Cetuximab-containing Chemotherapy Research Articles

Sequential administration of PD‑1 inhibitor and cetuximab causes pneumonia.

Severe drug-induced lung injury (DLI) has been reported to be associated with sequential administration of osimertinib, a third-generation tyrosine kinase inhibitor, following a programmed cell death ligand 1 (PD-L1) inhibitor. However, the relationship of sequential treatment with an anti-epidermal growth factor receptor (EGFR) antibody and PD-1 inhibitor with the risk of DLI remains to be elucidated. The present study conducted a retrospective review of the medical records of a total of 179 patients with head and neck cancer who had received treatment with cetuximab and/or a PD-1 inhibitor (nivolumab or pembrolizumab) at Chiba University Hospital (Chiba, Japan) between September 2014 and December 2020. The incidence of pneumonia and the clinical background characteristics of the patients were analyzed. The patients were classified into subgroups for analysis of the outcomes in this study: Patients who had received sequential, but not concurrent, cetuximab and PD-1 inhibitor treatment (Group C+P; n=43); patients who had received cetuximab-containing chemotherapy, but not a PD-1 inhibitor (Group C; n=101); and patients who had received PD-1 inhibitor-containing chemotherapy, but not cetuximab (Group P; n=35). The rates of DLI in the three groups were: Group C+P, 18.6%; Group C, 7.9%; and Group P, 11.4%. Prior use of ICI was not associated with any increase in the risk of DLI. DLI is seen frequently in patients receiving sequential PD-1 inhibitor and anti-EGFR antibody therapy.

The effect of primary tumour resection on patients with synchronous metastatic colorectal cancer treated with cetuximab-containing regimens.

This study aims to assess the effect of primary tumour resection (PTR) on patients with metastatic colorectal cancer (mCRC) treated with cetuximab. This retrospective cohort study was conducted in a tertiary cancer center in Turkey. Patients with mCRC between January 2009 and December 2020 were extracted from the electronic hospital management system. Patients with RAS wild-type synchronous metastatic left-sided colon or rectum cancer who had cetuximab-containing treatment protocol were included in the study. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcome was response rates. A total of 111 patients with mCRC were included in this study. PTR was performed in 57.7% of all patients. Fifty-nine (53.2%) and 52 (46.8%) patients had rectal and left colon tumours, respectively. The combination treatment with cetuximab was FOLFIRI in 62.2% and FOLFOX in 29.7% of all patients. In subgroup analysis, the median PFS was 7.9 and 9months in PTR (+) and PTR (-) patients, respectively. The difference between the groups was not statistically significant (P= 0.3). The median OS was 33 months in all patients. In subgroup analysis, the median OS was 39 and 27.9months in PTR (+) and PTR (-) patients, respectively. The difference between the groups was statistically significant (P= 0.002). After adjusting for confounding factors, PTR and ECOG performance score were the independent prognostic factors for OS. PTR improved the OS in patients with RAS wild-type synchronous left-sided colon or rectum cancer treated with cetuximab-containing chemotherapy regimens.

Tegafur-Uracil versus 5-Fluorouracil in Combination with Cisplatin and Cetuximab in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Propensity Score Matching Analysis.

