On prejudice and facts and choices

Abstract

The use of anticancer agents as oral formulations is likely to increase over the coming years. Most of the new compounds will be developments of targeted agents. Classical anti-neoplastic drugs have been available as oral medications for some time. Some of these compounds are analogues of their i.v. counterparts. When used in combination regimens these agents are always under threat of being substituted by their i.v. sisters, at least if one of the combination partners needs to be given intravenously. The CMF regimen is a prominent example. Instead of giving cyclophosphamide p.o. as in the original schedule, it was often injected together with methotrexate and 5-fluorouracil [1.Goldhirsch A. Coates A.S. Colleoni M. Castiglione-Gertsch M. Gelber R.D. Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference.International Breast Cancer Study Group. J Clin Oncol. 1998; 16: 1358-1362PubMed Google Scholar]. Convenience of application and concern of potential non-compliance may have been reasons for this practice or it was the myth that an injection is always better than any tablet. Cancer patients are considered to be more compliant as they have ‘too much to lose’ [2.Partridge A.H. Avorn J. Wang P.S. Winer E.P. Adherence to therapy with oral antineoplastic agents.J Natl Cancer Inst. 2002; 94: 652-661Crossref PubMed Scopus (451) Google Scholar]. Nevertheless, adherence to dose and schedule may be still a concern in case of a curatively intended therapy. Monochemotherapy and the adjuvant setting may be considered the ideal scenario for oral treatment to withstand the temptation of oncologists to use the intravenous alternative. 5-FU monotherapy usually modulated by folinic acid (orally available) used to be the one and only treatment option for metastatic colorectal cancer until quite recently [3.Folprecht G. Köhne CH. The role of new agents in the treatment of colorectal cancer.Oncology. 2004; 66: 1-17Crossref PubMed Scopus (34) Google Scholar]. Although this would have been the ideal situation as described above, the orally available alternatives such as ftorafur, UFT and capecitabine were only used in a few countries worldwide. The interest increased once infusional 5-FU appeared on the stage. Open tunnelled Hickman lines or skin-covered port-a-caths, that are necessary for prolonged 5-FU infusions, were identified as potentially risky devices due to potential complications such as infections and thromboses [4.Mueller B.U. Skelton J. Callender D.P. et al.A prospective randomized trial comparing the infectious and noninfectious complications of an externalized catheter versus a subcutaneously implanted device in cancer patients.J Clin Oncol. 1992; 10: 1943-1948Crossref PubMed Scopus (181) Google Scholar]. Furthermore, UFT and capecitabine were claimed to mimic infusional 5-FU at least pharmacologically [5.Mackean M. Planting A. Twelves C. et al.Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer.J Clin Oncol. 1998; 16: 2977-2985Crossref PubMed Scopus (253) Google Scholar]. Thus, both drugs were offered as an alternative to ‘unpleasant’ infusionial 5-FU. This notion was fuelled by the apparent and obvious preference of patients for pills over syringes especially as patients are always on the wrong side of the needle. One of the often cited publications in this respect is the one by Liu et al. [6.Liu G. Franssen E. Fitch M.I. Warner E. Patient preferences for oral versus intravenous palliative chemotherapy.J Clin Oncol. 1997; 15: 110-115Crossref PubMed Scopus (835) Google Scholar], in which 103 people expressed their preference for oral over i.v. treatment if efficacy was not compromised. A closer look at the group reveals that only about 50% were i.v. chemotherapy experts, while the other half were chemonaive amateurs, yet they expressed their general positive view on pills and disliked syringes. In another study, colorectal cancer patients received both the i.v. Mayo-regimen and oral UFT plus leucovorin thus served as their own controls [7.Borner M.M. Schöffski P, de Wit R, et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer.Eur J Cancer. 2002; 38: 349-358Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar]. This cohort preferred UFT/LV due to its lower toxicity, ease of administration and ability to take the medication at home. In the meantime the Mayo Clinic regimen was considered as the least active but most toxic alternative of 5-FU administrations [8.Saltz L.B. Another study of how to give fluorouracil?.J Clin Oncol. 