Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

Background

The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy.

Methods

We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (ρ).

Results

Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (ρ = 0.56). The correlation tended to be stronger in non-Asian trials (ρ = 0.74) than in Asian trials (ρ = 0.37). ORR and DCR did not strongly correlate with OS (ρ = 0.38 for ORR; ρ = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (ρ = 0.36).

Conclusions

PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.     

Adenokarzinome des Magens und gastroösophagealen Übergangs

Context

There is worldwide consensus that curative treatment of gastroesophageal adenocarcinoma can be optimized by a multidisciplinary approach.

Method

Literature research and analysis of clinical trials.

Results

In the USA adjuvant chemoradiotherapy is a standard of care for gastric cancer. Asian trials could show an improvement in survival by adjuvant chemotherapy. In Europe the recommendations are based on the British MAGIG trial and the French FNCLCC study. In these trials patients with adenocarcinoma of the stomach and gastroesophageal junction (GEJ) were treated with platinum 5-FU-based perioperative chemotherapy and overall survival could be significantly improved. For the treatment of adenocarcinoma of the GEJ preoperative radiochemotherapy is an equivalent standard. A significant improvement of survival could also be shown for this treatment.

Conclusion

The German S3 guidelines recommend perioperative chemotherapy for gastric tumors of at least stage uT3 and for GEJ adenocarcinoma either perioperative chemotherapy or preoperative radiochemotherapy.     

Advanced or metastatic gastric cancer in elderly patients: clinicopathological, prognostic factors and treatments

Purpose

To analyze the clinicopathological features, prognostic factors, treatment efficacy and safety among elderly patients with advanced or metastatic gastric cancer.

Methods

Three hundred and nineteen patients aged 65 years and older, diagnosed with advanced or metastatic gastric cancer, were followed and data were retrospectively collected, reviewed and analyzed.

Results

The elderly patients carried specific clinicopathological characteristics. Body mass index (BMI), number of metastatic lesions, ascites, Karnofsky performance score (KPS), tumor differentiation grade, lactate dehydrogenase (LDH) level, local treatment, and chemotherapy were the independent prognostic factors. Serum LDH level was superior to the serum CEA level in the prognosis of advanced or metastatic gastric cancer in older patients. Cisplatin-based regimen, chemotherapy cycles, metastatic lesions, LDH level, and supraclavicular lymph node metastasis were the independent prognostic factors in 220 patients receiving chemotherapy. The toxicity was mild and tolerable.

Conclusion

KPS, BMI and a well-differentiated histopathology were factors favoring longer survival, whereas elevated serum LDH and a greater number of metastatic lesions were associated with poor prognosis among those elderly patients. Cisplatin-based chemotherapy provided survival benefits and mild toxicity.     

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative,hormone-receptor-positive breast cancer in BOLERO-2

Background

The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR⁺) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757–62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported.

Methods

Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety.

Results

Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41–0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33–0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients.

Conclusion

Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR⁺/HER2^? advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.     

Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study

Background

The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients.

Methods

We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n?=?51; chemotherapy, n?=?50).

Results

Median overall survival in the Japanese subgroup was 15.9?months (95% confidence interval 12–25) for trastuzumab plus chemotherapy and 17.7?months (95% confidence interval 12–24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59–1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36–1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios.

Conclusions

After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.     

Progression-free survival results in postmenopausal Asian women: subgroup analysis from a phase III randomized trial of fulvestrant 500 mg vs anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON)

Background

The international, phase III FALCON study (NCT01602380) in postmenopausal patients with hormone receptor-positive, locally advanced/metastatic breast cancer (LA/MBC) who had not received prior endocrine therapy, demonstrated statistically significant improvement in progression-free survival (PFS) for patients who received fulvestrant 500 mg vs anastrozole 1 mg. This subgroup analysis evaluated PFS in Asian (randomized in China, Japan, or Taiwan) and non-Asian patients from the FALCON study.

Methods

Eligible patients (estrogen receptor- and/or progesterone receptor-positive LA/MBC; World Health Organization performance status 0–2; ≥ 1 measurable/non-measurable lesion[s]) were randomized. PFS was assessed via Response Evaluation Criteria in Solid Tumours version 1.1, surgery/radiotherapy for disease worsening, or death (any cause). Secondary endpoints included: objective response rate, clinical benefit rate, duration of response, and duration of clinical benefit. Consistency of effect across subgroups was assessed via hazard ratios and 95% confidence intervals (CIs) using a log-rank test. Adverse events (AEs) were evaluated.

