Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 12/28/14 For personal use only.
Review
Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer Expert Rev. Anticancer Ther. 14(8), 887–900 (2014)
Marcelo Garrido*1, Paula J Fonseca2, Jose Marı´a Vieitez2, Madalina Frunza3 and Angel J Lacave2,4 1 Hemato-Oncology Department, Pontifical Catholic University of Chile, Diagonal paraguay 319, Santiago de chile, Chile 2 Medical Oncology Department, Asturias Central University Hospital, Oviedo, Spain 3 Surgery Department, Asturias Central University Hospital, Oviedo, Spain 4 Sanatorio Nuestra Sen˜ora de Covadonga, Gijo´n, Spain *Author for correspondence: Tel.: +56 023 546 919 Fax: +56 022 472 327 [email protected]
informahealthcare.com
Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2-positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease. KEYWORDS: 5-fluorouracil • advanced gastric cancer • chemotherapy • cisplatin • docetaxel • targeted agents • trastuzumab
Gastric cancer was the most frequent cause of tumors until the first half of the twentieth century. Although the overall incidence has declined over the last 25 years, gastric cancer remains the fourth most common cancer and the second leading cause of cancer-related death worldwide [1]. Over 70% of these cancers occur in low-income countries, and the mortality rate in young cohorts in developed countries has risen [2]; gastric cancer may be among the top 10 leading causes of death by 2030 [3]. The high mortality rate of gastric cancer is a consequence of its capacity to produce metastases, especially in the liver and peritoneal cavity and in distant lymph nodes such as the left supraclavicular nodes (node of Virchow) and the left axillary nodes (node of Irish). Therefore, it is essential to develop effective treatments to treat gastric cancer. The present review addresses the treatment of advanced gastric cancer (AGC) and focuses on designing criteria for selecting the most appropriate first-line chemotherapy among multiple medical treatment approaches for treating a type of cancer for which there is no consensus on the appropriate gold standard 10.1586/14737140.2014.915194
regimen and for which the median overall survival (OS) rate, regardless of chemotherapy, has remained approximately 9–11 months for more than 30 years [4]. Methods
We performed a review of the English language published literature on chemotherapy and AGC. The search was performed in PubMed, The Cochrane Library and EMBASE and covered the time period from 1970 to 2013. The search strategy included diverse combinations of the following terms: ‘metastatic or AGC’, ‘stomach cancer’, ‘esophagogastric junction cancer’, ‘chemotherapy’, ‘targeted therapy’ and ‘Phase III study’. In topics without consistent Phase III studies, Phase II trials were included. Articles were also identified through searches of the major oncology congress, databases including those of American Society of Clinical Oncology, European Society of Medical Oncology, International Gastric Cancer Association and Latin American Society of Gastrointestinal Oncology databases. The references of selected papers also served as sources of additional information.
2014 Informa UK Ltd
ISSN 1473-7140
887
Review
Garrido, Fonseca, Vieitez, Frunza & Lacave
Who should be treated, & when should treatment begin?
The following patients most likely do not benefit from chemotherapy: frail 90 elderly, those with severe morbidity fac80 tors, those with severe ascites due to 70 peritoneal carcinomatosis and those with liver failure due to multiple metas60 tases. Patients who do not belong to the With chemotherapy 50% above groups should be rated by a med50 Without chemotherapy ical oncologist and should be offered 40% 40 chemotherapy; all of the studies that compared chemotherapy with BSC 30 showed that chemotherapy increased the quality of life and prolonged the OS rate. 20 A randomized study assessed whether the proper time to begin chemotherapy 10% 10% was once metastatic disease had been 10 diagnosed or in cases of bad symptomatic 5% 3% control. Patients receiving chemotherapy 2% from the beginning had an improved quality of life in 70% of the cases and a median OS of 8 months. Of the patients who were randomized to symptomatic treatment alone, only 25% experienced Figure 1. Overall survival of patients with advanced gastric cancer treated with an improvement in their symptoms with and without chemotherapy. a median OS time of 4 months, though half of them received chemotherapy at Chemotherapy compared with the best supportive care some point over the evolution of the disease. The results demIn the 1990s, at least three randomized studies were pub- onstrated that systemic chemotherapy could add both quantity lished that had been designed to verify whether chemother- and quality of life in AGC patients and that it should be initiapy had any benefit in the treatment of AGC compared with ated once metastatic disease had been diagnosed even in asympbest supportive care (BSC) [5–7]. In these trials, drug combi- tomatic patients [9]. nations containing 5-fluorouracil (5-FU) showed a 61% increase in survival rate with a hazard ratio (HR) of 0.39. Cytotoxic agents in AGC The median survival time of the groups treated with chemo- The classically active drugs are considered cytotoxic agents that therapy was 9–11 months compared with 3–4 months in the show at least 20% activity when used as first-line treatment [10]. groups without chemotherapy which represents a significant These drugs include 