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Annals of Oncology Advance Access originally published online on July 27, 2006
Annals of Oncology 2006 17(11):1665-1672; doi:10.1093/annonc/mdl174
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© 2006 European Society for Medical Oncology

gastrointestinal tumors

Correlation between tumor response to first-line chemotherapy and prognosis in advanced gastric cancer patients

W Ichikawa* and Y Sasaki

Department of Clinical Oncology, Saitama Medical School, Saitama 350–049, Japan

*Correspondence to: Dr W. Ichikawa, Department of Clinical Oncology, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, Saitama 350–049, Japan. Tel: +81-49-276-1711; Fax: +81-49-276-1711; E-mail: wataru{at}saitama-med.ac.jp


   Abstract
Top
 Abstract
introduction
 materials and methods
 results
 discussion
 Acknowledgements
 References
 
Background: In advanced gastric cancer, the relationship between tumor response and prognosis is far from clear.

Methods: We performed a pooled analysis on published data from 4593 patients in 25 randomized trials of first-line chemotherapy for advanced gastric cancer. A weighed analysis was used to investigate the correlation between objective response rate (RR) and time to progression (TTP) and overall survival time (OS).

Results: A moderate correlation was found between RR and TTP and OS (r = 0.49 and r = 0.45, respectively) in all 25 trials. In treatment arms without new drugs including irinotecan, taxanes, or oxaliplatin, RR also was associated with TTP and OS (r = 0.56 and r = 0.47, respectively). However, no association between RR and OS was found, whereas there was a moderate correlation between RR and TTP (r = 0.41) in treatment arms using new drugs.

Conclusions: Our results indicated that response to treatment was related to TTP and OS. The potential role of objective response as a surrogate in chemotherapy trials of advanced gastric cancer warrants further investigation, especially with regard to treatment with new drugs.

Key words: gastric cancer, overall survival, response rate, time to progression


   introduction
Top
 Abstract
 introduction
materials and methods
 results
 discussion
 Acknowledgements
 References
 
Significant survival benefit of 5-fluorouracil (5-FU)-based chemotherapy for advanced gastric cancer compared with best supportive care is reported [1–3]. However, no single regimen has emerged or been accepted as clearly superior over another. In Western countries, 5-FU combined with cisplatin and 5-FU combined with cisplatin plus epirubicin have been referred to as the standard chemotherapy for advanced gastric cancer, with the median overall survival time (OS) ranging from 7.3 to 10.5 months [4, 5]. In Japan, 5-FU monotherapy with a reported OS of 7.1 months still remains the reference arm of clinical trials for advanced gastric cancer [5, 6]. During the last few years, newly-developed drugs including irinotecan, taxanes, oxaliplatin, and oral fluoropyrimidines such as S-1 and capecitabine have been introduced into chemotherapy regimens [4]. Combination chemotherapy as first-line chemotherapy using these new drugs has augmented the increase of response rate (RR) over 50%, but has not extended the median survival time beyond 12 months in numerous clinical trials [4, 5].

The achievement of a response clearly has a major effect on prognosis in metastatic colorectal cancer [7] and metastatic breast cancer [8]. In a meta-analysis on individual patient' data, experimental 5-FU regimens were shown to be associated with a two-fold increase in RR over standard 5-FU regimens and with a 10% relative reduction in the odds of death in metastatic colorectal cancer [7]. This survival difference was entirely the result of the effect of experimental 5-FU regimens on RR (r = 0.38).

As for metastatic gastric cancer, two randomized phase III trials including 5-FU alone as a reference arm, and comparing it with cisplatin combined with 5-FU (CF), showed similar results: combination therapy of CF failed to demonstrate survival prolongation compared with 5-FU alone, while RR in the combination arm was superior to 5-FU alone arm [6, 9]. A recently reported phase III trial comparing CF regimen with combined regimes using with docetaxel, cisplatin, and 5-FU (DCF) demonstrated higher RRs in DCF regimen compared with CF regimen, with statistically significant prolongation of time to progression (TTP) and OS [10]. Another phase III trial comparing CF with irinotecan, 5-FU, and leucovorin (IF) failed to show the prolongation of survival, whereas the RR was higher in IF than CF [11]. These data suggest that the achievement of a response does not necessarily have a positive effect on survival in advanced gastric cancer patients. To date, however, the relationship between tumor response and survival in advanced gastric cancer is far less clear.

