First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

BACKGROUND: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. METHODS: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). RESULTS: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). CONCLUSIONS: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT. PATIENTS AND METHODS: Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF). RESULTS: In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable. CONCLUSION: Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

The role of plasma IDO activity as a diagnostic marker of patients with colorectal cancer.

High levels of indoleamine 2,3-dioxygenase (IDO) are involved in tumour escape mechanisms. The aim of this study is the evaluation of L-kynurenine of plasma as marker of diagnostic and prognostic in patients with colorectal cancer. The study included 78 patients with colorectal cancer, of whom 15 % were in stage I/II, 30 % in stage III, and 55 % in stage IV, and was compared with a control group of 70 healthy subjects. The receiver operating characteristic (ROC) curve analysis showed an area under the curve of 0.917, with a specificity of 100 % and with a sensitivity to detect cancer of the colon of 85.2 %, taking 1.83 µM as a cut-off point. The overall survival analysis also indicated that patients with low levels of L-kynurenine in plasma increased survival rate after 45 months of follow-up (P = 0.032). These results show that the plasma levels of L-kynurenine could be a good biomarker to differentiate individuals with colorectal cancer from healthy individuals.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Cancer chemotherapy reduces plasma total polyphenols and total antioxidants capacity in colorectal cancer patients.

Our aim was to investigate the effect of chemotherapy on plasma total antioxidant capacity and polyphenols in patients with colon cancer. Plasma samples were collected from 70 CRC patients under chemotherapy treatment, and 15 non-treated patients. The control group included 71 healthy individuals. Plasma ABTS and FRAP were measured as biomarkers of antioxidant total capacity and the total phenols as an indicator to determine the polyphenols levels in plasma. Treatment with chemotherapy protocols resulted in a significant decrease of ABTS (-24 %, p < 0.048), FRAP (-15 %, p < 0.046) and polyphenols (-46 %, p < 0.05) compared with the values of those not treated. The total antioxidant capacity was significantly lower (-18 % for ABTS and -12 % for FRAP) in patients with metastasis as compared with patients without metastasis. The plasma total phenols, were also decreased (-16 %, p = 0.005) in metastasis patients. The patients with colorectal cancer have decreased total antioxidant capacity and the values are lower in patients treated with chemotherapy. Furthermore, CEA tumor marker levels are associated with a lower plasma total antioxidant capacity, and therefore with the progress and development of the disease.

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

BACKGROUND: Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. MATERIALS AND METHODS: Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. RESULTS: In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4 months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. CONCLUSION: After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

BACKGROUND: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. METHODS: Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. RESULTS: A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS.

PURPOSE: The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested. METHODS: Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated. RESULTS: In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%. CONCLUSIONS: The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.

Seom guidelines for the treatment of gastric cancer 2015.

Gastric cancer is the fourth cause of death by cancer in Spain and a significant medical problem. Molecular biology results evidence that gastroesophageal junction tumors and gastric cancer should be considered as two independent entities with a different prognosis and treatment approach. Endoscopic resection in very early tumors is feasible. Neoadjuvant and adjuvant therapy in locally advanced resectable tumor increase overall survival and should be considered standard treatments. In stage IV tumors, platinum-fluoropyrimidine-based schedule, with trastuzumab in HER2-overexpressed tumors, is the first-line treatment. Different therapies in second line have demonstrated in randomized studies their clear benefit in survival improvement.

Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. A phase II study.

A phase II study was performed to assess the efficacy and toxicity of UFT (tegafur-uracil in the molar ratio 1:4) modulated with leucovorin (LV) in previously untreated patients with advanced colorectal carcinoma (CRC). 79 patients with measurable advanced colorectal cancer (CRC) and no prior chemotherapy were included. 75 patients were evaluable for toxicity and response. The regimen consisted of LV 500 mg/m2 administered intravenously on day 1, followed by oral UFT 390 mg/m2 on days 1-14. Patients received oral LV 15 mg every 12 h on days 2-14. Treatment was repeated every 28 days for a minimum of four courses per patient. Three hundred and ninety-eight cycles of chemotherapy were delivered (median five per patient). 7 patients (9%) had a complete response, and 22 a partial response for an overall response rate of 39%. Mild gastrointestinal toxicity was dose limiting: grade 3-4 diarrhoea appeared in 9% of patients. Other grade 3-4 toxicities were nausea/vomiting and mucositis in 4% of patients, gastric pain and leucopenia in 3%. Oral UFT modulated by oral LV is active in advanced CRC and can be administered on an outpatient basis with no significant toxicity requiring hospitalisation. Given its excellent tolerance profile and low toxicity, the regimen should be thoroughly studied and compared with 5-fluorouracil modulated by LV.

Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen.

