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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2395-2403 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.154 Multivariate Prognostic Factor Analysis in Locally Advanced and Metastatic Esophago-Gastric Cancer—Pooled Analysis From Three Multicenter, Randomized, Controlled Trials Using Individual Patient DataFrom the Department of Medicine, Department of Computing and Information, Royal Marsden Hospital, London and Surrey, UK Address reprint requests to David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, UK; e-mail: david.cunningham{at}icr.ac.uk
PURPOSE: To identify baseline prognostic factors and assess whether pretreatment quality of life (QoL) predicts survival in patients with locally advanced or metastatic esophago-gastric cancer. PATIENTS AND METHODS: Between 1992 and 2001, 1,080 patients were enrolled into three randomized, controlled trials assessing fluorouracil-based combination chemotherapy. All patients were required to complete the European Organization for Research and Treatment of Cancer core QoL questionnaire before random assignment.
RESULTS: Of the 1,080 patients randomly assigned, 979 (91%) died. Four independent poor prognostic factors were identified by multivariate analysis: performance status CONCLUSION: Four poor prognostic factors were identified and a simple prognostic index was devised. Information from this analysis can be used to aid clinical decision-making, help individual patient risk stratification, and serve as benchmark for the planning for future phase III trials.
Cancers of the esophagus and stomach accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000—more than lung, breast, or colorectal cancer.1 Many patients, especially with gastric cancer, present with distant metastasis. The 5-year survival rates for patients with distant disease are only 3.1% for esophageal and stomach cancer.2 In these patients, palliative chemotherapy is given with the intention of prolonging survival, relieving symptoms, and improving quality of life (QoL). Four randomized trials comparing combination chemotherapy with best supportive care in patients with gastric cancer found a survival advantage in favor of chemotherapy.3-6 Cisplatin and fluorouracil- (FU-) based chemotherapy regimens with or without another chemotherapeutic agent, have been used most commonly in previously untreated patients with advanced esophago-gastric (EG) cancer. New drugs, which have broadened the therapeutic options in colorectal cancer, such as irinotecan, oxaliplatin, and oral fluoropyrimidines, are now being evaluated in advanced EG cancer. Molecular targeted therapy against epidermal growth factor receptor (such as cetuximab) and vascular endothelial growth factor (such as bevacizumab) have also shown promising activity in colorectal cancer, and their roles in upper gastrointestinal cancer will need to be evaluated. Whereas several studies have investigated prognostic factors in EG cancer (mainly in resected patients),7-11 few have focused on patients with locally advanced or metastatic disease.12-14 Prediction of treatment outcome may allow identification of patients who would derive very little survival benefit from the current chemotherapeutic regimens, and these patients should be actively recruited into randomized trials evaluating novel agents. It would also allow risk stratification for patients in future phase III trials to ensure adequate assessment of new drugs. QoL is an important aspect of palliative cancer treatment. New therapy can be recommended, even in the absence of an impact on survival, if an improvement in QoL can be demonstrated.15 QoL includes global QoL as well as its physical, psychological, and social dimensions. Assessment of QoL provides detailed multidimensional information about patients' perception of their health. Several studies have shown that pretreatment QoL scores can predict survival in cancer patients.16-22 However, no studies have assessed whether baseline QoL scores carry prognostic information independent of other baseline factors in a large cohort of patients with advanced EG cancer recruited from randomized controlled trials. The aims of this analysis are to identify baseline patient- or tumor-related prognostic factors and to assess whether pretreatment QoL predicts survival in patients with locally advanced or metastatic EG cancer.
