Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

PURPOSE: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer. METHODS AND MATERIALS: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m(2) on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m(2) on Days 1-38; dose level II, irinotecan 40 mg/m(2) and capecitabine 1000 mg/m(2); and dose level III, irinotecan 50 mg/m(2) and capecitabine 1000 mg/m(2). Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4-5 weeks after termination of chemoradiotherapy. RESULTS: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only. CONCLUSION: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.     

Radiation recall phenomenon secondary to capecitabine: possible role of thymidine phosphorylase

Background: The first reported case of radiation (XRT) recall related to capecitabine described dermatitis in a previously radiated field in a breast cancer patient (Ortman; JCO). We previously reported the first case of recall syndrome manifesting as diffuse gastritis and duodenitis related to capecitabine with prior XRT with 5-FU in a pancreatic cancer patient (Saif; JARCET). We report here another pancreatic cancer patient with a radiation recall receiving capecitabine following capecitabine-XRT. Patients and methods: From April 2004 to June 2005, 20 patients with locally advanced pancreatic adenocarcinoma were treated with capecitabine 1,600 mg/m² daily with concomitant radiation (5040cGy) Monday–Friday (weekends off) for a total of 6 weeks, followed by capecitabine 2,000 mg/m² daily for 14 days every 3 weeks. One male patient with tumor in the neck and body of pancreas and not infiltrating the duodenum dropped hemoglobin to 7.3 g/dl at the end of the ninth week, and melena on rectal examination. Specimen of primary pancreatic ductal adenocarcinoma was obtained via EUS-guided biopsy before starting XRT on day 1 and utilized for RNA extraction. TP mRNA level was determined by real-time quantitative PCR (RT-Q-PCR). Results: Upper endoscopy revealed gastritis consistent with radiation toxicity. Colonoscopy was negative. Transfusion of three units of packed red blood cells (PRBCs) was given. The dose of capecitabine was reduced by 25%. His anemia continued to progress, a CT scan revealed 39% decrease in the tumor size (PR). Analysis of tumor specimen prior to the start of capecitabine-XRT showed TP expression of 183.16 (high). In addition to TP, DPD was 7.40, and TNF-alpha 4,114.56. Conclusion: We believe this case to be the second case of radiation recall presenting as diffuse gastritis in a patient receiving capecitabine after previous treatment with XRT. Further studies, including the role of TP are warranted into the pathogenesis of this unique phenomenon.     

Surgical Adjuvant Therapy for Colorectal Cancer: Current Approaches and Future Directions

Colon cancer is the fourth most common cancer worldwide. The role of systemic adjuvant chemotherapy in colorectal cancer patients with lymph node involvement has been established in a large number of clinical trials. However, its role in stage II colorectal cancer is less well established. 5-Fluorouracil has been the mainstay of therapy for the last four decades. With the development of novel chemotherapy and biological agents, we have entered into a new era for the treatment of colorectal cancer. The combination of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin has been shown to significantly improve disease-free survival and is now considered the standard of care for completely resected colon cancer in healthy patients. For rectal cancer patients with locally advanced tumors, neoadjuvant chemoradiation followed by adjuvant chemotherapy after surgery is the mainstay of treatment. The availability of oral chemotherapy agents has helped with the ease of administration and avoidance of indwelling catheters. A number of national clinical trials are under way to determine the role of targeted agents in combination with chemotherapy. The goal is to develop a regimen that would improve survival without excessive toxicity while maintaining quality of life. Patients should be encouraged to participate in clinical trials whenever feasible. Despite the advances, many patients will develop recurrent disease. It is of utmost importance to develop molecular markers that could predict which patients are at high risk for disease recurrence. Clinical trials are under way to address this issue. Thus, it will be advantageous to be able to tailor therapy individually, according to the risk of recurrence.     

Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study

PURPOSE: A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of capecitabine in women with measurable platinum-sensitive ovarian cancer or platinum-sensitive primary peritoneal cancer and to explore the ability of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) to predict response and toxicities. EXPERIMENTAL DESIGN: Patients were treated with a daily starting dose of 2500 mg/m2/day (divided in two doses given every 12 h) for 14 days of each 21-day cycle. Genotyping in the 5' and 3' ends of TS was performed in DNA from 23/23 pre-treatment blood specimens. Relative gene expression of TS, DPD, and TP was quantified in 18/21 paraffin-embedded tumor specimens. RESULTS: Of the 27 patients enrolled on study, 2 were never treated leaving 25 patients evaluable. Two patients (8.0%) achieved a partial response, 13 (52%) exhibited stable disease, 5 (20%) displayed increasing disease, and response could not be assessed in 5 (20%). The median time to progression and survival was 3.9 and 21.2 months, respectively. The most common serious toxicities were nausea/vomiting, gastrointestinal, and dermatological. There was one treatment-related death. TS expression was associated with severe nausea/vomiting (P = 0.039), but not with other severe toxicities. TS genotype or expression of DPD or TP was not associated with any of the severe toxicities. CONCLUSIONS: Based on the low response rate, this trial was closed after the first stage of accrual, the drug was not selected for further study in this patient population, and biomarker associations with response could not be assessed.     