Simple SummaryElderly patients with recurrent or metastatic head and neck squamous cell carcinoma are a unique subset because they are at increased risks of miserable prognosis. Although cisplatin, 5-fluorouracil plus cetuximab (EXTREME) is the most commonly used regimen, chemotherapy de-escalation strategy was suggested in elderly patients due to toxicity. Herein, an oral tegafur–uracil is usually substituted for 5-fluorouracil and combined with cisplatin plus cetuximab (UPEx) as a novel agent for elderly patients with recurrent or metastatic head and neck squamous cell carcinoma. The median progression-free survival was 5.4 months in UPEx and 5.8 months in EXTREME (p = 0.451). The median overall survival was 10.8 months in UPEx and 10.2 months in EXTREME (p = 0.807). Grade 3/4 adverse events were much fewer in UPEx than in EXTREME (p < 0.001). Our study demonstrated that UPEx is effective with improving safety profiles. We suggested UPEx might be a better treatment option for elderly patients with recurrent or metastatic head and neck squamous cell carcinoma.There are increasing incidences of elderly patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the treatment is not yet established. We conducted a propensity score matching analysis to evaluate the efficacy and safety of tegafur–uracil versus 5-fluorouracil in combination with cisplatin plus cetuximab in elderly patients with R/M HNSCC. Elderly patients with R/M HNSCC treated with cetuximab-containing chemotherapy were recruited into this study. In order to reduce the selection bias, propensity score matching was performed. Kaplan–Meier curves were plotted for progression-free survival (PFS) and overall survival (OS). Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria V3.0. After propensity sore matching, 54 patients with tegafur–uracil, cisplatin plus cetuximab (UPEx), and 54 patients with 5-fluorouracil, cisplatin plus cetuximab (EXTREME) were identified. The median PFS was 5.4 months in UPEx and 5.8 months in EXTREME (p = 0.451). The median OS was 10.8 months in UPEx and 10.2 months in EXTREME (p = 0.807). The overall response rate (ORR) and disease control rate (DCR) were insignificant in both arms, accounting for 61% versus 59% (p = 0.680) and 72% versus 70% (p = 0.732) in the UPEx arm and the EXTREME arm, respectively. A multivariate analysis showed that age and ECOG PS were, independently, predictors. Grade 3/4 adverse events were much fewer in UPEx than in EXTREME (p < 0.001). Both cetuximab-containing chemotherapies are effective in elderly patients with R/M HNSCC. Safety profiles are improved when tegafur–uracil is substituted for 5-fluorouracil. Further prospective studies are warranted to validate our conclusions.

Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR

Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.

Drug-induced interstitial lung disease in recurrent and/or metastatic head and neck cancer patients treated with cetuximab and/or nivolumab.

Drug-induced interstitial lung disease (DI-IP) is one of the most serious adverse reactions associated with the use of anticancer drugs. DI-IP prevalence among molecular-targeting drugs and immune checkpoint inhibitors (ICIs) is relatively high in Japanese patients. To assess the risk of cetuximab and/or nivolumab-related IP is important. The medical records of 138 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with cetuximab-containing chemotherapy and/or nivolumab monotherapy were retrospectively reviewed. The incidence of DI-IP with R/M HNSCC was 7.2%. DI-IP occurred more frequently in patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy than in patients with other regimens. However, tumor suppression was detected in all patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy, and two achieved a complete response. Although patients treated with cetuximab-containing chemotherapy following nivolumab showed dramatic efficacy, careful monitoring should be recommended.

First-line chemotherapy for head and neck squamous cell carcinoma. Optimal strategy

The study objective is to provide a rationale for the development of an individual treatment plan for patients with locally advanced squamous cell carcinoma of the larynx, hypopharynx, and oropharynx by selecting different regimens of induction chemotherapy according to biological characteristics of the tumor and functional status of the patient. Materials and methods . We developed an individual treatment plan for a patient with stage IV moderately differentiated oropharyngeal squamous cell carcinoma (cT4N2M0) characterized by extensive local distribution, pronounced clinical symptoms of respiratory failure, and bilateral conglomerates of metastatic lymph nodes. The treatment scheme included paclitaxel (80 mg/m 2 ), carboplatin AUC 2, and ce-tuximab (400 mg/m 2 loading dose, then 250 mg/m 2 ). The treatment was initially palliative. The patient received 6 injections once a week. Results. After a six-week course, we observed tumor resorption by more than 50 %, which allowed the second stage of treatment that included radical chemoradiotherapy with cetuximab. After summarizing our own experience, we found that the majority of patients with initially unresectable tumors, but in good overall physical condition responded to docetaxel, cisplatin, 5-fluorouracil (TPF) — based chemotherapy. Approximately half of them had complete tumor resorption, whereas 14.2 % of them had stabilization of the tumor process. Research literature shows that up to 30 % of patients receiving chemoradiotherapy with cisplatin fail to complete the planned treatment due to its toxicity; replacement of cisplatin with carboplatin and 5-fluorouracil results in mucositis and thrombocytopenia. By contrast, chemoradiotherapy with cetuximab significantly increases both 3-year and 5-year survival and demonstrates good tolerability. In patients with .severe nutritional deficiency, concomitant cardiac diseases, polyneuropathy, and impaired liver function, the preference should be given to less toxic treatment regimens. Conclusion. Cetuximab-containing chemotherapy regimens are the most effective treatment option in head and neck squamous cell carcinoma They can be used in patients with different functional status depending on the clinical situation.

