Update on clinical trials in colorectal cancer

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International Journal of Hyperthermia

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Update on clinical trials in colorectal cancer peritoneal metastasis Amandine Pinto, Clarisse Eveno & Marc Pocard To cite this article: Amandine Pinto, Clarisse Eveno & Marc Pocard (2017) Update on clinical trials in colorectal cancer peritoneal metastasis, International Journal of Hyperthermia, 33:5, 543-547, DOI: 10.1080/02656736.2017.1289565 To link to this article: https://doi.org/10.1080/02656736.2017.1289565

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INTERNATIONAL JOURNAL OF HYPERTHERMIA, 2017 VOL. 33, NO. 5, 543–547 http://dx.doi.org/10.1080/02656736.2017.1289565

Update on clinical trials in colorectal cancer peritoneal metastasis Amandine Pintoa, Clarisse Evenoa,b and Marc Pocarda,b a Sorbonne Paris Cite, CART, INSERM U965, Paris Diderot University, Paris, France; bSurgical Oncologic & Digestive Unit, Lariboisiere Hospital, AP-HP, Paris, France

ABSTRACT

ARTICLE HISTORY

Background/purpose: Peritoneal metastases (PM) arising from colorectal cancer (CRC) can be treated using cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in select patients. Objective: To review clinical trials that were reported during the 10th International Congress on Peritoneal Surface Malignancies and dedicated to the treatment of CRC-PM. Methods: Ten clinical trials were presented at the 10th Peritoneal Surface Oncology Group International (PSOGI) meeting in November 2016 in Washington DC. The flow charts of the studies were identified on ClinicalTrials.gov. Additional data were collected regarding the author’s presentations during the meeting. Results: Four trials (Dutch, French, Italian and Spanish) focussed on a preventive strategy to decrease the rate of CRC-PM. Inclusions were closed for the French study – ProphyloCHIP. Two trials were specific, with one American study dedicated to appendix cancer and one French study testing phase 1 intraperitoneal oxaliplatin drug administration. CRS and HIPEC for PM were compared in others trials with different intraperitoneal treatments without hyperthermia or with no intraperitoneal treatment or with intravenous chemotherapy. Inclusions were closed for the French study – PRODIGE 7. Conclusion: The number of recruiting trials evaluating CRS and HIPEC in the prevention or therapy of CRC PM is increasing, and these have been activated in the US and different European countries. It could be postulated that in less than a decade, clinical results will change the common practice and validate the impact of PSOGI on cancer treatment.

Received 26 January 2017 Accepted 28 January 2017 Published online 22 February 2017

Introduction Peritoneal metastasis (PM) is a relatively common mode for the spread of colorectal cancer (CRC), originating from T3 or T4 tumours. As a tumour specific location, no definite trial on PM for testing systemic chemotherapy for CRC has been reported. A recent publication on the ARCAD database reported a mean survival for patients having PM of 16.3 (13.5–18.8) months compared with 19.1 (18.3–19.8) months for patients having liver isolated metastasis [1]. Systemic chemotherapy associated with combining complete cytoreductive surgery (CRS) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed to treat colorectal cancer peritoneal metastasis (CRPM) to offer a new opportunity and possible prolonged survival as a cure [2]. The only trial devoted to the study of such a strategy is the Dutch trial published in 2003 [3]. The results were updated in 2008 after an eight-year follow-up [4]. In this study, 105 patients with PM of CRC were randomly assigned to palliative systemic chemotherapy (control group) or to CRS and HIPEC followed by palliative systemic chemotherapy (test group). In the test group, surgery was performed with the aim of complete cytoreduction (CC-0), and it included subtotal peritonectomy as well as omentectomy, if needed, and resection of other involved organs. Completeness of CONTACT Marc Pocard

[email protected]

