PURPOSE Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus ...continuous-infusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. PATIENTS AND METHODS A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio HR = 0.80; 95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.
The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year ...overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation.
Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens.
After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio HR, 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation.
The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.
Enhancing global access to cancer medicines Cortes, Javier; Perez‐García, Jose Manuel; Llombart‐Cussac, Antonio ...
CA: a cancer journal for clinicians,
March/April 2020, Letnik:
70, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. ...Limited access to timely diagnosis, to affordable, effective treatment, and to high‐quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff.
In addition to being present in tumor cells, many targets of signal transduction inhibitors are also found in normal tissue. Side effects attributable to the mechanism of action of molecular targeted ...agents thus represent “on‐target” modulation in normal tissues. These mechanism‐based toxicities can be pharmacodynamic effects of pathway inhibition and, in tumors depending on the inhibited pathway for proliferation, might be biomarkers of efficacy. The development of rash with tyrosine kinase inhibitors or monoclonal antibodies targeting the epidermal growth factor receptor is associated with superior outcomes in lung, head and neck, colorectal, and pancreatic cancer studies. Correlated with superior efficacy in retrospective analyses of large studies in advanced colorectal, breast, and renal cell carcinoma, arterial hypertension as an adverse event of antiangiogenic agents may also be a marker of effective target inhibition. An association between hypothyroidism and the activity of multitargeted tyrosine kinase inhibitors has been identified in renal cell carcinoma patients. Tumor growth addiction to the specific pathway that is effectively targeted may be the link between a mechanism‐based toxicity and efficacy. The biological basis for this correlation can be pharmacological, with higher drug exposure being associated with greater toxicity and antitumor activity, and can also be genetic, because single nucleotide polymorphisms play an important role in drug pharmacokinetic and pharmacodynamic processes. Investigators have proposed that interpatient differences and associated toxicities can be exploited for dose selection and titration, and clinical trials are currently exploring intrapatient “dosing‐to‐toxicity” strategies. Ultimately, the predictive value of a side effect of molecular targeted therapies requires validation in prospective trials.
摘要
信号转导抑制剂的许多靶点除见于肿瘤细胞, 也见于正常组织. 因此, 基于分子靶向药物作用机制产生的一些副作用往往代表正常组织中的 ”中靶” 调控效应. 这些机制相关毒性反应可以是通路抑制的某些药效学效应, 在这些通过抑制增殖通路的肿瘤中, 可能成为疗效的生物标记. 酪氨酸激酶抑制剂或靶向作用于表皮细胞生长因子受体的单克隆抗体在肺癌, 头颈部肿瘤, 结直肠癌和胰腺癌患者治疗过程中发生的皮疹的程度, 与这些患者的临床疗效成正相关. 对晚期结直肠癌, 乳腺癌, 肾细胞癌大样本研究的回顾性分析显示, 抗血管生成药物治疗过程中的血压升高不良事件与更好的疗效相关, 可提示靶标被有效抑制. 肾细胞癌中, 甲状腺功能减退与多靶点酪氨酸激酶抑制剂的活性相关. 药物有效地靶向作用于肿瘤生长所依赖的特异性通路, 可解释机制相关毒性反应与疗效之间的关联. 二者相关性的生物学基础既可以是药理学方面的, 药物暴露量高与毒性大, 抗肿瘤活性强相关; 也可以是遗传学方面的, 因为单核苷酸多态性对药物的药代学和药效学有重要影响. 研究人员建议, 可按患者间差异及关联毒性反应来选择不同的剂量和剂量滴定, 多项临床试验目前正在探索同一患者的“加量直至出现毒性反应”策略. 分子靶向药物这类副作用的预测价值最终还须经前瞻性试验的验证.
The various mechanism‐based toxicities of targeted agents, including rash associated with epidermal growth factor receptor inhibitors and hypertension/hypothyroidism associated with antiangiogenic drugs, are reviewed with the aim of assessing their utility as potential proof of pharmacodynamic effects or as predictive biomarkers.
