Author Affiliations: Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy (Petrelli F, Coinu A, Borgonovo K, Cabiddu M and Barni S)

Corresponding Author: Fausto Petrelli, MD, Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy (Tel: +39-36-3424420; Fax: +39-36-3424380; Email: faupe@libero.it)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60344-7

Published online February 27, 2015.

 

 

Contributors: PF proposed the study. PF and BS performed research and wrote the first draft. PF collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. PF is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Progression-free survival (PFS) has not been extensively investigated as a surrogate for survival in the first-line treatments of pancreatic cancer. The aim of this review was to evaluate PFS as a potential surrogate endpoint for overall survival (OS) in advanced pancreatic cancer in trials comparing poly-chemotherapy to gemcitabine alone.

 

DATA SOURCES: A systematic literature search in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted. The key words included randomized trial, first-line chemotherapy, pancreatic cancer, gemcitabine and poly-chemotherapy. Adjusted weighted linear regression was used to calculate R_S (Spearman's rank-order correlation coefficient) between PFS and post-progression survival (PPS) with OS (R_S) and between treatment effects on PFS and OS (R_HR).

 

RESULTS: A total of 30 trials including 8467 patients met the inclusion criteria. Correlation between the treatment effects on PFS and OS (R_HR=0.78) and between the endpoint PFS and OS was high across all studies (R_S=0.75). The slope of the regression line was 0.76±0.26, indicating that an agent producing a 10% risk reduction for PFS will provide a 7.6%±2.6% risk reduction for OS. Correlation between PPS and OS was very strong (R_S=0.71) and accounted for more than 50% of the whole OS variability (R²=0.57).

 

CONCLUSION: Because of the robust correlation with OS and the potential influence of PPS caused by the second line therapies, it may be justified to consider PFS as a surrogate endpoint in trials evaluating new cytotoxic agents when gemcitabine is the control arm.

 

(Hepatobiliary Pancreat Dis Int 2015;14:124-131)

 

KEY WORDS: pancreatic cancer; surrogate endpoints; progression-free survival; overall survival; correlation; randomized studies

Advanced pancreatic cancer (PC) is a fatal disease. Gemcitabine improves median progression-free survival (PFS) and overall survival (OS). In the last decade, various combination chemotherapies (doublets or triplets) have been compared with gemcitabine alone. Median OS has steadily increased and ranges from 5 to 11-13 months with more recent S-1 and oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (FOLFIRINOX) combinations.^{[1, 2]} OS remains the primary endpoint of almost all trials testing new agents compared with the standard of care. Gemcitabine monotherapy was approved after it was found to be superior to 5-fluorouracil in terms of clinical benefit (the primary efficacy measure) and OS improvement (a secondary endpoint). An increase in survival is however difficult to capture, requiring the enrolment of several hundred patients, a long time horizon to study completion, and a prolonged study follow-up. The careful analysis of other surrogate endpoints in metastatic PC has not been reported. For gastrointestinal tumors, a systematic evaluation of PFS surrogacy for OS has been performed only in colorectal cancer;^[3] PFS has not been demonstrated a valid surrogate endpoint in advanced gastric cancer.^[4] An intermediate endpoint, such as PFS, could enable more efficient assessment of new anti-neoplastic agents by reducing the time and costs associated with the design of randomized trials. The precise assessment of progression time, however, could potentially be biased by factors such as the performance of local instead of centralized analysis, precise objective evaluation of size reduction, and the interval between evaluations.

 

The exposure to second-line treatments and the recommendation of more effective treatments after first-line failure often mitigate any OS advantage associated with front-line therapy. Survival after progression following first-line treatment (post-progression survival, PPS), acquires even more weight now, in particular in colorectal, breast and lung cancer, where active agents are available in pre-treated patients.^[5-9] In advanced PC, only one trial compared an effective second-line chemotherapy (oxaliplatin+5-fluorouracil and folinic acid) with best supportive care in patients failing first-line gemcitabine, these combinations significantly increased OS for 2.5 months.^[10] In this trial, median OS was 4.8 months for the chemotherapy arm. In the FOLFIRINOX and gemcitabine+nab-paclitaxel phase III trials, median PPS were 4.7 and 3.0 months, respectively, accounting for more than 40% of OS and with about 40% of patients who received some kind of the second-line chemotherapy.