ß 2017 Informa UK Limited, trading as Taylor & Francis Group

KEYWORDS

Clinical trials – deep

cytoreduction was assessed at the end of surgery. Then, HIPEC was administered for 90 min using mitomycin-C. Only palliative surgery and no CRS was allowed in the control group, i.e., bypass surgery or ostomy, for relief of bowel obstruction. Safety results showed a higher morbidity and mortality in the test group (CRS and HIPEC) and, notably, a postoperative mortality of 8%. After a median follow-up of 21.6 months, 39% patients in the control group were alive compared with 55% patients in the test group (HR for death, 0.55; 95% CI, 0.32 to 0.95; p ¼ 0.03). Median overall survival in the control group was 12.6 months compared with 22.4 months in the test group. This trial was the first to demonstrate the positive effect of combined CRS and HIPEC on the survival of patients with PM of CRC and was pivotal in further development of the HIPEC strategy. However, both the design and results of this study have been highly challenged: (i) the benefit of CRS could not be separated from the hypothetical benefit of HIPEC; (ii) morbidity was important as surgical mortality and HIPEC could be less aggressive today; and (iii) systemic chemotherapy is far from recent oncologic systemic treatments. Using that pivotal trial, different national surgical groups have proposed mono-centric or multi-centric trials to improve treatment of PM of CRC.

Sorbonne Paris Cite, CART, INSERM U965, Paris Diderot University, Paris, France

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This update is proposed to review the clinical trials that were reported during the 10th International Congress on Peritoneal Surface Malignancies, which was dedicated to the treatment of CRC PM.

Material and methods Ten clinical trials were presented at the 10th PSOGI meeting in November 2016 in Washington DC during the first session of the congress. The decision of the organiser to start the congress with that subject illustrated the high impact of the subject of CRC on the oncologic community. Associated was the decision to perform prospective trials to convince participants that there is a place for HIPEC in colorectal oncologic surgery. The flow charts of the studies were identified on ClinicalTrials.gov. Additional data were collected regarding the authors’ presentations during the meeting. Results were divided regarding the target of the trial, treatment of a PM disease or a decrease in the risk of recurrence as a PM, which were named “proactive management for locoregional control” or “prophylactic HIPEC” (Table 1).

Results A. Treating peritoneal metastasis of colon cancer In contrast to the Dutch trial described above, the French PRODIGE 7 trial (ClinicalTrials.gov Identifier: NCT00769405) did not compare CRS and HIPEC versus palliative systemic chemotherapy but investigated the potential additional benefit of CRS and HIPEC over CRS alone. This larger multicentric study randomised 267 patients intraoperatively following complete CRS (CC-0 or CC-1) in 17 French centres with or without HIPEC with oxaliplatin. Six months of systemic chemotherapy (physician’s best choice) were scheduled and were performed before and/or after the HIPEC procedure. The majority of surgical teams selected a programme with three months of chemotherapy before CRS and HIPEC and three months after the procedure. The type of systemic chemotherapy was not predefined, and the oncologist was free to administer the therapy of his choice. Enrolment is now completed, and first survival results are expected in 2017. The median PCIs were 10 [range 1–25] and 9 [range 0–25] in the HIPEC group versus control group.

Franc¸ois Quenet reported the postoperative morbidity of the study during the meeting. Hospital stays were 18 (8–140) days (HIPEC group) versus 13 (1–62) days (control group; p < 0.001). Mortality at 30 days was 1.5%, which was comparable between the two groups. Morbidity at 30 days was not different with a grade 3–4–5 at 40.6% (HIPEC group) versus 35.9% (control group). Only intraperitoneal postoperative haemorrhage was more frequent in the HIPEC group, with a rate of 8.3% versus 2.3% in the control group (p ¼ 0.05). At 60 days, major morbidity (grade 3–4–5 of the Dindo classification) was higher in the HIPEC group with 24.1% versus 13.6% in the control group (p ¼ 0.03). The German COMBATAC trial (ClinicalTrials.gov Identifier: NCT01541344, EudraCT number: 2009–014040-11) promoted by University of Regensburg [5] was a smaller trial with an enrolment of 60 patients. The trial was designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy (FOLFOX or FOLFIRI) plus Cetuximab followed by CRS and bidirectional chemotherapy (HIPEC with intraperitoneal oxaliplatin at 400 mg/m2 and IV 5-FU). The trial was stopped after inclusion of 20 patients. Pompiliu Piso presented morbidity and mortality data. Cutaneous disease with rash and exanthema was the most frequent adverse event reported. The authors underlined that the first data indicated that preoperative systemic polychemotherapy including cetuximab in combination with CRS and bidirectional HIPEC is feasible and might not lead to increased morbidity and toxicity rates. The first survival data are expected in 2017. The ICARUS trial (trial ClinicalTrials.gov Identifier: NCT01815359) was conducted to compare early post-operative intraperitoneal chemotherapy (EPIC) and HIPEC for appendiceal and CRC. The exact name of the study was “Post-operative Intraperitoneal Chemotherapy (EPIC) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) After Optimal Cytoreductive Surgery (CRS) for Neoplasms of the Appendix, Colon or Rectum With Isolated Peritoneal Metastasis”. Garrett M Nash explained the inclusion criteria and concept of the study. The study was promoted by the Memorial Sloan Kettering Cancer Center from the USA. The procedure is a CRS with optimal surgical debulking. The drug used for HIPEC was mitomycin-C, and the drugs used for EPIC were FUDR and leucovorin. The study was a collaborative study in association with the following: The Cleveland

