ABSTRACT
Adjuvant therapy can reduce the risk of disease recurrence in patients with stage II-IV colorectal cancer. Recently, 3 monoclonal antibodies have been shown to improve clinical outcome in this group of patients. Bevacizumab is an antiangiogenesis agent that has been shown in clinical and preclinical models to reverse the effects of proangiogenic molecules. Bevacizumab is active in the adjuvant setting and in the treatment of metastatic disease. Cetuximab is targeted to the epidermal growth factor receptor. Panitumumab is a fully human immunoglobulin G2 antibody that also binds to the epidermal growth factor receptor. Combination therapies of monoclonal therapies and chemotherapy have resulted in better clinical outcomes than with either modality alone.
Subject(s)
Colorectal Neoplasms/drug therapy , Treatment Outcome , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Cetuximab , Chemotherapy, Adjuvant , Colorectal Neoplasms/mortality , Disease Progression , Drug Delivery Systems , Endothelial Growth Factors , Epidermal Growth Factor/drug effects , Humans , Neoplasm Recurrence, Local , PanitumumabABSTRACT
PURPOSE: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer. PATIENTS AND METHODS: Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients. RESULTS: Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m(2)/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m(2)/d but administered every 2 weeks. At 120 mg/m(2)/d, three of seven patients had dose-limiting but reversible asthenia, hyperbilirubinemia, and azotemia or acidosis; however, in the case of renal and hepatic adverse events, the events were related to pre-existing borderline abnormal organ function. Therefore, the recommended phase II dose for 3-AP administered by 96-hour IV infusion is 120 mg/m(2)/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg/m(2), with substantial inter-patient variability. There was no correlation between dose and clearance (R(2) = 0.0137). There were no objective responses, but there was prolonged stabilization of disease or decreases in serum tumor markers associated with stable disease in four patients. CONCLUSION: The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.
Subject(s)
Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Pyridines/adverse effects , Pyridines/pharmacokinetics , Thiosemicarbazones/adverse effects , Thiosemicarbazones/pharmacokinetics , Adult , Aged , Asthenia/chemically induced , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Female , Humans , Hyperbilirubinemia/chemically induced , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Prospective Studies , Pyridines/administration & dosage , Risk Factors , Thiosemicarbazones/administration & dosage , Uremia/chemically inducedABSTRACT
PURPOSE: To determine the clinical activity and the toxicity profile of the topoisomerase-I inhibitor, topotecan, in women with recurrent or advanced endometrial carcinoma. PATIENTS AND METHODS: A prospective, phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG). Patients had histologically confirmed advanced or recurrent endometrial carcinoma, measurable disease, no prior cytotoxic therapy, an ECOG performance status of 0 to 2, and evidence of disease progression while on progestins or after radiation therapy. Topotecan was administered at 1.5 mg/m(2) (or 1.2 mg/m(2) for patients with prior pelvic radiation) intravenously daily for 5 days every 3 weeks. RESULTS: A total of 44 patients were enrolled; 42 were eligible. The study was suspended because of unexpected toxicities, primarily sepsis and bleeding. After toxicity review, the study was reopened using lower doses of topotecan (1.0 mg/m(2) or 0.8 mg/m(2) for patients with prior radiation therapy). In addition, prophylactic use of growth factors was allowed after the first cycle, and patients with performance status of 2 were excluded. The major toxicities were hematologic and gastrointestinal. Among the 40 assessable patients, there were three (7.5%) complete responders and five partial responders (12.5%), for an overall response rate of 20%. The median duration of response was 8.0 months and of overall survival was 6.5 months. CONCLUSION: Topotecan is an active agent for the treatment of advanced endometrial carcinoma. At the doses and schedules initially used, toxicities were unacceptable; however, at the modified doses, toxicities were acceptable and clinical activity was preserved.