The importance of effective second-line chemotherapies for OS was clearly indicated by two phase III trials using irinotecan as a salvage option in metastatic colorectal cancer patients who failed to respond or had relapse after the first-line 5-FU and leucovorin therapy [12, 13]. Despite no clinical trails comparing any second-line chemotherapy with best supportive care for advanced gastric cancer patients, the reported RR ranging from 13% to 20% in phase II trials of second-line chemotherapy in gastric cancer was similar to colorectal cancer [14]. The development of effective second-line chemotherapy may decrease the impact of first-line chemotherapy on survival in advanced gastric cancer.

We therefore investigated the influence of RR in first-line chemotherapy on prognosis such as TTP and OS in advanced gastric cancer, and, in particular, the impact of availability of new drugs including irinotecan, taxanes, and oxaliplatin, by pooled analysis of published data.


   materials and methods
Top
 Abstract
 introduction
 materials and methods
results
 discussion
 Acknowledgements
 References
 
We reviewed the literature on first-line chemotherapy for advanced gastric cancer to explore the relationship between the response of tumor and prognosis. Prospective randomized trials (phase II–III) in patients with advanced gastric cancer treated with first-line systemic chemotherapy that were fully published in manuscript form (MEDLINE search using the key words ‘gastric cancer’ or ‘gastric carcinoma’ and ‘randomized’ or ‘randomised’ and ‘chemotherapy’) or presented at large international meetings [the European Society for Medical Oncology (ESMO), the European Council of Clinical Oncology (ECCO), and the American Society of Clinical Oncology (ASCO)] were reviewed.

From each trial, the information on reported RR, TTP and median OS were extracted. The response was determined according to various criterion. We included the trials in which response was evaluated according to the response criteria of World Health Organization (WHO), Southwest Oncology Group (SWOG), response evaluation criteria in solid tumors (RECIST), and Japanese Research Society for Gastric Cancer (JRSGC). For measurable lesions, the JRSGC criteria was the same as the standard definitions of WHO [6]. Three phase III trials reported by Cullinan et al. and Kelsen et al. were excluded from analysis, because the response was evaluated according to investigator defined criteria [15–17]. The data from 11 phase III trials and 14 randomized phase II trials on advanced gastric cancer were selected [6, 9–11, 18–38]. We divided the treatment arms into the ‘old’ treatment arms without new drugs including irinotecan, docetaxel, paclitaxel, or oxaliplatin, and the ‘new’ treatment arms including these new agents. Table 1 summarizes the design of all 25 trials used in our analysis. In 13 trials, the data of TTP were not available. The goal of the analysis was to correlate the reported TTP and OS with the reported RR. The Spearman rank correlation test was supplemented by simple linear regression. As a sensitivity analysis, a weighted regression was used, with weights proportional to the trial's sample size, as previously described by Grothey et al. [39]. P values reported are based on the weighted regression models, with a P-value < 0.05 taken to denote a statistically significant difference.


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  		Table 1 Basic characteristics and design of the studies used in the analysis

 

   results
Top
 Abstract
 introduction
 materials and methods
 results
discussion
 Acknowledgements
 References
 
Correlations among the RR and TTP and the reported median OS are illustrated in Table 2.


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  		Table 2 Correlation between the reported response rate and time to progression and overall survival time

 
The increase in RR correlated with the prolongation of TTP in 2144 patients of all 12 treatment arms in which the data of TTP were available (r = 0.49, P < 0.0001, Figure 1). Three were moderate correlations between RR and TTP in both ‘old’ regimens (1067 patients in 12 treatment arms) (r = 0.56, P = 0.0053) and ‘new’ regimens (1077 patients of 14 treatment arms (r = 0.41, P = 0.018).


Figure 1
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  		Figure 1 Regression plot and relationship between response rate and time to progression. Mathematical equation of regression (based on a weighted model-solid line): time to progression (months) = 1.73 + (% response rate x 0.09). r = 0.49, P < 0.0001. The solid dots represent ‘old’ treatment arms (r = 0.56, P = 0.0053), and the circles represent ‘new’ treatment arm (r = 0.41, P = 0.018).

