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Treatment of colorectal peritoneal metastases requires multidisciplinary efforts
Comment
With 8–20% of patients developing peritoneal metastases from colorectal cancer, this metastatic site ranks second or third in terms of incidence after the liver and lungs. The diagnosis of peritoneal metastases from colorectal cancer is mostly made at a very advanced stage because of the lack of specific symptoms of peritoneal metastases, and the low sensitivity of diagnostic imaging. Therefore, most patients with peritoneal metastases receive systemic chemotherapy similar to that given to patients with extra-peritoneal metastases. However, some patients are considered as candidates for curatively intended treatment consisting of complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy, which has substantially improved the prognosis of patients with peritoneal metastases. With this treatment, all visible peritoneal nodules are completely resected; highly concentrated local chemotherapy is then given to treat microscopic occult disease, combined with hyperthermia (42°C) to enhance chemotherapy efficacy. This combined treatment is the only one currently capable of prolonging survival similar to that obtained after resection of colorectal liver metastases,1,2 and 16% of patients who receive this treatment achieve 5-year survival without evidence of the disease.3 Consequently, the current recommendations for the treatment of peritoneal metastases from colorectal cancer include complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in selected patients (ie, a good general health status with limited and completely resectable peritoneal disease).4 The survival analysis of more than 10 000 patients with metastatic colorectal cancer treated in 14 first-line chemotherapy randomised studies reported by Jan Franko and colleagues5 underlines the different behaviour patterns of peritoneal metastases compared with that of other sites of metastasis. Peritoneal involvement confers a worse prognosis that could be the result of biological and histological particularities but also to lower chemosensitivity compared with other metastatic sites. Patients with peritoneal metastasis also tend to have a higher likelihood of having tumours
with mutations in BRAF and of having tumours with the signet-ring cell histological subtype. These characteristics have already been suggested by others.6,7 A better understanding of this metastatic disease will be essential to adapt the development of future treatments. Systemic chemotherapy is less effective against peritoneal metastases, so that even when associated with targeted treatments, all efforts should be expended by clinicians to try and obtain a complete resection, and patients should be referred to expert specialty care centres for this type of surgery as early as possible. To this end, a proactive attitude has been developed and assessed in a randomised study (Prophylochip NCT01226394) of patients at high risk of developing peritoneal metastases after resection of their primary tumour, and without any sign of recurrence after 6 months of adjuvant chemotherapy. Patients in this study are randomly assigned between the standard attitude (surveillance) and the proactive attitude, namely so-called second-look surgery and hyperthermic intraperitoneal chemotherapy. The preliminary results of this trial are expected next year. Referring patients to expert specialty care centres offering a curative treatment is the first lesson we can learn from the results reported by Franko and colleagues.5 The second lesson is that other therapeutic options, different from those offered to patients with stage IV colorectal cancer, should be developed, and efforts should be made by academia and pharmaceutical firms to search for new treatment options for patients with peritoneal metastases. The main advantage of the peritoneal cavity is that it is accessible to local treatment, which makes it possible to give chemotherapeutic agents locally. Local administration results in substantially increased drug concentration, which could potentially improve treatment efficacy. Nowadays, the development of the peritoneal port facilitates the administration of intraperitoneal chemotherapy and is well-tolerated. The combination of systemic plus intraperitoneal therapy could enhance response to chemotherapy, and render initially unresectable disease amenable
www.thelancet.com/oncology Published online October 12, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30490-9
Steve Gschmeissner/Science Photo Library
Treatment of colorectal peritoneal metastases requires multidisciplinary efforts
Lancet Oncol 2016 Published Online October 12, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30490-9 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30500-9
1
Comment
to surgery and thus improve survival. Alternatively, the use of immunotherapy could be beneficial as the peritoneum is capable of generating a local immune response. In view of the recent progress in immunotherapy with the development of immune checkpoint therapies (eg, anti-PD1 and anti-PD-L1), intraperitoneal administration of those molecules could restore an immune response and improve the efficacy of systemic cytotoxic therapy. Similarly, the systemic administration of antibodies directed against immune checkpoints associated with intraperitoneal administration of cytotoxic agents generating an immunogenic cell death,8 which has never been tested in these patients, could be efficient. In conclusion, peritoneal metastases from colorectal cancer exhibit different behaviour patterns than metastases in other organs, are more aggressive than metastases at other sites, and are less sensitive to systemic chemotherapy. Cure is possible in some patients and the data reported by Franko and colleagues should encourage researchers to develop new multidisciplinary approaches for patients with peritoneal metastases.
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*Diane Goéré, Maximiliano Gelli Department of Visceral and Surgical Oncology, Gustave Roussy, 94805 Villejuif Cedex, France [email protected] We declare no competing interests. 1
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Elias D, Faron M, Iuga BS, et al. Prognostic similarities and differences in optimally resected liver metastases and peritoneal metastases from colorectal cancers. Ann Surg 2015; 261: 157–63. Shen P, Thai K, Stewart JH, et al. Peritoneal surface disease from colorectal cancer: comparison with the hepatic metastases surgical paradigm in optimally resected patients. Ann Surg Oncol 2008; 15: 3422–32. Goéré D, Malka D, Tzanis D, et al. Is there a possibility of a cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Ann Surg 2013; 257: 1065–71. Sugarbaker P, Ryan D. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach? Lancet Oncol 2012; 13: 362–69. Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016; published online Oct 12. http://dx.doi. org/10.1016/S1470-2045(16)30500-9. Yaeger R, Cowell E, Chou JF, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 2015; 121: 1195–203. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011; 117: 4623–32. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31: 51–72.