Subject(s)
Antineoplastic Agents/therapeutic use , Endometrial Neoplasms/drug therapy , Topotecan/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Endometrial Neoplasms/mortality , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Prospective Studies , Survival Rate , Topotecan/adverse effects , United States/epidemiologyABSTRACT
PURPOSE: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. PATIENTS AND METHODS: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 microg/kg of filgrastim per day subcutaneously. RESULTS: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P =.027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P <.05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-microg/kg and 10-microg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). CONCLUSION: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 microg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Ovarian Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease Progression , Dose-Response Relationship, Drug , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Logistic Models , Middle Aged , Neoplasm Recurrence, Local , Neutropenia/chemically induced , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Platinum Compounds/administration & dosage , Proportional Hazards Models , Recombinant Proteins , Survival AnalysisABSTRACT
PURPOSE: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer PATIENTS AND METHODS: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. RESULTS: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. CONCLUSION: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.
Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Viral Vaccines/therapeutic use , Adenoviridae/immunology , Adult , Aged , Antigens, Viral/analysis , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Autopsy , Colorectal Neoplasms/pathology , Disease Progression , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Tissue Distribution , Treatment Failure , Viral Vaccines/administration & dosage , Viral Vaccines/adverse effectsABSTRACT
PURPOSE: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. PATIENTS AND METHODS: Treatment consisted of paclitaxel 135 mg/m(2) IV over 24 hours on days 1 to 2, cisplatin 100 mg/m(2) IP on day 2, and paclitaxel 60 mg/m(2) IP on day 8 administered every 21 days for six cycles. RESULTS: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. CONCLUSION: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.
Subject(s)
Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cisplatin/administration & dosage , Ovarian Neoplasms/therapy , Paclitaxel/administration & dosage , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Administration, Rectal , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/adverse effects , Disease-Free Survival , Drug Tolerance , Female , Humans , Infusions, Intravenous , Infusions, Parenteral , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Ovarian Neoplasms/surgery , Paclitaxel/adverse effectsABSTRACT
PURPOSE: To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. PATIENTS AND METHODS: Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 microg/m(2)/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. RESULTS: Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). CONCLUSION: This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/adverse effects , Camptothecin/therapeutic use , Carcinoma/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Antineoplastic Agents/adverse effects , Camptothecin/administration & dosage , Carcinoma/pathology , Disease Progression , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Middle Aged , Neutropenia/chemically induced , Ovarian Neoplasms/pathology , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
PURPOSE: To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. METHODS: An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. RESULTS: A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. CONCLUSION: With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.
Subject(s)
Antineoplastic Agents/adverse effects , Diarrhea/etiology , Diarrhea/therapy , Neoplasms , Radiotherapy/adverse effects , Algorithms , Anti-Bacterial Agents/therapeutic use , Antidiarrheals/therapeutic use , Diarrhea/mortality , Humans , Neoplasms/therapyABSTRACT
PURPOSE: ONYX-015 is a genetically modified adenovirus with a deletion of the E1B early gene and is therefore designed to replicate preferentially in p53-mutated cells. A Phase II trial of intralesional ONYX-015 was conducted in patients with hepatobiliary tumors to determine the safety and efficacy of such a treatment. EXPERIMENTAL DESIGN: All patients had biopsy-proven, measurable tumors of the liver, gall bladder, or bile ducts that were beyond the scope of surgical resection. Patients received intralesional injections of ONYX-015 at either 6 x 10(9) or 1 x 10(10) plaque-forming units/lesion up to a total dose of 3 x 10(10) plaque-forming units, and i.p. injections were allowed in patients with malignant ascites. The status of p53 was assessed by immunohistochemistry or Affymetrix GeneChip microarray analysis. Studies were conducted for viral shedding and for the presence of antiadenoviral antibodies before and after the injection of ONYX-015. Patients were assessed for response and toxicity. RESULTS: Twenty patients were enrolled, and 19 patients were eligible. Half of the patients had primary bile duct carcinomas. Serious toxicities (> grade 2) were uncommon and included hepatic toxicity (three patients), anemia (one patient), infection (one patient), and cardiac toxicity (one patient, atrial fibrillation). Sixteen patients were evaluable for response. Among these evaluable patients, 1 of 16 (6.3%) had a partial response, 1 of 16 (6.3%) had prolonged disease stabilization (49 weeks), and 8 of 16 (50%) had a >50% reduction in tumor markers. Of the 19 eligible patients, 18 (94.7%) had specimens available for p53 analysis. Fifteen of these 18 patients (83.3%) had evidence of p53 mutation by one or both methods, although the methods correlated poorly. Viral shedding was confined to bile (two of two patients) and ascites (four of four patients). Pretreatment adenoviral antibodies were present in 14 of 14 patients and increased by 33.2% after ONYX-015 treatment. CONCLUSIONS: Intralesional treatment with ONYX-015 in patients with hepatobiliary tumors is safe and well tolerated, and some patients had evidence of an anticancer effect. The high incidence of p53 mutations in these tumors makes this a logical population in which to test this therapy but precludes definitive evaluation about the necessity of a p53 mutation for ONYX-015 clinical activity.