Table 1. Prophylactic HIPEC for colon cancer. Characteristics of patients with primary colorectal cancer (CRC) identified in the literature as being at a high risk of developing peritoneal metastasis (PM) [15]. Name of the study Country Visible evidence of PM resected Ovarian metastasis resected Positive cytology either before or after cancer resection Adjacent organ involvement or cancer-induced fistula pT4 tumours Perforated cancer (spontaneous or iatrogenic perforation) Obstructed cancer pT3 mucinous cancer and pT3 signet ring cell cancer Positive lateral margin of excision Bleeding cancer CRC: colorectal cancer; PM: peritoneal metastasis.

ProphyloCHIP

COLOPEC

PROMENADE

HIPEC CORDOBA

France Yes Yes No No No Yes No No No No

Netherlands No No No No Yes Yes No No No No

Italy No No No No Yes No No Yes No No

Spain No No No No Yes No No No No No

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Clinic, Brigham and Women’s Hospital, University of Miami, University of Pittsburgh and Washington University School of Medicine. The study is still recruiting. The study was stratified on the origin of PM (appendix versus colorectal) and on the realisation of preoperative chemotherapy or not. The primary endpoint was three years' progression-free survival. To date, 94 patients have been randomised preoperatively, 63 appendix and 31 colorectal tumours. Mortality was null, and the grade 3–4 morbidity rate was 15%. The Swedish trial from Uppsala University (trial ClinicalTrials.gov Identifier: NCT01524094) was presented by Peter H Cashin. This trial was comparable to the historical Dutch trial comparing CRS and sequential EPIC (using 5-FU 550 mg/m2) with systemic chemotherapy alone. A total number of six cycles of EPIC were planned. The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p ¼ 0.04). After five years, 8 patients versus 1 patient were alive, respectively (p ¼ 0.02). The most important result of the trial was to confirm the superiority of the CRS and intraperitoneal chemotherapy arm, with results very similar to the other trials if the comparative arm was systemic chemotherapy alone. For that, 4/24 patients were considered as cured in the CRS and sequential EPIC arm, resulting in 17% with long-term survival, as reported previously [2]. The results were presented by Peter Cashin and are currently published [6]. Wake Forest University from USA and the National Cancer Institute presented a trial (trial ClinicalTrials.gov Identifier: NCT01580410) (NCI-2009–00947), comparing the toxicity profiles within 4 weeks of surgery of oxaliplatin (200 mg/m2) and mitomycin-C (40 mg; 30 mg first and 10 mg later) delivered via HIPEC in patients with peritoneal surface malignancies from primary appendiceal tumours. Edward A Levine presented the results and focussed the presentation on the feasibility and acceptance of the HIPEC protocol by the community. The study was a multicenter study with inclusion at MD Anderson Cancer Center and UPMC Hillman Cancer Center. Some of the results have been published [7]. For other participants, the facility for using mitomycin-C was underlined by Edward A Levine. Accrual is complete with 133 evaluable patients. The first survival data are expected in 2018. The last trial was reported by Franc¸ois Quenet from France. The NIPOX trial (Intensified Neoadjuvant Chemotherapy Combining IntraPeritoneal Oxaliplatin and systemic Folfiri in colorectal peritoneal carcinomatosis) is a phase 1–3 trial devoted to decreasing PM extension before the CRS and HIPEC procedure. The major inclusion criterion was a PCI above 17, which is considered as a poor survival rate in the case of CRS. The treatment protocol associated the intraperitoneal drug using oxaliplatin and a systemic drug using FOLFIRI. The first six cases were published recently and did not describe a major morbidity [8]. For one of the six cases, the patient presented with a good response and was operated on secondarily for CRS and HIPEC procedures. The NIPOX trial is open for recruiting.

