© 2006 European Society for Medical Oncology
editorial |
On prejudice and facts and choices
1 Department of Oncology and Hematology, Klinikum Oldenburg gGmbH, Oldenburg, Germany
2 Medizinische Klinik I, University Clinic, Dresden, Germany
(E-mail: onkologie{at}klinikum-oldenburg.de)
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
]. 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]. 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]. 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]. Furthermore, UFT and capecitabine were claimed to mimic infusional 5-FU at least pharmacologically [5]. 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], 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]. 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]. 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].
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 [10–12]. 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, 11] 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, 14]. 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]. 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] 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.
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With this background the paper by Twelves et al. [16
] 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]. Currently available data indicates that capecitabine may be more tolerable in combination with oxaliplatin rather than irinotecan [18]. In our EORTC trial 40015 [19] 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] 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] 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]. 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.
References
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  J Cassidy In response to: 'On prejudice and facts and choices', an editorial by Kohne and Folprecht Ann. Onc., September 1, 2006; 17(9): 1469 - 1471. [Full Text] [PDF]
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