5-FU, doxorubicin, epirubicin and cisdifference. Patients who did not receive chemotherapy had a platin, as well as the newer drugs docetaxel [11,12], paclitaxel [13], median survival time of 3–4 months, a 1-year survival rate irinotecan [14], capecitabine [15], S-1 [16] and oxaliplatin [17]. No studies conducted in Western countries have sufficiently of 10%, a 2-year survival rate of 5% and a 5-year survival rate of 2%. Patients treated with chemotherapy in most of validated the activity of mitomycin-C or carmustine (BCNU). the published studies had median survival times of Drugs with intermediate activity are considered to be those 9–10 months, a 1-year survival rate of 30–40% and a 2-year with 10% activity as a first-line treatment such as hydroxyurea, survival rate of 10%. However, from 3 years onward, the dacarbazine, chlorambucil and mechlorethamine. However, the survival curves of the patients treated with or without che- references concerning these agents are very old and have not motherapy did not differ (FIGURE 1). A meta-analysis published been confirmed by recent studies. This group of cytotoxic in 2010 examined 35 trials and included a total of agents with intermediate activity includes a third-generation 5726 patients in the OS analysis. The comparison of chemo- drug, topotecan. Etoposide received the most interest at the therapy and BSC consistently demonstrated a significant ben- end of the 1980s when the first study with a regimen of etopoefit in OS in favor of the group receiving chemotherapy side, adriamycin and platinum revealed a high response rate (HR: 0.37; 95% CI: 0.24–0.55) [8]. These results confirmed (RR) that was unfortunately not confirmed in subsequent studthe relative chemosensitivity of AGC and supported the ies. The activity of etoposide, adriamycin and platinum is 14% as a first-line treatment, 10% as a second-line treatment and search for better regimens. 888
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Overall survival of patients (%)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 12/28/14 For personal use only.
100
Expert Rev. Anticancer Ther. 14(8), (2014)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 12/28/14 For personal use only.
Challenges in first-line chemotherapy and targeted therapy in AGC
18% for oral etoposide. Pemetrexed has not yet been sufficiently studied. Currently, the following drugs are considered to be inactive (i.e., drugs with
Review
Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer Expert Rev. Anticancer Ther. 14(8), 887–900 (2014)
Marcelo Garrido*1, Paula J Fonseca2, Jose Marı´a Vieitez2, Madalina Frunza3 and Angel J Lacave2,4 1 Hemato-Oncology Department, Pontifical Catholic University of Chile, Diagonal paraguay 319, Santiago de chile, Chile 2 Medical Oncology Department, Asturias Central University Hospital, Oviedo, Spain 3 Surgery Department, Asturias Central University Hospital, Oviedo, Spain 4 Sanatorio Nuestra Sen˜ora de Covadonga, Gijo´n, Spain *Author for correspondence: Tel.: +56 023 546 919 Fax: +56 022 472 327 [email protected]
informahealthcare.com
Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2-positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease. KEYWORDS: 5-fluorouracil • advanced gastric cancer • chemotherapy • cisplatin • docetaxel • targeted agents • trastuzumab
Gastric cancer was the most frequent cause of tumors until the first half of the twentieth century. Although the overall incidence has declined over the last 25 years, gastric cancer remains the fourth most common cancer and the second leading cause of cancer-related death worldwide [1]. Over 70% of these cancers occur in low-income countries, and the mortality rate in young cohorts in developed countries has risen [2]; gastric cancer may be among the top 10 leading causes of death by 2030 [3]. The high mortality rate of gastric cancer is a consequence of its capacity to produce metastases, especially in the liver and peritoneal cavity and in distant lymph nodes such as the left supraclavicular nodes (node of Virchow) and the left axillary nodes (node of Irish). Therefore, it is essential to develop effective treatments to treat gastric cancer. The present review addresses the treatment of advanced gastric cancer (AGC) and focuses on designing criteria for selecting the most appropriate first-line chemotherapy among multiple medical treatment approaches for treating a type of cancer for which there is no consensus on the appropriate gold standard 10.1586/14737140.2014.915194
regimen and for which the median overall survival (OS) rate, regardless of chemotherapy, has remained approximately 9–11 months for more than 30 years [4]. Methods
We performed a review of the English language published literature on chemotherapy and AGC. The search was performed in PubMed, The Cochrane Library and EMBASE and covered the time period from 1970 to 2013. The search strategy included diverse combinations of the following terms: ‘metastatic or AGC’, ‘stomach cancer’, ‘esophagogastric junction cancer’, ‘chemotherapy’, ‘targeted therapy’ and ‘Phase III study’. In topics without consistent Phase III studies, Phase II trials were included. Articles were also identified through searches of the major oncology congress, databases including those of American Society of Clinical Oncology, European Society of Medical Oncology, International Gastric Cancer Association and Latin American Society of Gastrointestinal Oncology databases. The references of selected papers also served as sources of additional information.
