Abstract: No chemotherapy regimen showed a survival benefit better than 5-fluorouracil alone in a phase III trial for advanced gastric cancer in 1990s, and several new cytotoxic agents became available in late 1990s. Thereafter, a couple of phase III trials supported the substitution of infusional 5-fluorouracil by orally administered agents and the replacement of cisplatin by oxaliplatin in early 2000s. Furthermore, a substantial amount of information about the heterogeneity and the biological backgrounds of gastric cancer has been obtained from recent trials, and it is suggested that some cytotoxic agents would be well indicated. Trastuzumab has succeeded in showing a survival benefit for patients with Her-2 positive gastric cancer which accounts for about 10-20% of the cancer. This means that the door is opened to the new era of chemotherapy with molecular target agents and with individualization for advanced gastric cancer. The new approach in the development of molecular target agents, e.g., biomarker oriented strategy, for advanced gastric cancer should be studied in clinical trials in the near future.

Introduction

Gastric cancer is the second leading cause of death from malignancy worldwide because many of gastric cancer patients are diagnosed at an unresectable stage. In Japan where more than half of gastric cancer patients can be cured by early detection and surgical resection, it is the second most frequent cancer death after lung cancer. The prognosis of advanced (unresectable or recurrent) gastric cancer is poor. Development of effective chemotherapy regimens has been a very important goal. In 1990s there was no remarkable progress in chemotherapy for advanced gastric cancer, and in early 2000s new cytotoxic agents and optional treatments have emerged. In 2009, it was shown that molecular target agents are effective in treating gastric cancer. Presently, many molecular target agents have been investigated for advanced gastric cancer, and more rapid progress in chemotherapy, including individualized medicine, for gastric cancer can be expected.

In Late 1990s

In 1990s (Table 1), there were several phase III trials of combination chemotherapy regimens using active agents such as 5-fluorouracil, cisplatin, methotrexate, doxorubicin, etoposide, leucovorin, and mitomycin C. Randomized trials comparing systemic chemotherapy with best supportive care showed that 5-fluorouracil-based chemotherapy demonstrated a survival benefit, and thereafter the triplet chemotherapy with epirubicin, cisplatin, and 5-fluorouracil (ECF) showed a survival benefit over another triplet therapy with 5-fluorouracil, doxorubicin, and methotrexate (FAMTX) (Webb et al., 1997). These results concluded that ECF could be recognized as a standard care for advanced gastric cancer. However, there were no differences in overall survival in the phase III trials comparing among ECF, FAMTX, and combination chemotherapy with 5-fluorouracil plus cisplatin (FP) (Vanhoefer et al., 2000). Moreover, in three phase III trials conducted in the United States, Korea, and Japan that compared the combination chemotherapy based on FP with 5-fluorouracil alone, no combination chemotherapy showed a survival benefit over 5-fluorouracil alone in spite of higher response rate and longer progression free survival (Cullinan et al., 1994; Kim et al., 1993; Ohtsu et al., 2003). Thus, there was no consensus about the standard chemotherapy regimen for advanced gastric cancer in 1990s while FP was actually the most common chemotherapy regimen used worldwide.

In Early 2000s

In 2000s (Table 2), a few new agents such as oral fluoropyrimidine (capecitabine, S-1), irinotecan, taxanes (paclitaxel, docetaxel), and oxaliplatin were investigated for treating gastrointestinal cancers, and several phase III trials with these agents were initiated for gastric cancer. There were two trends in new drug development for gastric caner. One was substitution of infusional 5-fluorouracil by oral pyrimidine and replacement of cisplatin by oxaliplatin. In the phase III trial comparing capecitabine plus cisplatin (XP) to FP, XP showed non-inferiority to FP in overall survival (Kang et al., 2009). In the REAL-2 trial, in which four triplet regimens with epirubicin plus fluoropyrimidine (capecitabine vs. 5-fluorouracil) and platinum (oxaliplatin vs. cisplatin) by 2×2 factorial design were compared (Cunningham et al., 2008), it was concluded that 5-fluorouracil and cisplatin could be replaced by capecitabine and oxaliplatin, respectively. There were two studies conducted in Japan. In the JCOG 9912 study, monotherapy with S-1 showed non-inferiority to 5-fluorouracil (Boku et al., 2009). Furthermore, the SPIRITS trial showed that S-1 plus cisplatin brought a significantly longer survival than S-1 alone with acceptable toxicities (Koizumi et al., 2008). From these lines of evidence, it was concluded that combination chemotherapy with oral fluoropyrimidines (capecitabine or S-1) plus platinum (cisplatin or oxaliplatin) has a survival benefit over 5-fluorouracil alone, to which no combination chemotherapy regimens had been shown to be superior in the 1990s. In addition, combination chemotherapy of fluoropyrimidine plus platinum has been recognized to be a standard of care for advanced gastric cancer. Presently, the combination of fluoropyrimidines plus platinum has been the foundation for future progress.

