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ABSTRACT: XELOX is a 3-weekly chemotherapy combination of oral capecitabine and intravenous oxaliplatin. The central hypothesis that led to its development was that it would provide a convenient and cost-effective alternative to intravenous fluorouracil-based chemotherapy doublets, without compromising on anti-tumor efficacy. Recently its role in colorectal cancer has become more established in both the metastatic and adjuvant setting. Ongoing investigation of XELOX continues in a number of directions: its combination with novel biological agents, its efficacy and safety in the elderly, and the development of biomarkers that can predict its anti-tumor effect. This article provides a comprehensive and up-to-date synopsis of all pertinent clinical studies detailing this regimen and its promise for the future.
Expert review of gastroenterology & hepatology 02/2011; 5(1):9-19.
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ABSTRACT: Preclinical studies have suggested accelerated tumor growth, local invasion, and distant metastasis after withdrawal of treatment with some antiangiogenic agents. To investigate whether discontinuation of bevacizumab treatment is associated with accelerated disease progression or increased mortality, we retrospectively analyzed five randomized, placebo-controlled phase III studies in 4,205 patients with breast, colorectal, renal, and pancreatic cancer.
Time from treatment discontinuation to progressive disease or death was analyzed in patients discontinuing bevacizumab/placebo as a result of adverse events (AEs). Mortality rates were assessed at 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose in the following two groups: patients discontinuing bevacizumab/placebo as a result of AEs and patients discontinuing bevacizumab/placebo for any reason. In the same groups, time from treatment discontinuation to death was analyzed. Data on disease progression pattern were available and analyzed in four of the five studies.
In the pooled analysis, median time from discontinuation as a result of AEs to progression/death was 3.0 months (95% CI, 2.6 to 3.8 months) for placebo and 4.0 months (95% CI, 3.4 to 4.6 months) for bevacizumab (hazard ratio, 0.93; 95% CI, 0.79 to 1.10). Mortality rates from 30 days to 210 days after treatment discontinuation and time from discontinuation to death were similar in bevacizumab- and placebo-treated patients. In addition, similar patterns of disease progression were seen in bevacizumab- and placebo-treated patients.
This retrospective analysis of five placebo-controlled clinical trials does not support a decreased time to disease progression, increased mortality, or altered disease progression pattern after cessation of bevacizumab therapy.
Journal of Clinical Oncology 01/2011; 29(1):83-8. · 18.37 Impact Factor
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ABSTRACT: Angiogenesis, the process whereby tumors develop new blood vessels to facilitate growth and metastasis, is a pivotal event in tumorigenesis. It is tightly regulated by the VEGF system. Cediranib (AZD2171, Recentin; AstraZeneca, London, UK) is a novel and potent small-molecule inhibitor of VEGF signaling, with activity against the three VEGF receptors, as well as other targets. This article provides a comprehensive and up-to-date synopsis of all pertinent preclinical and clinical studies detailing this promising new therapy.
Future Oncology 06/2009; 5(4):421-32. · 3.16 Impact Factor
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Hendrik-Tobias Arkenau,
Dirk Arnold, Jim Cassidy,
Eduardo Diaz-Rubio,
Jean-Yves Douillard,
Howard Hochster,
Andrea Martoni,
Axel Grothey,
Axel Hinke,
Wolff Schmiegel,
Hans-Joachim Schmoll,
Rainer Porschen
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ABSTRACT: Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX.
This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity.
The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested similar outcome within the range of noninferiority. Grade 3/4 toxicities (thrombocytopenia-HR = 2.07, 95% CI, 1.42 to 3.03; P < .0002; diarrhea-HR = 1.34; 95% CI, 1.08 to 1.66; P < .0009; and grade 2/3 hand-foot-syndrome [HFS]-HR = 3.54; 95% CI, 2.07 to 6.05; P < .00001) were less prominent with FU-based regimens whereas neutropenia (HR = 0.15; 95% CI, 0.11 to 0.19; P < .00001) was lower in the CAP regimens.
The combination of CAP and OX resulted in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and HFS consistently more prominent in the CAP regimens.
Journal of Clinical Oncology 11/2008; 26(36):5910-7. · 18.37 Impact Factor
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ABSTRACT: The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI(trade mark)), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points.
