Continuous Capecitabine Research Articles

Efficacy, Safety and Cost Effectiveness of Metronomic Low Dose Versus Intermittent High Dose Capecitabine in Metastatic Breast Cancer

AIM: The aim of the study is to compare the toxicity and cost-effectiveness between metronomic and intermittent capecitabine as maintenance therapy in female patients with metastatic breast cancer. PATIENTS AND METHODS: All metastatic breast cancer patients with HER2 negative were included. The whole study population received six cycles of Docetaxel/Capecitabine then patients were randomized to either continuous (650 mg/m2 twice daily continuous) or intermittent Capecitabine (1000 mg/m2 twice daily every 21 days) as maintenance. RESULTS: The study included 51 patients, 26 in the metronomic arm and 25 in the continuous. The median number of maintenance cycles, as well as the partial response, was higher in the continuous (18 vs. 13 cycles, p: 0.031; p: 0.038). The continuous arm was tolerable with significant less Grade 3 and 4 toxicity regarding nausea, vomiting, hand and foot syndrome, neutropenia, and elevated liver enzymes. (p: 0.03, 0.045, 0.051, 0.048, 0.06, respectively). On multivariate analysis, only patients receiving treatment as first-line had a better clinical response (p: 0.03) especially in the triple-negative group (p: 0.07). The metronomic therapy was more cost-effective with a 35.9% reduction of cost. ($ 746 vs. $1164). The progression-free survival and overall survival were not significant between the two groups. CONCLUSION: Metronomic continuous capecitabine proved to be less toxic and more cost-effective.

Hepatic arterial therapy with oxaliplatin and systemic capecitabine for patients with liver metastases from breast cancer

ObjectivesHepatic arterial treatment (HAT) for liver metastases in patients with metastatic breast cancer (MBC) has only been investigated in few studies. Materials and methodsTwo phase II trials were initiated simultaneously to evaluate capecitabine in combination with oxaliplatin in patients with MBC and liver metastases. These two trials are reported together. Continuous capecitabine (1300 mg/m2) was combined with oxaliplatin (85 mg/m2) alternating between systemic treatment and HAT followed by degradable starch microspheres with EmboCept® S every second week. Four patients participated in a pharmacokinetic analysis of oxaliplatin. Each patient had samples taken when receiving oxaliplatin systemically and as HAT with and without EmboCept® S. ResultsTotally, 52 patients received HAT: 14 with liver metastases only and 38 patients with additional limited metastatic disease. The patients had previously received a median of 2 (range 0–6) chemotherapeutic regimens for MBC. The response rate was 42.3% (95% confidence interval (CI) 28.7–56.8%) with 7.7% complete and 34.6% partial responses. Median progression free survival was 10.8 months (95% CI 6.9–14.7 months) and median overall survival 27.6 months (95% CI 20.4–34.8 months). The toxicity was moderate with hand-foot syndrome (15.4%), neuropathy (9.6%), fatigue (9.6%), and abdominal pain (9.6%) being the most common grade 3 adverse events. There was no clear difference between systemic blood concentrations of oxaliplatin when given systemic or as HAT. ConclusionHAT oxaliplatin in combination with capecitabine is safe and efficient in patients with MBC. The results are promising with high response rates and a long median progression free and overall survival.

Abstract A43: Induction of systemic immune response by oxaliplatin-based neoadjuvant therapy and survival without metastatic progression in high-risk rectal cancer