Results

Of the 462 randomized patients, the Asian and non-Asian subgroups comprised 67 and 395 patients, respectively. In the Asian subgroup, median PFS was 16.6 and 15.9 months with fulvestrant and anastrozole, respectively (hazard ratio 0.81; 95% CI 0.44–1.50). In the non-Asian subgroup, median PFS was 16.5 and 13.8 months, respectively (hazard ratio 0.79; 95% CI 0.62–1.01). Secondary outcomes were numerically improved with fulvestrant vs anastrozole in both subgroups. AE profiles were generally consistent between Asian and non-Asian subgroups.

Conclusions

Results of this subgroup analysis suggest that treatment effects in the Asian patient subgroup are broadly consistent with the non-Asian population.

     

Outcomes of multiple salvage chemotherapy for advanced gastric cancer: implications for clinical practice and trial design

Purpose

We analyzed the natural history of advanced gastric cancer with sequential salvage chemotherapy following first-line treatment.

Methods

We studied 532 patients with unresectable gastric adenocarcinoma who were treated at Yonsei Cancer Center (2000–2008). The patients were managed with multiple sequential salvage chemotherapy as allowed by performance status and toxicity profiles. The tumor response was assessed every two cycles.

Results

Four hundred sixty patients received palliative chemotherapy and 72 received supportive care only. The median overall survival was 12.0 months for all patients, 12.1 months for the chemotherapy group, and 2.5 months for the supportive care group (P < 0.001). In the chemotherapy group, 87% received first-line chemotherapy, 47% second-line, 23% third-line, 9% fourth-line, and 3% fifth-line. Response rates were 24.8, 12.6, 10.9, 2.6, and 0% and disease control rates were 76.3, 60.1, 54.2, 54.2, and 53.3% for first- to fifth-line treatment, respectively. The median progression-free survival was 5.5, 3.4, 2.5, 1.9, and 2.0 months and overall survival was 12.1, 7.9, 5.5, 5.0, and 6.8 months. Performance status and metastatic pattern were consistent prognostic factors throughout salvage treatment.

Conclusions

Clinical trials may be feasible in second- or third-line salvage chemotherapy for gastric cancer. Future clinical trials in these settings should take into account the low response rate, short progression-free survival, and the prognostic factors for optimal trial design.     

Efficacy and cost-effectiveness of second-line chemotherapy in elderly patients with advanced gastric cancer

Purpose

Second-line chemotherapy has been shown to benefit patients with advanced gastric cancer (AGC), extending the overall survival (OS) and progression-free survival (PFS). This study aimed to assess the efficacy and cost-effectiveness of second-line treatment for elderly patients with AGC.

Methods

Medical records and follow-up information of elderly patients (≥70 years) with AGC who received second-line chemotherapy were collected. A Markov model comprising three health states PFS, progressive disease and death was developed to simulate the process of AGC. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables.

Results

Forty-three elderly patients with AGC receiving second-line chemotherapy were included in our study. The median OS was 6.0 months (95% confidence interval (CI) 3.90–8.10) and PFS was 3.1 months (95% CI 1.38–4.82). No treatment-related death occurred. The most frequently drug-related grade 3/4 AEs were diarrhea (2.3%), leukopenia (16.3%) and nausea (7.0%). The incremental cost-effective ratio was $18,223.75/QALY for second-line chemotherapy versus BSC, which was below the threshold of 3× the per capita GDP of China, $23,970.00.

Conclusion

Second-line chemotherapy was an optimal strategy for elderly AGC patients in China from the efficacy and cost-effectiveness perspective.

     

Gastrointestinal Cancer Educational Case Series: The History and Management of Complex Cases in GI Oncology. A 72 Year-Old Man with Metastatic Gastric Cancer

Introduction

Gastric cancer is the third most common cancer worldwide and the second leading cause of cancer deaths. Appropriate staging and treatment options relate to the stage of disease and performance status of the patient.

Case report

Here we present the case of a 72 year old male, with an initial presentation of apparently locally advanced gastric cancer. On discovery of metastatic disease, the utility of palliative gastrectomy, and first and second line chemotherapy are discussed.

Discussion

This case demonstrates the potential value of sequential lines of chemotherapy in good performance status patients with advanced gastric cancer. Further research will be necessary in order to assess the utility of newer targeted agents in this setting.     

Modified GTX as Second-Line Therapy for Advanced Pancreatic Adenocarcinoma

Background

Advanced pancreatic cancer remains a lethal disease with no standard treatment beyond first-line palliative chemotherapy. Gemcitabine, docetaxel, and capecitabine (GTX) is a regimen that has come into use for advanced pancreatic cancer despite a paucity of randomized data.