Subject(s)
Adenoviridae/immunology , Bile Duct Neoplasms/therapy , Gallbladder Neoplasms/therapy , Genes, p53 , Liver Neoplasms/therapy , Mutation , Viral Vaccines/toxicity , Viral Vaccines/therapeutic use , Adenoviridae/growth & development , Adult , Aged , Antibodies, Viral/blood , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Female , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/pathology , Humans , Injections, Intralesional , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Treatment Outcome , Viral Plaque Assay , Viral Vaccines/administration & dosageABSTRACT
PURPOSE: ONYX-015 is a chimeric, E1B-deleted adenovirus designed to replicate preferentially in p53-deficient tumor cells; however, little is understood about its actual replication potential in human tumors. We hypothesized that replication of a late viral gene, hexon, would demonstrate replication of virus in human tissues. EXPERIMENTAL DESIGN: In the course of a clinical trial, a patient with paired abdominal wall implants from a primary gall bladder carcinoma was injected with ONYX-015, 1 x 10(10) viral particles/lesion, followed by sequential excision of the lesions at 37 h and 7 days. Tissue sections were analyzed for evidence of viral replication. RESULTS: In situ Reverse transcription-PCR was used to measure expression of hexon. Strong signals were obtained in gland-forming tumor cells both at 37 h and at 7 days. Signal was predominantly observed in the cytoplasm. The signal was also observed in adjacent normal stromal cells. Analysis of p53 status of the tumor by immunohistochemistry and Affymetrix Genechip demonstrated an inactivating mutation in p53. Routine H&E staining of the tumor sections revealed no evidence of necrosis at 37 h or 7 days after injection of virus. Presence of viral protein at both 37 h and 7 days was confirmed by immunohistochemistry using antibodies directed against hexon, penton, and fiber proteins. CONCLUSIONS: Evidence for replication of hexon confirms that ONYX-015 is not only present but capable of replicating in tumor cells up to 1 week after intralesional injection and that replication is not confined to p53-mutated tumor cells.
