晚期结直肠癌的靶向治疗新进展

已经有多种分子靶向药物应用于肿瘤的治疗。有关西妥昔单抗和贝伐单抗应用于Ⅱ、Ⅲ期结直肠癌治疗,已得到令人鼓舞的临床结果。环氧化酶2(COX-2)抑制剂则可阻止腺瘤样息肉向恶性肿瘤转化。该文对此作一综述。     

晚期结直肠癌三线及三线以上治疗的研究进展

结直肠癌是消化道最常见恶性肿瘤之一,大多数结直肠癌患者就诊时已属中晚期,失去手术机会.化疗及分子靶向治疗为结直肠癌的有效治疗手段.目前,晚期结直肠癌的三线治疗尚无标准方案.全文对晚期结直肠癌的三线及三线以上治疗相关的临床研究进行了简要分析.     

晚期结直肠癌EGFR靶向治疗进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)靶向治疗药物在临床的应用成为关注的焦点.全文就EGFR在晚期结直肠癌靶向治疗中的研究进展作一综述.     

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer

Lessons Learned

• Antitumor activity was observed in the study population.
• Dose modifications of cabozantinib improve long-term tolerability.
• Biomarkers are needed to identify patient populations most likely to benefit.
• Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.

     

Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body’s own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.     

Anti-EGFR and Anti-VEGF Agents in First-Line Therapy for Advanced Colorectal Cancer

Outcomes for metastatic colorectal cancer have improved progressively with the incorporation of new drugs into standard treatment regimens. Most recently, targeted therapies against VEGF and EGFR have improved upon the prior standard for first-line therapy with FOLFOX or FOLFIRI. As attempts to combine anti-VEGF and anti-EGFR drugs have been unsuccessful, it is necessary to choose between them when beginning first-line therapy. This review summarizes the existing literature to best inform this decision. To date, three head-to-head trials have compared anti-EGFR and anti-VEGF therapy in RAS wild-type patients: PEAK, FIRE-3, and CALGB/SWOG 80405. PEAK and FIRE-3 suggested a survival advantage for anti-EGFR therapy over anti-VEGF therapy, though CALGB/SWOG 80405 did not. Results have emerged recently to suggest that tumors arising from the right colon are resistant to anti-EGFR therapy, and that any advantage of anti-EGFR therapy over anti-VEGF therapy may be limited to left-sided tumors.     

Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab

Background Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. Results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. Conclusions Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.     

Novel Targets in Advanced Colorectal Cancer

Purpose of Review

Although current guidelines suggest only testing for RAS and BRAF mutations as well as MMR deficiency in metastatic colon cancer, there are many other promising therapeutic targets that are being studied. We aim to review the recent literature and evidence behind some of these novel targets.

Recent Findings

Many of these targets such as NTRK, ROS, ALK, and HER2 are being studied in current clinical trials and hold great potential in changing the treatment landscape for metastatic colorectal cancer.

Summary

Current molecular testing algorithms may need to be expanded to allow better target discovery and for patients to benefit from more therapeutic options.

     

Sequential Versus Combination Therapy in the Treatment of Patients with Advanced Colorectal Cancer

Colorectal cancer (CRC) remains one of the most frequent cancer diagnoses and a leading cause of cancer-related deaths in the United States. Significant progress, however, has been made since the advent of single-agent 5-fluorouracil therapy. The addition of irinotecan and oxaliplatin to the cytotoxic armamentarium, mostly given in combination, has dramatically improved response rates, progression-free survival, and overall survival (Os). In recent years, the addition of biologic therapies, including bevacizumab, cetuximab, and panitumumab, has further contributed to improved outcomes. There have been recent data suggesting that sequential cytotoxic therapy, in the majority of patients, provides similar outcomes with regard to OS compared with combination chemotherapy. However, because of several limitations in the FOCUS and CAIRO trials, the data are difficult to apply to current treatment regimens. Although these data do help us further define patients who may benefit from sequential chemotherapy, the standard of care remains combination chemotherapy in the vast majority of patients. This approach will be further refined as progress is made in pharmacogenomics and in prognostic and predictive factors in treating patients with metastatic CRC.     

