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Biomedical subjects

Jeffrey W Clark

Publications and source records attributed to Jeffrey W Clark.

At least 37 records · Page 2Linked to original sources
PubMed2005

Patients undergoing treatment for pancreatic adenocarcinoma can mount an effective immune response to vaccinations.

BACKGROUND: Immunotherapy has been proposed as a novel treatment for pancreatic cancer. However, patients with pancreatic cancer have been observed to have depressed immune responses, suggesting that immunotherapy might have limited utility in this group of patients. We sought to determine whether patients undergoing postresection or primary medical treatment for pancreatic adenocarcinoma were immunocompetent. METHODS: We enrolled patients with pancreatic adenocarcinoma scheduled for postresection or primary chemotherapy and/or radiation therapy. At the initiation of therapy, the patients had an anergy panel placed and baseline blood work performed. During the first week of treatment, patients received tetanus toxoid (TT), Haemophilus influenzae and Pneumococcus vaccines. Twelve weeks after vaccine administration, IgG titers against the 3 administered vaccines were done, and lymphocyte proliferation assays in response to TT were performed. RESULTS: Eighteen patients were originally enrolled, and 14 patients completed all elements of the trial. Anergy panel responses were obtained for 15 patients who comprised the final study group; both pre- and postvaccination data were available for 14 patients. Nine of 15 patients demonstrated at least a 10-mm induration in response to mumps or Candida antigen (60% response rate, 95% confidence interval (CI) 32-84%). Thirteen of 14 patients demonstrated a > or =3-fold increase in IgG against one or more vaccines (93% response rate, 95% CI 66-100%). Nine of 14 patients (64% response rate, 95% CI 35-87%) demonstrated at least a 3-fold rise of lymphocyte proliferation against TT. CONCLUSIONS: Patients with pancreatic cancer were capable of mounting effective cellular and humoral responses to standard vaccines. These data suggest that immunotherapy for pancreatic cancer may be feasible and merits further investigation.

Adenocarcinoma↗
PubMed2005

A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma.

Chemotherapy options for esophagogastric adenocarcinoma remain limited. Irinotecan has demonstrated broad activity in a variety of epithelial malignancies. Forty-six patients with previously untreated, measurable, unresectable, or metastatic esophagogastric adenocarcinoma were enrolled. Patients received irinotecan (125 mg/m2 intravenously over 90 min weekly) for 4 consecutive weeks followed by a 2-week rest. Forty-three patients received at least one treatment and were evaluable for response and toxicity. One complete and five partial responses were observed, for an overall response rate of 14% (95% CI, 4-24%). Median survival for all 43 patients was 6.4 months (95% CI, 4.6-8.2 months). Grade 3 to 4 toxicity included 10 patients (23%) with neutropenia, 13 patients (30%) with late diarrhea, 6 patients (14%) with vomiting, and 6 patients (14%) with fatigue. We conclude that although single-agent irinotecan is an active agent for esophagogastric adenocarcinoma, the schedule utilized in this trial is associated with moderate toxicity. When used as a single-agent, a tri-weekly schedule may be preferable for this patient population.

Adenocarcinoma↗
PubMed2005

Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer.

SUMMARY BACKGROUND DATA: To analyze the effects of a treatment program of intraoperative electron beam radiation therapy (IOERT) and external beam radiation therapy and chemotherapy on the outcome of patients with unresectable or locally advanced pancreatic cancer. METHODS: From 1978 to 2001, 150 patients with unresectable and nonmetastatic pancreatic cancer received IOERT combined with external beam radiation therapy and 5-fluorouracil-based chemotherapy for definitive treatment. RESULTS: The 1-, 2-, and 3-year actuarial survival rates of all 150 patients were 54%, 15%, and 7%, respectively. Median and mean survival rates were 13 and 17 months, respectively. Long-term survival has been observed in 8 patients. Five patients have survived beyond 5 years and 3 more between 3 and 4 years. There was a statistically significant correlation of survival to the diameter of treatment applicator (a surrogate for tumor size) used during IOERT. For 26 patients treated with a small-diameter applicator (5 cm or 6 cm), the 2- and 3-year actuarial survival rates were 27% and 17%, respectively. In contrast, none of the 11 patients treated with a 9-cm-diameter applicator survived beyond 18 months. Intermediate survival rates were seen for patients treated with a 7- or 8-cm-diameter applicator. Operative mortality was 0.6%, and postoperative and late complications were 20% and 15%, respectively. CONCLUSIONS: A treatment strategy employing IOERT has resulted in long-term survival in 8 of 150 patients with unresectable pancreatic cancer. Survival benefit was limited to patients with small tumors. Enrollment of selected patients with small tumors into innovative protocols employing this treatment approach is appropriate.