Subject(s)
Adenoviridae/metabolism , Gallbladder Neoplasms/metabolism , Viral Vaccines/pharmacology , Blotting, Southern , Carcinoma/metabolism , Clinical Trials as Topic , Cytoplasm/metabolism , DNA Primers/pharmacology , Female , Gallbladder Neoplasms/pathology , Genes, p53 , Humans , In Situ Hybridization , Middle Aged , Necrosis , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Stromal Cells/metabolism , Time Factors , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
PURPOSE: Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. METHODS: This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. RESULTS: At dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. CONCLUSIONS: The maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Hydroxyurea/administration & dosage , Radiation-Sensitizing Agents/administration & dosage , Uterine Neoplasms/drug therapy , Uterine Neoplasms/radiotherapy , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Carcinoma, Squamous Cell/pathology , Combined Modality Therapy , Female , Humans , Hydroxyurea/adverse effects , Infusions, Parenteral , Middle Aged , Prospective Studies , Radiation-Sensitizing Agents/adverse effects , Uterine Neoplasms/pathologyABSTRACT
The E2F family plays a critical role in the expression of genes required for entry into and progression through S phase. E2F-mediated transcription is repressed by the tumor suppressor retinoblastoma protein (pRb), which results in sequestration of E2F in a multiprotein complex that includes pRb. Derepression of E2F results from a series of complex phosphorylation events mediated by cyclin D/cdk4 and cyclin E/cdk2. We have employed a novel 3-substituted indolinone compound, 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), which selectively inhibits cdk2 activity (Lane et al., Cancer Res 2001;61:6170-7) to investigate these events. Electrophoretic mobility gel shift assays were performed on SU9516-treated and -untreated HT-29, SW480, and RKO human colon cancer cell extracts. Treatment with 5 microM SU9516 prevented dissociation of pRb from E2F1 in all cell lines (HT-29>RKO>SW480). Treatment effects were time-dependent, demonstrating greater inhibition at 48 hr versus 24hr in HT-29 cells. Furthermore, E2F species were sequestered in complexes with p107, p130, DP-1, and cyclins A and E. After a 24-hr treatment with 5 microM SU9516, cyclin D1 and cdk2 levels decreased by 10-60%. These findings delineate a previously undescribed mechanism for SU9516-mediated cell growth arrest through down-regulation of cyclin D1, inhibition of cdk2 levels and activity, and pan-sequestration of E2F.
Subject(s)
CDC2-CDC28 Kinases , Cell Cycle Proteins , Cyclin-Dependent Kinases/antagonists & inhibitors , DNA-Binding Proteins , Imidazoles/pharmacology , Indoles/pharmacology , Intracellular Signaling Peptides and Proteins , Protein Serine-Threonine Kinases/antagonists & inhibitors , Transcription Factors/metabolism , Carrier Proteins/pharmacology , Cells, Cultured , Colonic Neoplasms/pathology , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , E2F Transcription Factors , E2F1 Transcription Factor , E2F2 Transcription Factor , E2F3 Transcription Factor , E2F5 Transcription Factor , HT29 Cells , Humans , Molecular Weight , Protein Serine-Threonine Kinases/metabolism , Retinoblastoma Protein/metabolismABSTRACT
Locoregional therapies are useful in treating patients with colorectal cancer metastatic to the liver. A prospective randomized phase II trial of hepatic artery embolization versus hepatic artery chemoembolization was conducted to evaluate the response rates and toxicities of these therapies in the second-line setting. Patients were required to have biopsy-proven adenocarcinoma of the colon or rectum metastatic to the liver, with the liver as the sole or predominant site of metastatic disease. All patients had measurable disease and had failed at least one prior systemic chemotherapy treatment for metastatic disease. Patients were randomized to receive either embolization therapy with polyvinyl alcohol foam (Ivalon) administered as a single agent or chemoembolization using polyvinyl alcohol foam mixed with 750 mg/m2 of 5-fluorouracil and 9 million units of interferon. Drugs