2014 Informa UK Ltd
ISSN 1473-7140
887
Review
Garrido, Fonseca, Vieitez, Frunza & Lacave
Who should be treated, & when should treatment begin?
The following patients most likely do not benefit from chemotherapy: frail 90 elderly, those with severe morbidity fac80 tors, those with severe ascites due to 70 peritoneal carcinomatosis and those with liver failure due to multiple metas60 tases. Patients who do not belong to the With chemotherapy 50% above groups should be rated by a med50 Without chemotherapy ical oncologist and should be offered 40% 40 chemotherapy; all of the studies that compared chemotherapy with BSC 30 showed that chemotherapy increased the quality of life and prolonged the OS rate. 20 A randomized study assessed whether the proper time to begin chemotherapy 10% 10% was once metastatic disease had been 10 diagnosed or in cases of bad symptomatic 5% 3% control. Patients receiving chemotherapy 2% from the beginning had an improved quality of life in 70% of the cases and a median OS of 8 months. Of the patients who were randomized to symptomatic treatment alone, only 25% experienced Figure 1. Overall survival of patients with advanced gastric cancer treated with an improvement in their symptoms with and without chemotherapy. a median OS time of 4 months, though half of them received chemotherapy at Chemotherapy compared with the best supportive care some point over the evolution of the disease. The results demIn the 1990s, at least three randomized studies were pub- onstrated that systemic chemotherapy could add both quantity lished that had been designed to verify whether chemother- and quality of life in AGC patients and that it should be initiapy had any benefit in the treatment of AGC compared with ated once metastatic disease had been diagnosed even in asympbest supportive care (BSC) [5–7]. In these trials, drug combi- tomatic patients [9]. nations containing 5-fluorouracil (5-FU) showed a 61% increase in survival rate with a hazard ratio (HR) of 0.39. Cytotoxic agents in AGC The median survival time of the groups treated with chemo- The classically active drugs are considered cytotoxic agents that therapy was 9–11 months compared with 3–4 months in the show at least 20% activity when used as first-line treatment [10]. groups without chemotherapy which represents a significant These drugs include 5-FU, doxorubicin, epirubicin and cisdifference. Patients who did not receive chemotherapy had a platin, as well as the newer drugs docetaxel [11,12], paclitaxel [13], median survival time of 3–4 months, a 1-year survival rate irinotecan [14], capecitabine [15], S-1 [16] and oxaliplatin [17]. No studies conducted in Western countries have sufficiently of 10%, a 2-year survival rate of 5% and a 5-year survival rate of 2%. Patients treated with chemotherapy in most of validated the activity of mitomycin-C or carmustine (BCNU). the published studies had median survival times of Drugs with intermediate activity are considered to be those 9–10 months, a 1-year survival rate of 30–40% and a 2-year with 10% activity as a first-line treatment such as hydroxyurea, survival rate of 10%. However, from 3 years onward, the dacarbazine, chlorambucil and mechlorethamine. However, the survival curves of the patients treated with or without che- references concerning these agents are very old and have not motherapy did not differ (FIGURE 1). A meta-analysis published been confirmed by recent studies. This group of cytotoxic in 2010 examined 35 trials and included a total of agents with intermediate activity includes a third-generation 5726 patients in the OS analysis. The comparison of chemo- drug, topotecan. Etoposide received the most interest at the therapy and BSC consistently demonstrated a significant ben- end of the 1980s when the first study with a regimen of etopoefit in OS in favor of the group receiving chemotherapy side, adriamycin and platinum revealed a high response rate (HR: 0.37; 95% CI: 0.24–0.55) [8]. These results confirmed (RR) that was unfortunately not confirmed in subsequent studthe relative chemosensitivity of AGC and supported the ies. The activity of etoposide, adriamycin and platinum is 14% as a first-line treatment, 10% as a second-line treatment and search for better regimens. 888
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4
3
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9
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Overall survival of patients (%)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 12/28/14 For personal use only.
100
Expert Rev. Anticancer Ther. 14(8), (2014)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 12/28/14 For personal use only.
Challenges in first-line chemotherapy and targeted therapy in AGC
18% for oral etoposide. Pemetrexed has not yet been sufficiently studied. Currently, the following drugs are considered to be inactive (i.e., drugs with
