Progression-free survival

Recent advances in the treatment of cancer of the colon and rectum now offer the potential to improve patient survival, but for many patients, improved disease- and progression-free survival represent equally important therapeutic outcomes. In the absence of the ability of a specific treatment to demonstrate improved survival, important outcome measures should include the effects of the treatment on patient symptoms, daily activities, performance status, and other quality-of-life indicators. Individualized patient care to balance the risks associated with treatment with the benefits of a specific treatment regimen is necessary to optimize patient outcomes. 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

Finally, these new inhibitors are forcing oncology researchers and clinicians to rethink the relationship between objective response rate and survival/progression-free survival. As a result, more and more phase II trials... 

The study population was stratified by T and N stage, pathology, and performance status. Patients received 35-39 fractions of daily radiotherapy and were randomized to concomitant cisplatin (100 mg/m2 on d 1,22, and 43) followed by three cycles of adjuvant cisplatin (80 mg/m2, d 1) and continuous infusion 5-FU (1000 mg/m2, d 1 —4) every 28 d. Overall, superiority of treatment was seen in the concomitant chemoradiation therapy arm in comparison to radiotherapy alone with the 3-yr progression-free survival (PFS) of 69% vs 24% (p < 0.001) and 3-yr OS of 78% vs 47% (p = 0.005). Hence, the recommended standard of care in treating patients with nasopharygneal carcinoma is concomitant chemoradiotherapy. 

Other studies evaluated the question of whether early delivery of radiation concurrently with chemotherapy was better than late delivery. A study performed by the C ALGB randomized patients to early (d 1, cycle 1), late (d 64, cycle 4), or no radiation therapy. The radiation therapy dose was 50 Gy over 6 wk. Chemotherapy used in this trial was cyclophosphamide, etoposide, and vincristine. The local recurrence rate for the early, late, and no radiation therapy arms was 49%, 68%, and 82%, respectively. The 2-yr progression-free survival rate was 15% for the early schedule arm vs 25% for the late schedule (p = 0.078). The 5-yr survival rate for the early, late, and no radiation therapy arms was 6.6%, 12%, and 3%, respectively (p = 0.007). The poor 5-yr survival rate for the early schedule was felt to be due to the significant decrease in chemotherapy dose needed for the early schedule group (4,49). 

In the third randomized trial of an MMPI (British Biotech Study 145) (12), patients with locally advanced or metastatic gastric cancer were randomized in a double-blind fashion to a low dose (10 mg bid) of marimastat or matching placebo. Marimastat 10 mg po bid, which had inferior survival compared to the higher dose of marimastat, was presumably selected as the active control arm for this trial based on its superior tolerability compared to high-dose marimastat. Patients randomized to marimastat had a trend to better overall survival (167 d vs 135 d p = 0.07) at the protocol stipulated endpoint of the study, and this statistical trend strengthened with an additional 6 mo of follow up (p = 0.048). Nevertheless, patients randomized to marimastat 10 mg po bid had statistically superior progression-free survival compared to patients randomized to placebo (p = 0.027). Marimastat 25 mg po bid, which was the most efficacious dose in British Biotech Study 128, was not tested in Study 145. 

M. Hutchings, A. Loft, M. Hansen, L.M. Pedersen, T. Buhl, J. Jurlander, S. Buus, S. Keiding, F. D Amore, A.M. Boesen, A.K. Berthelsen, L. Specht, FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107(1) (2006) 52-59. 

In certain cases more specific guidance is given. The FDA, for example, discuss various sensitivity analyses in relation to the analysis of progression-free survival in FDA (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologies . 

Abbreviations PFS, progression-free survival FL, follicular lymphoma EFS, event-free survival CR, complete reponse PR, partial response, significant... 

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