Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents.

There is an ongoing debate about the relative merits of overall survival (OS) and other metrics that can be used as primary end points in cancer clinical trials. Although survival time is arguably the most objective metric for assessing the efficacy of anticancer treatment, OS as a clinical-trial end point needs to be conceptually distinguished from increased survival time as a goal desired by patients, clinicians and public-health policy makers. OS presents several drawbacks as a primary end point that threatens to hamper further drug development, including the increase in the number of patients and the much longer follow-up required in a clinical trial. In many settings of first-line therapy for metastatic disease, median OS is currently two to four times longer than median progression-free survival. As a result, the analysis of OS may be increasingly confounded by the effect of salvage therapies used after disease progression. In this review, we use straightforward statistical reasoning and examples from the oncology literature to argue that OS should no longer be the primary end point of most future phase III cancer clinical trials that aim at assessing the efficacy of novel therapies in the setting of metastatic disease.

Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter?

BACKGROUND: In early breast cancer, adjuvant chemotherapy decreases the risks of recurrence and breast cancer mortality, and neoadjuvant treatment leads to equivalent long-term outcomes. A large number of clinical trials have attempted to refine systemic therapeutic strategies in early breast cancer, but little attention has been paid to the sequence of anthracyclines and taxanes. Based on preclinical observations, there is limited rationale to administer the taxane before the anthracycline. METHODS: We searched PubMed, the American Society of Clinical Oncology website, and clinicaltrials.gov with the goal of identifying published or ongoing studies that aimed at comparing reverse sequences of anthracyclines and taxanes. Given the nature and the small number of studies identified, we did not attempt to quantitatively pool the study results. RESULTS: We retrieved seven studies in the adjuvant setting and eight in the neoadjuvant setting: 10 randomized trials (only 2 were phase IIII), 3 retrospective studies, and 2 ongoing phase II trials. A total of nearly 5000 patients were included in such studies. None of the clinical trials has shown disadvantages in terms of efficacy or toxicity for sequences in which the taxane was administered first. In the neoadjuvant setting, studies have collectively shown similar or increased pathological complete response rates for sequences in which the taxane was administered first. CONCLUSION: Given the available information, there seems to be sufficient evidence to suggest that a taxane followed by an anthracycline is a sequence option that can be incorporated into daily clinical practice.

The geography of clinical cancer research: analysis of abstracts presented at the American Society of Clinical Oncology Annual Meetings.

BACKGROUND: The American Society of Clinical Oncology Annual Meeting is the largest forum for presentation of clinical research in oncology. We quantified the contribution of countries and assessed correlates of their presence at such meetings. METHODS: After stratifying abstracts according to category of presentation (oral, poster, and 'publication only'), we took a random sample of 10% of the studies presented at years 2001-2003 and 2006-2008. We assigned abstract nationality using the affiliation of authors. For multinational studies, we developed an algorithm to assign nationality. RESULTS: Of the 22 045 eligible abstracts, 2206 were analyzed and represented 71 countries: 905 (41%) abstracts were from a single institution, 969 (44%) were multicenter, uninational studies, and 332 (15%) were multinational studies. United States nationality was assigned to 49% of all abstracts and the next 14 countries with a higher number of studies accounted for 41%. There was a statistically significant temporal trend in the proportion of multinational studies. Also, multinational studies and abstracts with United States nationality were more frequently presented in oral and poster fashion and had more frequent involvement of the pharmaceutical industry. CONCLUSION: This study provides a geographic overview of clinical cancer research and indicates that multinational collaboration is increasing.

Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.

Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.

Progression-free survival and time to progression as primary end points in advanced breast cancer: often used, sometimes loosely defined.

BACKGROUND: The growing availability of active agents makes the development of novel therapies increasingly complex and the choice of end points critical. We assessed the frequency of use of efficacy end points in advanced breast cancer. METHODS: We searched PubMed for randomized trials published between 2000 and 2007 in 10 leading medical journals. We abstracted data on progression-free survival (PFS), time to tumor progression (TTP), response rate (RR) and overall survival. RESULTS: A total of 58 studies enrolled 23,371 assessable patients in 122 treatment arms. The primary end points most frequently used were RR and TTP (n=21 each), followed by PFS (n=14). In five of the trials using TTP as the primary end point, no definition of TTP was reported; in 13 of the other 16 cases, death was counted as an event, making TTP indistinguishable from PFS. Trials having PFS, TTP or time to treatment failure as the primary end point (n=36) had a higher mean number of patients than those using RR (P=0.061). CONCLUSION: Investigators seem to be frequently using PFS and TTP interchangeably in advanced breast cancer. Such use of terms may lead to confusion when results of different trials are compared, and uniform use of definitions seems in order.

Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer.

PURPOSE: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectal cancer received escalating doses of UFT (starting at 250mg/m(2)/d, with 50-mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). The UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery was performed 4 to 6 weeks after radiation and was followed by four 35-day cycles of fixed doses of UFT and LV (28 days of therapy each cycle). RESULTS: Fifteen patients were treated, and 13 received the full preoperative chemotherapy. All planned radiation was delivered successfully. The MTD of UFT with radiation was 350 mg/m(2)/d with 90 mg/d of LV. Diarrhea was the DLT. Sphincter-preserving surgery was performed in 12 of 14 patients. One patient had progressive disease before surgery. Pathologic evaluation of 14 resected specimens showed a complete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated.