 

Whether PFS represents an ideal surrogate endpoint in advanced PC is unknown. The present study was to find the correlation of PFS and PPS with OS and the surrogacy of PFS for OS.

 

 

We searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials and tried to identify randomized controlled trials from 2002 to 2013 in the first-line chemotherapy for patients with advanced PC. The search terms included ("gemcitabine") AND ("advanced" OR "metastatic" OR "unresectable") AND ("pancreatic cancer" OR "pancreatic adenocarcinoma" OR "ductal carcinoma of the pancreas" OR "adenocarcinoma of the pancreas"). Abstracts from major cancer conferences were included if the information was presented for at least one of the endpoints. Only publications in English were included. Further inclusion criteria were reports of either PFS, time-to-progression (TTP), or response rate (RR) along with OS. Only trials comparing gemcitabine alone to poly-chemotherapy were considered. Trials containing patients with unresectable PC were included because they were usually considered as having the prognosis of advanced disease. Exclusion criteria included the following: pure neoadjuvant chemotherapy trials or with prior chemotherapy for metastatic disease; trials investigating biological agents in the form of targeted therapy; and trials using different modes of chemotherapy infusion (e.g., regionally delivered) or radiotherapy. Trials were not included if they included patients with gastrointestinal cancers other than PC. Two investigators (Petrelli F and Coinu A) reviewed data for inclusion and exclusion, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.^[11] For each trial, reported data on sample size, chemotherapy regimens, median PFS (months), median PPS (months), RR (rate), and median OS (months) were extracted for all treatment arms.

 

Two correlations were calculated between summary statistics to determine surrogacy according to similar meta-analysis previously reported.^[12-14] Correlations were conducted using weighted linear regression with log transformation of all endpoints and weights proportional to the sample sizes. The first approach, termed outcome surrogacy, computed the correlation between median PFS, the potential surrogate endpoints, and median OS. The correlation was evaluated over all treatment arms and is called R_S (Spearman's rank-order correlation coefficient). A strong or very strong correlation (R_S 0.5-0.7 or >0.7) would be consistent with PFS as a surrogate measure for OS.^[15] This analysis was also performed individually for the gemcitabine monotherapy and poly-chemotherapy arms. The correlation between PPS and OS was calculated, and the R-squared (R²) coefficient (the proportion of variability of OS explained by variability of PPS) was also presented.

 

The second approach, termed trial-level surrogacy, assessed the correlation between the reported treatment effects on PFS (R_HR), the potential surrogate endpoint, and the reported treatment effects on OS, the relevant endpoint. A strong positive correlation would support PFS as a surrogate measure for OS.^[16]

 

To investigate possible reasons for heterogeneity, subgroup analyses were conducted: a) excluding the three more recent positive phase III trials;^{[1, 2, 17]} b) considering the Western countries alone trials; c) the date of publications (after 2008); d) the number of patients (>200); and e) phase III trials alone.

 

The 95% confidence intervals (CI) for R_S and R_HR were obtained using the percentile bootstrap. All reported P values corresponded to two-sided test, and those less than 0.05 were considered statistically significant. Analyses were performed with NCSS 2007 software (version 07.1.21, released June 1, 2011).