Summary Background No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good ...performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. Methods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov , number NCT01103323. Findings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Interpretation Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Funding Bayer HealthCare Pharmaceuticals.
Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. ...We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio HR 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 16% vs nine 8%), whereas rates of other adverse events were mostly similar between groups (223 94% vs 101 88%). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.
Cancer treatment has made significant strides towards the promise of personalized medicine. Recent scientific advances have shown that there are numerous genetic deregulations that are common in ...multiple cancer types, raising the possibility of developing drugs targeting those deregulations irrespective of the tumour type. Precision Cancer Medicine (PCM) was born out of accumulated evidence matching targeted agents with these tumour molecular deregulations. At the same time, the therapeutic armamentarium is rapidly increasing and the number of new drugs (including immune‐oncology agents) entering drug development continues to rise. These factors, added to strong collaboration with regulatory agencies, which have approved novel agents based on data obtained from phase 1/2 trials, have led to unprecedented evolution in the design of early‐stage clinical trials. Currently, we have seen rapid phase 1 dose‐escalation trials followed by remarkably large expansion cohorts, and are witnessing the emergence of new trials, such as adaptive studies with basket and umbrella designs aimed at optimizing the biomarker–drug co‐development process. Alongside the growing complexity of these clinical trials, new frameworks for stronger and faster collaboration between all stakeholders in drug development, including academic institutions and frameworks, clinicians, pharma companies and regulatory agencies, have been established. In this review article, we describe the main challenges and opportunities that these new trial designs may provide for a more efficient drug development process, which may ultimately help ensure that PCM becomes a reality for patients.
New clinical trial designs are helping optimize early drug development. An umbrella trial is a master protocol for which the patient's eligibility is defined by the presence of a tumour type that is substratified according to specific molecular alterations matched to different anticancer therapies. Basket trials include patients with different tumour types with a common molecular alteration who are treated with the same matched therapy.
Oxaliplatin combined with fluoropyrimidine improves survival in patients with stage III colon cancer. However, adjuvant chemotherapy with oxaliplatin is controversial in stage II and elderly ...patients.
We performed subgroup analyses of stage II and elderly patients randomly assigned fluorouracil with leucovorin (FL) ± oxaliplatin (FOLFOX4) in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study. Comorbidities, severe adverse events, second cancers, management of relapse and death as a result of causes than other colon cancer were studied.
Two thousand two hundred forty-six patients were enrolled. Overall, 899 patients had stage II disease, including 330 low-risk and 569 high-risk patients. A total of 315 patients were ages 70 to 75 years. For stage II patients, the hazard ratio (HR) for comparing FOLFOX4 with FL was 0.84 (95% CI, 0.62 to 01.14) for disease-free survival (DFS), 0.70 (95% CI, 0.49 to 0.99) for time to recurrence (TTR), and 1.00 (95% CI, 0.70 to 1.41) for overall survival (OS). There was no interaction between treatment and stage or age. Low-risk stage II patients did not benefit from oxaliplatin. In high-risk stage II patients, the HR comparing FOLFOX4 with FL was 0.72 (95% CI, 0.51 to 1.01) for DFS, 0.62 (95% CI, 0.41 to 0.92) for TTR, and 0.91 (95% CI, 0.61 to 1.36) for OS. In elderly patients, the HR comparing FOLFOX4 with FL was 0.93 (95% CI, 0.64 to 1.35) for DFS, 0.72 (95% CI, 0.47 to 1.11) for TTR, and 1.10 (95% CI, 0.73 to 1.65) for OS.
The results of these subset analyses show no statistically significant benefit (OS and DFS) for the addition of oxaliplatin to FL as adjuvant treatment for either stage II and elderly patients.