Abstract In locally advanced rectal cancer (LARC), local recurrence rates are low due to contemporary multimodal treatment regimens involving neoadjuvant chemoradiotherapy (CRT) and surgery. Metastatic progression however, represents a major challenge and is reported by 30-40% of cases in recent trials. Ongoing effort to combine treatment modalities, including immunotherapy, to best target systemic progression of colorectal cancer, would benefit from a better understanding of the biological and immune responses invoked from the different treatment modalities. In this report we investigated systemic immune activity invoked in LARC patients undergoing neoadjuvant regimens containing oxaliplatin (an agent known to cause immunogenic cell death), by assessing circulating levels of the fms-related tyrosine kinase 3 ligand (Flt3L). Flt3L is a potent hematopoietic factor with proliferating effects on mature dendritic cells (DC), whose elevated levels have also been demonstrated to reflect therapy-induced myelosuppression. LARC patients with mainly T3-4 disease from two independent cohorts (Oslo and Copenhagen) received neoadjuvant chemotherapy (NACT) and sequential CRT. All of the Oslo cohort patients underwent NACT consisting of 4 weeks of the Nordic FLOX regimen (oxaliplatin 85 mg/m2 on day 1 and bolus fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2 every second week) followed by long-course CRT (radiation to a total dose of 50 Gy and concomitant weekly oxaliplatin 50 mg/m2 and capecitabine 825 mg/m2 twice daily), and then surgery 8-12 weeks later. Eighty percent of Copenhagen cohort patients underwent NACT as 6-8 weeks of oxaliplatin 85 mg/m2 every second week and continuous capecitabine 650 mg/m2 twice daily. Less than 90% of patients had concomitant weekly oxaliplatin 50 mg/m2 during the long-course CRT to a total radiation dose of 54 Gy. Finally, 57% of patients received an additional 1-2 cycles of capecitabine with or without oxaliplatin following CRT completion. Patients had surgery 2-19 weeks after CRT completion. In both cohorts, Flt3L levels were measured in serum collected at baseline, following NACT and then the sequential CRT. Serum samples were stored at –80°C until analysis and Flt3L was quantified using ELISA or a customized Luminex Multiplex Assay (both from R&D Systems). In 39 randomly chosen samples covering all three sampling points, a strong correlation (r=0.96, p<0.01) was found between Flt3L levels measured by the single-parameter and multiplex assays. We found that median serum Flt3L levels were elevated upon completion of each sequential modality in both cohorts (n=73 and n=65). In the principal cohort (Oslo), an increase in levels of Flt3L upon NACT completion was correlated with a decline in hemoglobin and neutrophil counts (r=–0.38, p<0.01 and r= –0.36, p=0.01), possibly reflecting the myelosuppressive effect. Progression-free survival (PFS), with the majority of events being metastatic progression, was 68% and 71% in the two cohorts. For T4 cases in the Oslo cohort, a high Flt3L level following NACT was associated with a low risk for a PFS event (HR=0.22, 95% CI=0.06-0.72, p=0.01). Additionally, oxaliplatin dose reduction during CRT, aimed at maintaining patient compliance to radiotherapy, was also associated with advantageous PFS (HR=0.40, 95% CI=0.17-0.92, p=0.03). In conclusion, the neoadjuvant regimens might have caused repetitive myelosuppression resulting in elevated circulating Flt3L levels, thereby enhancing proliferation of mature dendritic cells and mediation of systemic tumor-targeting effects. Oxaliplatin-containing neoadjuvant therapy that causes normal tissue toxicity but does not compromise patient compliance to the radiotherapy, may condition DC to present shed tumor antigens to cytotoxic T cells, and thus enable eradication of occult microscopic tumor at distant sites in LARC patients prone to develop metastatic disease. Citation Format: Erta Kalanxhi, Sebastian Meltzer, Jakob Vasehus Schou, Finn Ole Larsen, Svein Dueland, Kjersti Flatmark, Benny Vittrup Jensen, Knut Håkon Hole, Therese Seierstad, Kathrine Røe Redalen, Dorte Lisbet Nielsen, Anne Hansen Ree. Induction of systemic immune response by oxaliplatin-based neoadjuvant therapy and survival without metastatic progression in high-risk rectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A43.

A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3)

AimsThis open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. Materials and methodsPatients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. ResultsBetween November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1–21. The most common phase II grade 3–4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7–9.4) and median overall survival was 10.9 months (confidence interval 7.7–13.7). ConclusionDCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.

