A phase 2 study for evaluating doxycycline 50 mg once daily and 100 mg once daily as preemptive treatment for skin toxicity in patients with metastatic colorectal cancer treated with an anti-EGFR and chemotherapy.

PURPOSE: To assess the efficacy, safety, and quality-of-life outcomes of doxycycline 50 or 100 mg once daily in the prevention of skin toxicity in patients undergoing chemotherapy plus anti-EGFR therapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Phase II, multicenter, single-arm, exploratory study was conducted in 7 Spanish hospitals. The primary study outcome was the incidence of ≥ grade 2 skin toxicities during the 6-week skin treatment period. Quality of life was assessed with the Dermatology Life Quality Index (DLQI) questionnaire. Patients had to receive either doxycycline 50 mg once daily in a first stage with 10 patients, or, if more than three patients presented ≥ grade 2 skin toxicities, the next 30 patients had to receive 100 mg once daily. RESULTS: Thirty-four patients with RAS wild-type mCRC were enrolled in the study. Ten patients were first treated with doxycycline 50 mg once daily, and the following 24 were treated with doxycycline 100 mg once daily. A total of 60.0% (95% CI 29.6-90.0) and 20.8% (95% CI 4.6-37.0) of patients who received doxycycline 50 mg/day and 100 mg/day, respectively, had at least one ≥ grade 2 skin toxicity. Patients treated with doxycycline 100 mg once daily experienced less QoL deterioration. Only 1 patient reported a mild doxycycline-related gastrointestinal adverse event. CONCLUSION: Our results suggest that doxycycline doses as low as 100 mg once daily are efficacious and well tolerated for the prevention of skin toxicity in patients with mCRC who undergo treatment with chemotherapy plus EGFR-targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03448731.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BACKGROUND: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.

The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.

SEOM-GEMCAD-TTD clinical guidelines for the adjuvant treatment of colon cancer (2023).

Colorectal cancer (CRC) has a 5-year overall survival rate of over 60%. The decrease in the rate of metastatic disease is due to screening programs and the population's awareness of healthy lifestyle. Similarly, advancements in surgical methods and the use of adjuvant chemotherapy have contributed to a decrease in the recurrence of resected disease. Before evaluating a patient's treatment, it is recommended to be discussed in a multidisciplinary tumor board. In stage II tumors, the pathologic characteristics of poor prognosis must be known (T4, number of lymph nodes analyzed less than 12, lymphovascular or perineural invasion, obstruction or perforation, poor histologic grade, presence of tumor budding) and it is mandatory to determine the MSI/MMR status for avoiding administering fluoropyridimidines in monotherapy to patients with MSI-H/dMMR tumors. In stage III tumors, the standard treatment consists of a combination of fluoropyrimidine (oral or intravenous) with oxaliplatin for 6 months although the administration of CAPOX can be considered for 3 months in low-risk tumors. Neoadjuvant treatment is not consolidated yet although immunotherapy is achieving very good preliminary results in MSI-H patients. The use of ctDNA to define the treatment and monitoring of resected tumors is only recommended within studies. These guidelines are intended to help decision-making to offer the best management of patients with non-metastatic colon cancer.

Economics of gastroenteropancreatic neuroendocrine tumors: a systematic review.

BACKGROUND: Despite current interest, enthusiasm and progress in the development of therapies for gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), there are substantial gaps in the published literature regarding cost-of-illness analyses, economic evaluation and budget impact analyses. Compounding the issue is that data on resource utilization and cost-effectiveness of different diagnostic and therapeutic modalities for GEP-NETs are scarce. METHODS: A systematic review on the economic impact of GEP-NETs was carried out using four databases: EMBASE, PubMed, the National Health Service Economic Evaluation Database and Cochrane review. Fully published articles from January 2000 to May 2017, in English and Spanish, were included. All articles that satisfied the inclusion criteria were included in the systematic review; summary descriptive statistics were used to describe the methodological characteristics. RESULTS: The 14 studies selected included cost-of-illness analyses (n = 4), economic evaluations (n = 7) and budget impact analyses (n = 3). Almost all studies were performed in the United States. Healthcare costs for patients with NETs included medication, outpatient visits, hospitalizations, and check-ups/tests. Reducing adverse events is an area where cost savings could be achieved; however, there was not enough evidence on the cost impact of adverse events. CONCLUSION: There is a lack of data related to resource utilization in the field of GEP-NETs. Therefore, cost-effectiveness and budget impact studies of existing and emerging treatments are urgently needed to help the decision-making process for patients with NETs.

Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC).

BACKGROUND: Axitinib, an antiangiogenic multikinase inhibitor (MKI), was evaluated in the compassionate use programme (CUP) in Spain (October 2012-November 2014). SUBJECTS AND METHODS: 47 patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC, n = 34) or medullary thyroid cancer (MTC, n = 13) with documented disease progression were treated with axitinib 5 mg b.i.d. The primary efficacy endpoint was objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Progression-free survival (PFS) and adverse events (AEs) were secondary objectives. Regulatory authorities validated the CUP, and all patients signed informed consent form. RESULTS: Axitinib was administered as first-line therapy in 17 patients (36.2%), as second-line in 18 patients (38.3%) and as third/fourth-line in 12 patients (25.5%). With a median follow-up of 11.5 months (0-24.3), ORR was 27.7% (DTC: 29.4% and MTC: 23.1%) and median PFS was 8.1 months (95% CI: 4.1-12.2) (DTC: 7.4 months (95% CI: 3.1-11.8) and MTC: 9.4 months (95% CI: 4.8-13.9)). Better outcomes were reported with first-line axitinib, with an ORR of 53% and a median PFS of 13.6 months compared with 16.7% and 10.6 months as second-line treatment. Twelve (25.5%) patients required dose reduction to 3 mg b.i.d. All-grade AEs included asthenia (53.2%), diarrhoea (36.2%), hypertension (31.9%) and mucositis (29.8%); grade 3/4 AEs included anorexia (6.4%), diarrhoea (4.3%) and cardiac toxicity (4.3%). CONCLUSION: Axitinib had a tolerable safety profile and clinically meaningful activity in refractory and progressive thyroid cancer regardless of histology as first-line therapy. To our knowledge, this is the first time that cross-resistance between MKIs is suggested in thyroid cancer, highlighting the importance of prospective sequential clinical studies.

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer.

PURPOSE: In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m2 i.v. on day 1, alternating with LV 20 mg/m2 i.v. and 5-FU 425 mg/m2 i.v. daily for five consecutive days, on days 22-26 (Mayo Clinic regimen). One cycle consisted of 6 weeks. RESULTS: A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16-44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients). CONCLUSIONS: The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.

Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer.

The purpose of this study was to investigate the efficacy and safety of combination chemotherapy using estramustine and vinorelbine in chemotherapy-naïve patients with hormone-resistant prostate cancer (HRPC). The patients (n = 54) received oral estramustine 840 mg/day on Days 1 to 14 and IV vinorelbine 25 mg/m(2) on Days 1 and 8 of every 3 wk cycle. The median number of cycles per patient was 9 (range, 1 to 27). Fifty-three patients were evaluable for toxicity and survival and 52 for prostate specific antigen (PSA) response. Median age was 68 (range, 46-80). PSA sustained decrease >50% was seen in 52% of patients (95% CI: 38-66%). A complete response was seen in 3 and a partial response in 12 of 25 patients with measurable disease, for an overall objective response of 60% (95% CI: 41-79%). Improvement in performance status was observed in 30 out of 43 evaluable for clinical benefit response. The median duration of response was 7 mo and median time to progression was 6 mo. The median survival time was 15 mo. The most common adverse event was mild gastrointestinal toxicity. In general, toxicity G3-4 was low: granulocytopenia Grade 3-4 (8%), thrombocytopenia Grade 3 (6%), and anemia Grade 3 (13%). Other Grade 3 toxicities included deep vein thrombosis (4%), hepatic (2%), cardiac ischemia (2%), fatigue (6%), and sensory neuropathy (2%). There were 2 treatment-related deaths (4%). We conclude that vinorelbine and estramustine as used in this trial is an efficacious and well-tolerated therapeutic regimen in the management of HRPC.

Oxaliplatin in combination with infusional 5-fluorouracil as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumors.

