Everardo D. Saad

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.

Overall Survival and Post-Progression Survival in Advanced Breast Cancer: A Review of Recent Randomized Clinical Trials

With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression.

Incidence and severity of hand-foot syndrome in colorectal cancer patients treated with capecitabine: a single-institution experience.

Background: Hand–foot syndrome (HFS) has been previously reported as a side effect in 45–56% of patients treated with capecitabine. However, the natural history of HFS has not been fully characterized. In this study, we investigate the incidence, severity, and time course of HFS. Design: Toxicity data collected for 41 patients treated in two clinical trials were analyzed for the occurrence of HFS. Proportions of patients developing HFS after capecitabine treatment were calculated, and the severity and time course of HFS were analyzed. Results: Twenty-eight (68.3%) of the 41 patients had at least one episode of HFS. Most patients had their first (92.9%) or most severe (67.9%) episode of HFS within the first two cycles of treatment. Eighty-nine percent of the HFS episodes were grade 1 or 2; only 11% were grade 3. Conclusions: HFS is common in patients treated with capecitabine, and usually starts within the first two cycles of therapy.

Pretreatment CA 19-9 level as a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine

SummaryBackground. Serum levels of CA 19-9 correlate with survival among patients with pancreatic cancer treated with surgery or radiation therapy. In addition, CA 19-9 responses have been shown to predict for a better prognosis among patients with advanced disease treated with chemotherapy. The present study evaluates the predictive role of CA 19-9 pretreatment levels and response among patients treated with gemcitabine.Methods. We retrospectively identified 28 patients with advanced pancreatic cancer and baseline elevations of CA 19-9 (>37 U/mL) who were treated with single agent gemcitabine. CA 19-9 response was defined as a ≥50% decline at any time after treatment. Survival was estimated with the Kaplan-Meier method, and curves were compared with the log-rank test.Results. Eleven patients (39%) had a CA 19-9 response. The median survival of responding patients was longer than that of non-responding patients (13.8 vs 8 mo, p=.0272). When pretreatment CA 19-9 levels were analyzed, patients who had CA 19-9 below the median for the entire sample (1212 U/mL) lived significantly longer than patients with a CA 19-9 above the median (14.9 vs 7.4 mo, p=.0013). On multivariable analysis, pretreatment CA 19-9 level was an independent, and stronger predictor of survival (p=.0005) than CA 19-9 response (p=.0497). Other variables were not associated with survival.Conclusions. CA 19-9 may be a useful adjunct to response evaluation is this setting. In addition to CA 19-9 responses, prechemotherapy levels of this marker seem to have strong prognostic significance.

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.

Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer.

Dolastatin-10 is a potent inhibitor of microtubule assembly derived from the sea hare, which displayed significant antitumor activity in preclinical models. We conducted a phase II study of dolastatin-10 in patients with advanced colorectal cancer and no prior chemotherapy for metastatic disease. Fourteen patients received doses ranging from 300 &mgr;g/m2 to 450 &mgr;g/m2 as an intravenous push every 21 days. There were no major objective responses. Toxicity was mainly hematologic, with grade III or IV granulocytopenia occurring in 9 of 42 treatment courses. Other toxic effects were generally mild. Dolastatin-10 lacks clinically significant activity in advanced colorectal cancer when used in this dose and schedule.

Overall Survival: Patient Outcome, Therapeutic Objective, Clinical Trial End Point, or Public Health Measure?

In recent years, improvements in systemic therapy for the most common types of advanced solid tumors have considerably expanded the therapeutic arsenal in medical oncology. The introduction of novel chemotherapy and hormonal agents in the 1990s and of various molecularly targeted therapies during the last decade has improved the outlook of patients with the most common malignancies, including metastatic breast cancer, 1-5 colorectal cancer, 6-8 prostate cancer, 9-11 head and neck cancer, 12,13 gastric cancer, 14,15 renal cell carcinoma, 16-18 non– small-cell lung cancer, 19-21 and pancreatic cancer. 22 The increasing availability of active agents makes clinical development of novel therapies progressively more complex. Also, because of the growing number of drugs, combinations, and sequences that require testing in clinical trials, and given the opportunity to test novel therapies in different lines of treatment, the choice of clinical trial end points has become more critical than ever before. Although improvements in overall survival (OS) remain the ultimate treatment goal in oncology, OS gain seems increasingly more elusive in clinical trials in settings in which effective post-trial therapy exists. This apparent contradiction is reflected in the literature by arguments in which the function of OS as an end point is not distinguished from its role as a treatment goal. Thus, in statements such as “prolongation of OS is generally the most relevant measure of clinical benefit in a randomized clinical trial of an experimental treatment,” 23(p2439) the different roles played by survival in clinical practice and in the trial setting are not distinguished. In this commentary, we propose that a clear distinction ought to be made among survival as a goal desired by patients, clinicians, clinical trialists, and public health policymakers.

A Systematic Review on Drug Interactions in Oncology

Objectives: To systematically review drug interactions in oncology. Methods: We searched PubMed for eligible articles and online databases abstracts of major oncology meetings from 2002 to 2005. Results: One study reported on the frequency of drug interactions. Interactions between chemotherapy and nonchemotherapy agents have been reported mostly in small clinical trials and case series. Interactions between chemotherapic agents have been reported mostly in Phase I studies. Few studies described fatal outcomes of drug interactions in cancer patients. Conclusion: Drug interactions comprise an important issue in oncology, but very limited data exist on their frequency and clinical consequences.

Survival Is Not a Good Outcome for Randomized Trials With Effective Subsequent Therapies

paragraph of the Discussion section where we stated that “...novel evidence is provided suggesting that loss of Nuc-pYStat5 is associated with elevated risk of failure of antiestrogen therapy. However, conclusive validationof theresponse-predictivevalueofNuc-pYStat5will requirequantitative analyses in tumors from patients randomized for antiestrogen therapy, and prospective analyses in a CLIA-certified laboratory to overcome additional limitations of retrospective studies.” This conclusion was also incorporated into the Abstract to relay to readers that further validation of this candidate predictive marker will be needed.

VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS

OBJECTIVES Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. METHODS We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylors framework, the German Institute of Quality and Efficiency in Health Cares (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). RESULTS A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. CONCLUSIONS Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiGs framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.