Observational study of first-line chemotherapy including cetuximab in patients with metastatic colorectal cancer: CORAL trial.

We aimed to clarify the clinical practice and outcomes of first-line cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Efficacy and safety were evaluated in each group classified by the European Society for Medical Oncology Guidelines 2012. This prospective observational study included patients with previously untreated metastatic colorectal cancer from 158 centers in Japan who started first-line cetuximab-containing chemotherapy from January 2012 to June 2013 and were followed for up to 3 years. The resection rates after chemotherapy were calculated and the overall survival was estimated using the Kaplan-Meier method for Group 1 (G1, potentially resectable), Group 2 (G2, not resectable and tumor-related symptoms) and Group 3 (G3, not resectable and asymptomatic). Of 578 patients, 562 were classified into G1 (n = 165), G2 (n = 224) or G3 (n = 173). The resection rate of any site was higher in G1 (57.0%) than in G2 (11.2%) and G3 (11.6%). G1, G2 and G3 showed median overall survivals (95% confidence interval) of 45.9 (38.1-not available), 16.7 (14.5-18.8) and 30.6 (23.2-34.8) months, respectively (P < 0.0001). The common tumor-related symptoms in G2 were pain, fatigue and anorexia, from which 31.7, 22.2 and 14.8% of the patients suffered at baseline. The expected efficacy and safety of first-line cetuximab-containing chemotherapy were demonstrated in patients with metastatic colorectal cancer under clinical practice in Japan. UMIN000007275.

108P - A pilot case-control study of second or third-line treatment with cetuximab-containing chemotherapy (cetux-chemo) in patients (pts) with metastatic colorectal cancer (mCRC) who were previously treated with cetux-chemo

108P - A pilot case-control study of second or third-line treatment with cetuximab-containing chemotherapy (cetux-chemo) in patients (pts) with metastatic colorectal cancer (mCRC) who were previously treated with cetux-chemo

P1-006 - Remarkable response to cetuximab-containing chemotherapy for tongue cancer refractory to immune checkpoint inhibitors

P1-006 - Remarkable response to cetuximab-containing chemotherapy for tongue cancer refractory to immune checkpoint inhibitors

A comparison of weekly paclitaxel and cetuximab with the EXTREME regimen in the treatment of recurrent/metastatic squamous cell head and neck carcinoma

BackgroundThe effectiveness of the combination chemotherapy of weekly paclitaxel and cetuximab has not yet been compared to that of the current standard regimen, EXTREME (combination of 5-fluorouracil, cisplatin and cetuximab). MethodsWe retrospectively reviewed the clinical records of R/M SCCHN patients who received cetuximab-containing chemotherapy as a first-line therapy; from these, patients receiving a weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME regimen (cohort B) were extracted. The responses, prognoses and adverse events of these two cohorts were evaluated. ResultsA total of 86 patients were included (cohort A, 49; cohort B, 36). Patients with histories of platinum-based chemotherapy were more frequently given the cohort A treatment. Though the response rates were similar in the two cohorts (45% in cohort A and 51% in cohort B; p=0.83), the progression-free survival (PFS) was significantly more favorable in cohort A by the log-rank test (6.0monthsvs 5.0months; p=0.027). In the Cox-regression hazard analyses, male gender (hazard ratio [HR]=2.1, p=0.010), older age (≥ 70 yo) (HR=5.0, p=0.018), PS 0 (HR=2.2, p=0.027), no history of platinum chemotherapy (HR=3.2, p=0.003) and the presence of a tracheostomy (HR=2.3, p=0.039) were favorable factors within cohort A. ConclusionIn selected R/M SCCHN patients, the combination of weekly paclitaxel and cetuximab could be the better treatment option than the EXTREME regimen.