Pharmacokinetic and pharmacodynamic comparison of fluoropyrimidine derivatives, capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR)

Purpose Capecitabine is a three-step prodrug that was rationally designed to be a more effective and safer alternative to its intermediate metabolite, 5-deoxy-5-fluorouridine (5-DFUR). We compared the pharmacokinetics/pharmacodynamics of these drugs in metastatic breast cancer patients.Methods Six patients received oral capecitabine at 1657 mg/m² twice daily and 17 received 5-DFUR at 400 mg three times daily. Both drugs were administered for 21 days followed by a 7-day rest.Results Median daily 5-DFUR AUC was significantly higher for capecitabine than for 5-DFUR (81.1 vs 32.6 mmol h/l; P=0.01). Following treatment with 5-DFUR, the median AUC and C_max of 5-DFUR tended to be higher in patients with a partial response (3.83 g h/ml and 4.88 g/ml) and stable disease (6.46 g h/ml and 4.96 g/ml) than in those with disease progression (2.53 g h/ml and 1.36 g/ml). The AUC and C_max of 5-DFUR was significantly related to overall survival.Conclusions These results support the superiority of capecitabine over 5-DFUR.     

Biweekly oxaliplatin combined with oral capecitabine (OXXEL regimen) as first-line treatment of metastatic colorectal cancer patients: a Southern Italy Cooperative Oncology Group phase II study

Oxaliplatin 100 mg/m² iv on day 1, and capecitabine 1,000 mg/m² orally bid from day 1 (evening) to day 11 (morning) were administered every 2 weeks (OXXEL regimen) to 38 patients as first-line treatment for metastatic colorectal carcinoma. A total of 318 cycles were administered, with a median of 8 (range, 4–12) cycles per patient. Response rate (RR) was 45% (95% confidence interval (CI), 29%–62%), with 7 complete responses and 10 partial responses; furthermore, 12 patients showed a stable disease, so that a disease control was achieved in 29 (76%) patients. RR was greater among patients with performance status 0 (52%), without weight loss (52%), younger than 65 years (50%), and previously unexposed to adjuvant chemotherapy (48%), while no correlation was found with the actually delivered oxaliplatin dose intensity. Overall, haematological side effects were negligible, with no case of grade 4 toxicity, and only one patient suffering from an episode of grade 3 neutropenic fever. Severe anaemia occurred in 4 (11%) patients, and grade 3 neuropathy affected 9 (24%) patients. Median progression-free survival was 7.9 (95% CI, 6.2–9.6) months, and median overall survival has not been reached yet. In conclusion, the OXXEL regimen resulted safe and active, and it deserves further evaluation in metastatic colorectal cancer patients.     

Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies

Purpose Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination.Patients and methods Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1–14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy.Results Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m² and capecitabine 825 mg/m² twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel.Conclusion The regimen consisting of docetaxel 30 mg/m² (days 1, 8) and capecitabine 825 mg/m² twice daily (days 1–14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 2003, Chicago, IL.     

Capecitabine in advanced hepatocellular carcinoma: A multicenter experience

BackgroundRecent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC).AimsTo evaluate capecitabine activity and safety in a wide cohort of advanced HCC patients.MethodsRetrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network.ResultsCapecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%).ConclusionsCapecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.     

Acute coronary syndrome induced by oral capecitabine

A 41-year-old woman who was undergoing oral chemotherapy with capecitabine for metastatic breast cancer presented with recurrent episodes of chest pain associated with electrocardiographic signs of diffuse ST segment elevation. After spontaneous pain relief, the electrocardiogram showed ischemic evolution in the anterior precordial leads. Coronary and ventricular angiography, performed 24 h later, showed normal coronary arteries and normal left ventricular function. After therapy with capecitabine was discontinued, the patient did not experience further episodes of chest pain. After a nine-month follow-up, she remains alive, with a good performance status and without clinical evidence of persistent ischemia.     

A Phase II Study of Gemcitabine and Capecitabine in Advanced Cholangiocarcinoma and Carcinoma of the Gallbladder: A Single-Institution Prospective Study

Aim To determine the clinical benefit response (CBR), time to tumor progression (TTP), overall survival, and effect on quality of life (QOL) of gemcitabine and capecitabine in patients with advanced biliary cancer. Methods Gemcitabine (1000 mg/m² IV over 30 minutes on days 1 and 8) and capecitabine (650 mg/m² orally twice daily for 14 days) were administered and repeated every 21 days. All patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Pancreatic Cancer Module (EORTC QLQ-C30-PAN 26) questionnaire on day 1 of each cycle. Cumulative QOL scores were calculated. The two-stage design required 17 patients to evaluate the confirmed response at nine weeks. Results Twelve patients with a median age of 54 years were enrolled. A median of eight cycles per patient were completed. With a median follow-up of 18.2 months, the CBR (two partial response and five stable disease) was 58% [95% confidence interval (CI) 28–85%]. Four out of seven patients with CBR had no decline in QOL with chemotherapy. The probability of survival at one year was 0.58. Median TTP and overall survival were 9.0 and 14.0 months, respectively. Nine patients had grade 3 or 4 toxicities. There were no treatment-related deaths. Conclusions Gemcitabine and capecitabine at this dose and schedule are well tolerated and effective and may offer clinical benefit and maintain QOL in patients with advanced biliary cancer. This regimen merits further investigation in the neoadjuvant setting.