Ncponc_2005_056.indd

Phase III trials in oncology: setting
standards of care?
Siegfried Seeber* and Ada H Braun
For many years, oncologists worldwide have unacceptable median survival data reported advised their patients to enroll in clinical trials for optimum assessment of treatments, In a recent randomized trial of trastuzumab plus monitoring and follow-up, and consequently docetaxel in 188 patients with HER2-positive meta- better survival and quality of life compared static breast cancer, only 48% of the taxotere-alone with routine management. Randomized phase control group were documented to receive the III studies that have survival as the primary antibody at progress! Yet it was concluded that the endpoint have been the indisputable basis for addition of trastuzumab to docetaxel “improves all setting new standards and launching new drugs, clinical outcome parameters, including survival”.3 combinations and multimodal treatment options Would this hold true if patients from the control into clinical oncology practice. Such studies may group had received vinorelbine plus trastuzumab be misleading, however, when enrolled patients after taxotere failure? Albeit active, the latter have not received optimum follow-up therapy after failure of assigned treatment.
Should such studies set new standards of care In recent licensing trials for agents targeted for our patients? For 197 unselected consecu- at breast cancer, restricted access to post-study tive patients treated in our center in the pre- chemo therapy has yielded ‘superior survival’ trastuzumab era (between 1 January 1995 and data for investigational drug combinations 31 December 1999), the median survival of versus single-agent therapy, with remarkably breast cancer patients first-line for treatment poor survival in all cohorts.1 A number of these of metastatic disease was 36 months, with a trials have resulted in approval of specific regi- 35% 4-year survival (C Pohlkamp, A Welt and S mens. In a study showing ‘superior survival’ Seeber, unpublished data). Of 146 patients with for capecitabine plus docetaxel compared with in operable liver metastases, 25% survived for over docetaxel alone (14.5 vs 11.5 months, respec- 48 months, and 14% for over 60 months—some tively) in 511 anthracycline-pretreated patients, for over 8 years. In many cases, clinical responses only 17% in the docetaxel-alone arm received were observed even in the sixth or seventh line (see post-study capecitabine and overall only 30% Supplementary Figure 1 online). These patients require close monitoring, early intervention at 5- fluorouracil.1 Especially given the very short progression, and individualized multimodal median times to treatment failure reported therapy employing effective drugs either singly (4.0 and 2.8 months, respectively), it is against or in adequate combinations, irrespective of their routine practice to offer only two-thirds of registration status. Dose-dense regimens should patients third-line chemo therapy. Capecitabine be used in critical phases and ‘softer’ interims was consequently registered for breast cancer involving oral maintenance therapy as well as therapy, with docetaxel as the mandatory locoregional treatment options (e.g. surgery, Correspondence
*West German Cancer
interventional radiology or hepatic artery infu- Gemcitabine was approved for combination sions). Experienced physicians are not impressed therapy only, because a licensing trial comparing by studies claiming a survival advantage of 15.4 gemcitabine plus paclitaxel with paclitaxel alone versus 12.7 months for docetaxel versus paclitaxel stated that “gemcitabine plus taxol provides in metastasized breast cancer,4 a result advertised significant overall survival advantage over taxol”.2 The advantage of combination over In stage IV non-small-cell lung cancer, it took Received 17 February 2005
sequential single-agent therapy is undetermined, 408 patients to prove that combining paclitaxel Accepted 14 July 2005
however. Again, unsatisfactory post-study access with carboplatin is as effective as vinorelbine www.nature.com/clinicalpracticedoi:10.1038/ncponc0284 to active agents probably accounted for the plus cisplatin,5 with equally poor median 2005 Nature Publishing Group
survival (8 months) and 1-year survival rates second-line oxaliplatin. Tournigand et al.,10 GLOSSARY
(38% vs 36%). In this and a similar ECOG trial comparing FOLFOX6 followed by FOLFIRI with ECCO
European Cancer
of four two-drug combinations, there was no the reverse sequence using a crossover design, routine crossover at treatment failure; nor did found no significant difference in survival.
the majority of patients receive adequate second- In conclusion, survival of patients with line or third-line treatment. However, second-line common metastatic cancers is determined not taxotere can prolong life in platinum-refractory only by the choice of first-line chemotherapy FIGO
International Federation of
patients, and third-line irinotecan can induce regimen but also by sequentially applied alter- significant responses lasting up to 1 year.6 native treatments at progression or relapse. In ovarian cancer, evidence-based medicine Phase III trials documenting superior survival usually favors taxol plus carboplatin as induction for any given primary chemotherapy in these regimen; standard therapy for colorectal cancer treatment, with topotecan or liposomal doxo- diseases often offer patients insufficient access to rubicin for platinum-resistant tumors. Phase salvage treatment and are therefore misleading. irinotecan, 5-fluorouracil and leucovorin III studies are underway with overall survival as Unfortunately, results emanating from such the primary endpoint.7 Our mono- institutional studies continue to give rise to restricted FOLFOX
Chemotherapy regimen for
analysis involves 77 unselected consecutive licensing of mandatory drug combinations, even patients with FIGO stage III or IV ovarian carci- though physicians need both monotherapeutic consisting of oxaliplatin, 5-fluorouracil and leucovorin noma, who, between 1 January 1993 and 31 and combined usage of active agents, according December 2003, received an average of six treat- to a patient’s history and preference—especially ment regimens, and early surgical interventions whenever applicable (C Brinkmann, J Hense cancer patients consisting of irinotecan, infusional and S Seeber, unpublished data). Therapies were Supplementary information is available on the
adjusted on an individualized basis following any Nature Clinical Practice Oncology website.
signs of disease progression, producing a median Competing interests
References
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Even colorectal cancer patients have suffered et al. (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin inferior survival in phase III studies because combinations in patients with previously untreated of constrained second-line treatment options. metastatic colorectal cancer. J Clin Oncol 22: 23–30
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2005 Nature Publishing Group

Source: http://professor-seeber.de/PDFs/Seeber,Braun09.05.pdf