The other trend was triplet chemotherapy with taxane added to fluoropyrimidine and platinum. In the phase III trial comparing triplet chemotherapy with 5-fluorouracil, cisplatin, and docetaxel (DCF) to FP, DCF showed a higher response rate, better progression free survival (PFS), and significantly longer survival than FP (Van Cutsem et al., 2006). This is the first study demonstrating a treatment regimen’s survival benefit over FP. However, because it was associated with severe hematological toxicities that caused febrile neutropenia in 30% of the patients, it has not generally been accepted as a new standard chemotherapy. Recently, the divided administration of docetaxel based on fluoropyrimidine plus cisplatin (modified DCF) has been investigated and its phase II study has shown that this regimen succeeds both in reduction of toxicity and in preservation of anti-tumor effects. As for irinotecan, none of its combination chemotherapies showed a survival benefit in three phase III trials (Boku et al., 2009; Imamura et al., 2008; Dank et al., 2008). The standard chemotherapy for the second line after failure in the first line chemotherapy with fluoropyrimidine plus platinum has not been established; irinotecan and taxanes have been generally used in clinical practice. Monotherapy with irinotecan showed a longer survival than best supportive care in the second line although this phase III study has not been completed because of slow patient accrual.

Molecular Target Agents

Several molecular target agents have been introduced to clinical practice, e.g., trastuzumab for breast cancer and bevacizumab, cetuximab, and panitumumab for colorectal cancer. For advanced gastric cancer, both bevacizumab (Shah et al., 2006) and cetuximab (Pinto et al., 2007) combined with cytotoxic chemotherapy showed very promising progression free survival of 8.3 months in their phase II trials. ToGA trial (an open-label randomized multicenter phase III study of trastuzumab in combination with a fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in patients with HER2 positive gastric cancer) showed a significantly longer survival in the trastuzumab arm than in the chemotherapy alone arm (Van Cutsem et al., 2009). Thus, trastuzumab is the first molecular target agent showing a survival benefit for advanced gastric cancer and its combination chemotherapy with cytotoxic agents is a new treatment option for Her-2 positive gastric cancer. The next large global trial of molecular target agents for gastric cancer is the AVAGAST trial which has been investigating a survival benefit of bevacizumab over fluoropyrimidine plus cisplatin. A phase III trial which compares cetuximab combined chemotherapy to chemotherapy alone is underway. A few phase I trials investigating combination chemotherapy of angiogenesis inhibitors such as sunitinib, sorafenib, cediranib, or axitinib with cytotoxic agents have been conducted for advanced gastric cancer.

Molecular target agents have been also investigated in the second or third line setting. A phase II study of sunitinib has shown partial response achieved in one patient and stable disease in eight out of 21 patients with gastric cancer in the second line setting (Bang et al., 2007). Everolimus (mTOR inhibitor) which is generally used for renal cancer also showed that 10 out of 16 patients had stable disease lasting 8 or more weeks in the second line setting for gastric cancer (Muro et al., 2008). Now, a phase III trial comparing everolimus monotherapy with best supportive care in the second or third line setting for advanced gastric cancer is on-going. A randomized phase II trial of nimotuzumab, an inhibitor of epidermal growth factor receptor (EGFR), in combination with irinotecan for the treatment of gastric cancer has been initiated.