 
The moderate correlation between RR and OS was observed in 4593 patients of all 55 treatment arms (r = 0.45, P <0.0001, Figure 2). Sixteen of all 17 ‘new’ treatment arms were plotted over the linear regression line (Figure 2). There were seven ‘old’ treatment arms which were compared with ‘new’ treatment arms in each clinical trial. Six arms of these seven ‘old’ treatment arms were plotted over the linear regression line. Three was a moderate correlation between RR and OS in ‘old’ regimens (3423 patients in 38 treatment arms) (r = 0.47, P < 0.0001), whereas no correlation was observed in ‘new’ regimens (1170 patients in 17 treatment arms) (r = 0.18, P = 0.12).


Figure 2
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  		Figure 2 Regression plot and relationship between response rate and overall survival time. Mathematical equation of regression (based on a weighted model-solid line): overall survival time (months) = 5.89 + (% response rate x 0.08). r = 0.45, P < 0.0001. The solid dots and the diamonds represent ‘old’ treatment arm (r = 0.47, P < 0.0001), and the circles represent ‘new’ treatment arm (r = 0.18, P = 0.12). The diamonds especially represent ‘old’ treatment arm compared with ‘new’ treatment arm in each clinical trials.

 

   discussion
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
Acknowledgements
 References
 
In this study, the RR in first-line chemotherapy had moderate correlations with TTP (r = 0.49) and OS (r = 0.45) in advanced gastric cancer patients. In terms of treatment generation, RR moderately correlated with both TTP and OS in ‘old’ treatment arms (r = 0.56 and r = 0.47, respectively), whereas, in ‘new’ treatment arms, there were no associations between RR and OS, although RR moderately correlated with TTP (r = 0.41). To the best of our knowledge, this is the first report to indicate the effect of RR in first-line on prognosis in advanced gastric cancer.

The correlation between RR and prognosis was moderate, not strong (r >0.8). Generally, objective response is evaluated in measurable lesions by imaging modalities such as computed tomography according to the defined response criteria. Gastric cancer progresses to systemic disease through various routes such as direct invasion, dissemination, lymphatic spread, or vascular spread, and recurs simultaneously in multiple sites [40]. Peritoneal dissemination, which occurs more commonly in gastric cancer than in colorectal cancer, is not defined often as a measurable lesion in clinical trials. In addition, the drugs could not be delivered sufficiently through the peritoneal-plasma barrier to the disseminated tumor cells in the peritoneal cavity [41]. Both the method to evaluate the objective response and the nature of advanced gastric cancer might explain the moderate correlation observed between RR and TTP.

In the field of advanced colorectal cancer, the induction of new active drugs including irinotecan and oxaliplatin could enable the development of more effective first-line and second-line chemotherapy, resulting in the prolongation of survival compared with OS when treated by 5-FU alone regimens [42]. The positive impact of irinotecan as second-line chemotherapy on OS was demonstrated in two phase III trials conducted in 5-FU refractory patients with advanced colorectal cancer [12, 13]. Subsequently, several phase III trials investigating combination regimens with 5-FU and leucovorin plus irinotecan or oxaliplatin as first-line therapy had achieved an RR of 39 to 56% and OS of 14.8 to 21.5 months, suggesting that combination of these agents is advantageous and they should be considered as standard regimens for advanced colorectal cancer [42]. Additionally, in a pooled analysis of 7 trials with a total 1991 patients, the percentage of patients who treated with 5-FU and leucovorin, and irinotecan and oxaliplatin at some point in their disease showed a strong correlation with the reported median OS, not the overall percentage of patients receiving any second-line therapy [39]. Grothey et al. re-analyzed data from 21 arms of 11 published phase III trials with 5768 patients with advanced colorectal cancer, with the addition of four large phase III trials [43]. The correlation between the percentage of patients receiving all three drugs and the reported OS remained unchanged. Interestingly, a multivariate analysis showed that only exposure to three drugs, but not use of a doublet regimen as first-line treatment (irinotecan or oxaliplatin plus 5-FU and leucovorin) was significantly associated with OS. Based on this reanalysis, in advanced colorectal cancer, the strategy of second-line chemotherapy appears to be more important than the choice of first-line chemotherapy with regard to higher response rate and longer progression free survival.