In spite of the high prevalence of advanced colorectal cancer in the elderly, we have little data on the efficacy and toxicity of chemotherapy in this age group. Raltitrexed is a thymidylate synthetase inhibitor with known activity in the treatment of advanced colorectal cancer. The objective of this study was to analyse the efficacy and tolerance of raltitrexed in elderly patients with advanced colorectal cancer. 92 patients diagnosed with advanced colorectal cancer aged >or=70 years were entered into the study. Raltitrexed was given at a dose of 3 mg/m(2) once every 3 weeks for a minimum of three cycles. A total of 511 cycles were given with a median of five cycles per patient. 20 out of the 90 patients evaluable for response achieved a partial response (PR) (22%, 95% Confidence Interval (CI): 17-36%), 43 (48%) remained stable and 27 showed progression (30%). The mean duration of response was 24 weeks and the progression-free interval was 15 weeks. The overall median survival was 41 weeks. 31 patients (39%, 95% CI: 28-50%) experienced a clinical benefit (improvement of the performance status without a worsening of symptoms or relief of symptoms without a worsening of the performance status). The main toxicities were gastrointestinal and haematological. 12 patients (13%) developed grade 3-4 side-effects: 7 had nausea/vomiting (8%), 6 a transaminase increase (7%), 4 asthenia (4%), 3 diarrhoea (3%), 2 neutropenia (2%), 2 anaemia (2%) and 1 thrombocytopenia (1%). Three toxic deaths occurred (3%). The group of patients with a creatinine clearance

Phase II study of carboplatin and 1-h intravenous etoposide and paclitaxel in a novel sequence as first-line treatment of patients with small-cell lung cancer.

PURPOSE: To evaluate the efficacy and tolerability of paclitaxel, carboplatin and etoposide when administered in combination to previously-untreated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients (n=95) with limited-stage disease (LSD; n=45) or extensive-stage disease (ESD; n=50) from 14 Spanish hospitals were entered into the study. Etoposide was administered 80 mg/m(2)/day intravenous (i.v.) on days 1, 2 and 3, paclitaxel 175 mg/m(2) i.v. on day 3 and carboplatin area-under-the-concentration-time-curve=6; i.v. on day 3, of a 3-week cycle, and repeated for up to 6 cycles. RESULTS: The overall response (OR) rate was 74% (n=70; 32 complete, 38 partial). Although the OR in LSD and ESD patients was similar (73 vs 74%, respectively), the percentage complete response was significantly higher among the former (49 vs 20%). The main toxicities were grade 3-4 neutropenia and febrile neutropenia (62 and 18%, respectively) and there were 3 toxic deaths. Other toxicities were rare or easily manageable. Disease-free survival and overall survival rates at 1 year were 53 and 70% in LSD and 18 and 39% in ESD patients, respectively. CONCLUSION: The results indicate that the combination of paclitaxel, etoposide and carboplatin has an anti-tumour activity in SCLC that is comparable to other combination regimens, and is well tolerated.

Treatment of advanced gastric cancer with the combination fluorouracil, leucovorin, etoposide, and cisplatin: a phase II study of the ONCOPAZ Cooperative Group.

A phase II study was performed to assess the efficacy and toxicity of the combination of 5-fluorouracil (5-FU), leucovorin (LV), etoposide, and cisplatin (FLEP) in patients with advanced gastric carcinoma. A total of 46 consecutive, previously untreated patients with unresectable, measurable gastric carcinoma were treated with 300 mg/m2 LV, 100 mg/m2 etoposide, 500 mg/m2 5-FU, and 30 mg/m2 cisplatin on days 1-3 every 28 days. All courses were given on an outpatient basis. A total of 169 courses of treatment were given. In all, 18 of the 46 patients (39%) had an objective response [95% confidence interval (CI), 25%-54%] and 2 (4%) patients experienced a clinical complete response. The median duration of response was 5 months. The main side effects were hematological and gastrointestinal. Grade 3-4 toxicity was encountered as follows: leukopenia, in 9.5% of the courses; anemia, in 3%; thrombocytopenia, in 3%; nausea/vomiting, in 4%; and diarrhea, in 5%. Hospitalization due to fever and granulocytopenia was required in 5 patients, 3 of whom died of sepsis. In conclusion, FLEP shows moderate activity in patients with advanced gastric carcinoma, albeit at the cost of a high degree of toxicity. For this reason we do not recommend its use.

Treatment of metastatic malignant melanoma with cisplatin plus tamoxifen.

A phase II study was performed to assess the efficacy and toxicity of the combination of cisplatin (CDDP) and tamoxifen (TAM) in patients with metastatic malignant melanoma (MM). A total of 31 consecutive previously untreated patients with unresectable measurable MM were given 100 mg/m2 CDDP every 21 days and 60 mg TAM every 12 h daily. All courses were given on an outpatient basis. A total of 119 courses of treatment were given. In all, 5 of the 31 patients (16%) had an objective response (95% confidence interval 5.3-34%) and 2 (6%) achieved a clinical complete response. The median duration of response was 7 months. The main side effect was gastrointestinal: 13% of the patients experienced grade 3/4 nausea/vomiting. Hematological or neurological toxicities were mild and rare. In conclusion, the combination CDDP-TAM has limited activity in MM, although its toxicity is tolerable. Our results do not allow us to recommend its use for the treatment of MM.