The Impact of Microsatellite Instability Status and Sidedness of the Primary Tumor on the Effect of Cetuximab-Containing Chemotherapy in Patients with Metastatic Colorectal Cancer.

Background: Colorectal cancer (CRC) has been reconsidered as a heterogeneous disease. Among advances of genomic analysis in CRC, the sidedness of tumors (left-sided colon vs. right-sided colon) and microsatellite instability (MSI)-high (H) tumors have been highlighted.Methods: We analyzed 153 CRC patients who were available for evaluation of MSI status and had been treated with cetuximab-containing chemotherapy between April 2008 and January 2013. KRAS mutational status was available in all 153 patients, but BRAF mutational status was only available in 72 patients (47.1%). We evaluated the impact of microsatellite instability status and location of the primary colon tumor on the effect of cetuximab-containing chemotherapy in patients with metastatic colorectal cancer.Results: MSI-H was detected in 3.9% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right and left-sided tumors. Right-sided tumors were significantly associated with a BRAF mutation (p=0.023). In addition, patient characteristics with an MSS tumor were not different from those with an MSI-H tumor. For all 153 patients, the most commonly used regimen that included cetuximab was irinotecan alone, irrespective of treatment line. There was no significant difference in treatment efficacy in either RR or disease control rate (DCR) between the MSI-H and MSS groups. There was also no difference in RR and DCR according to the location of the primary tumor (left side vs. right side). No significant difference in PFS was observed between the MSI-H and MSS groups (4.80 months vs. 5.80 months; p=0.238) or the left-side and right-side groups (6.10 months vs. 4.20 months; p=0.278). In a subgroup-analysis of 140 patients with wild-type KRAS, there was no difference in PFS following cetuximab-containing therapy based on MSI status or the location of the primary tumor.Conclusions: MSI status and the location of the primary tumor were not novel biomarkers for response to cetuximab-containing therapy in metastatic CRC. Further prospective validation of the prognostic or predictive capacity of MSI status and the sidedness of tumors is warranted.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer

ABSTRACTSeveral studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤ 19) / long (L; ≥ 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

Combined Analysis of EGFR and PTEN Status in Patients With KRAS Wild-Type Metastatic Colorectal Cancer.

To determine the relationship between the expression of phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and the clinical outcome of cetuximab-containing chemotherapy.A total of 158 consecutive mCRC patients with wild-type KRAS status who received chemotherapy with or without cetuximab, and for whom tumor tissue was available, were enrolled. The EGFR and PTEN expression was determined by immunohistochemistry (IHC).A total of 158 mCRC patients with wild-type KRAS status were enrolled in the study; 51 patients received chemotherapy combined with cetuximab, 107 patients received chemotherapy alone. Patients who received chemotherapy combined with cetuximab had longer overall survival (OS) compared with patients who received chemotherapy alone. High EGFR expression was detected in 60 patients (38.0%), while normal PTEN expression was detected in 60 patients (59.5%). The PTEN status was significantly related with the histological grade. For patients who received chemotherapy combined with cetuximab the median OS of patients with high-expression of EGFR was longer than the OS of patients with low EGRF expression; 25.0 versus 19.0 months, P = 0.002. For patient with normal PTEN the median OS were longer than the median OS for patients with loss of PTEN; 24.0 versus 19.0 months, P = 0.026. The overall response rate (ORR) had a borderline association with EGFR and PTEN expression (P = 0.055 and 0.048, respectively). In a multivariate analysis, ECOG PS, EGFR status, chemotherapy ± cetuximab, and the interaction of EGFR or PTEN and chemotherapy ± cetuximab were independent prognostic factors for OS.Our findings show that chemotherapy combined with cetuximab demonstrated encouraging antitumor activity for mCRC patients with wild-type KRAS status. Especially, those who have high EGFR expression or normal PTEN expression were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.

