For the capecitabine–fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin–cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P = 0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. Conclusions Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883.)

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Capecitabine and oxaliplatin for advanced esophagogastric cancer.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

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Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(07)70410-2.pdf

Gastroenteropancreatic neuroendocrine tumours.

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

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Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Colorectal cancer is one of the most commonly diagnosed malignant diseases, with an estimated 1,023,000 new cases and 529,000 deaths worldwide each year. This review considers recently developed cytotoxic chemotherapies and biologic agents that are effective against colorectal cancer and assesses their use as treatments for metastatic disease and as components of adjuvant therapy.

Systemic Therapy for Colorectal Cancer

Purpose To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. Patients and methods We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. Results The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P Conclusion Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

Oral Capecitabine Compared With Intravenous Fluorouracil Plus Leucovorin in Patients With Metastatic Colorectal Cancer: Results of a Large Phase III Study

PURPOSE: To establish the feasibility of concurrent radiotherapy and capecitabine and define the maximum-tolerated dose (MTD) in patients with rectal cancer. PATIENTS AND METHODS: Thirty-six patients with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a total irradiation dose of 50.4 Gy with 1.8 Gy/d in approximately 6 weeks. Capecitabine was administered at escalating doses from 250 to 1,250 mg/m2 bid (including weekends) for the duration of radiotherapy. The MTD was defined when two or more patients in a cohort of three or six patients experienced dose-limiting toxicities. RESULTS: Dose-limiting grade 3 hand-foot syndrome was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 bid. Other toxicities were generally rare and/or mild, with only one case of non–dose-limiting grade 3 diarrhea and a single patient with grade 3 skin toxicity. Myelosuppression consisted mainly of leukocytopenia, with a maximum severity of grade 2. Thus, a dosag...

Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer

Purpose: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. Patients and Methods: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m 2 administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/ LV) until disease progression or unacceptable toxicity. Results: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P .65); median time to treatment failure was 4.2 and 4.0 months (log-rank P .89); and median overall survival was 13.2 and 12.1 months (log-rank P .33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P < .00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P < .00001). Capecitabine also resulted in lower incidences (P < .00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 handfoot syndrome (P < .00001) and uncomplicated grade 3/4 hyperbilirubinemia (P < .0001) were reported more frequently with capecitabine. Conclusion: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent. J Clin Oncol 19:4097-4106. © 2001 by American Society of Clinical Oncology.

O ral C apecitabine C ompared W ith I ntravenous Fluorouracil P lus L eucovorin i n P atients W ith M etastatic Colorectal C ancer: R esults o f a L arge P hase I II S tudy

Purpose: To establish the feasibility of concurrent radiotherapy and capecitabine and define the maximumtolerated dose (MTD) in patients with rectal cancer. Patients and Methods: Thirty-six patients with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a total irradiation dose of 50.4 Gy with 1.8 Gy/d in approximately 6 weeks. Capecitabine was administered at escalating doses from 250 to 1,250 mg/m 2 bid (including weekends) for the duration of radiotherapy. The MTD was defined when two or more patients in a cohort of three or six patients experienced dose-limiting toxicities. Results: Dose-limiting grade 3 hand-foot syndrome was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m 2 bid. Other toxicities were generally rare and/or mild, with only one case of non‐dose-limiting grade 3 diarrhea and a single patient with grade 3 skin toxicity. Myelosuppression consisted mainly of leukocytopenia, with a maximum severity of grade 2. Thus, a dosage of 825 mg/m 2 bid is the recommended dose level for further evaluation. One pathologic complete remission of a T3N1 tumor and nine partial remissions were observed in 10 patients treated in the neoadjuvant setting. Conclusion: The recommended dose for phase II evaluation is capecitabine 825 mg/m 2 bid, administered without break during a conventional radiotherapy period of about 6 weeks. This combined-modality approach proved to be a feasible and well-tolerated treatment option with promising preliminary efficacy results in rectal cancer. J Clin Oncol 20:3983-3991. © 2002 by American Society of Clinical Oncology. URATIVE SURGICAL resection of primary rectal cancer is typically associated with a high rate of relapse, with up to 30% of patients developing recurrent disease. However, local tumor control and overall survival in patients with stage II and III rectal cancer is improved by the administration, before or after surgery, of radiation therapy in combination with fluorouracil (5-FU) chemotherapy. 1,2 Following the recommendation of the National Institutes of Health Consensus Development Conference, this strategy has become the standard therapy for patients with rectal cancer. 3 Attempts have been made to improve the efficacy of chemoradiotherapy through the inclusion of other agents such as leucovorin, levamisole, or nitrosourea, and modulation of the 5-FU administration schedule. Most of these strategies have failed to significantly improve the outcomes achieved with standard chemoradiotherapy. However, a randomized trial has shown that infusion of 5-FU throughout the entire course of radiotherapy prolongs both overall and disease-free survival and significantly decreases the rate of development of distant metastases compared with bolus 5-FU. 3 Nevertheless, this schedule requires indwelling catheters and ambulatory pumps and is more difficult to administer on an outpatient basis. Capecitabine (Xeloda, Hoffmann-La Roche, Inc, Nutley, NJ) is an oral fluoropyrimidine that generates 5-FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with healthy tissue. 4,5 The tumor-selective activation of capecitabine potentially enhances safety by minimizing systemic exposure to 5-FU. In clinical trials, capecitabine

Stefan Frings

Papers

Oral Capecitabine Compared With Intravenous Fluorouracil Plus Leucovorin in Patients With Metastatic Colorectal Cancer: Results of a Large Phase III Study

Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer

O ral C apecitabine C ompared W ith I ntravenous Fluorouracil P lus L eucovorin i n P atients W ith M etastatic Colorectal C ancer: R esults o f a L arge P hase I II S tudy

Phase I T rial E valuating t he C oncurrent C ombination o f Radiotherapy a nd C apecitabine i n R ectal C ancer