Phase II study with docetaxel (D), cisplatin (C) and continuous capecitabine (X) schedule (DCX) in advanced gastric cancer (AGC): ML21085. Final results.

e15520Background: Activity in first line in AGC with D, C and Fluorouracil (V325 study) has been described. Two studies evaluated schedules with X (REAL-2 and ML 17032). But there is no much inform...

Durable disease control in patients with metastatic breast cancer treated with single agent capecitabine.

e12522Background: Capecitabine is effective chemotherapy in metastatic breast cancer (MBC) and is usually given as a third line chemotherapy. Since there is no cumulative dose, if tolerability is good treatment can be given for long time until disease progression. However there are limited data of treatment duration in patients with MBC treated with single agent capecitabine. Methods: At the Institute for Oncology and Radiology of Serbia, a cohort of 24 MBC patients treated with single agent capecitabine and durable disease control have been analyzed. Durable disease control is defined as absence of disease progression during at least 24 months of continuous capecitabine treatment. All patients had progression during or after antracycline and taxane based chemotherapy +/-hormonal therapy +/-trastuzumab therapy. Lapatinib was not available at the time of treatment initiation in 3 patients with HER2 3+ MBC Dose of capecitabine ranged from 1500-2000 mg/m2 bd, days 1-14, q3w; tolerability and clinical evaluat...

PET/CT with Fluorodeoxyglucose During Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

ObjectiveThe aim of the present study is to evaluate the accuracy of Positron Emission Tomography/Computed Tomography (PET/CT) with Fluorodeoxyglucose ([18F]FDG) to predict treatment response in patients with locally advanced rectal cancer (LARC) during neoadjuvant chemoradiotherapy.Patients and methodsForty-one LARC patients performed [18F]FDG-PET/CT at baseline (PET0). All patients received continuous capecitabine concomitant to radiotherapy on the pelvis, followed by intermittent capecitabine until two weeks before curative surgery. [18F]FDG-PET/CT was also carried out at 40 Gy-time (PET1) and at the end of neoadjuvant therapy (PET2). PET imaging was analysed semi-quantitatively through the measurement of maximal standardised uptake value (SUVmax) and the tumour volume (TV). Histology was expressed through pTNM and Dworak tumor regression grading. Patients were categorised into responder (downstaging or downsizing) and non-responder (stable or progressive disease by comparison pretreatment parameters with clinical/pathological characteristics posttreatment/after surgery).Logistic regression was used to evaluate SUVmax and TV absolute and percent reduction as predictors of response rate using gender, age, and CEA as covariates. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Survivals were compared by the Log-Rank test.ResultsTwenty-three responders (9 ypCR, 14 with downstaged disease) and 18 non-responders showed differences in terms of both early and posttreatment SUVmax percent reduction (median comparison: responder = 63.2%, non-responder = 44.2%, p = 0.04 and responder = 76.9%, non-responder = 61.6%, p = 0.06 respectively). The best predictive cut-offs of treatment response for early and posttreatment SUVmax percent reduction were ≥57% and ≥66% from baseline (p = 0.02 and p = 0.01 respectively).Conclusions[18F]FDG-PET/CT is a reliable technique for evaluating therapy response during neoadjuvant treatment in LARC, through a categorical classification of the SUV max reduction during treatment.