and embolic material were administered via the hepatic artery as a slurry with polyvinyl alcohol foam. Fifty eligible patients were enrolled. There were 24 patients in the chemoembolization arm and 26 in the embolization arm. Sixty-four percent of patients in both treatment arms had the liver as the sole metastatic site. The most common National Cancer Institute common toxicity criteria grade 3/4 toxicities were diarrhea (17%) and hepatic toxicity (8%). There was 1 (4%) treatment-related mortality due to a hepatic abscess. Four patients (15.4%) treated with embolization had a partial response (PR), and 5 patients (20.8%) treated with chemoembolization had a PR. The median survival for all patients was 11 months (95% confidence interval [CI], 8-15 months). Survival in patients with extrahepatic disease was 8 months (95% CI, 6-10 months). Survival in patients with liver-only metastases was 15 months (95% CI, 10-17 months). Embolization of the liver as second-line therapy in patients with liver-predominant metastases is safe and effective. Median survivals are comparable to other second-line therapies
Subject(s)
Adenocarcinoma/secondary , Adenocarcinoma/therapy , Chemoembolization, Therapeutic/methods , Colorectal Neoplasms/pathology , Embolization, Therapeutic/methods , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoembolization, Therapeutic/adverse effects , Embolization, Therapeutic/adverse effects , Female , Fluorouracil/administration & dosage , Humans , Interferons/administration & dosage , Male , Middle Aged , Polyvinyls/therapeutic use , Prospective Studies , Survival RateABSTRACT
PURPOSE: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. METHODS: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m(2) by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m(2) CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 microg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. RESULTS: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. CONCLUSIONS: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Filgrastim , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Humans , Hydroxyurea/administration & dosage , Hydroxyurea/adverse effects , Infusions, Intravenous , Injections, Subcutaneous , Interferons/administration & dosage , Interferons/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Recombinant Proteins , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
OBJECTIVE: To determine the effect of a reduced radiotherapy dose on short- and long-term swallowing problems after organ-sparing treatment. DESIGN: Prospective case series. SETTING: Tertiary care referral center. PATIENTS: A consecutive sample of 29 patients with advanced oropharyngeal or hypopharyngeal cancer who were treated with intravenous hydroxyurea and concomitant hyperfractionated, accelerated radiotherapy. INTERVENTIONS: Initial experience with 74.4 Gy of radiation demonstrated severe long-term swallowing problems, prompting a dose reduction to 60.0 Gy. Eighteen patients were followed up for this study in the 74.4-Gy group, while 11 were in the 60.0-Gy group. MAIN OUTCOME MEASURES: Swallowing variables were assessed in both patient groups at 4 months and at 12 months following completion of therapy. RESULTS: Patient demographics and tumor characteristics were similar in each group, while significant differences were noted in the posttreatment clinical swallowing variables. Persistent severe odynophagia at 4 months (89% [16/18] vs 30% [3/10]) and at 12 months (64% [7/11] vs 11% [1/9]) was greater in the 74.4-Gy group (P =.002). Clinical signs of aspiration were also increased in the 74.4-Gy group, with 81% (13/16) vs 11% (1/9) at 4 months and 60% (6/10) vs 11% (1/9) at 12 months (P<.05). Most striking, however, was the incidence of long-term gastrostomy, with 78% (14/18) of patients receiving 74.4 Gy requiring gastrostomy feedings at 12 months compared with 18% (2/11) in the 60.0-Gy group (P =.002). Local control was unchanged by the altered dosing, with median follow-ups of 43.5 and 24.0 months in the 74.4-Gy and 60.0-Gy groups, respectively. CONCLUSION: Decreased radiation doses can maintain disease control and reduce treatment-related long-term swallowing complications.
