 1991 for patients with unresectable alpha-fetoprotein-positive hepatoma. METHODS: Over a 7.5-year period, three treatment regimens were sequentially utilized: (1) RTOG 83-19, (2) a Johns Hopkins Oncology Center Institutional Pilot Program, and (3) RTOG 88-23. Each treatment program began with an induction phase of external-beam hepatic irradiation (2100 cGy/7 fractions), with concurrent doses of intravenous chemotherapy intended to be radiosensitizing. After induction, patients received cycles of one of the following: (1) intravenous doxorubicin and 5-fluorouracil (5-FU) with or without 131I-polyclonal antiferritin (RTOG 83-19); (2) intrahepatic artery cisplatin (Hopkins Institutional Pilot); or (3) intrahepatic artery cisplatin with or without 131I-polyclonal antiferritin (RTOG 88-23). Analysis of survival results was performed with multivariate and Cox regression methods. RESULTS: The addition of intravenous 131I-polyclonal antiferritin to post-induction cycles of either intravenous doxorubicin and 5-FU or intrahepatic artery cisplatin did not enhance survival. Intrahepatic artery cisplatin treatment yielded median survival duration of 9.1 months and survival at 12 and 24 months of 37% and 9%, respectively. These results were significantly superior to those resulting from use of intravenous doxorubicin and 5-FU (P = 0.0001; median survival duration 3.6 months; 12- and 24-month survival results 17% and 4%, respectively). A significant survival difference for the cisplatin regimen remained even when patients were stratified by previously identified prognostic factors and the results were appropriately adjusted. CONCLUSION: Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities.
Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials.
Jaffee EM. Schutte M. Gossett J. Morsberger LA. Adler AJ. Thomas M. Greten TF. Hruban RH. Yeo CJ. Griffin CA.
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Preclinical studies with murine tumor models have demonstrated that tumor cell vaccines engineered to secrete certain cytokines in a paracrine fashion elicit systemic immune responses capable of eliminating small amounts of established tumor. In particular, tumors that express the cytokine GM-CSF produce potent systemic antitumor immune responses against poorly immunogenic murine tumors. These results have encouraged the development of paracrine-cytokine secreting tumor vaccines for gene therapy of human cancer. GM-CSF recruits professional antigen-presenting cells, which in turn activate effector T cells. These findings suggest that allogeneic as well as autologous tumor cells can be used as the tumor source for developing cancer vaccines. A major obstacle to creating genetically modified human allogeneic tumor vaccines is the absence of stable cell lines required for efficient gene transfer, because most human tumors isolated from primary surgical specimens fail to proliferate in long-term culture. We have developed a method for the routine generation of in vitro cell lines from primary tumors of the pancreas. This method overcomes the common problem of stromal and fibroblast overgrowth that can inhibit the in vitro expansion of many histologic types of tumors. In addition, we have analyzed 12 of these cell lines for cytokeritin and mutated K-ras expression to demonstrate that they derive from the original epithelial tumor tissue. The lines can be genetically modified to stably express the cytokine GM-CSF. These methods should be helpful to investigators attempting to establish cell lines from other histologic tumor types for the development of allogeneic genetically modified tumor vaccines.