Between 1992 and 2001, 1080 eligible patients were enrolled into three multicenter, prospective, randomized controlled trials conducted in the United Kingdom evaluating first-line treatment in patients with locally advanced or metastatic cancer of esophagus, esophago-gastric junction (EGJ), or stomach. The first study randomly assigned 256 patients between July 1992 and June 1995 to ECF regimen consisting of epirubicin (50 mg/m2 intravenously [IV]) and cisplatin (60 mg/m2 IV) once every 3 weeks with protracted venous infusion (PVI) FU (200 mg/m2/d), or FAMTX regimen consisting of methotrexate (1,500 mg/m2 IV) and FU (1,500 mg/m2 IV) on day 1 followed by doxorubicin (30 mg/m2 IV) on day 15 repeated every 4 weeks.23,24 The second study randomly assigned 574 patients between July 1995 and August 1998 to either ECF regimen or MCF regimen consisting of mitomycin C (MMC; 7 mg/m2 IV once every 6 weeks), cisplatin (60 mg/m2 IV every 3 weeks), and PVI FU (300 mg/m2/d).25 The third study randomly assigned 250 patients between July 1994 and February 2001 to either PVI FU (300 mg/m2/d) or PVI FU (300 mg/m2/d) with MMC (7 mg/m2 once every 6 weeks).26 A maximum treatment period of 24 weeks was planned in all three study protocols. All three randomized controlled trials had broadly similar eligibility criteria. Patients were required to have histologically confirmed inoperable adenocarcinoma, squamous cell carcinoma (SCC), or undifferentiated carcinoma of the esophagus, EGJ, or stomach; adequate hematologic, renal, and hepatic function and Eastern Cooperative Oncology Group performance status (PS) 0 to 2. The major eligibility differences were that the first study excluded patients with SCC, whereas the third study recruited patients with inoperable cancer due to comorbid conditions. Before randomization, written informed consent was obtained from all patients. All three studies were approved by the Scientific and Research Ethics Committees of the participating institutions. Results from all three studies have been published previously.23-26 All patients were required to complete the European Organization for Research and Treatment of Cancer core QoL questionnaire (EORTC QLQ-C30). This is a 30-item validated questionnaire incorporating five functional domains (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), and a global QoL scale.27 QoL scores were calculated according to standard guidelines yielding a range of 0 to 100. High scores in the functional and global QoL represented good QoL.
Statistical Analysis Factors included in these analyses were age, performance status (0 or 1 v 2), sex, site of primary tumor (esophagus v EGJ v stomach), presence of locally advanced or metastatic disease, previous gastrectomy or esophagectomy, sites of metastases (liver, peritoneum, or lung), tumor differentiation, hematologic parameters including hemoglobin, white cell count, and platelet count, and biochemical parameters including sodium, calcium, albumin, and alkaline phosphatase. Laboratory variables were initially coded as continuous variables and subsequently dichotomised with the cutoff points chosen at the median value of each variable. Multivariate logistic regression was used to determine factors predictive of chemotherapy response. After the baseline prognostic model was constructed, pretreatment QoL data were entered into the model to ascertain independent prognostic factors. Only the functional domains were used and each domain was tested against the baseline model separately. All end points were updated in July 2003. Analysis was performed using SPSS package version 12 (SPSS Inc, Chicago, IL).
Of the 1,080 patients randomly assigned between 1992 and 2001, 979 (91%) died. Table 1 shows the baseline demographic details of the pooled analysis and the three studies. The median survival for the whole group was 7.9 months. One-year survival was 30.1% (95% CI, 27.8% to 32.9%) and 2-year survival was 11.5% (95% CI, 9.6% to 13.5%). Figure 1 shows the overall survival for the whole group. Table 2 summarizes the results of the univariate analyses for patient- and tumor-related factors, as well as pretreatment quality of life. Age, sex, and location of primary tumor were not significant in univariate analyses.
The final multivariate baseline prognostic model (Table 3) is based on 817 patients with complete data and incorporates four poor prognostic factors: performance status  2, liver metastases, peritoneal metastases, and alkaline phosphatase 100 U/L. The 99% CI of each factor did not cross unity. The key variable with missing data was serum alkaline phosphatase, with data present on 823 patients only. The other three variables in the prognostic model were available in almost all 1,080 patients. However, there was no difference in survival between those patients included in the prognostic model and those excluded because of missing data (log-rank P = .992). Patients with performance status 2, peritoneal metastases, and alkaline phosphatase 100 U/L also had a significantly reduced probability of tumor response to chemotherapy (Table 4).