Patients (n=40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6-7 patients should a dose-limiting toxicity occur.
ZK 304709 was safely administered up to 360mg. However, above 90mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or pharmacodynamic end-points.
Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early.
European journal of cancer (Oxford, England: 1990) 10/2008; 44(15):2162-8. · 4.12 Impact Factor
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Jim Cassidy
Nature Clinical Practice Oncology 07/2008; 5(6):310-1. · 8.00 Impact Factor
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Journal of Clinical Oncology 06/2008; 26(13):2226-7; author reply 2228. · 18.37 Impact Factor
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Daniel G Haller, Jim Cassidy,
Stephen J Clarke,
David Cunningham,
Eric Van Cutsem,
Paulo M Hoff,
Mace L Rothenberg,
Leonard B Saltz,
Hans-Joachim Schmoll,
Carmen Allegra,
Joseph R Bertino,
Jean-Yves Douillard,
Bengt G Gustavsson,
Gerard Milano,
Michael O'Connell,
Youcef Rustum,
Josep Tabernero,
Frank Gilberg,
Florin Sirzén,
Chris Twelves
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ABSTRACT: We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability.
Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study).
In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR.
Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
Journal of Clinical Oncology 06/2008; 26(13):2118-23. · 18.37 Impact Factor
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Jim Cassidy,
Stephen Clarke,
Eduardo Díaz-Rubio,
Werner Scheithauer,
Arie Figer,
Ralph Wong,
Sheryl Koski,
Mikhail Lichinitser,
Tsai-Shen Yang,
Fernando Rivera,
Felix Couture,
Florin Sirzén,
Leonard Saltz
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ABSTRACT: To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).
The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.
The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.
XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.
Journal of Clinical Oncology 05/2008; 26(12):2006-12. · 18.37 Impact Factor
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Leonard B Saltz,
Stephen Clarke,
Eduardo Díaz-Rubio,
Werner Scheithauer,
Arie Figer,
Ralph Wong,
Sheryl Koski,
Mikhail Lichinitser,
Tsai-Shen Yang,
Fernando Rivera,
Felix Couture,
Florin Sirzén, Jim Cassidy
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ABSTRACT: To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).
Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS).
A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials.
The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
Journal of Clinical Oncology 05/2008; 26(12):2013-9. · 18.37 Impact Factor
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ABSTRACT: The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6-8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand-foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.
Expert Review of Anti-infective Therapy 05/2008; 8(4):547-51. · 2.65 Impact Factor
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Jim Cassidy
Journal of Clinical Oncology 12/2007; 25(31):5043-5; author reply 5045-6. · 18.37 Impact Factor
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ABSTRACT: This article aims to provide the reader with a broad overview of the current chemotherapeutic options available for the treatment of patients with metastatic colorectal cancer. The review includes discussion of both well established and experimental therapies.
Surgical Oncology 08/2007; 16(1):65-70. · 2.44 Impact Factor
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ABSTRACT: Capecitabine is an oral prodrug of 5-fluorouracil. It is being increasingly used in the treatment of colorectal cancer in both the adjuvant and metastatic settings. This review aims to explore the data in relation to the pharmacology and mode of action of capecitabine, followed by an in-depth review of the available clinical evidence for the use of capecitabine as a single agent, or in combination therapy, in the treatment of colorectal cancer. The pharmacoeconomic and medical resource use implications are also investigated. The future role of capecitabine in the treatment of colorectal cancer and the questions that remain to be answered with regard to its optimal use are considered.
Expert Review of Anti-infective Therapy 07/2007; 7(6):803-10. · 2.65 Impact Factor
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ABSTRACT: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX.
Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 400 mg/m(2) continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m(2) and 5-FU infusion increased to 600 mg/m(2); and cohort 3: erlotinib increased to 150 mg/d).
Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease.
The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.
Clinical Cancer Research 02/2007; 13(2 Pt 1):523-31. · 7.74 Impact Factor
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Expert Review of Anti-infective Therapy 04/2006; 6(3):305-8. · 2.65 Impact Factor
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ABSTRACT: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin.
Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61.
During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance.
There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.