 

 

We enrolled all publications which compared a gemcitabine alone arm with a poly-chemotherapy doublet or triplet arm. The trial's publication ranged from 2002 to 2013. A total of 30 trials^{[1, 2, 17-44]} qualified for this study, including a total of 8467 patients were included (Table, Fig. 1). Among these trails, 22 were phase III trials^{[1, 2, 17-20, 22-24, 26-28, 30-36, 38, 42,44]} and eight were randomized phase II trials.^{[21,25,29,37,39-41,43]} Twenty-seven studies^{[1,18-27,29-44]} compared gemcitabine alone with a chemotherapy doublet and three studies^[2,28,41] compared gemcitabine alone with a chemotherapy triplet. Overall, there were 30 gemcitabine alone arms (including two arms containing gemcitabine given at a fixed dose rate that was comparable to gemcitabine given a fixed dose rate+another agent), 31 doublet- and 3 triplet-containing arms, respectively. In two trials,^{[1, 33]} only the standard dose gemcitabine arms were included in analysis because the third comparator arms (S1 and gemcitabine fixed dose rate) are not standard monotherapy regimens. Trial sampling ranged from 19 to 861. Trials with the large weight on overall analysis were the phase III trials of Ueno et al^[1] and Von Hoff et al.^[17]

 

A total of five trials used TTP or time-to-treatment failure or RR as the primary endpoint.^{[21, 24, 29, 40, 44]} In contrast to PFS, TTP uses progression events as the only outcome of interest and disregards death from any cause. Because both TTP and PFS endpoints are unaffected by subsequent therapies, they were used interchangeably for this analysis and were referred to as PFS as previously conducted in similar meta-analyses of colorectal and metastatic breast cancer.^{[5, 8, 9]} For all trials, median PFS and OS were 3.8 and 6.7 months. In four trials,^{[2, 17, 28, 40]} where HR for OS was significant, and there was also a significant difference in median PFS or TTP in favor of the experimental arms.

 

The evaluation, as reported in the method section, was performed through two different steps. First, the simple correlation should be considered between PFS or TTP and OS (reported as medians in months) for all arms, and then for gemcitabine and experimental arms separately. Second, it is necessary for surrogacy demonstration to evaluate if any increase in PFS (the surrogate candidate) is fully captured by increase in OS (the main endpoint). Both presented as HRs.

 

A total of 57 arms reported values for PFS/TTP and OS in 30 trials. In the analysis of all treatment regimens, PFS correlated well with OS (R_S=0.75; 95% CI: 0.62-0.85; P<0.0001; R²=0.6, P<0.0001, Fig. 2).

 

The outcome surrogacy equation is median OS=2.68+ 1.17×median PFS. PPS accounted for 57% of the OS variability (R²), and correlation with OS was very strong (R_S=0.71; 95% CI: 0.55-0.81; P<0.0001).

 

Restricting the analysis to the gemcitabine alone arms, a strong correlation among treatment effects was observed; however, the lower limit of CI was poor (R_S=0.64; 95% CI: 0.35-0.82; P=0.0003). Conversely, the correlation of PPS with OS was very strong (R_S=0.89; 95% CI: 0.77-0.95; P<0.0001).

 

In the poly-chemotherapy arms (n=33 arms), the correlation among endpoints was similarly very strong (R_S=0.76; 95% CI: 0.55-0.88; P<0.0001). The correlation with PPS was less strong (R_S=0.70; 95% CI: 0.46-0.84; P<0.0001).

 

A total of 21 pairs of HRs for PFS and OS between treatment arms were reported in 18 trials. In the analysis of all treatment regimens, treatment effects on PFS and OS were very strongly correlated (R_HR=0.78; 95% CI: 0.49-0.91; R²=0.69, Fig. 3).

 

The slope of the regression equation, the estimated change in HR of OS per unit change in HR of PFS, was 0.65 with a standard error of 0.12 (HR_OS=0.2668+0.76×HR_PFS). This means that a treatment associated with a 10% reduction of progression risk translated into a 7.6% reduction in risk of death.