Progressive multifocal leukoencephalopathy with concurrent Richter's syndrome.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infectious disease caused by the JC virus. It was originally described in patients with chronic lymphocytic leukemia (CLL). Richter's syndrome, or transformation to large cell Lymphoma, occurs in approximately 3% of patients with CLL, and carries a poor prognosis. We report a patient with documented PML and concurrent Richter's transformation outside the central nervous system. Before establishing a definitive diagnosis of PML, radiation therapy to the presumed lymphomatous brain lesion had been considered, raising the issue of whether stereotactic brain biopsy should be considered in every patient in a similar situation. Although this is likely a rare occurrence, patients with Richter's transformation documented at an extra-neural site and a brain lesion may benefit from the establishment of an infectious diagnosis which would influence therapy.

Other fluorinated pyrimidines in the treatment of solid tumors.

Researchers, primarily in Japan, Europe, and the United States, have evaluated several new fluorinated pyrimidines in recent years. Most of these drugs are orally active prodrugs of fluorouracil (5-FU), and some also contain modulators of its pharmacological properties. S-1 is a rationally developed combination of tegafur, a prodrug of 5-FU; CDHP, an inhibitor of 5-FU catabolism; and potassium oxonate, an inhibitor of 5-FU-induced diarrhea. S-1 underwent phase I and II trials in Japan, where it is now approved for use in the treatment of advanced gastric cancer. Two phase I studies conducted recently in Europe and the United States identified diarrhea as the dose-limiting toxicity of S-1. BOF-A2, which contains a 5-FU prodrug and CNDP, an inhibitor of 5-FU catabolism, demonstrated clinical activity in preliminary studies in Japan. This article summarizes the preclinical and clinical development of S-1 and BOF-A2.

A phase I study. Preoperative UFT/leucovorin and radiation therapy in rectal cancer.

The use of combined modality regimens has been well established in the treatment of stages II and III rectal cancer. The most common chemotherapy regimens used include continuous-infusion 5-FU delivered with the help of a central venous catheter and the use of portable pumps. These regimens are expensive and can potentially develop line problems. The availability of the oral agent UFT in combination with oral leucovorin prompted the development of an all-oral chemotherapy regimen that could be combined with radiotherapy. At The University of Texas M. D. Anderson Cancer Center, we routinely use combined chemotherapy and radiotherapy preoperatively for the treatment of rectal cancers, and decided to conduct a phase I trial in which UFT and leucovorin was used instead of the conventional 5-FU. The preliminary results are encouraging and seem to demonstrate the feasibility of this approach.

[Evidence-based medicine]. / Medicina baseada em evidências.

Evidence-based medicine has been described as a new approach to teaching and practicing clinical medicine. Although the search for evidence is an established practice among physicians, what is being proposed is the systematic gathering and critical interpretation of data, which can then be used in the appropriate context. The main objective is to provide better care for patients. This is accomplished by transforming clinical problems in specific questions to be answered by searching the literature for the levels of evidence favoring the possible interventions for one particular case. This has to be done in a systematic and conscientious fashion. Through its method, evidence-based medicine places less value on clinical experience, the study understanding of pathophysiology, and common sense; instead, it emphasizes observation, levels of evidence, and critical interpretation of original literature. In this manner, evidence-based medicine may be seen by the authoritarian physician as a threat. Other obstacles to the acceptance of the method include lack of time and lack of familiarity with computers. One important limitation of evidence-based medicine is the incomplete or contradictory evidence available in many areas of clinical medicine, or the so-called "grey zones". We outline the main aspects of evidence-based medicine, expecting a growing interest among brazilian physicians for this useful clinical tool.

Case report: hand-foot syndrome induced by the oral fluoropyrimidine S-1.

Hand-foot syndrome (HFS) is a relatively common side effect of fluorouracil (5-FU) chemotherapy that has also been associated with the oral fluoropyrimidine capecitabine. Interestingly, HFS is virtually unknown to result from treatment with UFT, a combination of tegafur and uracil. Tegafur is a prodrug of 5-FU and is a component of S-1, another oral fluoropyrimidine active in a variety of solid tumors. We know of only one previously described case of S-1-induced HFS and the case reported here is the first to provide full documentation of this occurrence. The pathophysiology of chemotherapy-induced HFS remains unknown and very little pathological information is available. Treatment consists of topical emollient therapy, although pyridoxine has occasionally been beneficial. The study of HFS may provide an important insight into the pharmacology of fluoropyrimidines and allow for effective preventive strategies for this side effect of chemotherapy.

Phase I trial of i.v. administered tirapazamine plus cyclophosphamide.

Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four other patients had grade 1 ototoxicity. Grade 1 and 2 muscle cramps were observed at all dose levels. Other toxic effects observed included fatigue, nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase. Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support, the recommended doses of tirapazamine and cyclophosphamide when administered in this schedule are 260 and 1000 mg/m(2), respectively.