www.thelancet.com/oncology Published online October 12, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30490-9
With 8–20% of patients developing peritoneal metastases from colorectal cancer, this metastatic site ranks second or third in terms of incidence after the liver and lungs. The diagnosis of peritoneal metastases from colorectal cancer is mostly made at a very advanced stage because of the lack of specific symptoms of peritoneal metastases, and the low sensitivity of diagnostic imaging. Therefore, most patients with peritoneal metastases receive systemic chemotherapy similar to that given to patients with extra-peritoneal metastases. However, some patients are considered as candidates for curatively intended treatment consisting of complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy, which has substantially improved the prognosis of patients with peritoneal metastases. With this treatment, all visible peritoneal nodules are completely resected; highly concentrated local chemotherapy is then given to treat microscopic occult disease, combined with hyperthermia (42°C) to enhance chemotherapy efficacy. This combined treatment is the only one currently capable of prolonging survival similar to that obtained after resection of colorectal liver metastases,1,2 and 16% of patients who receive this treatment achieve 5-year survival without evidence of the disease.3 Consequently, the current recommendations for the treatment of peritoneal metastases from colorectal cancer include complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in selected patients (ie, a good general health status with limited and completely resectable peritoneal disease).4 The survival analysis of more than 10 000 patients with metastatic colorectal cancer treated in 14 first-line chemotherapy randomised studies reported by Jan Franko and colleagues5 underlines the different behaviour patterns of peritoneal metastases compared with that of other sites of metastasis. Peritoneal involvement confers a worse prognosis that could be the result of biological and histological particularities but also to lower chemosensitivity compared with other metastatic sites. Patients with peritoneal metastasis also tend to have a higher likelihood of having tumours
with mutations in BRAF and of having tumours with the signet-ring cell histological subtype. These characteristics have already been suggested by others.6,7 A better understanding of this metastatic disease will be essential to adapt the development of future treatments. Systemic chemotherapy is less effective against peritoneal metastases, so that even when associated with targeted treatments, all efforts should be expended by clinicians to try and obtain a complete resection, and patients should be referred to expert specialty care centres for this type of surgery as early as possible. To this end, a proactive attitude has been developed and assessed in a randomised study (Prophylochip NCT01226394) of patients at high risk of developing peritoneal metastases after resection of their primary tumour, and without any sign of recurrence after 6 months of adjuvant chemotherapy. Patients in this study are randomly assigned between the standard attitude (surveillance) and the proactive attitude, namely so-called second-look surgery and hyperthermic intraperitoneal chemotherapy. The preliminary results of this trial are expected next year. Referring patients to expert specialty care centres offering a curative treatment is the first lesson we can learn from the results reported by Franko and colleagues.5 The second lesson is that other therapeutic options, different from those offered to patients with stage IV colorectal cancer, should be developed, and efforts should be made by academia and pharmaceutical firms to search for new treatment options for patients with peritoneal metastases. The main advantage of the peritoneal cavity is that it is accessible to local treatment, which makes it possible to give chemotherapeutic agents locally. Local administration results in substantially increased drug concentration, which could potentially improve treatment efficacy. Nowadays, the development of the peritoneal port facilitates the administration of intraperitoneal chemotherapy and is well-tolerated. The combination of systemic plus intraperitoneal therapy could enhance response to chemotherapy, and render initially unresectable disease amenable
www.thelancet.com/oncology Published online October 12, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30490-9
Steve Gschmeissner/Science Photo Library
Treatment of colorectal peritoneal metastases requires multidisciplinary efforts
Lancet Oncol 2016 Published Online October 12, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30490-9 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30500-9
1
Comment
to surgery and thus improve survival. Alternatively, the use of immunotherapy could be beneficial as the peritoneum is capable of generating a local immune response. In view of the recent progress in immunotherapy with the development of immune checkpoint therapies (eg, anti-PD1 and anti-PD-L1), intraperitoneal administration of those molecules could restore an immune response and improve the efficacy of systemic cytotoxic therapy. Similarly, the systemic administration of antibodies directed against immune checkpoints associated with intraperitoneal administration of cytotoxic agents generating an immunogenic cell death,8 which has never been tested in these patients, could be efficient. In conclusion, peritoneal metastases from colorectal cancer exhibit different behaviour patterns than metastases in other organs, are more aggressive than metastases at other sites, and are less sensitive to systemic chemotherapy. Cure is possible in some patients and the data reported by Franko and colleagues should encourage researchers to develop new multidisciplinary approaches for patients with peritoneal metastases.
2
*Diane Goéré, Maximiliano Gelli Department of Visceral and Surgical Oncology, Gustave Roussy, 94805 Villejuif Cedex, France [email protected] We declare no competing interests. 1
2
3
4
5
6
7
8
Elias D, Faron M, Iuga BS, et al. Prognostic similarities and differences in optimally resected liver metastases and peritoneal metastases from colorectal cancers. Ann Surg 2015; 261: 157–63. Shen P, Thai K, Stewart JH, et al. Peritoneal surface disease from colorectal cancer: comparison with the hepatic metastases surgical paradigm in optimally resected patients. Ann Surg Oncol 2008; 15: 3422–32. Goéré D, Malka D, Tzanis D, et al. Is there a possibility of a cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Ann Surg 2013; 257: 1065–71. Sugarbaker P, Ryan D. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach? Lancet Oncol 2012; 13: 362–69. Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016; published online Oct 12. http://dx.doi. org/10.1016/S1470-2045(16)30500-9. Yaeger R, Cowell E, Chou JF, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 2015; 121: 1195–203. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011; 117: 4623–32. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31: 51–72.
www.thelancet.com/oncology Published online October 12, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30490-9