It is expected that these molecular target agents will bring further success in improving the efficacy and toxicity profiles of chemotherapy regimens for advanced gastric cancer.

Personalization

Gastric cancer shows a heterogeneous behavior such as peritoneal metastasis and hematological metastasis. In the subset analysis of the two Japanese phase III trials, JCOG9912 (Boku et al., 2009) and GC0301/TOP002 (Imamura et al., 2008), which had combination chemotherapy containing irinotecan (irinotecan plus cisplatin in JCOG9912 and irinotecan plus S-1 in GC0301/TOP-002) as a test arm, both of these irinotecan containing arms showed favorable survival in the subset of the patients having target lesions defined by Response Evaluation Criteria In Solid Tumors (RECIST ver. 1.0) compared to control arms (5-fluorouracil and S-1, respectively). On the contrary, in the SPIRITS trial (Koizumi et al., 2008) which showed a survival benefit of S-1 plus cisplatin in the generalized analysis among all trial participants, the hazard ratio of S-1 plus cisplatin compared with S-1 was near 1.0 in the subset of patients who had target lesions. On the other hand, peritoneum is one of common metastatic sites from gastric cancer, and it is well known that irinotecan often causes severe toxicities in patients with complications of bowel obstruction due to peritoneal metastasis. In the subset of patients who had peritoneal metastasis in both trials of JCOG9912 (Boku et al., 2009) and GC0301/TOP-002 (Imamura et al., 2008), the survival of patients who were treated with irinotecan-containing regimens was substantially worse than that in control arms, while irinotecan showed favorable survival in the subset of patients without peritoneal metastasis. It is thought that some of the cytotoxic agents might have optimal indications, and contraindications.

The toxicities of S-1 have been reported to be more severe in Caucasian patients (Ajani et al., 2005) than in Asians, resulting in different recommended doses for combination chemotherapy of S-1 plus cisplatin. While S-1 plus cisplatin showed a significant superiority to 5-fluorouracil plus CDDP in a Chinese trial using doses of S-1 administered in a Japanese trial (SC-101 study) (Jin et al., 2008), it did not show a similar superiority in the Western trial with doses recommended for Caucasians (FLAGS) (Ajani et al., 2009). Differences in toxicities, e.g., diarrhea, caused by tegafur and uracil were also observed between Japanese and American patients. It was concluded that there may be some ethnic differences in the tolerability of oral fluoropyrimidine. Although all present global phase III trials adopt a unified dose now, it can be recommended that optimal drugs and doses in each region may be adopted for maximum benefit-to-toxicity ratio.

There have been reports about biomarkers that can predict responders and non-responders to molecular target agents. Gefitinib showed remarkable effects for the patients who have some specific somatic mutations close to the region encoding the adenosine triphosphate-binding pocket of the kinase domain of EGFR, and cetuximab is not effective for colorectal cancer patients having mutations in the K-ras gene. As mentioned above, trastuzumab showed a survival benefit in patients with Her-2 positive gastric cancer in the ToGA trial (Van Cutsem et al., 2009) in spite of the low proportion of Her-2 positivity (10-20%). Here, ToGA trial has generated an important finding that some gastric and breast cancers share the therapeutic benefit from a targeted therapy drug (trastuzumab) based on the common biomarker (Her-2). Lapatinib, which has been shown to be therapeutically active to Her-2 positive breast cancer after failure of trastuzumab, has also been investigated for advanced gastric cancer. In other words, ToGA trial has opened the door to personalized medicine for advanced gastric cancer.

Now, personalized medicine is a very important issue to be investigated for molecular target agents. Because many gene abnormalities and growth factors have been reported to be involved in gastric cancers, there should be specific biomarkers that could be good targets for certain molecular target agents. Because it is relatively straightforward to take tumor tissues by endoscopic biopsy before and after chemotherapy, gastric cancer is considered to be a productive field for translational research starting from the early stages of new drug development.