Methods

We have used a modified schedule of this regimen in the second-line setting aimed at biomodulating the activity of capecitabine by both docetaxel and gemcitabine. This report describes our experience with the use of modified GTX in nine patients with advanced pancreatic cancer as second-line chemotherapy.

Conclusion

In our series, the median overall survival was 8 months (range 5.2–10.8). Prospective studies of this regimen in the second-line setting are warranted.     

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.     

Out-of-pocket payment and cost-effectiveness of XELOX and XELOX plus bevacizumab therapy: from the perspective of metastatic colorectal cancer patients in Japan

Objective

The purpose of our study was to estimate the out-of-pocket payment and cost-effectiveness of capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab from the perspective of patients with metastatic colorectal cancer (MCRC).

Methods

Based on the NO16966 and NO16967 trials, the mean out-of-pocket payment was calculated from patient-level data. Out-of-pocket payments for 16 cycles (11 months) of first-line chemotherapy and 8 cycles (5 months) of second-line chemotherapy were included. In addition, incremental cost-effectiveness ratios (ICERs) for first-line bevacizumab were calculated by dividing the difference of the out-of-pocket payment by the difference of the mean number of progression-free survival (PFS) years or quality-adjusted PFS (QAPFS) years.

Results

The mean out-of-pocket payments for middle-income patients under 70 years of age were JPY 328,000 for 16 cycles of first-line XELOX and JPY 376,000 for XELOX plus bevacizumab. The mean out-of-pocket payment for 8 cycles of second-line XELOX was calculated to be JPY 175,000. Middle-income patients over 70 years of age were required to pay JPY 61,000 and JPY 72,000 for first-line XELOX and XELOX plus bevacizumab, respectively. The ICERs of middle-income patients <70 years of age were JPY 430,000/PFS-year and JPY 720,000/QAPFS-year, and those of middle-income patients >70 years of age were JPY 100,000/PFS-year and JPY 170,000/QAPFS-year.

Conclusions

We clarified the out-of-pocket payment and cost-effectiveness of chemotherapy of MCRC patients in Japan. Our previous survey shows it is highly possible that many patients prefer to pay that incremental out-of-pocket payment to gain one additional QAPFS year. However, our cost-effectiveness analysis was not conducted from the perspective of society or healthcare payers.     

Docetaxel,oxaliplatin, and capecitabine combination chemotherapy for metastatic gastric cancer

Background

The incorporation of docetaxel into the cisplatin and fluorouracil backbone has been demonstrated to be an active combination in metastatic gastric cancer. Nevertheless, this regimen is burdened by nonnegligible toxicity. We hypothesized that replacing cisplatin and fluorouracil with oxaliplatin and capecitabine should be an active and safe option for metastatic gastric cancer patients.

Methods

In this phase II study, we tested the activity of docetaxel in combination with oxaliplatin and capecitabine (DOC) as a first-line treatment. DOC was administered as follows: docetaxel (60 mg/m²) and oxaliplatin (100 mg/m²) on day 1, and capecitabine (500 mg/m²) was administered orally twice daily given continuously, with cycles repeated every 3 weeks. The primary endpoint was the overall response rate.

Results

Forty-eight patients entered the study. All patients had metastatic disease (stage IV). None of the patients had previously received chemotherapy for advanced disease. Performance status was 0, 1, and 2 in 25, 58, and 17 % of patients, respectively; 13 patients (27 %) had adenocarcinoma of the gastroesophageal junction, and 29 patients (60.5 %) had two or more metastatic sites. The overall response rate was 52.1 %. Progression-free survival and overall survival were 6.9 and 12.6 months, respectively. The treatment was well tolerated with no treatment-related deaths. The most common grade 3–4 toxicity was neutropenia (41 %).

Conclusions

DOC is an effective and tolerated first-line treatment, and the lower dose of docetaxel and oxaliplatin used in this study compared with other similar regimens does not seem to hamper the antitumor activity.     

Gemcitabine and docetaxel,an effective second-line chemotherapy for lung metastasis of urothelial carcinoma

Background

The objective of this study was to evaluate the efficacy of a gemcitabine and docetaxel (GD) combination as a second-line treatment for patients with metastatic urothelial carcinoma (UC) after failure of first-line treatment with platinum-based chemotherapy.