Efficacy of cetuximab-containing chemotherapy with or without bevacizumab in prior chemotherapies.

e14591 Background: Cetuximab and bevacizumab have been shown to improve survival of metastatic colorectal cancer (mCRC) patients, but the best sequence of them is still unknown. The aim of this stu...

Contradictory KRAS mutation test results in a patient with metastatic colon cancer

The KRAS oncogene is mutated in 40‒50% of colorectal cancers and confers resistance to EGFR-targeted therapy. In the clinic, agents such as cetuximab or panitumumab target the EGFR receptor for therapeutic benefit. Cetuximab was approved by the FDA in 2012 as first-line therapy for KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer, in combination with FOLFIRI (5-fluorouracil, irinotecan, leucovorin). Herein we report a case of metastatic colon cancer with conflicting testing results for the KRAS oncogene from two different reference laboratories. The discordant reports complicated the decision-making process regarding the administration of targeted anti-EGFR personalized therapy. As the second test result was wild-type from the same original pathological specimen, the patient was treated with cetuximab-containing combination chemotherapy and appeared to have a response after prior disease progression. It is unclear whether the observed response was fully due to regression of wild-type KRAS-containing tumor or any component of antibody-dependent cellular cytotoxicity to a heterogeneous tumor in this patient.

KRAS mutation detection by high-resolution melting analysis significantly predicts clinical benefit of cetuximab in metastatic colorectal cancer

Background:Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are restricted to KRAS wild-type (WT) metastatic colorectal cancers (mCRCs), usually identified by direct sequencing, that may yield false negative results because of genetic heterogeneity within the tumour. We evaluated the efficiency of high-resolution melting analysis (HRMA) in identifying KRAS-mutant (MUT) tumours.Methods:We considered 50 mCRC patients scored as KRAS-WT by direct sequencing and treated with cetuximab-containing chemotherapy, and tested the correlations between HRMA findings and response rate (RR), progression-free (PFS) and overall survival (OS).Results:Aberrant melting curves were detected in four (8%) cases; gene cloning confirmed these mutations. Response rate (RR) of HRMA KRAS-WT patients was 28.3%. There was no response in HRMA KRAS-MUT patients. Disease control rate (responsive plus stable disease) was 58.7% in HRMA KRAS-WT patients and 25% in HRMA KRAS-MUT patients. There was no correlation between HRMA KRAS status and RR (P=0.287) or disease control (P=0.219). Median PFS (4.8 vs 2.3 months; hazard ratio (HR)=0.29, P=0.02) and OS (11.0 vs 2.7 months; HR=0.11, P=0.03) were significantly longer for the HRMA KRAS-WT than for HRMA KRAS-MUT patients.Conclusions:High-resolution melting analysis identified 8% more KRAS-MUT patients not responding to cetuximab-containing regimens, suggesting that HRMA may be more effective than direct sequencing in selecting patients for anti-EGFR antibodies.

KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m2 weekly and 1650 mg/m2/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m2 on 1 week before radiation, and 250 mg/m2 weekly thereafter. Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus capecitabine regimen was not associated with improved clinical outcome compared with chemoradiation without cetuximab.

High-resolution melting analysis (HRMA) for KRAS mutational study in patients with metastatic colorectal cancer (mCRC pts).