Clinical trials of molecular target agents should focus on the specific sets of patients and should be combined with optimal cytotoxic agents at optimal doses according not only to patients’ clinical and genetic backgrounds but also to biological manifestations of gastric cancers. In the future, a paradigm shift from the disease-specific new drug development to the biomarker-oriented investigation is gaining momentum. Clinical trials for patients with various kinds of tumors who are expected to be excellent responders due to the expression of certain biomarkers should objectively compare the effects of molecular target agents with those of the established standard chemotherapy regimen for each disease.

Conclusion

Until now, many clinical trials of conventional cytotoxic agents have been conducted, and the clinical outcomes of advanced gastric cancer patients have been improved. Furthermore, a lot of information about the heterogeneity and the biological backgrounds of gastric cancer has been accumulated. Recently, new drug development has been focusing on molecular target agents, and the door to personalized chemotherapy for advanced gastric cancer has just been opened. New approaches in the development of molecular target agents should be explored in the future.

References

Ajani JA, Faust J, Ikeda K, Yao JC, Anbe H, Carr KL, Houghton M, Urrea P. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 23(28):6957-65, 2005.

Ajani JA, Rodriquez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses. Annual Meeting of ASCO, abstract #4511, 2009.

Bang Y, Kang Y, Kang W, Boku N, Chung H, Lanzalone S, Lechuga MJ, Sherman L, Chao R, Sobrero A. Sunitinib as second-line treatment for advanced gastric cancer: preliminary results from a phase II study. Annual Meeting of ASCO, abstract #4603, 2007.

Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, et al. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol 10(11):1063-9, 2009.

Cullinan SA, Moertel CG, Wieand HS, O’Connell MJ, Poon MA, Krook JE, Mailliard JA, Tschetter LK. Controlled evaluation of three drug combination regimen versus fluorouracil alone in the therapy of advanced gastric cancer. J Clin Oncol 12:412-6, 1994.

Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR. Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer. N Engl J Med 358:36-46, 2008.

Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol 19:1450-7, 2008.

Imamura H, IIishi H, Tsuburaya A, Hatake K, Imamoto H, Esaki T, Kato M, Furukawa H, Hamada C, Sakata Y. Randomized phase III study of irinotecan plus S-1 (IRIS) versus S-1 alone as first-line treatment for advanced gastric cancer (GC0301/TOP-002). ASCO Gastrointestinal Symposium, abstract #5, 2008.

Jin M, Lu H, Li J, Shen L, Chen Z, Shi Y, Song S, Qin S, Liu J, Ouyang X. Randomized 3-armed phase III study of S-1 monotherapy versus S-1/CDDP (SP) versus 5-FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC-101 study. Annual Meeting of ASCO, abstract #4533, 2008.

Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20(4):666-73, 2009.

Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, Kang YK, Shin DB, Kim HT, Kim HJ, et al. A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 71:3813-8, 1993.

Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9(3):215-21, 2008.

Muro K, Boku N, Yamada Y, Nishina T, Doi T, Takiuchi H, Tajima T, Takahashi A, Fujita Y, Ohtsu A. Multicenter phase II study of RAD001 for previously treated metastatic gastric cancer (MGC): Preliminary results. Annual Meeting of ASCO, abstract #4541, 2008.

Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable advanced gastric cancer: the Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21(1):54-9, 2003.

Pinto C, Di Fabio F, Siena S, Siena S, Falcone A, Cascinu S, Rojas Llimpe FL, Stella G, Schinzari G, Artale S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 18(3):510-7, 2007.

Shah MA, Ramanathan RK, Ilson DH, Levnor A, D’Adamo D, O’Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24(33):5201-6, 2006.

Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24(31):4991-7, 2006.

Van Cutsem E, Kang Y, Chung H, Shen L, Sawaki A, Lordick F, Hill J, Lehle M, Feyereislova A, Bang Y. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Annual Meeting of ASCO, abstract #LBA4509, 2009.

Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Planker M, Santos JG, Piedbois P, Paillot B, et al. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18(14):2648-57, 2000.

Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15(1):261-7, 1997.

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