Methods

From June 2006 to January 2012, 38 patients with metastatic UC previously treated with platinum-based chemotherapy received GD therapy. This consisted of gemcitabine 800 mg/m² and docetaxel 40 mg/m² on days 1 and 8 of each 21-day cycle as second-line chemotherapy. All the patients were evaluated for toxicity and assessed every cycle by imaging. We analyzed the efficacy of GD as second-line chemotherapy in the follow-up study.

Results

The median number of GD treatment cycles was 4 (range 2–9); the objective response rate was 47.4 %; and the median progression-free survival and median overall survival were 4.1 and 10.8 months, respectively. Univariate and multivariate analyses on the GD treated group showed that the existence of lung metastases was the only prognostic factor for tumor response. Grade 3 treatment-related toxicity included neutropenia (31.6 %) and thrombocytopenia (15.8 %), and only one patient with grade 4 toxicity had thrombocytopenia (2.6 %).

Conclusions

The GD regimen as second-line chemotherapy was especially effective for lung metastatic UC and yielded favorable results in patients whose first-line platinum-based chemotherapy had failed. Given the safety and benefit profile seen in this study, a large prospective study is warranted to consider the potential utility of GD chemotherapy as a second-line for UC.     

Single-agent chemotherapy compared with combination chemotherapy as second-line treatment in extensive-stage small cell lung cancer: a retrospective analysis

Objective

This retrospective analysis evaluates the clinical outcomes of extensive-stage small cell lung cancer (SCLC) patients who received second-line chemotherapy after platinum-based first-line chemotherapy, especially focusing on efficacy and toxicity between single-agent and combination chemotherapy.

Methods

We retrospectively reviewed 193 patients who received second-line chemotherapy for extensive-stage SCLC. Patients relapsing or progressing beyond 90 days were defined as sensitive recurrence patients, and below 90 days as refractory recurrence patients. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis.

Results

138 patients received combination chemotherapy and 55 received single-agent treatment. The objective response rate (ORR) was 25.4 % in the combination group and 9.1 % in the single-agent group (p = 0.012). The disease control rate (DCR) was 65.2 and 34.5 %, respectively, (p < 0.001). The progression-free survival (PFS) was 3.80 months in the combination group and 2.13 months in the single-agent group (p = 0.001). In the sensitive recurrence group, the median PFS was 3.80 months in combination group and 3.23 months in single-agent group (p = 0.092). In the refractory recurrence group, the median PFS was 2.83 and 1.30 months, respectively (p = 0.001). The grade III/IV toxicity in single-agent group is much lower than the combination group (56.4 vs. 74.6 %, p = 0.013).

Conclusion

Our retrospective data suggest a potential role of prolonging the PFS for combination treatment in extensive-stage SCLC second-line treatment, especially for the refractory recurrence patients, but with more toxicity as compared to single-agent.     

A phase II study of biweekly mitomycin C and irinotecan combination therapy in patients with fluoropyrimidine-resistant advanced gastric cancer: a report from the Gastrointestinal Oncology Group of the Japan Clinical Oncology Group (JCOG0109-DI Trial)

Background

Preclinical studies have shown that mitomycin C (MMC) acts synergistically with irinotecan (CPT-11). In this phase II study, we evaluated the efficacy and toxicity of MMC/CPT-11 therapy as second-line chemotherapy for patients with fluoropyrimidine-resistant advanced gastric cancer.

Methods

Eligible patients had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens or had relapsed within 6?months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of MMC (5?mg/m²) and CPT-11 (150?mg/m²) administered i.v. every 2?weeks. The primary endpoint was the response rate (RR). Our hypothesis was that this combination therapy was efficacious when the lower boundary of the 95% confidence interval (CI) of the RR exceeded 20% of the threshold RR.

Results

Between April 2002 and July 2003, 45 eligible patients were registered and analyzed. Among the 45 patients, 40 (89%) had previously received chemotherapy for metastasis and 24 (53%) had a performance status (PS) of 0. Thirteen partial responses were obtained among the 45 patients, resulting in an overall RR of 29% (95% CI, 16?C42%). The median time to progression was 4.1?months, and the median survival time was 10?months, with a 1-year survival rate of 36%. Grade 4 neutropenia was observed in 29% of the patients, whereas febrile neutropenia occurred in 9%. The incidence rates of grade 3 nausea and diarrhea were 13 and 2%, respectively.

Conclusions

Although this study did not achieve the per-protocol definition of activity, the progression-free survival and overall survival appeared to be promising, with acceptable tolerability. Thus, MMC/CPT-11 therapy as second-line chemotherapy for fluoropyrimidine-resistant advanced gastric cancer presents a potential treatment option in patients with a good PS.     