 

Three recent positive phase III trials with S1, nab-paclitaxel and FOLFIRINOX enrolled the 25% of the patient population.^{[1, 2, 17]} After exclusion of these three trials, the correlation PFS/OS and treatment effect PFS with treatment effect on OS were still significant (R_S=0.65, P<0.0001 and R_HR=0.79, P=0.0004). The slope of this regression line was 0.69±0.138. This means that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 6.9%±1.38% risk reduction for OS. The correlation was significant for studies with >200 patients (R_S=0.80, P<0.00001; R_HR=0.66, P=0.01), for non-Asian studies (R_S=0.74, P<0.00001; R_HR=0.85, P=0.0001), recent publications (R_S=0.78, P<0.00001; R_HR=0.85, P=0.0007) and phase III trials only (R_S=0.79, P<0.00001; R_HR=0.69, P=0.008).

 

 

OS is the gold standard among primary endpoints for almost all trials investigating new agents in solid tumors. However, the discovery of a small OS benefit associated with an experimental treatment is often flawed by the treatments prescribed at progression or by cross-over from control to experimental arms. The delivery of second-line therapies to PC patients who maintain performance status may offer an outcome benefit, even if small, for this population, and can weaken the eventual OS benefit of new front-line agents.^[45-48] In the pooled analysis performed by Teo and McDermott,^[46] there was a clear correlation between the percentage of patients who received subsequent chemotherapy in the first-line trials and the reported median OS. However, OS, because of limited life expectancy with this condition and the short PPS, has been considered the mainstay endpoint in clinical trials, and use of PFS could be questionable in a large randomized trial.

 

Intermediate endpoints, such as PFS, are used as surrogates for OS in other settings. The evaluation of surrogacy has been confirmed and validated only in colorectal and ovarian cancer.^{[3, 48]} An ideal surrogate endpoint (e.g. PFS) would correlate with the true endpoint (OS), and should totally capture the actual treatment effect on the true endpoint. The present study is, to our knowledge, the first extensive analysis of endpoint surrogacy in PC. As for now, data about surrogacy between PFS, or other intermediate endpoints, and OS are needed in PC. Validation of PFS surrogacy as a basis for using PFS as a primary endpoint in randomized trials investigating activity of new cytotoxic agents, could offers two principal benefits: i) more rapid evaluation of novel therapies for their potential benefits through numerically smaller randomized trials obviating to the demonstration of an OS improvement; and ii) "eluding" the detrimental effect of post-progression salvage treatments, exploring only the pure drug activity.

 

The correlation between PFS and OS (endpoint surrogacy), however, is robust and significant to potentially consider PFS a valid surrogate endpoint of survival in PC studies comparing gemcitabine alone with poly-chemotherapy. PPS also correlates with OS and accounts for up to 57% of total OS variability. In our analysis, the percent risk reduction (treatment effect) calculated from HR for OS showed a significant association with the percent risk reduction calculated from HR for PFS, indicating that the effect of treatment on PFS predicts the effectiveness of treatment on OS. The results were particularly significant in recent large phase III trials according to subgroup analysis. Because the HR takes into account the whole variety of events for each treatment arm, it may be more meaningful than a single time-point estimate such as median PFS. Given that the present review focuses on surrogate endpoint at the trial-level only, this significant result suggests a strong correlation between the HRs for the two endpoints but should be confirmed even at the level of individual patient data. These results are similar to those presented in a similar way in colorectal cancer, where R_S is 0.74. This finding demonstrated the association between PFS and OS and supported the use of PFS as a definitive endpoint of clinical benefit.^[12]

 

When analysis was separated according to type of treatment (gemcitabine only or poly-chemotherapy), the correlation between PFS and OS was weaker for gemcitabine arms compared to multi-agent schedules. Accordingly, the correlation with PPS was higher in monotherapy vs poly-chemotherapy arms (0.89 vs 0.70). This is likely explained by post-progression treatment of patients after failure of gemcitabine (e.g., platinum agents, irinotecan or fluoropyrimidines combinations). This could mean that the use of multi-agent treatments as first-line treatment has a greater impact on PFS, resulting in a very strong correlation with OS too. In contrast, gemcitabine is associated with low median PFS, and has a minimal impact on OS. The impact of PPS on global OS variability is more pronounced.