Role of metronomic capecitabine in advanced hepatocellular carcinoma.

e15119 Background: Hepatocellular carcinoma is one of the top five cancers in countries where viral hepatitis is an endemic disease like Pakistan. Its incidence is rising continuously. Limited options are available for advanced stage disease in old and frail patients. These are intolerant to chemotherapy and biological therapy. Moreover, cost of biological therapy render their use limited in limited resource country. There is a desperate need for a treatment that is effective as well as minimal toxic to these patients so that quality of life is improved in this population. Methods: This study is aimed at testing the efficacy of low dose capecitabine (1000 mg daily in two divided doses) in newly diagnosed advanced hepatocellular carcinoma. Patients were planned to receive this treatment for three months followed by response assessment using ultrasound findings and alpha fetoprotein (AFP) levels compared to baseline findings. Various quality of life parameters including pain score, appetite, weight gain and performance status were also assessed. Results: Total of seventy patients were enrolled. Fifty five patients completed the treatment for three months and were available for evaluation. Two patients (3.6%) had complete response, twelve (21.8%) had partial response, nineteen (34.5%) had stable disease and twenty two (40%) had progressive disease. Thirty nine patients (70.9%) showed significant reduction in AFP levels. Pain score improved in forty two (76.4%) patients, appetite was increased in thirty seven patients (67.2%), weight was gained in twelve patients (21.8%) and performance status was improved in seventeen patients (30.9%). Six patients had one or more episode of grade 2 diarrhea, four patients developed encephalopathy and only one patients developed hand foot syndrome. Conclusions: Low dose continuous capecitabine is effective in advanced hepatocellular carcinoma with excellent tolerability and minimal toxicity.

Phase I trial of docetaxel (D), cisplatinum (C), and continuous capecitabine (CAP) (TCX) in advanced esophagogastric cancer (AEC).

e14587 Background: This phase I study assessed the combination of D, C, and continuous CAP in AEC to develop a regimen of acceptable toxicity to take forward to phase II study. Methods: Patients with AEC were treated in cohorts of 3, at one of 3 dose levels (DL). DL0: D at 60 mg/m2 IV on day 1, C at 60 mg/m2 IV on day 1, CAP at 1,000 mg/m2 per day in two divided doses days 1-21, every 3 weeks. DL1: CAP increased to 1,250 mg/m2 per day. DL2: D increased to 75 mg/m2 IV day 1 and CAP to 1,250 mg/m2 per day. Prophylactic colony stimulating factors were not used. Patients received a maximum of 6 cycles. Blood counts and biochemistry were assessed twice weekly and daily for grade 3/4 abnormality. Results: Between 1.11.07 and 24.6.09 15 patients were enrolled: male/female:14/1, WHO PS:0/1:10/5, median age 63 yr (range 46-69), primary site oesophagus/GOJ/stomach:7/3/5, adeno/squamous:14/1, T2/3/4:2/9/4, N0/1/2:1/13/1, M0/1:1/14. 6 patients were treated at DL0, 6 at DL1 and 3 at DL2. All patients received 6 cycles apart from 2 at DL 1 who received 3 because of disease progression. Dose intensity: DL0: D 95%, C 100%, CAP 85%; DL1: D 91%, C 98.2%, CAP 79%; DL2: D 86%, C 100%, CAP 79%. There were no deaths on chemotherapy or within 30d of the last dose. The main dose limiting toxicity was febrile or infective neutropenia developing in 1/6 DL0, 2/6 DL1 and 3/3 DL2 (see table of most common treatment-related adverse events below: serious toxicity is gr 3 unless specified gr 4). The maximum length of gr 4 neutropenia was 5d. Best response (RECIST): 1 CR, 11PR, 2 SD and 1PD. 11 patients received second-line chemotherapy. Median and 1 yr overall survival: 17.5m and 60%. Median and 1 yr progression-free survival: 7m and 27%. Conclusions: TCX DLO is recommended for further study in a phase II trial. Encouraging response and survival were seen. [Table: see text]

Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer

We compared oral capecitabine, administered intermittently or continuously, versus classical cyclophosphamide, methotrexate, and fluorouracil (CMF) as first-line chemotherapy for women with advanced breast cancer unsuited to more intensive regimens. Three hundred twenty-three eligible women were randomly assigned to capecitabine administered intermittently (1,000 mg/m(2) twice daily for 14 of every 21 days; n = 107) or continuously (650 mg/m(2) twice daily for 21 of every 21 days; n = 107), or to classical CMF (oral cyclophosphamide 100 mg/m(2) days 1 to 14 with intravenous methotrexate 40 mg/m(2) and fluorouracil 600 mg/m(2) on days 1 and 8 every 28 days; n = 109). The primary end point was quality-adjusted progression-free survival (PFS); secondary end points included PFS, overall survival (OS), objective tumor response, and adverse events. Intermittent and continuous capecitabine were to be compared first and, if similar (P > .05), combined for definitive comparisons versus CMF. Quality-adjusted PFS (P = .2), objective tumor response rate (20%; P = .8), and PFS (median, 6 months; hazard ratio [HR], 0.86; 95% CI, 0.67 to 1.10; P = .2) were similar in women assigned capecitabine versus CMF. OS was longer in women assigned capecitabine rather than CMF (median, 22 v 18 months; HR, 0.72; 95% CI, 0.55 to 0.94; P = .02). Febrile neutropenia, infection, stomatitis, and serious adverse events were more common with CMF; hand-foot syndrome was more common with capecitabine. Capecitabine improved OS by being similarly active, less toxic, and more tolerable than CMF. Capecitabine is a good first-line chemotherapy option for women with advanced breast cancer who are unsuited to more intensive regimens.

Phase II study with docetaxel (D), cisplatin (C), and continuous capecitabine (CAP) combination (TCX) in advanced gastric cancer: Preliminary data.

e14611 Background: Activity in first line in advanced gastric carcinoma with D, C and CAP has been describe. But there is no much information about continuous treatment with capecitabine in this setting. We performed this study in order to obtain data in this patients. Methods: Patients (pts) were enrolled if they had the main subsequent criteria: histologically confirmed diagnosis of advanced gastric cancer (AGC) (local advanced or metastatic disease); normal renal and hepatic function; no myocardial infarction or angina pectoris; no uncontrolled severe diseases or active infections. Treatment schedule: D at fixed dose of 75 mg/m2 on day 1, C at fixed dose of 60 mg/m2 on day 1, CAP at fixed dose of 1,300 mg/m2 in two daily administration from day 1 to day 21, every 3 weeks. Colony stimulating factors were used as a primary profilaxis. Dose-limiting toxicity (DLT): Grade (G) 3 non-haematological or G4 haematological. Study design: Open phase II trial. Primary endpoint was response rate (RR). Secondary endpoints were time to progression (TTP), overall survival (OS), toxicity and quality of life. Results: 45 pts were enrolled. We present preliminary results of 41pts. Median age of 61 years (range 32-80). Median number of cycles per pt was 5 (range 1-6). Total cycles administered: 172. Main G1-2 toxicities were: diarrhea 22%, neurotoxicity 18%. Cumulative G3-4 toxicities were: neutropenia 6.9%, neutropenia febril 3.4%, mucositis 2%, asthenia 9%. Median received-dose intensity (DI) of D: 72.5 mg/m2 (96.7% of recommended-DI), C 51 mg/m2 (84.3%), CAP 1083.0 mg/m2/day (83.37%) per patient. Efficacy: 36 pts were assessable for response:18 (50%) had partial response, 10 (27.8%) had stable disease and 8 (22.2%) had progression. At moment of the last analysis 16 (39%) were exitus. Mean OS was 17.8 months (CI 95% 14.4-21.2). Conclusions: The combination TCX is tolerable without G3-4 toxicity and preliminary data show very high activity. On behalf ACROSS group.

