On 2014 Jun 18, Gauthier Bouche commented:

We would like to thank the authors for carrying out this very important update and for emphasizing that patients with locally advanced rectal cancer should be informed of the lack of consensus about adjuvant chemotherapy after preoperative chemoradiotherapy. As the authors point out in their discussion, ’the control of occult distant disease is becoming a major objective in treatment strategies’. They indicate upfront chemotherapy as one relevant option being tested in a large randomised trial (PRODIGE 23). Our international collaborative group interested in ‘financial orphan therapies’ - i.e. therapies with high clinical but no or low commercial value - has identified over the years several therapeutic options that we think could prevent distant metastasis in patients with locally advanced rectal cancer. We would like to list three promising strategies supported by clinical and biological evidence. These strategies carry a low toxicity risk, are low cost and are easy to administer.

Cimetidine is an H2-receptor antagonist which has been used for decades as an oral drug in the prevention and treatment of gastro-duodenal ulcers. Cimetidine has demonstrated a strong anticancer effect (Kubecova M, 2011) that is unlikely to be explained by one single mechanism. Amongst other things, cimetidine inhibits cancer cell adhesion via E-selectin inhibition (Matsumoto S, 2002), increases the antigen-presenting capacity of dendritic cells (Kubota T, 2002), increases lymphocyte infiltration in tumours (Lin CY, 2004) and reduces accumulation of myeloid-derived suppressive cells (Zheng Y, 2013), which may all contribute to the clinical findings in colorectal cancer patients. A 2012 Cochrane Meta-Analysis reviewed the five randomised trials performed in colorectal cancer patients and concluded that ‘cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers’ (Deva S, 2012). The main unanswered question is duration of treatment. The randomized trial currently ongoing in 120 colorectal cancer patients in New-Zealand and Australia (ACTRN12609000769280) which aims to look at the effect of perioperative cimetidine should answer this question. Recruitment in this trial has been completed and 45% of all patients have a primary rectal cancer (http://meetinglibrary.asco.org/content/122801-143).

Polysaccharide-K (PSK) is isolated and purified from the cultured mycelium of the Basidiomycete Coriolus versicolor. It was first approved as an oral anticancer drug in Japan in 1976 under the name of Krestin® and its use has been restricted to colorectal, gastric and small-cell lung cancer after re-evaluation by the Japanese authority in 1989 (Maehara Y, 2012, Fujiwara Y, 1999). Several randomized trials of various quality have been performed over the past four decades in Japan which overall indicate a benefit in colorectal cancer patients (Maehara Y, 2012). The drug is now available as a generic in Japan (Fujiwara Y, 1999). The most critical question is whether similar outcomes would be found in a non-Japanese population. Since this therapy has shown excellent safety and is already commercially available in Japan, this question could be easily tested in randomized trials. Mechanistically and according to the wealth of literature available from Japanese researchers, PSK seems to have multiple mechanisms of action, from direct anticancer activity to immune-mediated effects (Maehara Y, 2012). Obviously, any project or trial outside of Japan should involve Japanese clinicians and researchers experienced with PSK.

Ketorolac is a Non-Steroidal Anti-Inflammatory Drug (NSAID) approved in the EU and in the USA and available for injection in the management of postoperative pain. In 2010, Forget et al. found in a retrospective study that breast cancer patients undergoing mastectomy who had received one single injection of ketorolac during surgery had a 63% reduction in the risk of recurrence compared to patients who did not, even after adjustment for known confounders (Forget P, 2010). This association was confirmed in patients receiving either ketorolac or diclofenac and undergoing breast-conserving surgery (Forget P, 2014), as well as in patients undergoing lung cancer surgery (Forget P, 2013). The work from Ben Eliyahu’s group provides a biological rationale for this, even though Ben Eliyahu used etodolac in combination with propranolol and the design of the mice experiments is different from the human observations (Benish M, 2008). Retrospective data in colorectal cancer patients should be available soon from the group of Patrice Forget (personal communication) and will hopefully further support this hypothesis. The potential benefit of perioperative administration of ketorolac will have to be balanced against a potential risk of anastomotic leakage. A meta-analysis of randomized trials indicates a non-significant doubling of the risk (2.4% in patients not receiving NSAID vs. 5.1% receiving NSAID within 48 hours of surgery Burton TP, 2013), but such increase has not been observed when only one single dose of NSAID was administered. This will however need to be taken into consideration when designing a trial of perioperative ketorolac in colorectal cancer patients.