Optimizing Colorectal Cancer Care in Older Patients

Colorectal cancer is a disease affecting mainly older people, a fact that is becoming more apparent with the global population aging. However, this patient group is more likely to be subjected to suboptimal treatment due to a number of factors, but most commonly as a result of the physician’s weakness to recognize those fit for the full spectrum of cancer therapy. In this regard, clinical screening tests, such as the Comprehensive Geriatric Assessment, can be invaluable in guiding treatment decisions. Fluoropyrimidine-based adjuvant chemotherapy clearly confers a survival advantage in older individuals with node-positive disease; however, the benefit from the administration of oxaliplatin-based regimens is less clear. Palliative chemotherapy also has an important role in managing metastatic disease, and with the use of novel targeted agents it can potentially prolong survival and improve quality of life. The management of rectal cancer in this population can present a challenge, since it appears that the optimal treatment of chemoradiation followed by total mesorectal excision can be applied in select few. Indeed, the morbidity and mortality rates in older people treated with these combined modalities can be too high, guiding many physicians to opt for more conservative approaches, directed at providing palliation and local control, especially in those with limited life expectancy. In conclusion, in order to provide the best care in an older colorectal cancer patient, we need to individualize our approach, selecting the right patient for the right treatment.     

Liver-Directed Therapy in Metastatic Colorectal Cancer

Approximately 50–70 % of patients with colorectal cancer ultimately develop colorectal liver metastases. Determining which patients may benefit from aggressive treatment has historically been achieved through clinical predictive models. However, factors such as radiographic response to neoadjuvant therapy should also be taken into consideration. Recently, molecular markers have emerged as an adjunct to clinical-pathologic factors and provide a surrogate for tumor biology. With improved understanding of tumor biology, the likelihood of recurrence can be better predicted. However, when feasible, the best chance for cure entails surgical resection as a part of multimodal therapy, and select patients can achieve prolonged median survival. Alternatively, ablation techniques may be used in conjunction with surgery or as isolated therapy in patients who are not candidates for surgical resection. Transarterial therapy may also provide clinical benefit in certain patient subsets with unresectable disease. These strategies have allowed for a more tailored approach to patients with colorectal liver metastases.     

卡培他滨维持治疗老年晚期转移性结直肠癌的生存分析

目的 评价卡培他滨维持治疗老年晚期转移性结直肠癌的疗效及安全性。方法 自2007年8月1日—2011年8月1日在辽宁医学院附属第一医院完成一线化疗后达到疾病控制（CR+PR+SD）的老年晚期转移性结直肠癌患者接受两种不同的治疗策略（按患者自己意愿）。治疗组30例,予卡培他滨维持治疗（卡培他滨常规量为1 000 mg/m2,每日2次,连用2周,休息1周,每21天为1周期）;对照组48例,观察直至疾病进展再接受进一步治疗。观察两组患者的疾病进展时间（TTP）、总生存期（OS）及不良反应。结果 维持治疗组和对照组的中位疾病进展时间分别为10.3月、6.5月,差异有统计学意义（P=0.000231）;中位总生存期分别为31.4月、18.4月,差异有统计学意义（P=0.000319）。维持治疗组的主要不良反应为手足综合征、消化道反应、较轻的血液学毒性及肝肾功能损害。结论 卡培他滨维持治疗通过延长老年晚期转移性结直肠癌患者的疾病进展时间和总生存期可使其获益且耐受性良好,值得扩大样本进一步研究。     

Evolving Treatment of Advanced Colorectal Cancer

Advances in colorectal cancer treatment have led to improved outcomes for patients. A number of cytotoxic agents, alone and in combination, have shown activity. The addition of the newer, so-called “targeted” agents to standard chemotherapy drugs and regimens has also modestly improved outcomes. Progress in our knowledge and understanding of molecular pathways has led to the identification of markers critical in determining response or nonresponse to some of the targeted agents. This review discusses the available therapies in metastatic colorectal cancer and describes some of the molecular markers implicated in activity and resistance to current targeted therapies.     

沙利度胺联合方案治疗晚期结直肠癌临床观察

目的探讨沙利度胺联合方案治疗晚期结直肠癌的疗效及安全性。方法45例经病理证实的晚期结直肠癌患者随机分为治疗组和对照组。治疗组22例接受沙利度胺联合卡培他滨和奥沙利铂治疗,对照组23例仅接受卡培他滨联合奥沙利铂治疗。3周为1周期,至少2周期化疗,评价疗效。研究无进展生存期(PFS)、客观有效率（ORR）、疾病控制率（DCR）,并观察安全性及不良反应。结果治疗组DCR为68.2%,而对照组为43.5%,差异有统计学意义（P＜0.05）, PFS 、ORR及患者生活质量两组间差异无统计学意义(P＞0.05)。结论沙利度胺联合方案治疗晚期结直肠癌可显著提高疾病控制率且耐受性良好,值得临床进一步研究。