Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial

Klaver, Charlotte E. L.; Wisselink, D D; Punt, Cornelis J.A.; Snæbjörnsson, Pétur; Crezee, J.; Aalbers, Arend G. J.; Brandt, Alexandra; Bremers, André J. A.; Burger, Jacobus W. A.; Fabry, Hans; Ferenschild, Floris T. J.; Festen, Sebastiaan; Grevenstein, Wilhelmina M U van; Hemmer, Patrick H. J.; Hingh, Ignace H. J. T. de; Kok, Niels F. M.; Musters, Gijsbert D.; Schoonderwoerd, Lotte; Tuynman, Jurriaan B.; Ven, Anthony W. H. van de; Westreenen, Henderik L. van; Wiezer, Marinus J.; Zimmerman, D. D. E.; Zweeden, Annette A. van; Dijkgraaf, Marcel G. W.; Tanis, Pieter J.; Andeweg, Caroline S.; Bastiaenen, Vivian P.; Bemelman, Willem A.; Bilt, Jarmila D. W. van der; Bloemen, Johanne G.; Boer, Frank C. den; Boerma, Djamila; Huinink, Daan ten Bokkel; Brokelman, Walter J.A.; Cense, Huib A.; Consten, Esther C. J.; Creemers, Geert-Jan; Crolla, Rogier M. P. H.; Dekker, Jan-Willem T.; Demelinne, Jennifer; Det, Marc J. van; Diepen, Karin K. van; Diepeveen, Marjolein; Duyn, Eino B. van; Ende, Esther D. van den; Evers, Pauline; Geloven, A. A. W. van; Harst, Erwin van der; Heemskerk, Jeroen; Heikens, Joost T.; Hess, Daniël A.; Inberg, B.; Jansen, J. B. M. J.; Kloppenberg, F. W. H.; Kootstra, Thomas J.M.; Kortekaas, R. T.; Los, Maartje; Madsen, Eva; Mijle, Huub C J van der; Mol, Linda; Neijenhuis, Peter A.; Nienhuijs, Simon W.; Nieuwenhof, Loes van den; Peeters, Koen; Polle, Sebastiaan W.; Pon, Jolien; Poortman, Pieter; Radema, Sandra A.; Ramshorst, Bert van; Reuver, Philip R. de; Rovers, Koen P.; Schmitz, Roderick F.; Sluiter, Nina R.; Sommeijer, Dirkje W.; Sonneveld, D.J.A.; Sprundel, T C van; Veltkamp, Sanne C.; Vermaas, Maarten; Verwaal, Victor J.; Wassenaar, Emma C. E.; Wegdam, Johannes A.; Wilt, Johannes H. W. de; Westerterp, Marinke; Wit, Fennie; Witkamp, Arjen J.; Woensdregt, Karlijn; Zaag, Edwin S. van der; Zournas, Mandy

doi:10.1016/s2468-1253(19)30239-0

Cited by 220 publications

(156 citation statements)

References 30 publications

(37 reference statements)

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“…Current strategies involving HIPEC to avoid the growth of microscopic peritoneal spread into overt metastases have failed to demonstrate a benefit in randomized trials, but patients were selected for these adjuvant treatments based on clinical-pathological features only. 37,38 Previous series of palliative s-CT have reported the association of CRC-PMs with mutated BRAF 4,11,21,39 or wild-type PIK3CA. 40 In our series, the BRAF and PIK3CA mutation profile was comparable with all-type metastatic CRCs, thus not supporting their potential association with PM development; however, our series included only highly selected patients amenable to curative-intent surgery, who likely represent a different setting than palliative s-CT series.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

et al. 2020

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Background. Selecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone. Methods. We reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes. Results. The primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43-0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05-4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03-2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03). Conclusions. BRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression. Peritoneal metastases (PMs) from colorectal cancer (CRC) are still a significant healthcare problem and an important cause of disease-related death following liver and lung metastases. 1,2 Because of the current limitation of imaging in detecting small-volume peritoneal disease, CRC-PMs are frequently diagnosed at an advanced stage. 3

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Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

et al. 2020

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“…In the Dutch randomized multicenter COLOPEC trial in patients with stage II-III colon cancer with a c/pT4 or perforation, peritoneal metastasis-free survival was assessed after receiving 30 min oxaliplatin-based HIPEC following adjuvant chemotherapy [43]. After 18 months, peritoneal metastasis-free survival was not significantly improved (76.2% in control-arm vs. 80.9% in HIPEC-arm), which can partly be attributed to bias favoring the control arm, as metastases could be detected earlier during the HIPEC in the experimental arm.…”

Section: Discussionmentioning

confidence: 99%

The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines

Helderman

Löke

Verhoeff

et al. 2020

Cells

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Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC. Methods: The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38–43 °C/60 min). Results: Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat. Conclusion: Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC.

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“…Apart from the standard HIPEC application as curative treatment of synchronous and metachronous PC, another application of HIPEC has emerged in the last years, adjuvant HIPEC in patients with locally advanced colorectal cancer (pT4) or perforated colorectal cancer without visible PC [20][21][22]. The intention of adjuvant or rather prophylactic HIPEC is to prevent metachronous PC in high-risk patients.…”

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confidence: 99%

“…K short review strate a significant difference in peritoneal diseasefree survival or overall survival. [20,21]; however, the amount of available data are rather small to jump to a conclusion and ongoing high-quality trials are still open (e.g. COLOPEC II, PROMENADE and HIPECT4) [22][23][24].…”

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confidence: 99%

Do we still need CRS and HIPEC in colorectal cancer in times of modern chemotherapy and immunotherapy?

Gasser

Kogler

Lorenz

et al. 2020

memo

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Summary Peritoneal carcinomatosis from colorectal cancer is associated with a poor prognosis and is usually treated with systemic chemotherapy and immunotherapy alone. In patients with isolated peritoneal carcinomatosis (PC) without nonperitoneal metastases, however, cytoreductive surgery (CRS) has been shown to significantly improve outcome and to achieve even cure in selected patients in combination with systemic therapy. The additional use of a hyperthermic intraperitoneal chemotherapy (HIPEC) is primarily indicated to control microscopical residual tumor tissue in the peritoneal cavity after successful CRS. Another more recent option is the application of an adjuvant HIPEC to prevent peritoneal carcinomatosis in high risk patients with pT4 cancer or perforated cancer at the time of or after primary surgery. The aim of this short review is to highlight the corresponding available literature and assess the role of CRS and HIPEC in the context of modern chemotherapy and immunotherapy.

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Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial

Cited by 220 publications

References 30 publications

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines

Do we still need CRS and HIPEC in colorectal cancer in times of modern chemotherapy and immunotherapy?

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