Journal of Clinical Oncology 08/2005; 23(21):4719-25. · 18.37 Impact Factor
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Chris J Twelves,
Charles A Butts, Jim Cassidy,
Thierry Conroy,
Fillippo de Braud,
Eduardo Diaz-Rubio,
Josep M Tabernero,
Patrick Schoffski,
Arie Figer,
Rene Brunet,
Johannes Grossmann,
Alberto F Sobrero,
Eric J Van Cutsem
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ABSTRACT: The tumor-activated fluoropyrimidine capecitabine achieves response rates superior to those of bolus 5-fluorouracil/leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer (CRC), with favorable safety and fewer hospitalizations. Capecitabine is also at least as effective as bolus 5-FU/LV in the adjuvant setting, again with a favorable safety profile. Improved outcomes with capecitabine versus bolus 5-FU/LV in the adjuvant setting have been shown in overall trial populations and in patients aged >or= 70 years. Capecitabine/oxaliplatin (XelOx) is a safe and active combination for the first-line treatment of metastatic CRC.
This post hoc analysis of a large phase II trial compared data from older and younger patients treated with first-line XelOx: oxaliplatin 130 mg/m(2) intravenously on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks.
The median age of the overall population (N = 96) was 64 years (range, 34-79 years), including 52 younger patients (< 65 years of age) and 44 older patients (>or= 65 years of age). Both age groups received a median of 8 cycles (range, 1-26 cycles) of XelOx. The XelOx regimen had similar high activity in both groups, with response rates of 58% (95% CI, 43%-71%) and 52% (95% CI, 37%-68%) in younger and older patients, respectively. In addition, time to disease progression and overall survival were similar in both groups (P > 0.5 for both outcomes). The XelOx regimen also had a favorable safety profile, with no clinically relevant differences between older and younger patients. The overall incidence of adverse events (including grade 3/4), dose reductions, and withdrawals because of adverse events were similar in both groups.
In the context of an aging population, XelOx provides a highly effective and tolerable first-line treatment for patients with metastatic CRC.
Clinical Colorectal Cancer 07/2005; 5(2):101-7. · 1.68 Impact Factor
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Chris Twelves,
Alfred Wong,
Marek P Nowacki,
Markus Abt,
Howard Burris,
Alfredo Carrato, Jim Cassidy,
Andrés Cervantes,
Jan Fagerberg,
Vassilis Georgoulias, [......],
Joseph McKendrick,
Marek Pawlicki,
Riccardo Rosso,
Johannes Schüller,
Jean-François Seitz,
Borut Stabuc,
Jerzy Tujakowski,
Guy Van Hazel,
Jerzy Zaluski,
Werner Scheithauer
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ABSTRACT: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting.
We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines.
Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001).
Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.
New England Journal of Medicine 06/2005; 352(26):2696-704. · 53.30 Impact Factor
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Jim Cassidy
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ABSTRACT: One of the most widely used cytotoxic agents is 5-fluorouracil. The use of infusional regimens has become commonplace and with this has come a realization of the limitations of this mode of administration. A number of oral fluoropyrimidines have been developed. Of these, capecitabine is the most established, with registrations in most countries for breast and colorectal cancer. The trials with this agent have mainly attempted to show equivalence with a "standard" intravenous comparator. In most cases, this endpoint has been met or exceeded. In addition, the trials have demonstrated reduced toxicity (except for hand-foot syndrome), and aspects of patient acceptability and cost-effectiveness have been integrated into these studies. Patients seem to prefer oral therapy but not at the expense of anticancer activity. However, the absence of intravenous access devices and complications associated with their use is a major bonus for oral therapy. The drawbacks are somewhat less obvious. Some patients are concerned that oral therapy is in some way inferior (ie, soft option) to intravenous chemotherapy. Compliance with oral therapy is always questionable. Although very few trials in which compliance has been formally assessed have been performed, the issue of overcompliance has not been addressed; in other words, there may be a problem of patients continuing to take the medication even in the face of toxicity and advice to stop treatment. Oral chemotherapy requires just as much care as intravenous chemotherapy and probably requires more attention to patient education and involvement in care decisions.
Clinical Colorectal Cancer 05/2005; 5 Suppl 1:S47-50. · 1.68 Impact Factor