Phase II trial of combination therapy with metronomic capecitabine (C) and fulvestrant (F) in the treatment of hormone receptor-positive metastatic breast cancer (HR+ MBC).

e11087 Background: The standard approach to HR+ MBC is sequential single endocrine agents, but in the current era of adjuvant AI therapy, alternatives to AIs for first line MBC endocrine treatment are desirable. We designed this trial to assess the feasibility, safety and efficacy of a combined chemoendocrine approach with continuous low dose oral chemotherapy (metronomic) along with a potentially non-cross resistant estrogen receptor down regulator. Methods: Eligible patients (pts) in this single arm, multicenter trial had HR +, HER2- biopsy proven MBC, were post-menopausal, had no prior chemotherapy for metastatic disease, had evaluable or measurable disease by RECIST criteria, and no prior exposure to C or F. C was given at a fixed divided dose of 1500-2000 mg, depending on weight, continuously daily without interruption. F was given IM at standard 250 mg after loading doses. Cycles were 28 days, with assessment for response Q 2 cycles. Primary endpoints were progression free survival (PFS) and time to progression (TTP). Results: 42 pts were accrued, 41 are evaluable. Mean age 64.5 years (range 37-85), 37% African American, ECOG 0/1/2: 17/20/4; ER+ 40, PR+ 27, prior endocrine therapy 21, prior adjuvant chemo 16. The median (range) cycles delivered were 8 (2-27+), with 12 pts receiving 12 or more months of therapy. As of 1/1/11, 17 pts remain on study. Discontinuation occurred due to disease progression in 18, toxicity in 2, investigator discretion in 3 and 1 withdrew consent. The only grade 3/4 toxicity occurring in >5% of pts was grade 3 hand/foot syndrome in 4 (9.8%). Dose reduction of C occurred in 12 (29.3%) pts, typically during cycles 2-8. F was given in full dose in 383/391 (97.7%) total cycles delivered. Overall response rate was 22%, with 2 (4.9%) achieving CR and 29 (70.7%) pts with stable disease. The clinical benefit rate (CR+ PR+ stable > 6 months) was 53.7 %. The PFS and TTP were both [median (95% CI)] 10.87 (7.26- NR) months. Conclusions: Metronomic continuous capecitabine and fulvestrant monthly following loading dose is feasible, well tolerated even with prolonged periods of administration in HR+ MBC, and is effective in maintaining PFS and TTP.

EXPERT-C: A randomized phase II European multicenter trial of neoadjuvant chemotherapy (capecitabine/oxaliplatin) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined high-risk rectal cancer.

360 Background: We previously demonstrated the feasibility of administering neoadjuvant chemotherapy before CRT and TME in patients with MRI selected poor prognosis rectal cancer (Chua Y J et al Lancet Oncol 2010). This trial evaluates the addition of the anti-EGFR antibody cetuximab to this treatment strategy. KRAS and BRAF mutations have been established as predictive for lack of response to anti-EGFR therapy in metastatic colorectal cancer. Methods: Patients with newly diagnosed, histologically confirmed, MRI defined high risk rectal adenocarcinoma were randomised to receive 4 cycles of capecitabine 1,700mg/m2 with oxaliplatin 130mg/m2 (CAPOX) followed by CRT, 45Gy/25# + 5.4Gy/3# boost with concurrent continuous capecitabine 1,650mg/m2/day, TME and 4 cycles of adjuvant CAPOX (EXPERT) or the same regimen with the addition of cetuximab (400mg/m2 loading dose week 1, followed by 250mg/m2/week) (EXPERT-C). The primary endpoint is complete response (CR) (defined as pathological complete response or radiological complete response in patients who decline surgery) in KRAS and BRAF wild type tumours. Secondary endpoints include radiological response to CRT, CR in both KRAS wild type and mutant patients, R0 resection rates, progression free and overall survival and safety. Results: Between 2005-2008, 165 eligible patients were recruited from 15 centres (EXPERT n=81, EXPERT-C n=84). 99% of patients had performance status 0-1, 98% had ≥ T3 disease, 56% had an involved or threatened circumferential resection margin and 72% had evidence of extramural venous invasion determined by MRI. The current median follow up is 30 months. 72/81 (89%) and 79/84 (94%) of patients completed neoadjuvant CRT and 72/81 (89%) and 77/84 (92%) patients underwent curative-intent surgery on the EXPERT and EXPERT-C arms respectively. Two patients declined surgery. Conclusions: The primary and secondary endpoints will be analyzed in October 2010 and will be presented at the meeting. [Table: see text]