 

In large phase III trials that led to FDA approval of new cancer drugs, Amir and colleagues^[49] investigated PFS, a potential surrogate endpoint of survival. They found that there is a strong correlation between PFS and OS when PPS is short, especially less than 12 months. This is the case for PC, where the median PPS in our analysis was 3.1 months and fell in a range between 0 and 8 months. In a survey of French medical oncologists, PFS was the preferred surrogate endpoint in PC, chosen by 81% of survey participants.^[50]

 

Different intermediate endpoints as 1-year OS and RR could be taken into consideration. However, the evaluation of response in PC is flawed by the rich tumor stromal content characteristic of PC.^[51] Conversely, 1-year (or six-month) time point could reasonably be taken as the surrogate of final OS. Conroy et al^[2] reported that FOLFIRINOX may lead to a 3-fold higher rate of 1-year OS. Other surrogate endpoints, such as a decrease of CA19-9 during treatment, have been investigated in randomized studies and pooled analyses of phase III trials. A recent pooled analysis of prospective studies enrolling patients with advanced PC treated with gemcitabine-containing regimens showed that a decline of CA19-9 after the second cycle of chemotherapy was not predictive of improved OS or TTP.^[52] The authors concluded that CA19-9 levels, while useful for disease prognosis, are not useful as a surrogate endpoint in clinical trials.

 

Our analysis has some obvious limitations. First, this is a meta-analysis of published trials. An exhaustive validation of surrogate endpoint requires a systematic assessment through individual patient data. The median PFS was not presented in two studies (four arms), and PFS/HR was available in only 21 out of 30 trials. The PFS evaluation could vary among trials, and this could increase time-point capture of progression date. The time interval between assessments should be the same across study arms, and at sufficiently frequent intervals to capture early any progression events. Any adjustment according to the confounding effect of any second-line therapy cannot be performed. Third, both TTP and time-to-treatment failure were considered in addition to PFS but both are credible endpoints because unaffected by subsequent therapies. Finally, other potential surrogate endpoints (such as quality of life, time to worsening of symptoms or clinical benefit) were not assessed.

 

Our literature-based analysis, however, included all randomized controlled trials of first-line chemotherapy for advanced PC to date, as well as recent trials that evaluated combination regimens containing nab-paclitaxel or the multi-agent FOLFIRINOX scheme. This analysis is the first to examine the correlation between PFS and OS in advanced PC and the importance of PPS. The very strong correlation between PFS and OS suggest that PFS could be further explored as a potential surrogate of OS in PC.

 

New agents, such as targeted therapies, were assessed, but none, except the anti-EGFR erlotinib, showed a statistically significant benefit in term of both PFS and OS. Predictive biomarker has prospectively shown to predict outcome benefit of patients treated with gemcitabine, to allow avoiding ineffective treatments in patients with a low likelihood of benefit.^[53] hENT over-expressing tumor, for example, seems to be associated with gemcitabine resistance. Standardized reporting of trial results is also essential in the future design of randomized trials. Strict assessment of progression time and a statistical adjustment accounting for subsequent treatments is required in future studies to better understand OS benefits in PC as well as in other solid tumors. In a disease with a short median OS, the availability of all active agents is probably needed early, in the upfront lines of therapy. However, a sequential policy of chemotherapy administration should be further explored in advanced setting, with predefined second-lines including agents not offered as first-line.

 

Even if OS probably still drives any investigation of new drugs in randomized trials in PC, the present analysis of 30 trials confirms that PFS may be an appropriate surrogate endpoint for OS, in the first-line treatment of advanced PC using chemotherapy. Additional endpoints in PC, including tumor- or patient-related biomarkers, have been implemented for other diseases, and should be explored in advanced PC as well.

 

 

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