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B. HIPEC in patients with colon cancer at high risk for peritoneal metastasis (i) Prophylactic indication (ii) Proactive management for locoregional control The French Prophylochip (or PRODIGE 15) trial (ClinicalTrials.gov Identifier: NCT01226394) investigated a potential favourable effect of HIPEC in colorectal patients at risk of developing colorectal peritoneal metastasis. Diane Go er e presented the trial and inclusion. Intended accrual was 160 patients from 18 French centres. Inclusion criteria at the time point of colectomy were the following: resected to minimal synchronous peritoneal metastasis, ovarian metastases and/or tumour perforation. All patients were then treated for six months with adjuvant systemic chemotherapy, as a rule FOLFOX-4. Then, in the presence of peritoneal recurrence, patients received best-choice therapy and were excluded from the study. In the absence of clinical or radiological recurrence, patients were randomised into surveillance alone or exploratory laparotomy and HIPEC whether they had PM or not during the second look laparotomy. The end-point was disease-free survival at three years. The study is now closed for inclusion, and the first survival results are expected at the end of 2017. The Dutch COLOPEC (ClinicalTrials.gov Identifier: NCT02231086) [9] investigated the oncological effectiveness of adjuvant HIPEC with oxaliplatin, following a curative resection of a T4 or intra-abdominally perforated colon carcinoma in preventing the development of peritoneal metastasis. Intended accrual was 174 patients but has been up-scaled to 200 patients. Patients who underwent curative resection for a UICC category T4 (or perforated) colon cancer were randomised to receive adjuvant HIPEC performed simultaneously with colectomy or as a staged procedure (less than 10 days or 5–8 weeks postoperatively). Standard adjuvant systemic chemotherapy is given within three weeks after HIPEC in both study groups. Secondary aims were to determine the incidence of peritoneal metastasis in pT4 and perforated colon cancer as determined by laparoscopy, as a new gold standard, to identify molecular parameters indicating highrisk of developing peritoneal metastasis and to determine treatment-related morbidity of open and laparoscopic adjuvant HIPEC. Presence or absence of peritoneal recurrence is evaluated 18 months postoperatively by CEA and CT thorax/ abdomen, and in the absence of radiological signs of recurrence, a diagnostic laparoscopy was performed. A feasibility study was recently published [10]. The study has already recruited 90% of the intended patients (n ¼ 181). Pieter Tanis from Amsterdam University reported that the COLOPEC trial is expected to be completed in 2017. He noted that for the first 90 cases, at the time of exploration for adjuvant HIPEC, 9/90 patients were found to have metastasis (peritoneal and/ or liver). The first oncological results are expected at the beginning of 2018. The third study proposed was named PROMENADE (ClinicalTrials.gov Identifier: NCT02974556), which was presented by Paolo Sammartino from the University of Roma, La Sapienza. This Italian group made a pilot comparative phase

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2 study with encouraging results [11]. The experimental group received “Proactive management”. Colon cancer patients (high-risk T3 and T4) without peritoneal or systemic metastases were operated on with curative intent. Simultaneously, patients will undergo infracolic omentectomy, appendectomy, liver round ligament ablation and a bilateral oophorectomy in women. At the end of the surgical procedure, an intravenous infusion of 400 mg/m2 of 5-FU and 20 mg/m2 of leucovorin will be administered followed by HIPEC with oxaliplatin 460 mg/m2. Standard adjuvant systemic chemotherapy (FOLFOX or CAPOX regimens for six months) was performed in cases of pT3 tumours with poor prognostic factors and pT4 tumours if lymph-node metastases were present. The study has already recruited patients, but the complete recruitment is not planned. The fourth study discussed was named HIPECT4 (ClinicalTrials.gov Identifier: NCT02614534), which was presented by Alvaro Arjona-Sanchez from the Hospital Universitario Reina Sofıa, from Spain. The study is recent and was started at the end of 2015. Inclusion criteria were similar to the PROMENADE study and could be associated with patients having a T4 lesion. HIPEC was delivered at the end of the colonic resection and was performed using mitomycin-C at 40 mg. Inclusion of 200 patients is planned, and they will be randomised. Surgeons from Spain just developed a national group that could probably help with the development and conduction of specific Spanish trials in HIPEC.