A phase I dose escalation study of continuous oral capecitabine in combination with oxaliplatin and pelvic radiation (XELOX-RT) in patients with locally advanced rectal cancer

Purpose: To determine the maximum tolerated dose (MTD) of continuous oral capecitabine plus oxaliplatin and pre-operative pelvic radiotherapy (XELOX-RT).Patients and methods: Patients with clinically unresectable rectal cancer or for whom resection with histologically clear (R0) surgical margins was unlikely received continuous capecitabine (500–825mg/m2 twice daily, 7 days/week), oxaliplatin 2-h intravenous infusion (130mg/m2 days 1 and 29) and pelvic radiotherapy (Monday–Friday for 5 weeks, total dose 45Gy in 25 daily 1.8Gy fractions). The MTD was the capecitabine dose causing dose-limiting toxicities (DLTs; treatment-related grade 3/4 toxicities) in one-third or more of patients treated per dose level.Results: Eighteen patients received three dose levels. The MTD was capecitabine 825mg/m2 twice daily: DLTs occurred in two of six patients (grade 3 diarrhoea, rectal pain with local skin reaction). No DLTs occurred in six patients receiving capecitabine 650mg/m2 twice daily. Grade 3/4 toxicity was rare, with minimal myelosuppression. Although predominantly a dose-finding study, XELOX-RT showed promising activity. Fourteen patients had histologically confirmed R0 resections and five had a pathological complete response.Conclusions: The recommended dose for further study is capecitabine 650mg/m2 twice daily with oxaliplatin and radiotherapy. XELOX-RT showed promising antitumour activity. Further evaluation is underway.

Phase one dose finding study of capecitabine (Xeloda ®), radiotherapy and cisplatin in the treatment of locally advanced squamous cervical cancer

Objective. A dose escalation study was performed for patients with locally advanced squamous carcinoma of cervix to determine the maximum tolerated dose (MTD) of daily capecitabine when combined with weekly cisplatin and radiotherapy. MTD would be reached if at least 2 out of 6 at any particular dose level developed Grade 3 or 4 diarrhoea, mucositis, skin or bladder toxicity or Grade 4 neutropenia associated with fever lasting more than 7 days or Grade 3 or 4 thrombocytopenia. The secondary endpoints were to define the toxicity profile, compliance with treatment, late radiation effects and to determine the tumour responses. Methods. Thirteen patients were enrolled (7 Stage II b, 6 Stage III b). Cisplatin was given weekly at 40 mg/m 2 (maximum 70 mg) concurrently with radiotherapy. Two doses of capecitabine were studied 300 mg/m 2 bid (cohort 1) and 450 mg bid (cohort 2). Results. One patient in cohort 1 developed Grade 3 diarrhoea and 2 patients had Grade 3 leucopenia. Two patients in cohort 2 developed Grade 4 leucopenia and neutropenic fever; one of these patients also had Grade 3 diarrhoea and thrombocytopenia. Only 1 patient had Grade 1 palmar–plantar erysthrodysesthesia. Three patients have developed late (RTOG/ECOG) Grade 3 toxicity bladder or vaginal mucosa at 6, 9 and 15 months. The MDT of continuous capecitabine, when given with pelvic radiotherapy and weekly cisplatin, is 450 mg m 2 bid. Conclusions. The recommended dose of capecitabine in this combination is 300 mg/m 2 bid. The regimen was well tolerated and the compliance was high. Progression-free survival at 12 months was 69.2%, and at 24 months, it was 49.2% (SE 15.4%) with an overall survival of 57.7% (SE 15.0%) at 24 months. Further evaluation of this regimen in a phase II/III study is warranted.