Subject(s)
Deglutition Disorders/prevention & control , Hypopharyngeal Neoplasms/radiotherapy , Mouth Neoplasms/radiotherapy , Oropharyngeal Neoplasms/radiotherapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Combined Modality Therapy , Deglutition Disorders/epidemiology , Deglutition Disorders/etiology , Dose Fractionation, Radiation , Dose-Response Relationship, Radiation , Female , Humans , Hydroxyurea/administration & dosage , Hypopharyngeal Neoplasms/mortality , Hypopharyngeal Neoplasms/pathology , Logistic Models , Male , Middle Aged , Mouth Mucosa , Mouth Neoplasms/mortality , Mouth Neoplasms/pathology , New York City/epidemiology , Oropharyngeal Neoplasms/mortality , Oropharyngeal Neoplasms/pathology , Prospective Studies , Radiotherapy/adverse effects , Stomatitis/epidemiology , Stomatitis/etiology , Stomatitis/prevention & control , Survival Analysis , Weight LossABSTRACT
The purpose of this study was to determine the safety of irinotecan and capecitabine in patients with advanced solid tumors. Thirty-four patients received 122 courses of irinotecan 200 to 300 mg/m(2) as an intravenous infusion during 30 minutes on day 1 and capecitabine 1,500 to 3,000 mg/d orally 12 hours apart starting on day 2 for 14 days, repeated every 21 days (one course). Three to seven patients were treated in six dose-escalation cohorts. Three of 7 (43%) patients treated with irinotecan 300 mg/m(2) and capecitabine 2,300 mg/d had course 1 dose-limiting toxicity (DLT) defining maximum tolerated dosage (MTD). Fatigue and diarrhea were the major DLTs, and other events included neutropenia, anorexia, and hand-foot syndrome. At one dose level below the MTD, none of 7 patients treated with irinotecan 275 mg/m(2), and capecitabine 2,300 mg/d (36 courses) had course 1 DLT. Grade III to IV toxicities beyond course 1 included neutropenia (11% of all courses), fatigue (3.4%) and hand-foot syndrome (3.4%). There were only two episodes of febrile grade II neutropenia. There were no toxic deaths. Transient antitumor response was noted in one patient with irinotecan and 5-fluorouracil-refractory colon cancer. The combination of irinotecan 275 mg/m(2) and capecitabine 2,300 mg/d represents a safe, favorable, and convenient outpatient regimen warranting further phase II evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Deoxycytidine/analogs & derivatives , Gastrointestinal Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Camptothecin/administration & dosage , Capecitabine , Deoxycytidine/administration & dosage , Female , Fluorouracil/analogs & derivatives , Humans , Infusions, Intravenous , Irinotecan , Lung Neoplasms/drug therapy , Male , Maximum Tolerated Dose , Middle AgedABSTRACT
Interleukin-1 (IL-1) is a cytokine critical to inflammation, immunological activation, response to infection, and bone marrow hematopoiesis. Cyclophosphamide downmodulates immune suppressor cells and is cytotoxic to a variety of tumors. A phase I trial of IL-1 and cyclophosphamide was conducted by the Eastern Cooperative Oncology Group. This study evaluated 3 dose levels and 3 schedules in patients with solid tumors. The goal was to evaluate the hematopoietic supportive care effect and possible antitumor effect. Toxicity was fever, chills, hypotension, nausea/emesis, hepatic, and neutropenia. Toxicity increased with dose increases of interleukin-1. Treatment at all dose levels resulted in significant increases in total white blood cell (WBC) counts above baseline. Nadir WBC and nadir absolute neutrophil counts were not significantly different by dose level of IL-1 or schedule of IL-1. Toxicity due to IL-1 at higher doses prohibited further evaluation of this agent for hematopoietic support, particularly in view of the activity and tolerability of more lineage-specific hematopoietic cytokines. Therapeutic interventions in the role of IL-1 in inflammatory conditions and cancer may be further informed by our definition of its clinical and biological effects in this evaluation of dose and schedule.
Subject(s)
Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation , Interleukin-1alpha/immunology , Interleukin-1alpha/therapeutic use , Neoplasms/therapy , Adult , Aged , Cyclophosphamide/administration & dosage , Disease Progression , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Interleukin-1alpha/administration & dosage , Interleukin-1alpha/adverse effects , Male , Middle Aged , Neoplasms/immunology , Transplantation, HomologousSubject(s)
Adenoviridae/metabolism , Antineoplastic Agents/administration & dosage , Carcinoma/therapy , Mouth Neoplasms/therapy , Adenoviridae/genetics , Antineoplastic Agents/metabolism , Carcinoma/virology , Clinical Trials as Topic , Humans , Immunohistochemistry , In Situ Hybridization , Injections, Intralesional , Mouth Neoplasms/virology , Viral VaccinesABSTRACT
PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Drugs, Chinese Herbal/administration & dosage , Phytotherapy/methods , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/pharmacokinetics , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/pharmacokinetics , Half-Life , Humans , Irinotecan , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leucovorin/pharmacokinetics , Male , Mice , Middle AgedABSTRACT
PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.