- Email: [email protected]
Personalised therapy for localised gastric and gastro-oesophageal adenocarcinoma
Comment
In their Article1 in The Lancet Oncology, Salah Al-Batran and colleagues compared perioperative therapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) with perioperative therapy with epirubicin, cisplatin, and fluorouracil or epirubicin, cisplatin, and capecitabine (ECF/ECX) in patients with localised gastric or gastroesophageal junction adenocarcinoma. The primary endpoint of the study was the proportion of patients with pathological complete response, which was defined by the Becker criteria and reviewed centrally. The results show that 20 (16%; 95% CI 10–23) of 128 patients in the FLOT group achieved a pathological complete response compared with eight (6%; 3–11) of 137 patients in the ECF/ECX group. This difference was significant (p=0·02) in favour of FLOT and the authors therefore suggest that use of FLOT is appropriate in the preoperative setting. We congratulate the authors for completing this large prospective study and taking on the tedious task of central pathology review. However, we would like to discuss several issues of concern. First, the primary endpoint of pathological complete response without incorporation of patient benefit (such as overall survival) in the research plan diminishes the value of these results. The authors did not report overall survival or progression-free survival or whether the achievement of pathological complete response was associated with an overall survival or progression-free survival benefit because these outcomes are included in the phase 3 part of the trial. As discussed by the authors, traditionally, preoperative chemotherapy leads to a pathological complete response in less than 10% of patients (often closer to 3%).2 Achievement of a pathological complete response by more than 10% of patients in the FLOT group could easily be an anomaly (the 95% CIs are overlapping between the treatment groups, which suggests that the results are less likely to be robust). The authors appropriately discuss the OEO5 study,3 the results of which showed that two cycles of cisplatin and fluorouracil was equivalent to four cycles of ECF/ECX in terms of overall survival and progressionfree survival. The duration of chemotherapy cycles used in the FLOT4 trial would therefore be hard to justify.
Triplet drug regimens produce considerably more toxic effects than doublet drug regimens; a 30-day mortality rate of 4% associated with ECF/ECX is clearly unacceptable, but even a 30-day mortality rate of 2% associated with FLOT in a potentially curable population raises concerns. We support the use of cytotoxic doublet drug regimens (a platinum compound and a fluoropyrimidine) for about 8 weeks in the preoperative setting as appropriate. Preoperative cytotoxic therapy has reached its plateau and future strategies will have to incorporate new drugs (eg, immuno-oncology agents or targeted agents); to accommodate such strategies, doublet drug regimens will be a better approach than triplet drug regimens. The clinical relevance of the findings from histological assessments will be affected by a few issues. First, the Lauren classification can be difficult to establish on preoperative biopsies, which is evident in this study because 23% of tumours were unclassifiable. Second, differences between preoperative biopsies and resection specimens using the Lauren classification exists in about 20% of cases, and preoperative therapy substantially changes the morphology of the tumour, further confounding the difficulty in classification.4 Third, discordance in histological classification of gastric adenocarcinoma among pathologists is considerable.5 With regard to the use of taxanes for gastric adenocarcinoma, we point out that level 1 evidence has established that docetaxel provides modest overall survival advantage in the first-line advanced cancer setting, whereas no such evidence exists for epirubicin.6 We have no particular reason to believe that FLOT (a modification of the original docetaxel, cisplatin, and fluorouracil [DCF] regimen) would provide an advantage in the localised gastric cancer setting over DCF. Thus the results presented in this Article1 are limited in importance because data to document patient benefit associated with pathological complete regression or treatment group are not provided. However, we fully support the preoperative strategies for this patient population because these strategies compel experts from various disciplines
www.thelancet.com/oncology Published online October 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30521-6
GJLP/Science Photo Library
Personalised therapy for localised gastric and gastro-oesophageal adenocarcinoma
Lancet Oncol 2016 Published Online October 21, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30521-6 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30531-9
1
Comment
to communicate and develop a consensus strategy before initiation of any therapy. Not only will clinicians of all disciplines benefit from such interactions, but also the patients, who are the true beneficiaries. Additionally, we remain enthusiastic that considerable research opportunities are yet to be explored in patients with localised gastric cancer. Among these include the empiric use and investigation of preoperative chemoradiation (CRITICS-II and TOPGEAR [NCT01924819]) and, more importantly, classification of gastric cancer based on molecular subtypes (TCGA study7 or Samsung study8) to personalise therapy in either preoperative or postoperative settings. *Brian Badgwell, Mariela Blum, Jeannelyn Estrella, Jaffer Ajani Department of Surgical Oncology (BB), Department of Gastrointestinal Medical Oncology (MB, JA), Department of Pathology (JE), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]
2
We declare no competing interests. 1
2
3
4
5
6
7 8
Al-Batran S-E, Hofheinz RD, Pauligk C, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol 2016; published online Oct 21. http://dx.doi.org/10.1016/S1470-2045(16)30531-9. Fields RC, Strong VE, Gonen M, et al. Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma. Br J Cancer 2011; 104: 1840–47. Alderson D, Langley RE, Nankivell MG, et al. Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: Results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072). J Clin Oncol 2015; 33 (suppl): 4002. Flucke U, Monig SP, Baldus SE, et al. Differences between biopsy- or specimen-related Lauren and World Health Organization classification in gastric cancer. World J Surg 2002; 26: 137–40. Shibata A, Longacre TA, Puligandla B, et al. Histological classification of gastric adenocarcinoma for epidemiological research: concordance between pathologists. Cancer Epidemiol Biomarkers Prev 2001; 10: 75–78. Van Cutsem E, Moiseyenko VM, Tjulandin S, 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 2006; 24: 4991–97. Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202–09. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015; 21: 449–56.