The UFT/leucovorin/etoposide regimen for the treatment of advanced gastric cancer. Oncopaz Cooperative Group.

Gastric cancer is the most chemosensitive adenocarcinoma among digestive neoplasms. A few years ago, we performed a phase II trial with the FLEP regimen, in which fluorouracil (5-FU) and leucovorin are combined with etoposide and cisplatin (Platinol). This regimen resulted in a 39% response rate and high toxicity. Then we used the combination UFT (tegafur and uracil)/leucovorin/etoposide: UFT 390 mg/m2/day orally on days 1 to 14; leucovorin 500 mg/m2 i.v. day 1, and 15 mg/12 h orally on days 2 to 14; and etoposide 100 mg/m2 i.v. on day 1 and then 200 mg/m2/day orally on days 2 and 3. Forty-six patients received a median of five courses. Five patients (11%) achieved a complete response and 12 (26%) a partial response, for an overall response rate of 37%. The response rate was 50% in patients with an Eastern Cooperative Oncology Group performance status of 0 to 1. Grades 3 to 4 toxicities appeared as follow: 17% of patients had diarrhea, 11% had nausea/vomiting, and 13% of patients had anemia. One patient died of neutropenia and sepsis. The median survival time was 9 months. In summary, UFT/leucovorin/etoposide is effective and moderately toxic in patients with advanced gastric cancer. A new trial with UFT/leucovorin/epirubicin is ongoing.

Phase II trial of carboplatin and tegafur (Ftorafur) as induction therapy in squamous-cell carcinoma of the head and neck.

Cisplatin and 5-fluorouracil by continuous infusion combination produces a high response rate in squamous-cell carcinoma of the head and neck (SCCHN). Carboplatin (CBDCA) is a cisplatin analogue with lower emetic potential and nephrotoxicity, although the myelosuppression potential is higher. Tegafur (ftorafur, FT) is an analogue of 5-fluorouracil. It is absorbed well in its oral form and has moderate gastrointestinal and hematologic toxicity. This clinical trial tested the association of CBDCA i.v. plus FT p.o. in patients with SCCHN who had not been previously treated. Twenty-one patients were evaluable for response; the overall response was 62% (33% complete response, 29% partial response). Toxicity was moderate in most of the patients, although there was a treatment-related death.

Phase II trial of cisplatin and tegafur (Ftorafur) as initial therapy in squamous-cell carcinoma of the head and neck.

Cisplatin and 5-fluorouracil infusion combination produces a high response rate in squamous-cell carcinoma of the head and neck. Tegafur (Ftorafur) is an analog of 5-fluorouracil, and its oral form is well absorbed. This agent has a moderate toxicity. We report a study to determine the efficacy of the cisplatin (100 mg/m2, day 1) and tegafur (1,000 mg/m2 daily for 21 days) combination. Thirty-nine patients entered the study; 36 were evaluable for response. Overall response was 94%, with a 22% complete response. Toxicity was moderate. We conclude that the cisplatin and tegafur combination is active in untreated patients with head and neck cancer.

Randomized phase II trial comparing two chemotherapy combinations for non-small cell lung cancer. Mitomycin, ifosfamide, and cisplatin versus vindesine, ifosfamide, and cisplatin.

Two chemotherapy regimens for advanced NSCLC given on an outpatient basis were evaluated in a prospective phase II trial: mitomycin, ifosfamide, and cisplatin (MIP) vs vindesine, ifosfamide, and cisplatin (VIP). This study included 100 patients. Prognostic factors were well balanced between the arms. Objective response rates (CR: MIP 0%, VIP 4%; PR: MIP 24%, VIP 18%) and survival (median time: 7 months in both arms) were in the standard range usually reported. Subjective and symptomatic improvement have been assessed. Toxicity was moderate, manageable, and mostly reversible. We believe that investigation for new ambulatory schemes must continue.

Non-small-cell lung cancer (NSCLC): chemotherapy in advanced disease. Our experience in ten years.

This is a review of the therapeutic schedules used in our service during the past 10 years for the therapy of advanced non-small-cell lung cancer. During the first years, nonrandomized trials were conducted and several combinations were tested: MACC (methotrexate, doxorubicin, cyclophosphamide, and CCNU), cisplatin-etoposide, and cisplatin-vindesine. The results of these trials were invariably discouraging: objective responses hardly reached 30%, while the survival was around 15 months in the best case. On December 1985 a new randomized trial, based on the combination MIP (mytomicin, ifosfamide, cisplatin) was designed; 60.7% of objective responses were achieved, with 9 complete remissions (17.6%) and 22 partial remissions (43.1%). Median survival was 15 months. In order to reduce the toxicity of this combination, carboplatin was substituted for cisplatin. Unfortunately, results were very poor. No complete remission, and only 5 partial responses (20%) were achieved. At the present time, a new randomized trial is being conducted. In it, MIP combination is compared with VIP (vindesine, ifosfamide, cisplatin). Preliminary results have shown no differences between both arms in response, toxicity, or survival. New therapeutic approaches, as neoadjuvant therapy, are being explored.