Adult↗
PubMed2004

Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.

CONTEXT: In the past, cancer patients entering phase 1 studies confronted the prospects of high risk and unlikely benefit. Over the last decade, cancer drugs under development have become more targeted, and the clinical research environment has become more scrutinized. The impact of these changes on the risks and benefits to patients who participate in phase 1 cancer trials is unknown. OBJECTIVE: To determine trends in the rates of treatment-related (toxic) death, objective response, and serious toxicity and to identify factors associated with these outcomes. DATA SOURCES: We searched abstracts and journal articles reporting the results of phase 1 cancer treatment trials originally submitted to annual meetings of the American Society of Clinical Oncology (ASCO) from 1991 through 2002. STUDY SELECTION: We focused on published single-agent trials that enrolled patients with advanced solid tumors and excluded studies testing agents already approved by the US Food and Drug Administration at the time of the ASCO presentation. DATA EXTRACTION: Multiple observers independently extracted information on trial design, location, sponsorship, types of tumors treated, drug class, route of administration, and clinical outcomes. DATA SYNTHESIS: The overall toxic death rate for 213 studies (involving 6474 cancer patients) published in peer-reviewed journals was 0.54%, while the overall objective response rate was 3.8%. Toxic death rates decreased over the study period, from 1.1% over the first 4 years of the study (1991-1994) to 0.06% over the most recent 4-year period (1999-2002) (P<.01). Response rates also decreased but by proportionally much less. After adjusting for characteristics of the experimental trials and the investigational agents, the odds of a patient dying from an experimental treatment while participating in a trial submitted during the most recent 4-year period were less than one tenth those of a patient participating in a trial submitted during the first 4-year period (odds ratio, 0.09; 95% confidence interval, 0.01-0.67; P = .009). In comparison, the adjusted odds of a patient experiencing an objective response over the same time periods decreased by approximately half (odds ratio, 0.46; 95% confidence interval, 0.32-0.66; P<.001). CONCLUSIONS: The level of risk experienced by cancer patients who participate in phase 1 treatment trials appears to have improved over the 12-year period from 1991 through 2002. Because toxic death rates have decreased more quickly than have objective response rates, the ratio of risk to benefit may have also improved. These changes relate in part to the targeted and less-toxic nature of newer cancer drugs and are coincident with the increased attention that has been paid to the safety of clinical research over the time period we analyzed.

Antineoplastic Agents↗
PubMed2004

A Phase II trial of gemcitabine for metastatic neuroendocrine tumors.

BACKGROUND: Treatment with traditional cytotoxic chemotherapy regimens containing streptozocin or dacarbazine has resulted in only marginal benefit for patients with metastatic neuroendocrine tumors. The use of these regimens has been further limited by their potential toxicity. Gemcitabine is generally well tolerated and possesses demonstrated activity against a wide range of malignancies. The authors assessed the efficacy of gemcitabine in the treatment of patients with metastatic neuroendocrine tumors. METHODS: Eighteen patients with metastatic neuroendocrine tumors were treated with gemcitabine administered on a standard weekly schedule. Patients were followed for evidence of toxicity, response, and survival. RESULTS: Gemcitabine was well tolerated. However, no radiologic or biochemical responses were observed. Although the majority of patients (65%) experienced disease stabilization as their best response to therapy, the overall median survival duration was only 11.5 months. CONCLUSIONS: The minimal activity of gemcitabine highlighted the need for novel treatment approaches.

Adult↗
PubMed2004

Gemcitabine-associated thrombotic microangiopathy.

BACKGROUND: Gemcitabine-associated thrombotic microangiopathy (TMA) is believed to be very rare, with an estimated incidence rate of 0.015%. Indications for gemcitabine are expanding, and comprehensive characterization of this complication is therefore important. METHODS: The authors performed a retrospective chart review of all cases with gemcitabine-associated TMA diagnosed at Partners Healthcare System (Boston, MA) between January 1997 and February 2002. RESULTS: Nine patients with gemcitabine-associated TMA were identified. Diagnosis was aided by clinical and laboratory features. Renal biopsy confirmed the diagnosis in two patients. The cumulative incidence of gemcitabine-associated TMA was 0.31% (8 cases among 2586 patients) when only the 8 patients with TMA who were treated at clinics associated with the current study were considered (1 patient with a TMA syndrome was transferred from another institution). The median patient age was 53 years, and the median time to development of a TMA syndrome after the initiation of gemcitabine was 8 months (range, 3-18 months), with a cumulative dose ranging from 9 to 56 g/m(2). New or exacerbated hypertension was a prominent feature in 7 of 9 patients and preceded the clinical diagnosis by 0.5-10 weeks. Treatment of TMA included discontinuation of gemcitabine, antihypertensive therapy, plasma exchange, and dialysis. Outcomes are known for all nine patients. Six patients remain alive, whereas three have died of disease progression. No patient died as a direct result of TMA, but two developed kidney failure requiring dialysis, and one developed chronic renal insufficiency. CONCLUSIONS: In the current series, the largest single-institution study to date, the incidence of gemcitabine-associated TMA was higher than previously reported (0.31% vs. 0.015%). Seven of nine patients developed new or exacerbated hypertension, which could be a useful early identifier of patients with gemcitabine-associated TMA syndromes.

Adult↗
PubMed2004

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. RESULTS: The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. CONCLUSIONS: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.

Adult↗
PubMed2004

Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.

Adenocarcinoma↗
PubMed2004

Adjuvant therapy for pancreatic cancer: an evolving paradigm.

Pancreatic cancer is the fourth leading cause of death in men and fifth in women in the United States. The median survival is 8 to 12 months for patients with locally advanced and unresectable disease and only 3 to 6 months for those with metastatic disease at presentation. Surgical resection offers the only potentially curative treatment. However, only 15% to 20% of patients present with tumors amenable to resection at initial diagnosis. Even for those who undergo resection, the prognosis remains poor. The 5-year survival following pancreaticoduodenectomy is only about 25% to 30% for node-negative tumors and 10% for node-positive tumors. Because of the dismal outcome for patients with resectable pancreatic cancer, adjuvant therapy has been administered in an attempt to improve the local control and overall survival. This review highlights historic and current perspectives of adjuvant therapy in resected pancreatic cancer.

Adult↗
PubMed2004

A phase I trial of daily oral 4'- N -benzoyl-staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies.

PURPOSE: 4'- N -Benzoyl-staurosporine (PKC412) is an orally available staurosporine derivative that inhibits protein kinase C. The objectives of this phase I trial were to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetics of PKC412 when co-administered with 5-Fluorouracil (5-FU). EXPERIMENTAL DESIGN: PKC412 was given daily with a 21-day continuous i.v. infusion of 5-FU 200 mg/m2/day, repeated every 4 weeks. The PKC412 dose was escalated by a modified continual reassessment method. The steady-state plasma pharmacokinetics of 5-FU, PKC412, and two of its circulating metabolites were determined during the first cycle of therapy. RESULTS: A total of 33 patients were treated with 70 cycles (median: 2, range: 1-4) of PKC412 at doses ranging from 25 to 225 mg/day. No significant toxicities were encountered with doses up to 150 mg/day. Among nine patients treated with 225 mg/day of PKC412, one experienced grade 3 fatigue and nausea, another developed grade 3 hyperglycemia, and three had grade 2 emesis and stomatitis, leading to early treatment discontinuation. Minor responses consisting of a 40-45% tumor reduction were observed in two patients, one with gall bladder carcinoma and one with breast cancer. Mean values of steady-state pharmacokinetic variables for both PKC412 and 5-FU were comparable to single agent studies. CONCLUSIONS: The recommended phase II dose of PKC412 is 150 mg/day when combined with a continuous infusion of 200 mg/m2/day 5-FU. The dose limiting toxicity was grade 2 emesis and stomatitis and the regimen showed indications of activity. There was no evidence of a pharmacokinetic interaction between the two drugs.

Administration, Oral↗
PubMed2004

A phase II study of docetaxel in patients with metastatic carcinoid tumors.