An international panel of multidisciplinary experts convened to develop recommendations for the management of patients with liver metastases from colorectal cancer (CRC). The aim was to address the ...main issues facing the CRC hepatobiliary multidisciplinary team (MDT) when managing such patients and to standardize the treatment patients receive in different centers. Based on current evidence, the group agreed on a number of issues including the following: (a) the primary aim of treatment is achieving a long disease‐free survival (DFS) interval following resection; (b) assessment of resectability should be performed with high‐quality cross‐sectional imaging, staging the liver with magnetic resonance imaging and/or abdominal computed tomography (CT), depending on local expertise, staging extrahepatic disease with thoracic and pelvic CT, and, in selected cases, fluorodeoxyglucose positron emission tomography with ultrasound (preferably contrast‐enhanced ultrasound) for intraoperative staging; (c) optimal first‐line chemotherapy—doublet or triplet chemotherapy regimens combined with targeted therapy—is advisable in potentially resectable patients; (d) in this situation, at least four courses of first‐line chemotherapy should be given, with assessment of tumor response every 2 months; (e) response assessed by the Response Evaluation Criteria in Solid Tumors (conventional chemotherapy) or nonsize‐based morphological changes (antiangiogenic agents) is clearly correlated with outcome; no imaging technique is currently able to accurately diagnose complete pathological response but high‐quality imaging is crucial for patient management; (f) the duration of chemotherapy should be as short as possible and resection achieved as soon as technically possible in the absence of tumor progression; (g) the number of metastases or patient age should not be an absolute contraindication to surgery combined with chemotherapy; (h) for synchronous metastases, it is not advisable to undertake major hepatic surgery during surgery for removal of the primary CRC; the reverse surgical approach (liver first) produces as good an outcome as the conventional approach in selected cases; (i) for patients with resectable liver metastases from CRC, perioperative chemotherapy may be associated with a modestly better DFS outcome; and (j) whether initially resectable or unresectable, cure or at least a long survival duration is possible after complete resection of the metastases, and MDT treatment is essential for improving clinical and survival outcomes. The group proposed a new system to classify initial unresectability based on technical and oncological contraindications.
摘要
召集多国专家组成一个国际多学科专家小组，共同商讨制定用于结直肠癌（CRC）肝转移患者的治疗推荐意见。本共识旨在解决CRC肝胆多学科团队（MDT）在治疗此类患者中面临的主要问题，以及对患者在不同中心接受的治疗进行标准化。基于目前的证据，专家小组在以下方面达成共识：（a）治疗的主要目的是在肿瘤切除后获得较长的无病生存（DFS）时间；（b）采用高质量横断面影像学方法进行可切除性评估，根据当地医生的专业技能，可采用核磁共振（MRI）和/或腹部计算机断层扫描（CT）对肝脏疾病进行分期，采用胸部和盆腔CT对肝外病灶进行分期，在部分病例，可采用氟脱氧葡萄糖正电子发射断层显像（FDG‐PET）联合超声（优选对比增强超声）术中分期；（c）最佳一线化疗‐‐联合靶向治疗的双药或三药化疗方案‐‐推荐用于潜在可切除患者；（d）在该情况下，应至少给予4个疗程一线化疗，每2个月评估一次肿瘤缓解情况；（e）通过实体瘤缓解评估标准（传统化疗）或并非基于肿瘤大小的形态学变化（抗血管生成药物）评估的缓解情况与生存结局明确相关；影像学技术目前尚不能准确诊断完全病理学缓解，但高质量影像学技术对患者的管理至关重要；（f）化疗时间应尽可能短，在肿瘤未发生进展的情况下，一旦在技术上可行，就应切除肿瘤；（g）转移灶数目或患者年龄不应作为手术联合化疗的绝对禁忌证；（h）对于同时性转移灶，不建议在切除原发CRC手术期间进行肝脏大手术；在部分选择性病例中，采用逆向手术方法（先进行肝脏手术）可获得与传统方法同样好的效果；（i）对于CRC肝转移灶可切除的患者，围术期化疗可能与DFS结局略改善有关；（j）无论初始时转移灶可否切除，在完全切除转移灶后患者可能获得治愈，或至少获得较长的生存时间，MDT对于改善临床和生存结局是必需的。专家组建议采用一套基于技术和肿瘤学禁忌证的新系统来对初始时不可切除病灶进行分类。
Recommendations developed by an international panel of multidisciplinary experts for the management of patients with liver metastases from colorectal cancer are presented.
Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic ...targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma.
Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.
Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.
RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
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