All four factors have a similar order of magnitude, therefore they can be combined into a simple prognostic score without loss of relevant information. Patients with no risk factor were categorized as good risk group (n = 239), those with one or two risk factors were categorized as moderate risk group (n = 487), and those with three or four risk factors were categorized as poor risk group (n = 91). Figure 2 shows the survival of these three risk groups. There were highly significant survival differences among the three risk groups (log-rank P < .00001). Median survival for good, moderate, and poor risk groups was 11.8 months, 7.4 months, and 4.1 months, respectively. One-year survival rates for good, moderate, and poor risk groups were 48.5% (95% CI, 41.9% to 54.7%), 25.7% (95% CI, 22.5% to 29.7%), and 11% (5.6% to 18.4%), respectively. Compared to the good risk group, the moderate risk group had a nearly two-fold (hazard ratio [HR], 1.92; 99% CI, 1.53 to 2.4), and the poor risk group had a 3.5-fold (HR, 3.59; 99% CI, 2.57 to 5.02) increased risk of death.
When pretreatment QoL data were tested against the baseline prognostic models, physical functioning (P = .003), role functioning (P < .001), and global QoL (P < .001) had significant prognostic impact. Table 5 shows the final multivariate models with QoL. Factors with borderline significance in multivariate analysis were retained with QoL data analysis, and therefore the final QoL models did not always have the same baseline prognostic factors. Even when PS was analyzed separately as 0, 1, and 2, global QoL and role functioning remained significantly prognostic (data not shown).
In this analysis, individual patient data were pooled from 1,080 patients with locally advanced or metastatic EG cancer. Performance status, presence of liver and/or peritoneal metastases, and serum alkaline phosphatase level were identified as significant prognostic factors. A simple prognostic index was developed and patients in different risk groups had varying survival. Information about all four prognostic factors are readily available to clinicians before commencing treatment which would aid clinical decision-making and risk stratification. The strength of this analysis lies in the data, which were derived from three of the largest randomized controlled trials ever conducted in the advanced disease setting.23-26 More than 90% of patients died, and therefore the survival data are mature. All patients received fluorouracil-based chemotherapy with the majority (88%) given PVI FU. The studies included have established ECF as one of the reference treatment regimens in advanced EG cancer.23-25 In addition, the older age group with comorbid conditions was included in the study evaluating PVI FU with or without MMC.26 Therefore, the cohort of patients included in this pooled analysis reflects the wide spectrum of patients seen in routine clinical practice. Whereas several studies have identified prognostic factors post primary surgery, no studies have identified prognostic factors in a large cohort of patients with locally advanced or metastatic disease. A recently reported study analyzed 350 patients with metastatic or inoperable esophageal cancer treated within six consecutive nonrandomized studies with cisplatin-based chemotherapy.13 Poor performance status, extensive disseminated disease, and elevated lactate dehydrogenase level were associated with poor survival on multivariate analysis, although significance levels of < .05 were used, rather than < .01 as used in our study, to account for multiple statistical testing. Similar to our data, patients with zero, one, two, or three risk factors had very different survival in this study. In our study, there was a highly significant survival difference between locally advanced and metastatic disease in univariate analysis. However, there were significant interactions among sites of metastases, number of metastatic sites, and whether the disease was locally advanced or metastatic. Therefore, we elected to include the sites of metastases in the final multivariate model in order to evaluate the most significant sites of metastases that would impact on survival. Liver and peritoneal metastases were found to be significantly prognostic, and they are among the most common sites of metastases in EG cancer. In our analysis, presence of peritoneal disease represented clinically or radiologically evident disease, for example, peritoneal deposits or omental cakes seen on computed tomography scan or cytologically confirmed malignant ascites. These patients have been shown to have poor prognosis31 with poor response to chemotherapy as demonstrated by our multivariate logistic regression analysis on tumor response. This contrasts with 20% to 30% of patients initially thought to be resectable on conventional imaging and subsequently found to have peritoneal deposits on laparoscopic staging.32 These patients had a better, although still modest, survival compared to those with gross peritoneal metastases. It has been shown that disseminated tumor cells in the peritoneum adversely affect the survival, especially if the tumor cells were detected by immunocytologic methods rather than cytology alone,33 but their prognostic significance is less clear cut than gross peritoneal metastases. Recently, a randomized study has shown that aggressive surgical cytoreduction followed by hyperthermic intraperitoneal chemotherapy improved survival in patients with peritoneal carcinomatosis of colorectal origin34, and such multimodality therapy has also been evaluated in EG cancer.35 Therefore, in the future, aggressive therapy directed against peritoneal deposits may influence the survival in selected patients with EG cancers. In another study evaluating 125 patients with peritoneal carcinomatosis from gastric cancer, liver metastasis was found to be a highly significant poor prognostic factor31—an observation confirmed by our data.
