A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced ...colorectal cancer.
Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses.
Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients.
Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.
Background
Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of ...death or disease recurrence after radical surgery for CC remains uncertain.
Materials and Methods
This is a substudy conducted in patients with high‐risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine‐oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse‐free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes.
Results
Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow‐up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio HR, 1.51; 95% confidence interval CI, 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS.
Conclusions
Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine‐oxaliplatin chemotherapy. Larger studies and longer follow‐up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC.
Implications for Practice
The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low‐dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.
摘要
背景。2 型糖尿病 (T2DM) 与结肠癌 (CC) 风险增加有关，而二甲双胍的使用似乎具有保护作用。然而，二甲双胍的使用对 CC 根治性手术后死亡或疾病复发风险的影响仍不确定。
材料和方法。这是在 TOSCA 试验中随机分组的高风险 II 期或 III 期 CC 患者中进行的亚组研究，比较了 3 个月和 6 个月的氟尿嘧啶 ‐ 奥沙利铂辅助化疗。本研究的目的是调查辅助化疗期间二甲双胍暴露对总生存 (OS) 和无复发生存 (RFS) 的影响。我们还评估了 T2DM 或二甲双胍剂量对临床预后的影响。
结果。在参加 TOSCA 试验的 3 759 名患者中，本研究纳入了 133 名糖尿病患者(9.2%)和 1 319 名非糖尿病患者(90.8%)。排除 13 例无二甲双胍暴露信息的糖尿病患者后，76 例 T2DM 患者(63.3%)被定义为二甲双胍使用者，44 例(36.7%)为非二甲双胍使用者。 60.4 个月中位随访后，26 例(21.7%)患者复发，16 例(13.3%)死亡。二甲双胍的使用既不与 OS 相关 校正风险比 (HR)，1.51；95% 置信区间 (CI)，0.48‐4.77；p = 0.478 1，也不与 RFS 相关(HR，1.56；95% CI，0.69‐3.54；p = 0.288 1)。同样，我们发现 T2DM 或二甲双胍剂量与 OS 或 RFS 之间没有关联。
结论。在使用氟尿嘧啶 ‐ 奥沙利铂辅助化疗治疗已切除 CC 的患者中二甲双胍的使用和 T2DM 对 OS 或 RFS 没有影响。需要更大规模的研究和更长时间的随访来阐明二甲双胍在改善 CC 患者预后方面的潜在功效。
实践意义:抗糖尿病药物二甲双胍在结肠癌预防和治疗中的作用备受争议。虽然低剂量二甲双胍在两项前瞻性研究中降低了结直肠腺瘤的发病率，但其对已经确诊的结肠癌患者的影响尚不明确。本研究在 TOSCA 研究的背景下调查了二甲双胍对接受辅助化疗的已切除结肠癌患者存活率的潜在影响。我们未发现二甲双胍的使用或剂量与患者存活率之间存在任何关联。需要前瞻性研究以得出关于二甲双胍对结肠癌复发和生存率的影响的确切结论。
The antidiabetic compound metformin has emerged as a promising antineoplastic drug. Type 2 diabetes mellitus is associated with increased risk of colon cancer, against which metformin use seems to be protective. This article is a timely report on the association between metformin use and survival of diabetic patients with colon cancer.
Lessons Learned
The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.
This study explored the activity of ...dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two‐stage phase II study in patients with AR‐positive/estrogen receptor‐positive/human epidermal growth receptor 2‐negative metastatic BC.
Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity.
Background
Androgen receptors (AR) are expressed in most breast cancers, and AR‐agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR‐positive metastatic breast cancer (MBC).
Methods
A two‐stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)‐positive (resistant to AIs) and the other with triple‐negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple‐negative cohort was closed early.
Results
Twelve patients with ER‐positive MBC were enrolled. DHEA‐related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER‐positive disease whose tumor had AR gene amplification. There was wide inter‐ and intra‐patient variation in serum levels of DHEA and its metabolites.
Conclusion
DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.
经验获取
• 虽然雄激素受体 (AR) 存在于大多数乳腺癌 (BC) 中，但是，人们将其作为治疗靶点进行的开发利用十分有限。
• 本研究探索了脱氢表雄酮(DHEA，一种可在 BC 细胞中转化为雄激素的前体)与芳香化酶抑制剂(可阻止 DHEA 转化为雌激素)在两阶段 II 期研究中联合治疗 AR‐阳性/雌激素受体‐阳性/人类表皮生长受体 2‐阴性的转移性 BC 患者的活性。
• 虽然耐受性良好，但是，在 12 名患者中仅有 1 名患者维持了长时间的临床获益，而且，研究在第一阶段之后因活性较差而关闭。
摘要
背景。雄激素受体 (AR) 存在于大多数乳腺癌中，AR‐激动剂在此类肿瘤中具有一些活性。我们研究了雄激素前体脱氢表雄酮 (DHEA) 和芳香化酶抑制剂 (AI) 联合治疗 AR‐阳性转移性乳腺癌 (MBC) 患者的安全性和活性。
方法。我们在两个患者队列中执行了一项两阶段 II 期研究，一个队列中的患者为雌激素受体 (ER)‐阳性(对 AI 耐药)，另一个队列中的患者为三阴性 MBC。按照 100 mg/天的剂量口服 DHEA。AI 联合治疗旨在防止 DHEA 转化为雌激素。主要终点为临床获益率。三阴性队列提前关闭。
结果。12 名 ER‐阳性 MBC 患者加入研究。4 名患者报告与 DHEA 相关的不良反应，包括 2 级疲劳、红斑和转氨酶升高以及 1 级困倦和肌肉骨骼痛。在 1 名 ER‐阳性疾病患者中观察到临床获益，该患者的肿瘤出现 AR 基因扩增。DHEA 及其代谢物的血清水平在患者之间和患者内部的变化较大。
结论。虽然 DHEA 显示出良好的安全性，但是，它在 MBC 中的活性较差。尽管可以改进剂量和患者的选择，但是，血清水平变化性高可能会妨碍 DHEA 在这种设定中的进一步开发。
•High body mass index (BMI) plays a key role in the development of several cancer types, including colon cancer.•To date, the prognostic impact of BMI in colon cancer is not fully elucidated.•In this ...post-hoc analysis of TOSCA trial, obesity with BMI ≥30 kg/m2 was an independent prognostic factor for relapse-free survival and overall survival.•BMI could provide additional and clinical important prognostic information in stage II/III colon cancer patients.•Body composition measurement should be tested to better classify visceral fat and refine risk assessment.
High body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients.
Patients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses.
Overall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m2 was reported (HR >30 vs <25 1.57, 95% CI 1.00-2.47, p = 0.049; HR >30 vs <30 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS.
In our study, obesity with BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.
-BMI plays a key role in colon cancer, despite its prognostic impact is not fully elucidated.-Our study aimed to evaluate the prognostic impact of BMI in stage II/III colon cancer patients included in the TOSCA trial.-BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in stage III colon cancer patiens.
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Background: To compare efficacy and safety of E and AA in the treatment of metastatic, castration-resistant prostate cancer. Methods: Efficacy and safety of E and AA were ...compared using the data of the PREVAIL, AFFIRM, COU-AA-302 and COU-AA-301 trials. All the data extracted from the selected trials were reported ad Hazard Ratio (HR) or Odds Ratio (OR). Overall survival was assumed as index of efficacy, and was the primary end point of our analysis, all the side effects, grade III-IV side effects, serious side effects, side effects leading to treatment discontinuation or death were assumed as indexes of safety and were the secondary end points of our analysis. Overall survival was assessed both in the entire population and in the subgroups of patients chemotherapy-naïve or docetaxel-resistant. An alpha error of 5% was assumed as index of statistical significance. Results: The outcome of 5191 patients were reviewed. 1671 patients had been treated with E, 1339 with AA and 2181 with placebo. Comparing E vs AA no differences were observed for overall survival in the entire population (HR = 0.955, IC95% = 0.796-1.144, p = 0.616), overall survival in chemotherapy-naïve patients (HR = 0.947, IC95% = 0.723-1.24, p = 0.692), overall survival in docetaxel-resistant patients (HR = 0.961, IC95% = 0.753-1.228, p = 0.75), all side effects (OR = 0.414, IC95% = 0.054-3.196, p = 0.463), grade III-IV side effects (OR = 1.36, IC95% = 0.253-7.318, p = 0.72), serious side effects (OR = 0.742, IC95% = 0.137-4.006, p = 0.729), side effects leading to treatment discontinuation (OR = 0.743, IC95% = 0.132-4.193, p = 0.736), and side effects leading to death (OR = 0.572, IC95% = 0.089-3.657, p = 0.556). Conclusions: Although E and AA differ for pharmaceutical structure and mechanism of action, they seem to be comparable both for indication (pre- or post-docetaxel treatment in patients with metastatic, castration-resistant prostate cancer), and for efficacy or safety (in chemotherapy-naïve and docetaxel-resistant patients). It follows that compliance, patients characteristics and costs can play a role in the decision making process of clinical practice.
