Targ Oncol (2015) 10:125–133 DOI 10.1007/s11523-014-0322-0
ORIGINAL RESEARCH
Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer T. Kogawa & A. Doi & M. Shimokawa & T. M. Fouad & T. Osuga & F. Tamura & T. Mizushima & T. Kimura & S. Abe & H. Ihara & T. Kukitsu & T. Sumiyoshi & N. Yoshizaki & M. Hirayama & T. Sasaki & Y. Kawarada & S. Kitashiro & S. Okushiba & H. Kondo & Y. Tsuji
Received: 2 January 2014 / Accepted: 9 May 2014 / Published online: 27 May 2014 # Springer International Publishing Switzerland 2014
Abstract Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4–8 weeks after the start of T. Kogawa (*) : A. Doi : T. Osuga : T. Kimura : M. Hirayama : Y. Tsuji Department of Medical Oncology, KKR Sapporo Medical Center Tonan Hospital, Kita1-Nishi6, Chu-ou-ku, Sapporo, Hokkaido 060-0001, Japan e-mail:
[email protected] A. Doi : F. Tamura : T. Mizushima : T. Kimura : S. Abe : H. Ihara : T. Kukitsu : T. Sumiyoshi : N. Yoshizaki : M. Hirayama : H. Kondo The Center for Digestive Disease, KKR Sapporo Medical Center Tonan Hospital, Sapporo, Hokkaido, Japan T. Sasaki : Y. Kawarada : S. Kitashiro : S. Okushiba Department of Surgery, KKR Sapporo Medical Center Tonan Hospital, Sapporo, Hokkaido, Japan M. Shimokawa Department of Cancer Biostatistics Laboratory, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, Japan T. M. Fouad Department of Medical Oncology, The National Cancer Institute, Cairo University, Cairo, Egypt
treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P=0.0001). Patients with early skin toxicity showed significantly longer overall survival (P= 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P=0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab. Keywords Colorectal cancer . Cetuximab . Early skin reaction . Early tumor shrinkage
Introduction Cetuximab is a promising epidermal growth factor receptor (EGFR) targeting monoclonal antibody used to treat patients with advanced colorectal cancer. Cetuximab-containing treatments have resulted in higher overall response rates (ORRs) and longer progression-free survival (PFS) and overall survival (OS) than other chemotherapy regimens for patients with metastatic colorectal cancer, not only as first-line treatment [1, 2] but also as second-line [3] and third-line treatment [4, 5]. Metastatic colorectal cancers were assumed to be incurable until secondary resectability of colorectal cancer with liver metastases was achieved through combination treatments, particularly cetuximab-containing regimens [6]. Cetuximabcontaining treatments yielded ORRs 16–24 % higher than those of other combination regimens such as bevacizumabcontaining regimens [1, 2]. Though ORR is not a reliable surrogate marker for outcome, cetuximab has been shown to
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render initially unresectable colorectal cancer with metastases resectable by causing significant tumor shrinkage [6–8]. Unfortunately, cetuximab causes unfavorable skin reactions, and some colorectal cancers do not respond to it. Therefore, determining cetuximab response early is important to avoid unnecessary adverse events and to switch to another potentially effective treatment. Studies suggest that highgrade and early-onset cetuximab-related tumor changes and adverse effects are predictors of response to therapy. In a subanalysis of a prospective randomized clinical trial, severe skin toxicity (grade ≥2) was shown to be a good predictor of response in patients treated with cetuximab-containing regimens [1, 4]. Early onset of hypomagnesemia [9] and early tumor shrinkage [10] have also been shown to predict response. We hypothesized that early tumor shrinkage of more than 20 % for 4–8 weeks after the start of treatment, any skin toxicity within the first 2 weeks after the start of treatment, and high skin toxicity grade (grade ≥2) are predictors of response to cetuximab in patients with unresectable colorectal cancer. We also investigated the relationships between these factors and survival outcomes.
Patients and methods Study design and patient eligibility criteria We searched the colorectal cancer database at KKR Sapporo Medical Center Tonan Hospital (Japan) for patient treatment records and identified 85 patients with histologically confirmed advanced colorectal cancer treated with cetuximab with or without cytotoxic agents. Advanced colorectal cancer was defined as colorectal cancer with unresectable distant metastases in the liver, lungs, or nonregional lymph nodes and unresectable locally advanced disease (T4 classification by the Union for International Cancer Control system) at the time of the start of treatment. The medical records of patients treated with cetuximab-containing regimens between October 1, 2008, and September 30, 2011, were reviewed, and followup continued until September 30, 2012. We collected data on patient demographics, treatment, response, adverse effects, date of disease progression, and date of death. Patients were excluded from our analyses if they had received any radiation therapy, chemotherapy, immunotherapy, or growth factors ≤2 weeks before cetuximab administration. Patients who had recent (within 1 week of the start of cetuximab treatment) or concurrent treatment with chronic steroid-based therapy and patients with acute or chronic infection or inflammatory disease were ineligible. Patients who received any other targeting agent without disease progression on the cetuximab-containing regimen were ineligible. Patients who did not have computed tomography [11] evaluation results or missing KRAS status were ineligible.
Targ Oncol (2015) 10:125–133
Among the 85 initially screened cases, 5 were excluded owing to the halting of cetuximab administration during the first treatment. In those five cases, the patients were switched to panitumumab owing to an infusion reaction in three cases and to the patients declining to continue treatment in two cases. Among the remaining 80 cases, 17 cases were excluded because of unknown KRAS status, and 1 case was excluded owing to missing CT evaluation timing. Thus, we included 62 cases in our final cohort. Ethical approval of the study was obtained from the Institutional Review Board of KKR Sapporo Medical Center Tonan Hospital. Standard criteria for anticancer treatment suitability were used at our institution. Baseline CT assessment was performed