We can deduce from the Bosset et al. article that there is an early peak of recurrence in the first two years, as more than 50% of the DFS events occurred during this period. This is in line with data from DeMicheli for breast (Demicheli R, 2010) and lung (Demicheli R, 2012) cancer and is another argument to target the perioperative period with drugs such as NSAID or cimetidine to prevent recurrence (Demicheli R, 2008).

There are other options which could be considered. However, the strategies we propose have a common theme. Our goal is to address the fact that the perioperative period is one that is characterized by a systemic immune and pro-angiogenic milieu that is found in a typical wound healing response. Such a response is characterized by a post-operative surge of cytokines and growth factors into the systemic circulation that may awaken dormant micrometastases, thus accounting for the early recurrence pattern seen following surgery for many types of cancer (Retsky M, 2013). Thus short-term perioperative treatments aimed at countering such a response could have long-term beneficial consequences. Finally, these treatment options represent low-hanging fruits which, if their efficacy were to be proven in trials, could be rapidly implemented in practice in most places in the world with minimal toxicity and at a reasonable cost. We sincerely hope to see others supporting this type of research.

Gauthier Bouche, Anticancer Fund, Strombeek-Bever, Belgium

Pan Pantziarka, Anticancer Fund, Strombeek-Bever, Belgium & The George Pantziarka TP53 Trust, London, UK

Lydie Meheus, Anticancer Fund, Strombeek-Bever, Belgium

Patrice Forget, Department of Anesthesiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

Vidula Sukhatme, GlobalCures, Inc; Newton MA 02459, USA

Vikas P. Sukhatme, GlobalCures, Inc; Newton MA 02459, USA & Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA

The authors declare that they have no competing interests.

On 2014 Jun 18, Gauthier Bouche commented:

We would like to thank the authors for carrying out this very important update and for emphasizing that patients with locally advanced rectal cancer should be informed of the lack of consensus about adjuvant chemotherapy after preoperative chemoradiotherapy. As the authors point out in their discussion, ’the control of occult distant disease is becoming a major objective in treatment strategies’. They indicate upfront chemotherapy as one relevant option being tested in a large randomised trial (PRODIGE 23). Our international collaborative group interested in ‘financial orphan therapies’ - i.e. therapies with high clinical but no or low commercial value - has identified over the years several therapeutic options that we think could prevent distant metastasis in patients with locally advanced rectal cancer. We would like to list three promising strategies supported by clinical and biological evidence. These strategies carry a low toxicity risk, are low cost and are easy to administer.

Cimetidine is an H2-receptor antagonist which has been used for decades as an oral drug in the prevention and treatment of gastro-duodenal ulcers. Cimetidine has demonstrated a strong anticancer effect (Kubecova M, 2011) that is unlikely to be explained by one single mechanism. Amongst other things, cimetidine inhibits cancer cell adhesion via E-selectin inhibition (Matsumoto S, 2002), increases the antigen-presenting capacity of dendritic cells (Kubota T, 2002), increases lymphocyte infiltration in tumours (Lin CY, 2004) and reduces accumulation of myeloid-derived suppressive cells (Zheng Y, 2013), which may all contribute to the clinical findings in colorectal cancer patients. A 2012 Cochrane Meta-Analysis reviewed the five randomised trials performed in colorectal cancer patients and concluded that ‘cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers’ (Deva S, 2012). The main unanswered question is duration of treatment. The randomized trial currently ongoing in 120 colorectal cancer patients in New-Zealand and Australia (ACTRN12609000769280) which aims to look at the effect of perioperative cimetidine should answer this question. Recruitment in this trial has been completed and 45% of all patients have a primary rectal cancer (http://meetinglibrary.asco.org/content/122801-143).

Polysaccharide-K (PSK) is isolated and purified from the cultured mycelium of the Basidiomycete Coriolus versicolor. It was first approved as an oral anticancer drug in Japan in 1976 under the name of Krestin® and its use has been restricted to colorectal, gastric and small-cell lung cancer after re-evaluation by the Japanese authority in 1989 (Maehara Y, 2012, Fujiwara Y, 1999). Several randomized trials of various quality have been performed over the past four decades in Japan which overall indicate a benefit in colorectal cancer patients (Maehara Y, 2012). The drug is now available as a generic in Japan (Fujiwara Y, 1999). The most critical question is whether similar outcomes would be found in a non-Japanese population. Since this therapy has shown excellent safety and is already commercially available in Japan, this question could be easily tested in randomized trials. Mechanistically and according to the wealth of literature available from Japanese researchers, PSK seems to have multiple mechanisms of action, from direct anticancer activity to immune-mediated effects (Maehara Y, 2012). Obviously, any project or trial outside of Japan should involve Japanese clinicians and researchers experienced with PSK.

Ketorolac is a Non-Steroidal Anti-Inflammatory Drug (NSAID) approved in the EU and in the USA and available for injection in the management of postoperative pain. In 2010, Forget et al. found in a retrospective study that breast cancer patients undergoing mastectomy who had received one single injection of ketorolac during surgery had a 63% reduction in the risk of recurrence compared to patients who did not, even after adjustment for known confounders (Forget P, 2010). This association was confirmed in patients receiving either ketorolac or diclofenac and undergoing breast-conserving surgery (Forget P, 2014), as well as in patients undergoing lung cancer surgery (Forget P, 2013). The work from Ben Eliyahu’s group provides a biological rationale for this, even though Ben Eliyahu used etodolac in combination with propranolol and the design of the mice experiments is different from the human observations (Benish M, 2008). Retrospective data in colorectal cancer patients should be available soon from the group of Patrice Forget (personal communication) and will hopefully further support this hypothesis. The potential benefit of perioperative administration of ketorolac will have to be balanced against a potential risk of anastomotic leakage. A meta-analysis of randomized trials indicates a non-significant doubling of the risk (2.4% in patients not receiving NSAID vs. 5.1% receiving NSAID within 48 hours of surgery Burton TP, 2013), but such increase has not been observed when only one single dose of NSAID was administered. This will however need to be taken into consideration when designing a trial of perioperative ketorolac in colorectal cancer patients.

We can deduce from the Bosset et al. article that there is an early peak of recurrence in the first two years, as more than 50% of the DFS events occurred during this period. This is in line with data from DeMicheli for breast (Demicheli R, 2010) and lung (Demicheli R, 2012) cancer and is another argument to target the perioperative period with drugs such as NSAID or cimetidine to prevent recurrence (Demicheli R, 2008).

There are other options which could be considered. However, the strategies we propose have a common theme. Our goal is to address the fact that the perioperative period is one that is characterized by a systemic immune and pro-angiogenic milieu that is found in a typical wound healing response. Such a response is characterized by a post-operative surge of cytokines and growth factors into the systemic circulation that may awaken dormant micrometastases, thus accounting for the early recurrence pattern seen following surgery for many types of cancer (Retsky M, 2013). Thus short-term perioperative treatments aimed at countering such a response could have long-term beneficial consequences. Finally, these treatment options represent low-hanging fruits which, if their efficacy were to be proven in trials, could be rapidly implemented in practice in most places in the world with minimal toxicity and at a reasonable cost. We sincerely hope to see others supporting this type of research.

Gauthier Bouche, Anticancer Fund, Strombeek-Bever, Belgium

Pan Pantziarka, Anticancer Fund, Strombeek-Bever, Belgium & The George Pantziarka TP53 Trust, London, UK

Lydie Meheus, Anticancer Fund, Strombeek-Bever, Belgium

Patrice Forget, Department of Anesthesiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

Vidula Sukhatme, GlobalCures, Inc; Newton MA 02459, USA

Vikas P. Sukhatme, GlobalCures, Inc; Newton MA 02459, USA & Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA

The authors declare that they have no competing interests.