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e20676
Background: Elderly and patients with ECOG PS ≥ 2 often present with medical and physiological characteristics that make the selection of their treatment more challenging. ...Single-agent vinorelbine improves survival and quality of life compared with best supportive care. At constant effectiveness between two treatments formulations patient preference must be taken into account. Methods: Stage IIIB or IV NSCLC patients candidates to receive a first line chemotherapy with Vinorelbine alone due to age ≥ 70 and Eastern Cooperative Oncology Group (ECOG) Performance status ≤2 or age ≤ 70 but ECOG PS ≥ 2, could enter the study. Patients were randomized to receive: • Arm A: first cycle of IV vinorelbine (30 mg/m2) and second cycle of oral vinorelbine (60mg/m2) • Arm B: first cycle of oral vinorelbine followed by a second cycle of IV vinorelbine. In both arms vinorelbine was administered at day 1 and day 8 every 3 weeks. From the third cycle onwards patients had to choose to continue with oral or intravenous vinorelbine. The dosage of oral vinorelbine could be subsequently increased to 80 mg/m2 at physician’s choice. Treatment continued until disease progression, intolerable toxicity or patient refusal. The primary objective of the study was the patient preference for oral or intravenous vinorelbine. Results: Ninety-three patients entered the study and were randomized. Sixty-two were able to complete the first two cycles and to express a preference (32 in Arm A and 30 in Arm B). Forty-five out of 62 were males and 17 females. Median age was 80 (72-89). Nineteen patients had an ECOG PS of 0, 39 a PS of 1 and 4 a PS of 2 (30.7%, 62.9% and 6.4% respectively). Eighteen patients (29%) decided to continue with IV vinorelbine while 44 patients (71%) expressed a preference for oral vinorelbine p = 0.001 (Gart's test). Regarding secondary enpoints, median OS was 5.7 (4.7-7.7) and 5.5 (3.8-9.1) months and median PFS was 3.5 (2.4-4.4) and 3.5 (3.5-5.0) for arm A and arm B respectively. Conclusions: The study has clearly demonstrated that elderly or frail patients with NSCLC prefer to receive an oral rather than an intravenous chemotherapy. The reasons for the choice were expressed in a questionnaire still in evaluation. Clinical trial information: nct01848613.
Malignant pericardial mesothelioma is an uncommon variety of a primary malignant cardio-pericardial tumor and it is a highly lethal and fortunately rare cardiac neoplasm. The presentation of ...pericardial mesothelioma is aspecific and pathologically mesothelioma is not the most common among primary tumors of the pericardium. It is characterized by atypical solid growth of mesothelium with formation of atypical cavities surrounded by fibrous stroma. Antemortem diagnosis is difficult and distant metastases are extremely rare. Radical surgery can be used to treat localized mesothelioma. The treatment for advanced primary pericardial mesothelioma is usually palliative because the tumor is resistant to radiotherapy and chemotherapy. The prognosis is unfavorable. The median survival from the onset of symptoms is six months. In this paper we report two cases of patients with primary mesothelioma of the pericardium without a definite history of asbestos exposure.
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Background: To assess the role of chemotherapy in metastatic, hormone-naïve prostate cancer, we presents the preliminary data of a pooled analysis comparing the outcome of patients ...with metastatic hormone-naïve prostate cancer. Methods: A pooled analysis of the outcome of randomized clinical trials approaching the role of docetaxel in metastatic hormone-naïve prostate cancer was performed using a random effect model. The final outcome of all the patients enrolled into the trials was the primary end point of our analysis. The pooled final result was reported as pooled Hazard Ratio and 95% Confidence Interval. The between-the trials heterogeneity was assessed using the I
2
test. An α-error of 5% was identified as index of statistical significance. Overall survival of the entire population enrolled into the trials was the outcome of the preliminary analysis, while no subgroup analysis was performed in this preliminary phase of a multi-steps analysis. Results: Three trials (the CHAARTED, the STAMPEDE and the GETUG-AFU 15 trial) were considered eligible and included into the analysis. A pooled Hazard Ratio of 0.76 (95% Confidence Interval of 0.59-0.98, p = 0.037) was detected for overall survival, with an I
2
of 67.8. The pooled datum was obtained observed the outcome of 951 patients treated with docetaxel plus androgen blockade and 1338 with androgen blockade alone. Conclusions: Although the between-the-trials heterogeneity seems to suggest caution in the final interpretation of the results, a significant reduction of the risk of death can be obtained with docetaxel in the treatment of metastatic hormone-naïve prostate cancer. Our preliminary analysis, including all the patients with metastatic hormone-naïve prostate cancer, seems to suggest a role of docetaxel in all the patients with metastatic disease; further data are probably needed to detect its role in some different subclasses of patients (patients with high burden of the disease, fit or unfit patients, elderly patients).
Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, ...non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.
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