2003; 21: 3711-3712Crossref PubMed Scopus (7) Google Scholar]. Infusional 5-FU is regarded as the more optimal approach, as response rate, progression free survival (or time to progression) and overall survival as well as toxicity were all (significantly) in favor of infusion over bolus administration [9.Meta-analysis Group In Cancer Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.J Clin Oncol. 1998; 16: 301-308Crossref PubMed Scopus (1032) Google Scholar]. Unfortunately, randomized trials sponsored by the pharmaceutical industry compared the oral compounds not to infusional 5-FU but to the Mayo-Clinic regimen probably at a request of the regulatory agencies [10.Hoff P.M. Ansari R. Batist G. et al.Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.J Clin Oncol. 2001; 19: 2282-2292Crossref PubMed Scopus (1041) Google Scholar, 11.Van Cutsem E. Twelves C. Cassidy J. et al.Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.J Clin Oncol. 2001; 19: 4097-4106Crossref PubMed Google Scholar, 12.Carmichael J. Popiela T. Radstone D. et al.Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.J Clin Oncol. 2002; 20: 3617-3627Crossref PubMed Scopus (281) Google Scholar]. Capecitabine hosted by Hoffmann-La Roche has best survived the bumpy roads of randomized trials in the US and ‘rest of the world’ studies. The two trials [10.Hoff P.M. Ansari R. Batist G. et al.Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.J Clin Oncol. 2001; 19: 2282-2292Crossref PubMed Scopus (1041) Google Scholar, 11.Van Cutsem E. Twelves C. Cassidy J. et al.Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.J Clin Oncol. 2001; 19: 4097-4106Crossref PubMed Google Scholar] confirmed the hypothesis that capecitabine would at least produce equivalent response rates compared with i.v. bolus 5-FU/LV (defined as a difference of no more than 10%). In fact, the response rate was superior and statistically significant in one study. As time to progression and overall survival looked similar it was generally accepted that the two treatments were not different in these endpoints also, although the statistics were not powered for such a conclusion. The results of two further papers on a combined analysis of these two studies were not surprising [13.Van Cutsem E. Hoff P.M. Harper P. et al.Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.Br J Cancer. 2004; 90: 1190-1197Crossref PubMed Scopus (363) Google Scholar, 14.Cassidy J. Twelves C. Van Cutsem E. et al.First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.Ann Oncol. 2002; 13: 566-575Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar]. A better toxicity profile in favour of capecitabine compared with the (toxic) Mayo-regimen was confirmed. The report, however, taught us caution in cases where patients have an impaired renal function. Additionally, questions on the correct dosing for capecitabine appeared [15.Ratain M.J. Dear doctor: we really are not sure what dose of capecitabine you should prescribe for your patient.J Clin Oncol. 2002; 20: 1434-1435Crossref PubMed Scopus (30) Google Scholar]. A comparison of an oral fluoropyrimidine to infusional 5-FU is not available but would be important to understand better the relative toxicity and efficacy of these two approaches. So, how do we assess the efficacy, which patients in the Liu et al. [6.Liu G. Franssen E. Fitch M.I. Warner E. Patient preferences for oral versus intravenous palliative chemotherapy.J Clin Oncol. 1997; 15: 110-115Crossref PubMed Scopus (835) Google Scholar] study did not want to be compromised if oral therapy was to be used? According to Table 1 we might draw the following conclusion: The infusional De Gramont regimen is more active and less toxic than capecitabine.Table 1Efficacy and toxicity of i.v. 5-FU/FA and capecitabineCapecitabine vs. Mayo [23.Twelves C. Capecitabine as first-line treatment in colorectal cancer. pooled data from two large, phase III trials.Eur J Cancer. 2002; 38: 15-20Abstract Full Text Full Text PDF PubMed Google Scholar, 24.Cassidy J. Twelves C. Van Cutsem E. et al.First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.Ann Oncol. 2002; 13: 566-575Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar]Mayo vs. de Gramont [25.de Gramont A. Bosset J.F. Milan C. et al.Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.J Clin Oncol. 