BACKGROUND: We previously reported a 35% overall response rate (ORR) with biweekly 5-fluorouracil (5-FU) continuous infusion (TTD [Spanish Cooperative Group for Digestive Tumour Therapy] schedule) plus irinotecan as first-line therapy in elderly patients with metastatic colorectal cancer (mCRC). The present study also was carried out in elderly patients to determine the efficacy and safety of the same 5-FU schedule plus oxaliplatin. PATIENTS AND METHODS: Patients (aged ≥72 years old) with mCRC, measurable disease, ECOG (Eastern Cooperative Oncology Group) ≤2, and no prior treatment were treated with oxaliplatin 85 mg/m(2) plus 5-FU 3000 mg/m(2) as a 48-hour infusion every 2 weeks. RESULTS: The study included 134 patients, of whom, 129 were eligible. The main comorbidities were hypertension (44%), diabetes (17%), and chronic obstructive pulmonary disease (11%). The ORR and disease control rate (ORR plus stable disease) were 52% and 80%, respectively. With a median follow-up of 14 months, the median progression-free survival and overall survival were 9.1 and 16.3 months, respectively. The most frequent grade 3/4 adverse events included neutropenia (16%), diarrhea (11%), and grade 3 neurotoxicity (18%). No correlation was found between efficacy or safety and comorbidities. CONCLUSIONS: To our knowledge, this is the largest phase II prospective study in elderly patients with mCRC. The observed efficacy and safety of this schedule compared favorably with those reported in this population, including regimens with monoclonal antibodies.

Elderly patients with advanced colorectal cancer derive similar benefit without excessive toxicity after first-line chemotherapy with oxaliplatin-based combinations: comparative outcomes from the 03-TTD-01 phase III study.

PURPOSE: Healthy elderly patients with metastatic colorectal cancer may benefit from chemotherapy as much as the younger population. This analysis compares the outcomes of first-line oxaliplatin plus fluoropyrimidines in elderly versus young patients. PATIENTS AND METHODS: 348 patients were randomized to capecitabine 1000 mg/(m2 12 h), days 1-14 plus oxaliplatin 130 mg/m2 day 1, every 3 weeks or weekly infusional 5-FU 2250 mg/m2 over 48 h plus bimonthly oxaliplatin 85 mg/m2. We evaluated response rate, time to progression, overall survival and toxicity according to age. RESULTS: ORR for elderly and young patients were 34.9% and 44.7%, respectively (p=0.081). Median TTP did not differ between the two groups: 8.3 months for patients > or =70 years and 9.6 months for those <70 years (p=0.114). Median OS was 16.8 months and 20.5 months for the > or =70 and <70 years groups, respectively (p=0.74). With XELOX, mild paresthesia and an increase in transaminase levels were more frequent for young patients, whereas grade 3/4 diarrhea was higher in those > or =70 years (25% vs. 8%, p=0.005). For FUOX, only paresthesia was significantly lower in patients > or =70 years (53% vs. 71%, p=0.032). CONCLUSION: Elderly patients with MCRC benefit from first-line oxaliplatin-fluoropyrimidine combinations as much as younger patients, without increased toxicity.

Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial.

PURPOSE: The aim of this phase III trial was to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose fluorouracil (FU) plus oxaliplatin (FUOX) regimens as first-line therapy for metastatic colorectal cancer (MCRC). PATIENTS AND METHODS: A total of 348 patients were randomly assigned to receive XELOX (oral capecitabine 1,000 mg/m2 bid for 14 days plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks) or FUOX (continuous-infusion FU 2,250 mg/m2 during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks). RESULTS: There were no significant differences in efficacy between XELOX and FUOX arms, which showed, respectively, median time to tumor progression (TTP; 8.9 v 9.5 months; P = .153); median overall survival (18.1 v 20.8 months; P = .145); and confirmed response rate (RR; 37% v 46%; P = .539). The safety profile of the two regimens was similar, although there were lower rates of grade 3/4 diarrhea (14% v 24%) and grade 1/2 stomatitis (28% v 43%), and higher rates of grade 1/2 hyperbilirubinemia (37% v 21%) and grade 1/2 hand-foot syndrome (14% v 5%) with XELOX versus FUOX, respectively. CONCLUSION: This randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower RR and survival. XELOX can be considered as an alternative to FUOX.