We also found elevated serum alkaline phosphatase level to be an independent prognostic factor to liver metastasis and PS. This may reflect the underlying tumor burden rather than the presence or absence liver metastasis. Even when PS was analyzed separately as 0, 1, and Our simple prognostic index has allowed identification of three distinct risk groups. Compared with the good risk group, the moderate risk group had a nearly two-fold increase in the risk of death, whereas the poor risk group had a 3.5-fold increase in the odds of death. There was a difference of 7.7 months in median survival and 37.5% in 1-year survival between the good and the bad risk groups. Our index can be used in a similar fashion to the International Prognostic Index for aggressive non-Hodgkin's lymphoma37, allowing risk stratification in future phase III trials and to inform clinical decision-making. Whereas some of these factors are already used for stratification in current randomized controlled trials, our index allows uniform, systematic use of these prognostic factors and informs discussion with patients of their prognosis. It may help to identify a group of patients that benefit most from intensified combination treatment and/or novel targeted therapy. Furthermore, in the future, molecular markers predictive of survival can be incorporated into our simple model in a similar fashion seen in non-Hodgkin's lymphoma38 to evaluate whether additional prognostic information has been obtained by these molecular markers, which are likely to require sophisticated and expensive laboratory investigations. However, our prognostic index requires validation and this will be carried out using the data from our current randomized phase III study with a 2 x 2 factorial design evaluating oxaliplatin in place of cisplatin and capecitabine instead of PVI FU in the ECF regimen. This study aims to recruit 1,000 patients and is expected to finish recruitment in the next 2 years. In our analysis, there were no survival differences among patients with esophageal, EGJ, or gastric cancers. This suggests that the effect on survival from palliative chemotherapy is of similar magnitude in different primary anatomic locations. Therefore, there is no definite need for future phase III studies to distinguish patients with tumors from different anatomic origins if they have advanced disease. Metastatic SCC of the esophagus has been shown to have a better survival than adenocarcinoma using population data from Surveillance, Epidemiology, and End Results.11 However, as there were only 50 patients with SCC in our cohort, we did not evaluate the survival of patients with SCC compared with adenocarcinoma by either univariate or multivariate analyses. Weight loss at presentation has been shown by our group previously to be an important prognostic factor in patients with gastric or EGJ cancer.39 The poorer outcome from treatment in patients with weight loss appeared to be as a result of shorter overall duration of treatment secondary to more frequent and prolonged treatment breaks from toxicity, rather than reduced tumor responsiveness to treatment.39 However, weight loss is subject to recall bias,40,41 therefore we did not investigate this factor in our present analysis.