1997; 15: 808-815Crossref PubMed Scopus (943) Google Scholar]MayoCapecitabineMayoDe GramontResponse rate16.7%25.2%14.5%32.6%Progression free survival4.7 mo.4.6 mo.5.0 mo.6.3 mo.Overall survival12.8 mo.12.9 mo.13.0 mo.14.2 mo.Grade 3/4 toxicity All39.2%41.1%23.9%11.1% Neutropenia22.8%2.3%7.3%1.9% Stomatitis/Mukositis14.7%‡Stomatitis.1.3%‡Stomatitis.12.7%†Mucositis;1.9%†Mucositis; Diarrhea12.2%13.1%7.3%2.9% Hand-foot-syndrome0.3%17.1%0%*Cutaneous toxicity;1.0%*Cutaneous toxicity;Significant differences are in bold italic.* Cutaneous toxicity;† Mucositis;‡ Stomatitis. Open table in a new tab Significant differences are in bold italic. With this background the paper by Twelves et al. [16.Twelves C. Gollins S. Greve R. Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer.Ann Oncol. 2006; 17: 239-245Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar] is of great interest. The authors report on the acceptance of capecitabine in ‘expert’ patients having the experience with capecitabine and the bi-weekly infusional 5-FU regimen (LV5FU2) either given as an outpatient or as an inpatient treatment. The design needs some comments: What is the reference treatment? Probably not the Mayo-regimen as we know for some time. What about in-patient De Gramont? Certainly not. This may be an individual treatment decision in cases where patients are frail or not fit enough to receive this regimen on an outpatient basis. We would consider outpatient LV5FU2 (or the European variants like the German AIO or Spanish TTD) regimen as a reference thus this comparison for us is the most important one. The results are somewhat intriguing. Probably not surprisingly compared with the administration of infusional 5-FU as an inpatient, patients preferred outpatient capecitabine. However, about 50% of those patients who predicted capecitabine as their favorite outpatient therapy later chose the outpatient infusional 5-FU regimen to continue treatment with, and this was due to a better tolerance of infusional 5-FU over capecitabine. In addition, self-reported quality of life using the FACT-C questionnaire was in favor of LV5FU2 (outpatient) relative to capecitabine. As differences in quality of life between regimens are rarely reported this observation is remarkable! Thus, patients in general prefer outpatient treatment and oral or infusional 5-FU may be two treatment options. To generalize that tablets are the preferred treatment may be a prejudice and largely depends on the comparator. Nevertheless, it is nice to have the choice to better meet the patient's need. However, as capecitabine is probably not equally effective to infusional 5-FU as initial first-line treatment, does capecitabine in combination with oxaliplatin or irinotecan have a similar activity and safety profile relative to the infusional regimens such as FOLFOX and FOLFIRI? Phase II data indicate promising activity for capecitabine plus oxaliplatin or irinotecan [17.Folprecht G. Köhne CH. The role of new agents in the treatment of colorectal cancer.Oncology. 2004; 66: 1-17Crossref PubMed Scopus (34) Google Scholar]. Currently available data indicates that capecitabine may be more tolerable in combination with oxaliplatin rather than irinotecan [18.Jordan K. Grothey A. Kellner O. et al.Randomized phase II trial of capecitabine plus irinotecan vs capecitabine plus oxaliplatin as first-line therapy in advanced colorectal cancer (ACRC): results of an interim analysis.Proc Am Soc Clin Oncol. 2002; 21 (Abstr no 2225)Google Scholar]. In our EORTC trial 40015 [19.Köhne C.H. de Greve J. Bokemeyer C. et al.Capecitabine plus irinotecan versus 5-FU/FA/irinotecan +/- celecoxib in first line treatment of metastatic colorectal cancer. Safety results of the prospective multicenter EORTC phase III study 40015.J Clin Oncol. 2005; 23: 3525Crossref Google Scholar] we observed an excess of toxic death associated with capecitabine plus irinotecan relative to infusional 5-FU plus irinotecan in a total of 85 patients. These deaths were due to gastrointestinal toxicity mainly diarrhea and also thrombembolic events or a combination of both. We therefore decided to terminate the study. The results of the larger CAIRO-study with a similar design have to be awaited until further conclusions can be drawn. But combinations of capecitabine with both oxaliplatin and irinotecan are probably currently best placed within clinical trials. The Tree 1 and Tree 2 [20.Hochster H.S. Welles L. Hart L. et al.Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 Studies.J Clin Oncol. 2005; 23 (Abstr no. 3515): 354Google Scholar] study compared capecitabine and oxaliplatin with the use of infusional 5-FU plus oxaliplatin. This study was amended later to add bevacizumab to all arms due to the positive results that appeared with this agent. While the comparison of the response rates and time to progression indicates a higher response rate for patients receiving the VEGF antibody all arms including capecitabine had a somewhat lower objective response rate. Also, data of the recent, albeit underpowered, study comparing capecitabine plus oxaliplatin relative to an infusional 5-FU and oxaliplatin regimen [21.Arkenau H. Schmoll H.J. Kubicka S. et al.Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC) Results of the safety and efficacy analysis.J Clin Oncol. 2005; 23: 3507Crossref Google Scholar] did not confirm the hypothesis of non-inferiority of capecitabine and oxaliplatin. While the response rates of just below 50% were quite similar, the median progression-free survival of capecitabine plus oxaliplatin was one month below that of infusional 5-FU plus oxaliplatin and the 95% confidence interval of the hazard ratio exceeded the pre-specified boundaries of non-inferiority. One may accept these data as a clinically not relevant difference. However, a 2-month difference in the PFS of bolus vs. Infusional 5-FU was statistically significant and for quite a few patients truly clinically relevant because primary tumor progression could be delayed and patients could receive second-line treatment. One gets the impression that capecitabine in combination with oxaliplatin or irinotecan may have a somewhat lower efficacy but the clinical relevance of this difference needs to be determined. Can one regimen of capecitabine with oxaliplatin be the solution of the confusion associated with all the FOLFOX variants? What will be the place of capecitabine in the world of more complex regimens including weekly or bi-weekly intravenous infusions of cetuximab or bevacizumab? With hand-foot syndrome likely to be associated with capecitabine, how is the tolerance if the acne-like skin lesion associated with cetuximab are added to the toxicity? The question may not be limited to safety or efficacy. Does this substitution of infusional 5-FU by capecitabine in these complex and antibody including regimens really affect the general quality of life compared with the intravenous administration of 5-FU? Would it not be helpful to have an intravenous device to ease the frequent intravenous applications of the monoclonal antibodies? Finally, is it really worth answering all these questions within clinical trials in times of limited resources and truly more important questions? If patients are started on capecitabine plus oxaliplatin and later when the disease is progressive switch over to FOLFIRI at least for the second-line treatment an intravenous device will be necessary. So why not implant this device at the beginning of first line treatment and use it for the continuum of care for patients with metastatic disease as the rate of thrombo-embolic complications in larger series is rather low (0.3–2.5%) [22.Verso M. Agnelli G. et al.Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.J Clin Oncol. 2003; 21: 3665-3675Crossref PubMed Scopus (457) Google Scholar]. Also, for those patients who are already taking oral medication to control heart disease, hypertension and/or diabetes, to add 4–5 rather large tablets of capecitabine in the morning and another 4–5 in the evening may not be desirable for every patient. In Europe, more randomized phase III or randomized phase II trials are investigating capecitabine plus irinotecan or oxaliplatin in combination with bevacizumab than do studies in the US. Is this because investigators in Europe are more convinced of the benefit of capecitabine or is it because in Europe both capecitabine and bevacizumab are distributed by the same pharmaceutical company? In fact regulatory hurdles are (too) high for investigator initiated trials thus the economic pressure is enormous to find a sponsor for studies. While it is great to have choices for our patients to decide on regimens, the limited choices to study drugs and their combinations within clinical trials may in the end reduce the choices of treatment options for our patients.