Sensitivity to previous irinotecan treatment does not predict the efficacy of combination chemotherapy with cetuximab plus irinotecan for wild-type KRAS metastatic colorectal cancer

The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n = 60) and a group given off-protocol treatment (n = 27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n = 23), stable disease (n = 38), or progressive disease (n = 26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (ρ) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (ρ = 0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan.     

西妥昔单抗联合放化疗治疗晚期头颈部恶性肿瘤

目的 观察西妥昔单抗联合放化疗治疗晚期头颈部恶性肿瘤（HNSCC）的有效性和安全性.方法 2007年11月至2010年5月经病理证实的26例晚期HNSCC患者,接受西妥昔单抗联合放化疗治疗.西妥昔单抗静脉滴注给药,首剂400mg/m2,后续剂量250mg/m2,每周1次,连用5~12周.其中23例患者同时接受放疗,原发灶剂量为60~74.25Gy,转移淋巴结为60~72Gy.18例患者同时接受化疗,方案为PF或TPF.结果 评估患者近期疗效和急性不良反应.所有患者在治疗后3个月时进行疗效评价：完全缓解（CR）65.4%（17/26）,部分缓解（PR）15.38%（4/26）,稳定（SD）11.5%（3/26）,进展（PD）3.8%（1/26）,术后无法评价疗效1例.其中19例初治的HNSCC患者中,CR73.7%（14/19）,PR15.7%（3/19）,SD5.3%（1/19）,PD5.3%（1/19）;7例复发或转移的患者中,CR42.8%（3/7）,SD28.6%（2/7）,PD28.6%（2/7）.治疗中出现的主要不良反应包括口咽黏膜炎、舌黏膜炎和特异性痤疮样皮疹.26例患者均完成随访,中位随访时间11个月,随访中5例PD,疾病进展时间（TTP）为4~22个月,中位数为7个月,生存时间4~33个月,中位数为11个月.10例初治鼻咽癌患者无一出现转移或复发.结论 西妥昔单抗联合放化疗治疗晚期HNSCC,近期疗效满意,痤疮样皮疹为药物特异性副作用,未出现影响治疗进行的严重特异性不良反应.     

Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy

Background.

Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes.

Methods.

A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists.

Results.

Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed.

Conclusions.

Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified.     

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild‐Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial

PurposeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5‐fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two‐group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases (CLM) and BRAF/RAS wild‐type.Patients and MethodsPatients were enrolled to receive cetuximab (500 mg/m²) plus mFOLFOXIRI (oxaliplatin 85 mg/m², irinotecan 165 mg/m², folinic acid 400 mg/m², 5‐fluorouracil 2,800 mg/m² 46‐hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety.ResultsBetween February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%–48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%–36.4%; p = .010) compared with those in control group. Progression‐free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups.ConclusionAddition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM.Implications for PracticeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases and BRAF/RAS wild‐type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression‐free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver‐limited metastasis.     

Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

BackgroundCirculating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome.Patients and methodsPatients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m²) and cetuximab (500 mg/m²) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK.ResultsOne-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR) = 2.98 (95% CI 1.53–5.80, p = 0.001) and 2.84 (1.46–5.53, p = 0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect.ConclusionThe value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.     

Phase I study of cetuximab in combination with 5-fluorouracil,mitomycin C and radiotherapy in patients with locally advanced anal cancer

Background5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination.Methods and materialsPatients with locally advanced anal cancer, T2 (≥4 cm)–4N0–3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule.ResultsThirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46–70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3–4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%.ConclusionThe MTDs were determined as 5FU 800 mg/m² on RT days 1–4 and 29–32 and MMC 8 mg/m² on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer.     

FOLFIRI化疗方案及其与西妥昔单抗联用治疗晚期结肠癌分析

目的比较西妥昔单抗（爱必妥）联合FOLFIRI化疗方案治疗晚期结肠癌与单纯FOLFIRI化疗方案治疗晚期结肠癌的疗效。方法将我院2008年1月至2009年12月58例采用西妥昔单抗联合FOLFIRI化疗治疗的结肠癌患者作为观察组,将我院2006年1月至2007年12月只使用了FOLFIRI化疗方法治疗的49例结肠癌患者作为对照组。比较两组患者的治疗后生存状况。结果观察组的病情缓解率和治疗后生存质量都好于对照组,毒副作用两组患者反应都不明显。结论FOLFIRI方案联合西妥昔单抗治疗晚期结肠癌,比单独的FOLFIRI化疗方案取得了更好的治疗效果,可明显缓解患者病情,提高患者生存率和生活质量,毒副反应也较轻,处于患者可耐受范围之内。     

Anti-angiogenic therapies for metastatic colorectal cancer:Current and future perspectives

Colorectal cancer(CRC)is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the United States,with about 142820 new cases and 50830 deaths expected in 2013.Metastatic disease(mCRC)remains a challenge for oncologists worldwide due to its potential comorbidities.Recently,chemotherapy regimens containing 5-fluorouracil,leucovorin,oxaliplatin and irinotecan combinations are a standard of care in the metastatic disease.Currently,biological therapies involving vascular endothelial growth factor and epidermal growth factor receptor pathways,such as bevacizumab and cetuximab,have emerged as good option for improving mCRC patient survival.Now,aflibercept plus standard chemotherapy has also been approved in second line regimen for mCRC patients.Our review will discuss novel biological drugs and their indications for mCRC patients and will bring future perspectives in this regard.     

In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6+/-2.9 and 18.0+/-2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6+/-2.3 and 14.4+/-3.2 days respectively) or cetuximab (Td=13.4+/-2.9 and 14.5+/-2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.