515 Background: The use of anti EGFR monoclonal antibodies cetuximab and panitumumab is restricted to KRAS wild-type (WT) mCRC pts. Standard method for KRAS testing is direct sequencing. To overcome its limited sensitivity, novel techniques have been developed. However there is little concordance on the clinical significance of more sensitive tests. HRMA is very sensitive and economic and allows rapid detection of DNA sequence variations based on specific sequence-related melting profile. Here we report the evaluation of therapeutic effects of cetuximab in direct sequencing tested WT pts, according to their HRMA mutational status. Methods: We retrospectively evaluated 50 (35 males, 15 females) mCRC pts with WT KRAS status by direct sequencing. Median age was 61 years (range 29 – 77). Most (40%) pts had liver metastases and 24% had multi-organ disease. They received second- or third-line cetuximab-containing chemotherapy, with irinotecan (n=25) or with combination regimen (22 FOLFIRI and 3 FOLFOX). Twenty-eight pts were treated in second-line and 22 in third-line. KRAS mutation status was reassessed in all pts using HRMA. Results: All 50 pts were evaluated for tumor response, PFS and OS. In 4 (8%) pts, KRAS mutations were only identified by HRMA. The response rate of HRMA KRAS WT pts was 28.3%, with 1 complete (2.2%) and 12 partial (26.1%). No response was observed in HRMA KRAS MT (3/4 with a progression as best response). Stable disease rates were 30.4% (14/46 pts) and 25% (1/4 pts) in HRMA WT and MT cases respectively. Disease control rate (objective responses plus stable disease) was 58.7% in HRMA KRAS WT pts and 25% in HRMA KRAS MT. No significant correlation was found between HRMA-KRAS status and response rate (p=0.287) or disease control rate (p=0.219). However, median PFS (5.1 versus 2.5 months; HR=0.34, p=0.04) and median OS (11.3 versus 3.2 months; HR=0.11, p=0.03) were significantly longer for HRMA KRAS WT pts compared to HRMA KRAS MT. Conclusions: These data show a significant difference in clinical outcome between HRMA KRAS WT and MT pts receiving a cetuximab-containing second- or third-line treatment, suggesting that techniques more sensitive than direct sequencing could better select pts for cetuximab-based treatment.

Pneumatosis Intestinalis After Cetuximab-containing Chemotherapy for Colorectal Cancer

Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor, is an effective chemotherapeutic agent for patients with metastatic colorectal cancer. Whereas several specific adverse reactions to cetuximab such as skin rash and nail toxicity have been reported, there have been few reports of pneumatosis intestinalis related to cetuximab-containing chemotherapy. We describe here three patients with colorectal cancer who developed pneumatosis intestinalis during treatment with cetuximab-containing chemotherapy, which developed after 7, 19 and 47 weeks of cetuximab treatment, and discovered on routine follow-up computed tomographic scans for response evaluations. None of these patients complained of abdominal pain, showed signs of peritoneal irritation on physical examination or had elevated serum concentrations of acute inflammatory markers. Following cessation of cetuximab and conservative medical treatment, all three patients showed complete resolution of pneumatosis intestinalis on abdominal pelvic computed tomographic scans.

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer

The efficacy and safety of cetuximab for irinotecan-intolerant patients has not yet been evaluated in detail. We retrospectively analyzed the efficacy and safety of cetuximab monotherapy for patients with metastatic colorectal cancer (MCRC) that was intolerant to irinotecan. Among 105 patients who received cetuximab-containing chemotherapy until March 2010, 22 patients were treated with cetuximab monotherapy due to irinotecan intolerance. Cetuximab was given at the approved dosage to all patients. The performance status was 2 or 3 in 17 patients (77%). All but 1 patient had wild-type KRAS tumors. The causes of irinotecan intolerance were icterus (n=9; 41%; median serum total bilirubin, 6.3mg/dl), symptomatic peritoneal metastasis or obstruction (n=8; 36%), and thrombocytopenia (n=1; 5%). Four patients (18%) refused irinotecan due to previous irinotecan-associated toxicity. Two patients achieved a partial response with an apparent drop of serum bilirubin, for a response rate of 9.1%. The median progression-free survival and overall survival were 1.6 and 3.5months, respectively. No grade 3 or 4 adverse events or treatment-related deaths were experienced. Cetuximab monotherapy for irinotecan-intolerant MCRC is feasible. However, the overall efficacy was modest in the present cohort, despite the fact that most of the patients had wild-type KRAS tumors; further effective therapies should be evaluated to improve the prognosis of this patient population.