UNLABELLED: Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel. Although the treatment was well tolerated, no objective radiologic responses were observed. Novel, more effective agents are needed for this disease. BACKGROUND: Traditional combination chemotherapy regimens containing streptozocin, doxorubicin, and 5-fluorouracil have yielded disappointing results in patients with metastatic carcinoid tumors. The lack of efficacy of these combinations, together with their toxicity, has led to efforts to investigate therapeutic agents that are potentially more active and tolerable. We, therefore, assessed the efficacy of docetaxel in the treatment of patients with metastatic carcinoid tumors. METHODS: Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel, administered at a dose of 75 mg/m2 every three weeks. Patients were followed for evidence of toxicity, response, and survival. RESULTS: Docetaxel was well tolerated in this patient population. However, no objective radiologic responses were noted in any of the 21 patients. Of the 13 patients who were evaluable for biochemical responses to therapy, four (31%) experienced decreases in 24-hour urinary 5-hydroxyindole acetic acid (5HIAA) excretion of greater than 50%. The clinical course of the patients enrolled in this study was marked by a high incidence of radiologically stable disease (81%), a median progression-free survival time of 10 months, and a median overall survival time of 24 months. CONCLUSION: Although treatment with docetaxel results in biochemical responses in patients with metastatic carcinoid tumors, the lack of more significant antitumor activity demonstrates the need for novel, more effective agents in this disease.

Adult↗
PubMed2004

Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors.

BACKGROUND: The combination of streptozocin and doxorubicin has been considered the standard palliative chemotherapy regimen in patients with advanced pancreatic endocrine tumors (PETs). However, a recent review failed to confirm high antitumor activity in patients with advanced PETs. METHODS: We retrospectively reviewed the records of 16 consecutive patients who received streptozocin and doxorubicin for advanced PETs at Dana Farber/Partners Cancer Care institutions. Baseline patient characteristics, radiographic response to therapy, treatment-related toxicity, progression-free and overall survival were analyzed. RESULTS: One patient demonstrated an objective partial response to therapy (objective response rate [ORR], 6%; 95% confidence interval [CI], 0-18%). Six patients achieved stable disease (38%; 95% CI, 14-62%) and 9 patients demonstrated disease progression on initial restaging (56%; 95% CI, 33-77%). The median progression-free survival and overall survival were 3.9 months (95% CI, 2.8-8.8) and 20.2 months (95% CI, 9.7-37.4), respectively. CONCLUSIONS: In this retrospective cohort, the combination of streptozocin and doxorubicin failed to demonstrate substantial antitumor activity in patients with advanced PET. Our findings underscore the need for new therapeutic options in this patient population.

Adult↗
PubMed2004

Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer.

The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future.

Adult↗
PubMed2003

Phase I clinical trial and pharmacokinetic study of the spicamycin analog KRN5500 administered as a 1-hour intravenous infusion for five consecutive days to patients with refractory solid tumors.

PURPOSE: The spicamycin analogue KRN5500 is a nucleoside-like antibiotic with broad spectrum activity against human solid tumor models. It appears to possess a novel mechanism of action directed against the endoplasmic reticulum and Golgi apparatus with effects on protein processing. A Phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic behavior of KRN5500 given as a 1-h i.v. infusion for 5 consecutive days every 3 weeks. EXPERIMENTAL DESIGN: Adult patients with refractory solid tumors, good performance status, and normal to near normal renal, hepatic, and hematological function were eligible for the study. At least three patients were evaluated at each dose level, and a modified Fibonacci algorithm was used for dose escalation. The MTD was based on the occurrence of severe toxicity during the first cycle of therapy. The plasma pharmacokinetics of KRN5500 was characterized during the first week of dosing. RESULTS: Characteristics of the 26 patients entered into the study were as follows: 13 males and 13 females; median age, 54.5 years (range, 40-70 years); and Eastern Cooperative Oncology Group performance status 0-1. A majority had refractory colorectal carcinoma (17 of 26 patients) with at least two prior regimens of therapy. The dose of KRN5500 was escalated from 0.8 to 4.9 mg/m(2)/day in five dose levels, and the MTD was 2.9 mg/m(2)/day. All dose-limiting toxicities were nonhematological and included pulmonary toxicities, hyperglycemia, fatigue, hepatotoxicity, and ataxia, with one fatality due to interstitial pneumonitis. Clinically significant toxicities occurring in multiple patients that were not dose-limiting included nausea/vomiting, diarrhea, fatigue, neurological symptoms, hyperbilirubinemia, hyperglycemia, lymphopenia, and thrombocytopenia. There were no objective responses, although 3 of 17 evaluable patients exhibited disease stabilization for 5-6 cycles. The pharmacokinetics for the first dose of KRN5500 was biexponential and linear across all five dose levels. Mean values of pharmacokinetic parameters were as follows: total plasma clearance, 6.15 +/- 2.37 liters/h/m(2); apparent volume of distribution at steady state, 6.56 +/- 1.98 liters/m(2); biological half-life, 1.29 +/- 0.37 h; and mean residence time, 1.07 +/- 0.31 h. Clearance was significantly lower (P = 0.011) in the eight patients who were at least 65 years old (4.6 +/- 1.6 liters/h/m(2)) as compared with the 18 younger patients (7.1 +/- 2.3 liters/h/m(2)). Peak plasma concentrations of KRN5500 in the cohort receiving the MTD ranged from 350 to 400 ng/ml. CONCLUSIONS: The MTD of KRN5500, when given as a 1-h i.v. infusion for 5 consecutive days, was 2.9 mg/m(2)/day. The only suggestion of therapeutic activity observed in this study was disease stabilization in three patients with chemorefractory colorectal cancer. Administering KRN5500 as a continuous i.v. infusion with the objective of prolonging systemic exposure to potentially cytotoxic concentrations of the drug should be considered.

Adult↗
PubMed2003

A Phase I study of 9-nitrocamptothecin given concurrently with capecitabine in patients with refractory, metastatic solid tumors.

BACKGROUND: 9-Nitrocamptothecin (9-NC) is an orally available camptothecin analog with antineoplastic activity that results from the inhibition of DNA topoisomerase I. Previous studies have suggested that it has significant clinical efficacy. The primary toxicities of 9-NC include gastrointestinal upset, cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m(2) per day. Capecitabine is a prodrug of 5-fluorouracil that is approved for use in patients with metastatic breast carcinoma and colorectal carcinoma, and it offers the convenience of oral administration. This trial examined the combination of these two oral agents in patients with metastatic solid tumors. METHODS: Capecitabine was administered twice daily at a total daily dose of 1300 mg/m(2) per day for 14 days followed by a 1-week break. 9-NC was taken daily 5 days per week for 2 weeks in a dose-escalation scheme. The starting dose was 0.5 mg/m(2) per day, and cohorts of 3 patients were enrolled until the dose level reached 1.25 mg/m(2) per day. RESULTS: Twenty-one patients were evaluable for toxicity and response, and nausea and emesis were the dose-limiting toxicities. Despite antiemetic prophylaxis with 5-hydroxytryptamine-3 antagonists, 2 of 3 patients at the 1.0 mg/m(2) per day dose level had Grade 2-3 nausea; while at the MTD of 0.75 mg/m(2) per day, 3 of 14 patients had Grade > or = 2 nausea. The incidence of hand-foot syndrome, stomatitis, diarrhea, and myelosuppression did not exceed that expected with capecitabine alone, suggesting that 9-NC does not exacerbate these side effects. No objective responses were seen. Stable disease was observed in 9 patients (43%) with a median duration of 11 weeks, including 3 patients with responses that lasted from 20 weeks to 40 weeks. CONCLUSIONS: The combination of 9-NC and capecitabine with the current schedule was limited in dose by nausea and had minimal clinical efficacy in a group of patients with refractory solid tumors.

Administration, Oral↗
PubMed2003

Combined modality therapy for rectal and colon cancer.

Combined modality therapy (CMT) with radiation therapy and chemotherapy plays an important role in the management of rectal cancer. Postoperatively, pelvic irradiation and 5-fluorouracil-based chemotherapy have been used to improve local control and survival for high-risk patients after local excision, as well as for patients undergoing abdominoperineal or low anterior resection. For patients treated preoperatively, CMT can also be used to facilitate sphincter-sparing surgery for distal rectal tumors. Preoperative CMT in conjunction with surgery and intraoperative radiation therapy has been useful for patients with locally advanced and recurrent rectal cancer as well. While chemotherapy has benefit for patients with stage III colon cancer above the peritoneal reflection, the role of CMT is less well defined. Retrospective reviews suggest improved local control and survival in subgroups of patients treated with postoperative radiation therapy and chemotherapy. Active areas of investigation in CMT for colorectal cancer include the integration of biologic predictors, radiation modulators, and novel systemic agents.

Chemotherapy, Adjuvant↗