However, when irinotecan or oxaliplatin was not available for both first-line and second-line chemotherapy for advanced colorectal cancer, an increase in RR could translate into an increase in OS for patients with advanced colorectal cancer treated by 5-FU-based regimens [7]. These data were concordant with ours, indicating a positive correlation between RR and OS in ‘old’ treatment arms, in which new drugs were not available for the treatment for advanced gastric cancer.

The RR in first-line chemotherapy had a moderate correlation with TTP, regardless of treatment generation. The reported TTP ranging from 4.7 to 6.5 months seems to have reached a plateau at an RR near 40% (Figure 1). Indeed, even in non-randomized phase II studies indicating the RR over 50% (51–74%), the TTP ranged from 4.8 months to 6.5 months [44-46]. When the RR exceeds a certain threshold point, maybe 40–50%, the quality of response, such as the rate of complete response, not the quantity of response such as RR, might contribute to the prolongation of TTP. Further studies are needed to confirm this speculation.

The reported OS in six of seven ‘old’ treatment arms compared with ‘new’ treatment arms were longer as compared with the calculated OS by the linear regression line between RR and OS (Figure 2). Taken together with the progress of chemotherapy for advanced colorectal cancer [39, 42, 43], this observation might be explained by the treatment effect of second-line chemotherapy, but at this time, it is impossible to investigate the direct influence of second-line chemotherapy on OS, because detailed information on the second-line chemotherapy was available only in one phase III trial reported by Ohtsu et al. [6]. Thus, we cannot directly conclude that the availability of effective second-line chemotherapy results in a positive impact on survival.

Although the primary objective of phase II trial is evaluation of the RR, not TTP or OS, we included the data on randomized phase II trials into this analysis. There were 22 ‘old’ treatment arms and three ‘new’ treatment arms in phase III trials and 16 ‘old’ treatment arms and 14 ‘new’ treatment arms in randomized phase II trials. This unbalanced proportion of phase II and phase III trials among two treatment generations might have influenced our results. However, the RR was set as the primary endpoint in several old phase III trials by Cocconi et al. [22, 29] and Vanhoefer et al. [26], as pointed out by Ajani [47]. In the pooled analysis to investigate the effect on survival, when the number of phase III trials is small, the survival data obtained in randomized phase II trials are tried to be combined with those in phase III trials [48], despite the criticism reported by Goffin et al. [49]. In addition to the inclusion of phase II trials in this study, we recognize that the nature of the analysis conducted raises a question of inherent bias, especially, when comparing ‘old’ treatment arms with ‘new’ treatment arms, since, as time progresses trials, improvements in supportive care or earlier detection of advanced disease might affect our results, as mentioned by Grothey et al. [39]. This study was performed by a pooled analysis on published data, not a formal meta-analysis based on individual patient data, therefore, this study should be viewed as hypothesis-generating.

Nevertheless, our data may have major clinical implications. First, albeit based on limited data obtained in three phase III trials and phase II trials including relatively small number of patients, treatment effect on response did not predict treatment effects on OS especially in the ‘new’ treatment arms, hypothesizing that response might not be considered a valid surrogate as an indicator for survival for the purpose of testing new treatments. Second, the TTP of about 5 months is considered to be a threshold point regardless of the increasing RR. Thus, a regimen that can cross the threshold of approximately 5 months for TTP in a phase II trial should to be selected as the experimental arms for future phase III trials. The third implication is the possibility that effective second-line chemotherapy may affect outcome in advanced gastric cancer. The number of patients who received second-line therapy, and the regimens used, should be documented and described in future publications concerning each study. Additionally, a uniform approach for second-line chemotherapy should be prescribed in the study protocol [50].

Our results do not provide direct or conclusive evidence on the influence of tumor response to first-line chemotherapy on the prognosis of advanced gastric cancer. For further consideration, we have to wait for more data obtained in several on-going phase III trials of ‘new’ treatment arms. In addition, formal meta-analyses based on individual patient data or well-designed clinical trials may confirm our hypothesis.


   Acknowledgements
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
 Acknowledgements
References
 
The authors are indebted to Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review, and Mr Nobutaka Samejima for helpful discussions of this manuscript. This work was supported, in part, by a Grant-in-Aid for Scientific Research from Ministry of Education, Culture, Sports and Technology.

Received for publication May 10, 2006. Revision received June 18, 2006. Accepted for publication June 21, 2006.


   References
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
 Acknowledgements
 References
 
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