Pretreatment quality of life has been shown to have prognostic value in esophageal cancer in a previous study of 92 operable and inoperable patients.16 Only physical functioning was found to be significant in this study. In our analysis, better physical and role function, as well as global QoL, significantly predicted better survival. We had data from a large number of patients all using the same validated QoL assessment instrument (EORTC QLQ C-30), allowing more statistical power to detect smaller QoL differences. In addition, these QoL scores independently predicted survival while performance status, a unidimensional tool completed by an observer, remained in the multivariate model. Even when PS was analyzed separately as 0, 1, and In first-line treatment, a number of randomized studies have been performed to establish a superior chemotherapy regimen. The EORTC randomly allocated 399 gastric cancer patients into FAMTX, cisplatin/FU given over 5 days (FUP), and etoposide/bolus FU/leucovorin (ELF).42 There were no significant differences in OS among the three arms. The Japan Clinical Oncology Group study has also recently reported a randomized study of 280 patients evaluating FUP, FU alone, or uracil-tegafur/MMC.43 Again, no survival differences were seen among the three arms. However, ECF has been shown to produce a superior survival to FAMTX23,24, and its activity was further confirmed in the largest randomized study ever conducted in this disease.25 The favorable safety profile of ECF has now been demonstrated in over 1,000 patients in randomized controlled trials.23-25,44 Preliminary data from a study comparing docetaxel/cisplatin/FU (DCF) and FUP has shown a survival benefit for DCF, although there are some concerns with the hematologic toxicity.45 However, survival remains poor for these patients and new drugs are being evaluated, although few randomized phase III data on survival are available. Taxanes such as paclitaxel and docetaxel are active single agents in esophageal cancer with response rates of 15% to 30%. Combinations of paclitaxel and cisplatin with or without fluorouracil have been tested in two phase II studies with prohibitive gastrointestinal and hematologic toxicities resulting in treatment-related death and necessitating hematopoietic growth factor support.46,47 Apart from the previously mentioned study evaluating DCF, docetaxel has also been tested in a randomized phase II study of 85 patients, combined with either irinotecan or FU. Docetaxel/irinotecan produced a response rate of 31%, whereas docetaxel and FU had a response rate of 25.6%. Time to progression and survival were similar in both arms. However, docetaxel/irinotecan was associated with a high rate of grade 3/4 diarrhea, nausea and vomiting, and febrile neutropenia, although stomatitis was more frequent in the docetaxel/FU arm. In another nonrandomized phase II study, docetaxel/irinotecan produced a response rate of 26% with high incidence of grade 3/4 leucopenia and febrile neutropenia prompting protocol amendment to decrease the doses of both drugs.48 Irinotecan has been evaluated as part of the combination therapy with cisplatin in esophageal cancer with promising results.49-51 In a randomized phase II study, irinotecan combined with FU suggested a better survival compared with irinotecan/cisplatin.52 In the previously mentioned phase III study evaluating oxaliplatin and capecitabine as substitution of cisplatin and FU in the ECF regimen, preliminary results on the first 204 patients showed that in the comparison with the platinum-containing regimen, oxaliplatin produced a response rate of 42.7%, whereas cisplatin produced a response of 32.6%. In the comparison between the fluoropyrimidine-containing regimen, capecitabine produced a response rate of 41.1%, whereas FU produced a response of 35%. Both capecitabine and oxaliplatin appear to have promising activity in EG cancer.44 In conclusion, four poor prognostic factors have been identified in patients receiving first-line treatment for locally advanced or metastatic EG cancer. A simple prognostic index has been developed with distinct survival rates among the different risk groups. Baseline QoL predicted survival in patients with EG cancer. Information from this analysis can be used to aid clinical decision-making, help individual patient risk stratification, and serve as a benchmark for the planning of future phase III trials.
The authors indicated no potential conflicts of interest.
We would like to thank all the investigators who contributed patients into these trials (in alphabetical order): H. Anderson (Wythenshaw Hospital, Manchester), Michael Crawford (Airedale, Keighley), F. Daniels (Derriford Hospital, Plymouth), P. Harper (Guy's Hospital, London), T. Hickish (Royal Bournemouth and Poole Hospitals, Bournemouth and Poole), Mark Hill (Kent Oncology Centre, Maidstone), T. Iveson (Salisbury District Hospital, Salisbury), J. Joffe (St James Hospital, Leeds), M. Leahy (Christie Hospital, Manchester), F. Lofts (St George's Hospital, London), M. Mackean (University of Glasgow, Glasgow), J. Mansi (St George's Hospital, London), M. Nicholson (Aberdeen Royal Infirmary, Aberdeen), J. Scarffe (Christie Hospital, Manchester), M. Seymour (Cookridge Hospital, Leeds), and J. Valle (Christie Hospital, Manchester).
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