www.thelancet.com/oncology Published online October 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30521-6
In their Article1 in The Lancet Oncology, Salah Al-Batran and colleagues compared perioperative therapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) with perioperative therapy with epirubicin, cisplatin, and fluorouracil or epirubicin, cisplatin, and capecitabine (ECF/ECX) in patients with localised gastric or gastroesophageal junction adenocarcinoma. The primary endpoint of the study was the proportion of patients with pathological complete response, which was defined by the Becker criteria and reviewed centrally. The results show that 20 (16%; 95% CI 10–23) of 128 patients in the FLOT group achieved a pathological complete response compared with eight (6%; 3–11) of 137 patients in the ECF/ECX group. This difference was significant (p=0·02) in favour of FLOT and the authors therefore suggest that use of FLOT is appropriate in the preoperative setting. We congratulate the authors for completing this large prospective study and taking on the tedious task of central pathology review. However, we would like to discuss several issues of concern. First, the primary endpoint of pathological complete response without incorporation of patient benefit (such as overall survival) in the research plan diminishes the value of these results. The authors did not report overall survival or progression-free survival or whether the achievement of pathological complete response was associated with an overall survival or progression-free survival benefit because these outcomes are included in the phase 3 part of the trial. As discussed by the authors, traditionally, preoperative chemotherapy leads to a pathological complete response in less than 10% of patients (often closer to 3%).2 Achievement of a pathological complete response by more than 10% of patients in the FLOT group could easily be an anomaly (the 95% CIs are overlapping between the treatment groups, which suggests that the results are less likely to be robust). The authors appropriately discuss the OEO5 study,3 the results of which showed that two cycles of cisplatin and fluorouracil was equivalent to four cycles of ECF/ECX in terms of overall survival and progressionfree survival. The duration of chemotherapy cycles used in the FLOT4 trial would therefore be hard to justify.
Triplet drug regimens produce considerably more toxic effects than doublet drug regimens; a 30-day mortality rate of 4% associated with ECF/ECX is clearly unacceptable, but even a 30-day mortality rate of 2% associated with FLOT in a potentially curable population raises concerns. We support the use of cytotoxic doublet drug regimens (a platinum compound and a fluoropyrimidine) for about 8 weeks in the preoperative setting as appropriate. Preoperative cytotoxic therapy has reached its plateau and future strategies will have to incorporate new drugs (eg, immuno-oncology agents or targeted agents); to accommodate such strategies, doublet drug regimens will be a better approach than triplet drug regimens. The clinical relevance of the findings from histological assessments will be affected by a few issues. First, the Lauren classification can be difficult to establish on preoperative biopsies, which is evident in this study because 23% of tumours were unclassifiable. Second, differences between preoperative biopsies and resection specimens using the Lauren classification exists in about 20% of cases, and preoperative therapy substantially changes the morphology of the tumour, further confounding the difficulty in classification.4 Third, discordance in histological classification of gastric adenocarcinoma among pathologists is considerable.5 With regard to the use of taxanes for gastric adenocarcinoma, we point out that level 1 evidence has established that docetaxel provides modest overall survival advantage in the first-line advanced cancer setting, whereas no such evidence exists for epirubicin.6 We have no particular reason to believe that FLOT (a modification of the original docetaxel, cisplatin, and fluorouracil [DCF] regimen) would provide an advantage in the localised gastric cancer setting over DCF. Thus the results presented in this Article1 are limited in importance because data to document patient benefit associated with pathological complete regression or treatment group are not provided. However, we fully support the preoperative strategies for this patient population because these strategies compel experts from various disciplines
www.thelancet.com/oncology Published online October 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30521-6
GJLP/Science Photo Library
Personalised therapy for localised gastric and gastro-oesophageal adenocarcinoma
Lancet Oncol 2016 Published Online October 21, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30521-6 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30531-9
1
Comment
to communicate and develop a consensus strategy before initiation of any therapy. Not only will clinicians of all disciplines benefit from such interactions, but also the patients, who are the true beneficiaries. Additionally, we remain enthusiastic that considerable research opportunities are yet to be explored in patients with localised gastric cancer. Among these include the empiric use and investigation of preoperative chemoradiation (CRITICS-II and TOPGEAR [NCT01924819]) and, more importantly, classification of gastric cancer based on molecular subtypes (TCGA study7 or Samsung study8) to personalise therapy in either preoperative or postoperative settings. *Brian Badgwell, Mariela Blum, Jeannelyn Estrella, Jaffer Ajani Department of Surgical Oncology (BB), Department of Gastrointestinal Medical Oncology (MB, JA), Department of Pathology (JE), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]
2
We declare no competing interests. 1
2
3
4
5
6
7 8
Al-Batran S-E, Hofheinz RD, Pauligk C, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol 2016; published online Oct 21. http://dx.doi.org/10.1016/S1470-2045(16)30531-9. Fields RC, Strong VE, Gonen M, et al. Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma. Br J Cancer 2011; 104: 1840–47. Alderson D, Langley RE, Nankivell MG, et al. Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: Results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072). J Clin Oncol 2015; 33 (suppl): 4002. Flucke U, Monig SP, Baldus SE, et al. Differences between biopsy- or specimen-related Lauren and World Health Organization classification in gastric cancer. World J Surg 2002; 26: 137–40. Shibata A, Longacre TA, Puligandla B, et al. Histological classification of gastric adenocarcinoma for epidemiological research: concordance between pathologists. Cancer Epidemiol Biomarkers Prev 2001; 10: 75–78. Van Cutsem E, Moiseyenko VM, Tjulandin S, 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 2006; 24: 4991–97. Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202–09. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015; 21: 449–56.
www.thelancet.com/oncology Published online October 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30521-6