Preliminary data on weekly irinotecan (CPT) with continuous capecitabine (X) in metastatic colorectal cancer (MCRC) patients (pts)

3755 Background: X (Xeloda) has superior activity and improved safety compared to bolus 5-FU/LV in 1st-line MCRC. Addition of irinotecan (CPT) to 5-FU/LV improves efficacy. In combination, X should preserve the safety advantages of protracted infusions of 5-FU while improving convenience for pts. Continuous X monotherapy (666 mg/m2 twice-daily) is safe and effective in MCRC (Van Cutsem, JCO 2000). Methods: X was given as a fixed dose of 1000 mg twice daily plus intravenous CPT 75 mg/m2 weekly, for the 1st 4 weeks of each 6-week cycle. Pts ≥65 years old received reduced doses (CPT 60 mg/m2; X 750 mg twice-daily). Study objectives were efficacy and safety. Results: Of 52 pts enrolled, all were evaluable for safety and 49 for response: 35 men (67%), 17 women (33%); median Karnofsky PS 90 (70–100), median age 65 (39–78). 36 pts (69%) had colon cancer, 11 rectal (21%) and 5 both (10%). Most common metastatic sites were liver (79%), nodes (58%), lung (33%), and soft tissue (13%). At diagnosis, 63% of pts had metastases. 14 pts (27%) had received prior adjuvant 5-FU. Mean treatment duration is 112 days. Most common grade 3/4 clinical adverse events were diarrhea (19% G3), nausea/vomiting (12% G3). Overall, G3/4 toxicity was more frequent in pts ≥65 years (38 vs 27%) as was GI toxicity (35 vs 23%). Only 1 pt experienced grade 3 HFS and there was no G3/4 stomatitis. Responses (PR+CR) were seen in 9 pts (1 CR) with an additional 5 unconfirmed responses, producing an overall response rate of 29%. Disease control (CR+PR+SD) was seen in 65% of pts. Disease control rates were similar in pts <65 and ≥65 years (63% vs. 68%). Median progression-free and overall survival in the elderly also compare favorably (TTP 5.3 vs. 5.2 months; OS 13.2 vs. 14.9 months). Conclusion: Safety and efficacy of X with CPT is now established in several schedules, with intermittent X + CPT (Patt, ASCO 2003) favored for phase III development. The continuous fixed-dosing regimen described here may be suited to elderly pts as efficacy was not compromised despite the initial 25% dose reduction. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech; GlaxoSmithKline Genentech GlaxoSmithKline Hoffmann La Roche

Preliminary data on weekly irinotecan (CPT) with continuous capecitabine (X) in metastatic colorectal cancer (MCRC) patients (pts)

3755 Background: X (Xeloda) has superior activity and improved safety compared to bolus 5-FU/LV in 1st-line MCRC. Addition of irinotecan (CPT) to 5-FU/LV improves efficacy. In combination, X should preserve the safety advantages of protracted infusions of 5-FU while improving convenience for pts. Continuous X monotherapy (666 mg/m2 twice-daily) is safe and effective in MCRC (Van Cutsem, JCO 2000). Methods: X was given as a fixed dose of 1000 mg twice daily plus intravenous CPT 75 mg/m2 weekly, for the 1st 4 weeks of each 6-week cycle. Pts ≥65 years old received reduced doses (CPT 60 mg/m2; X 750 mg twice-daily). Study objectives were efficacy and safety. Results: Of 52 pts enrolled, all were evaluable for safety and 49 for response: 35 men (67%), 17 women (33%); median Karnofsky PS 90 (70–100), median age 65 (39–78). 36 pts (69%) had colon cancer, 11 rectal (21%) and 5 both (10%). Most common metastatic sites were liver (79%), nodes (58%), lung (33%), and soft tissue (13%). At diagnosis, 63% of pts had me...