Discussion The possibility of performing a CRS and HIPEC procedure in the case of PM from CRC is accepted in many countries and textbooks. However, the balance between a positive impact regarding patients having prolonged survival and the negative impact regarding human and economic costs is still debated. The major critical aspect against the HIPEC procedure for colon cancer is based on the heterogeneity of the different procedures that are actually opposed to the recent advances in drug development for CRC. Regarding this, treatment protocols proposed by the different surgical teams are innovative, ambitious and all different. In fact, each national group has proposed a trial or a treatment protocol reflecting the national level of HIPEC acceptance. In the case of a country with a low level of acceptance, the trial is devoted to convincing results, and in the case of a country with a high level of acceptance, the trial is devoted to increasing the rate of patients amenable to a complete surgical resection. The NIPOX treatment proposed by the French group of Franc¸ois Quenet used intraperitoneal chemotherapy to obtain a secondary resectability, which has to be compared with a neo-adjuvant systemic chemotherapy. In contrast, the treatment proposed by Edward A Levine was focussed on the best cases, represented by patients selected to have a resectable PM for appendix tumours and

is devoted to convincing others of the feasibility and positive results regarding survival rates. The concept to consider is that, in the case of localised abdominal cancer, spreading of a microscopic tumour could be induced during surgery, which is partially accepted by many oncologic surgeons. Most likely, the best demonstration of that theory is offered in gastric cancer, a tumour primary lesion that is able to frequently recur as a peritoneal metastatic process. In a recent published paper, Japanese authors demonstrated that free peritoneal cells are present in a minority of cases at the beginning of the gastric cancer surgery and are increased during surgery [12]. At the end of the gastric resection, they were able to detect free cells in the peritoneal cavity and to create tumours on nude mice using these cells. For that reason, using HIPEC as a complementary procedure after a complete abdominal tumour resection is proposed for different primary cancers. A recent paper proposed to use HIPEC as an adjuvant per-operative procedure in the case of pancreatic cancer [13]. In that study, patients with pancreatic cancer underwent resection (adapted to the tumour location), and HIPEC was performed for 60 min, at 42.5–43  C with gemcitabine at a dose of 1000 mg/m2 after tumour resection and before the reconstruction of the alimentary tract. Authors claimed that the results confirmed the concept because PM occurrence was limited for the patients. Offering a similar procedure in the case of a less morbid surgical resection, such as colon cancer, is legitimate and has been proposed by many HIPEC teams. Most likely, the first reported experience with the concept was from a French surgeon named E Chouillard in 2009 [14]. A very recent publication was devoted to that subject for patients who were operated on for colon cancer in a prospective bicentric study (Milan and Bologne from Italy) [15]. Inclusion criteria were resected synchronous ovarian or minimal peritoneal metastasis or primary colon cancer penetrating the visceral peritoneum. The patient prophylactic HIPEC group consisted of 22 cases compared with 44 cases without HIPEC. With multivariate analysis, HIPEC was correlated with lower PM cumulative incidence [hazard ratio (HR) 0.04, 95% CI 0.01–0.31; p ¼ 0.002] and better OS (HR 0.25, 95% CI 0.07–0.89; p ¼ 0.039) and progression-free survival (HR 0.31, 95% CI 0.11–0.85; p ¼ 0.028) [15]. Of course, these results warrant future confirmation in a phase 3 trial. Other teams actually carried out the same project. In China, a trial conducted by Ding Ke-Feng, from Zhejiang University (NCT 02179489), was opened in 2014 and is currently recruiting. Patients with pT4 colon cancer or metastases to the ovary will be randomised to receive mitomycin-C based HIPEC or not. The primary end-point is three years of disease-free survival. The increase in the number of proposed or published with a very recent delay prophylactic studies has been noticed by many observers. This is considered as the real new fact for HIPEC CRC treatment procedures. Because surgeons are able to understand the risk factors of peritoneal recurrence, in the case of CRC, and because the morbidity of HIPEC procedure decreases drastically, the time is coming for a prophylactic strategy [16].

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Disclosure statement

[7]

None reported for A. Pinto and C. Eveno. M. Pocard is expert consultant for GAMIDA company. M. Pocard had commercial relation with ROCHE, SANOFI, ETHICON company, Capnomed.

[8]

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