Top

Published in:

01-12-2016 | Original Research Article

Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)

Authors: Akihito Tsuji, Yu Sunakawa, Wataru Ichikawa, Masato Nakamura, Mitsugu Kochi, Tadamichi Denda, Tatsuro Yamaguchi, Ken Shimada, Akinori Takagane, Satoshi Tani, Masahito Kotaka, Hidekazu Kuramochi, Kaoru Furushima, Junichi Koike, Yutaka Yonemura, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima

Published in: Targeted Oncology | Issue 6/2016

Abstract

Background

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.

Patients and Methods

We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman’s rank correlation coefficient.

Results

In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r _s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r _s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r _s = 0.587, r _s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities.

Conclusions

Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

https://static-content.springer.com/image/art%3A10.1007%2Fs11523-016-0445-6/MediaObjects/11523_2016_445_Figa_HTML.gif

Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer. 2001;92:1331–46.CrossRefPubMed

Saltz LB, Meropol NJ, Loehrer Sr PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.CrossRefPubMed

Folprecht G, Lutz MP, Schoffski P, Seufferlein T, Nolting A, Pollert P, et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol. 2006;17:450–6.CrossRefPubMed

Galizia G, Lieto E, De Vita F, Orditura M, Castellano P, Troiani T, et al. Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer. Oncogene. 2007;26:3654–60.CrossRefPubMed

Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1:1311–8.PubMed

Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.CrossRefPubMed

Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.CrossRefPubMed

Heinemann V, Stintzing S, Modest DP, Giessen-Jung C, Michl M, Mansmann UR. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer. 2015;51:1927–36.CrossRefPubMed

Giessen C, Laubender RP, von Fischervon WL, Schalhorn A, Modest DP, Stintzing S, et al. Early tumor shrinkage in metastatic colorectal cancer: retrospective analysis from an irinotecan-based randomized first-line trial. Cancer Sci. 2013;104:718–24.CrossRefPubMed

10.

Modest DP, Laubender RP, Stintzing S, Giessen C, Schulz C, Haas M, et al. Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial. Acta Oncol. 2013;52:956–62.CrossRefPubMed

11.

Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015;26:1188–94.CrossRefPubMed

12.

Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764–75.CrossRefPubMed

13.

Mansmann UR, Sartorius U, Laubender RP, Giessen CA, Esser R, Heinemann V. Quantitative analysis of the impact of deepness of response on post-progression survival time following first-line treatment in patients with mCRC. Ann Oncol. 2013;24 Suppl 4:iv14-iv15.

14.

Fakih M, Wong R. Efficacy of the monoclonal antibody EGFR inhibitors for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17 Suppl 1:S3–17.PubMedPubMedCentral

15.

Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22:1535–46.CrossRefPubMed

16.

Lenz H-J, Lee F-C, Yau L, Koh HA, Knost JA, Mitchell EP, et al. MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) vs FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2016;34 Suppl 4S:abstr 493.

17.

Stintzing S, Modest DP, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran S, Heintges T, Lerchenmueller C, Kahl C, Seipelt G, Kullmann F, Scheithauer W, Held S, Giessen C, Moehler M, Jagenburg A, Jung A, Kirchner T, Heinemann V. Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol. 2014;25 Suppl 5:v1-v41.

18.

Ichante J, Adenis A, Malka D, Francois E, Boucher E, Chauffert B, Pignon J, Ychou M, Pierga J, Montoto-Grillot C, Conroy T, Ducreux M, GI group of FNCLCC. Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with 5FU plus irinotecan plus leucovorin (FOLFIRI) or capecitabine plus irinotecan XELIRI plus bevacizumab. J Clin Oncol. 2011;29 Suppl:abstr e 14041.

19.

Sommeijer DW, Shi Q, Meyers JP, Sjoquist KM, Hoff PM, Seymour MT, Cassidy J, Goldberg RM, Douillard J-Y, Hecht JR, Hurwitz H, Tournigand C, Tebbutt NC, Aranda E, Souglakos J, Kabbinavar FF, Chibaudel B, De Gramont A, Sargent DJ, Zalcberg JR, for the ARCAD Group. Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database. J Clin Oncol. 2013;31 Suppl:abstr 3520.

Title: Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)
Authors: Akihito Tsuji
Yu Sunakawa
Wataru Ichikawa
Masato Nakamura
Mitsugu Kochi
Tadamichi Denda
Tatsuro Yamaguchi
Ken Shimada
Akinori Takagane
Satoshi Tani
Masahito Kotaka
Hidekazu Kuramochi
Kaoru Furushima
Junichi Koike
Yutaka Yonemura
Masahiro Takeuchi
Masashi Fujii
Toshifusa Nakajima
Publication date: 01-12-2016
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 6/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-016-0445-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Patients and Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2016

Anti-EGFR Agents: Current Status, Forecasts and Future Directions

Retraction Note to: The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials

Role of C-Jun N-terminal Kinase in Hepatocellular Carcinoma Development

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

ᅟ

Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer