Strategic Insight into the Combination Therapies for Metastatic Colorectal Cancer

Round 1

Reviewer 1 Report

Interesting paper

Very good english language

Correct and elegant analysis of studies published in literature

Complete absence of metastatic peritoneal studies . A chapter should be dedicated to the combined treatement for case with peritoneal metastases (10 % cases) and those bearing both peritoneal an hepatic metastases.

Even colorectal metastatic lung setting should be considered.

Author Response

Reviewer #1

Interesting paper

Very good english language

Correct and elegant analysis of studies published in literature

Response:

Thank you for your comment and interest in our manuscript.

Complete absence of metastatic peritoneal studies . A chapter should be dedicated to the combined treatement for case with peritoneal metastases (10 % cases) and those bearing both peritoneal an hepatic metastases.

Even colorectal metastatic lung setting should be considered.

Response:

Thank you for raising these sharp points. We have added a chapter that focused on the management of peritoneal metastases and pulmonary metastases. In short, Analysis and Research in Cancers of the Digestive System (ARCAD) database revealed that a median OS was shorter in patients with peritoneal metastasis compared to liver and lung metastasis (16.3 vs 19.1 vs 24.6 months, HR, 0.79 and 0.61)[1]. From the analysis of a prospectively expanded single-institutional database with over 2400 CRC cases, systemic chemotherapy tended to improve the median survival (17.9 vs 7.03 months, p=0.054) compared to the era of treatment without chemotherapy or 5-Fluorouracil-only[2]. Furthermore, adding bevacizumab into first-line chemotherapy improved overall median survival (11 vs 7.5 months, HR, 0,7) in patients with peritoneal metastasis only and extraperitoneal metastases including liver or lung[3]. Thus, the same strategy as advanced CRC without peritoneal metastases should be considered for patients with peritoneal metastatic CRC although the efficacy remains unsatisfactory. Regarding lung metastases, surgical resection has been a standard treatment option for CRC patients. However, the efficacy of pri-operative chemotherapy after lung metastasectomy remains controversial. The meta-analysis including eight studies demonstrated that peri-operative chemotherapy such as oxaliplatin- or irinotecan-containing regimens had a clinical benefit with better OS (HR, 0.83, p<0.05) and PFS/RFS/DFS(HR, 0.67, p<0.05) in patients after surgical resection[4].

Reference

1. Franko, J.; Shi, Q.; Meyers, J.P.; Maughan, T.S.; Adams, R.A.; Seymour, M.T.; Saltz, L.; Punt, C.J.A.; Koopman, M.; Tournigand, C.; et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomized trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016, 17, 1709-1719, doi:10.1016/s1470-2045(16)30500-9.
2. Kerscher, A.G.; Chua, T.C.; Gasser, M.; Maeder, U.; Kunzmann, V.; Isbert, C.; Germer, C.T.; Pelz, J.O. Impact of peritoneal carcinomatosis in the disease history of colorectal cancer management: a longitudinal experience of 2406 patients over two decades. Br J Cancer 2013, 108, 1432-1439, doi:10.1038/bjc.2013.82.
3. Razenberg, L.G.; van Gestel, Y.R.; Lemmens, V.E.; de Hingh, I.H.; Creemers, G.J. Bevacizumab in Addition to Palliative Chemotherapy for Patients With Peritoneal Carcinomatosis of Colorectal Origin: A Nationwide Population-Based Study. Clin Colorectal Cancer 2016, 15, e41-46, doi:10.1016/j.clcc.2015.12.006.
4. Li, Y.; Qin, Y. Peri-operative chemotherapy for resectable colorectal lung metastasis: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2020, 146, 545-553, doi:10.1007/s00432-020-03142-9.

Reviewer 2 Report

1. Please add discussion of CAIRO-5 trial (https://doi.org/10.1016/

S1470-2045(23)00219-X) in the session of "ii) Which is better for the first line, cetuximab/panitumumab or bevacizumab in RASWT tumors?".

2. Please add discussion of T-DXd trial(DESTINY CRC01: https://doi.org/10.1038/s41467-023-38032-4) and add table.

3. In the HER2 status discussion, please also consider the correlation between HER2 amplification and the efficacy of anti-EGFR antibody.

4. In the session of "2.3.2. Targeting BRAF in combination with upstream blocking", please also add the FIRE4.5 trial and ANCHOR trial to the discussion and table.

Author Response

Reviewer #2

1. Please add discussion of CAIRO-5 trial (https://doi.org/10.1016/S1470-2045(23)00219-X) in the session of "ii) Which is better for the first line, cetuximab/panitumumab or bevacizumab in RASWT tumors?".

Response:

Thank you for your critical comment. The statement ‘Also recently, in an open-label, multicentre, randomized, phase III CAIRO5 study, FOLFOXIRI plus bevacizumab regimen demonstrated superior clinical benefit over FOLFOX/FOLFIRI plus bevacizumab in patients with initially unresectable liver metastasis and a right-sided RAS^Mut or BRAF^V600E mCRC’ has been added to the end of this section.

2. Please add discussion of T-DXd trial(DESTINY CRC01: https://doi.org/10.1038/s41467-023-38032-4) and add table.

Response:

Thank you for your important comment. The statement ‘Furthermore, T-DXd has recently shown solid results with 45.3% of ORR, 6.9 months of PFS, and 15.5 months of OS in the patients with HER2-positive (immunohistochemistry, IHC3+ or IHC2+/in situ hybridization, ISH+) CRC in DESTINY-CRC01 study. Of note, no clinical response was observed in HER2-negative (IHC2+/ISH- and IHC1+) patients.’ has been added. Also, the results of this study have been added and revised in Table 1.

3. In the HER2 status discussion, please also consider the correlation between HER2 amplification and the efficacy of anti-EGFR antibody.

Response:

Thank you for raising this important point. We have added the statement ‘Similarly, HER2 amplification has been reported to be a negative biomarker for the response to anti-EGFR antibody therapy and screening test for HER2 should be considered before the treatment in mCRC patients[1,2].’

4. In the session of "2.3.2. Targeting BRAF in combination with upstream blocking", please also add the FIRE4.5 trial and ANCHOR trial to the discussion and table.

Response:

Thank you for your comment. We have added these two trials (FIRE4.5 and ANCHOR) at the end of this section.

Reference

1. Ross, J.S.; Fakih, M.; Ali, S.M.; Elvin, J.A.; Schrock, A.B.; Suh, J.; Vergilio, J.A.; Ramkissoon, S.; Severson, E.; Daniel, S.; et al. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018, 124, 1358-1373, doi:10.1002/cncr.31125.
2. Sartore-Bianchi, A.; Amatu, A.; Porcu, L.; Ghezzi, S.; Lonardi, S.; Leone, F.; Bergamo, F.; Fenocchio, E.; Martinelli, E.; Borelli, B.; et al. HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer. Oncologist 2019, 24, 1395-1402, doi:10.1634/theoncologist.2018-0785.