A phase II study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma

Purpose

Adjuvant chemotherapy trial of TS-1 for gastric cancer study demonstrated that postoperative S-1 chemotherapy for 1 year improved overall survival of locally advanced gastric cancer (LAGC) patients. The goals of this study were to evaluate the feasibility and efficacy of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy.

Methods

In this single-center, open-label, phase II study, patients with potentially resectable adenocarcinoma of the stomach or gastroesophageal junction were eligible. For neoadjuvant chemotherapy, docetaxel 50 mg/m² on day (D) 1, oxaliplatin 100 mg/m² on D1, and S-1 40 mg/m² bid orally on D1–14 were administrated every 3 weeks for three cycles. After DOS chemotherapy, gastrectomy was performed, and then, adjuvant S-1 40 mg/m² bid was given on D1–28 every 6 weeks for 1 year. The primary endpoints were the proportion of patients who did not experience grade 3 or 4 toxicities (except grade 3 neutropenia) and R0 resection rates.

Results

A total of 41 patients were enrolled. All patients completed three planned cycles of neoadjuvant chemotherapy without disease progression. Eighteen patients (43.9 %) did not experience any grade 3–4 toxicity (except grade 3 neutropenia) during the neoadjuvant chemotherapy. All patients underwent surgery, and R0 resection was achieved in 40 patients (97.6 %).

Conclusion

Neoadjuvant DOS chemotherapy could be performed safely with a high R0 resection rate in LAGC patients. A phase III trial is currently underway.     

A Phase II Study of Capecitabine,Oxaliplatin, and Bevacizumab in the Treatment of Metastatic Esophagogastric Adenocarcinomas

Background.

Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas.

Methods.

Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m² BID on days 1–14, and oxaliplatin 130 mg/m² with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor.

Results.

Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome.

Conclusions.

Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.     

Therapie des fortgeschrittenen Magenkarzinoms

Context

In the metastatic setting treatment goals are palliative. Chemotherapy can prolong survival, improve symptoms and can help to maintain a better quality of life.

Objective

The aim of this study was to discuss the new treatment options and the existing results in advanced gastric cancer.

Material and methods

Treatment recommendations are given in consideration of updated literature (Pubmed, MEDLINE and manual search).

Results

Combination chemotherapy including a platinum compound and a fluoropyrimidine are regarded as the gold standard of care. Oxaliplatin can substitute for cisplatin while capecitabine or S1 can substitute for infusional 5-FU. In elderly patients oxaliplatin has advantages compared with cisplatin. Triplet combinations containing a platinum salt, a fluoropyrimidine and a taxane or (with less evidence) an anthracycline are more efficacious but also expose patients to more side effects. Second line chemotherapy is indicated for patients who progress during or after first line chemotherapy. The monoclonal antibody trastuzumab has been shown to prolong survival when combined with cisplatin and 5-FU or capecitabine in gastric cancer patients with overexpression of the growth factor HER2.

Conclusion

The therapeutic options for advanced gastric cancer have significantly increased. Presently, there are several effective treatment regimens available.     

Evaluation of Hypertension as a Marker of Bevacizumab Efficacy

Background

Predictive factors for efficacy of vascular endothelial growth factor pathway-targeted therapies have not been identified or confirmed. Hypertension has been observed as a side effect to anti-vascular endothelial growth factor therapy. The goal of our study was to retrospectively assess if hypertension induced during treatment with bevacizumab was associated with clinical outcome in metastatic colorectal cancer patients treated with bevacizumab.

Patients and methods

We conducted a retrospective chart review of patients with colorectal cancer treated with bevacizumab at Lombardi Comprehensive Cancer Center from 2004 to 2008.

Results

Eighty-four patients with metastatic colorectal cancer were eligible. Eighteen patients (21%) developed grades 3 hypertension. Twelve patients (14%) developed grade 2 hypertension. Six patients (7%) developed grade 1 hypertension. Median overall survival (OS) was 29 months and progression-free survival (PFS) was 10 months. Patients with any grade hypertension while on bevacizumab had an adjusted hazard ratio for death of 0.32 (p?=?0.03) and adjusted risk of progression of 51% (p?=?0.02) compared to those without hypertension (HTN). When stratified by metastatic disease, patients presenting with metastases who developed HTN had better OS and PFS (p?=?0.03 and 0.01.) Among patients without metastases at diagnosis, those with HTN on bevacizumab had better OS and PFS but results were not statistically significant (p?=?0.60 and 0.62, respectively).

Conclusions

Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving bevacizumab.