Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey.

BACKGROUND: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting. PATIENTS AND METHODS: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed. RESULTS: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS. CONCLUSIONS: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed.

Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the Colon Life nomogram.

Background: Regorafenib and TAS-102 have recently demonstrated statistically significant survival gains in patients with refractory metastatic colorectal cancer (mCRC). Life expectancy ≥12 weeks was an inclusion criterion in registrative trials, and the identification of proper clinical selection tools for the daily use of these drugs in heavily pre-treated patients is needed to improve the cost-benefit ratio. We aimed at building a nomogram able to predict death probability within 12 weeks from the date of assessment of refractory mCRC. Patients and methods: Four hundred eleven refractory mCRC patients with ECOG performance status (PS) ≤2 receiving regorafenib, TAS-102 or other treatments were used as developing set. Putative prognostic variables were selected using a random forest model and included in a binary logistic model from which the nomogram was developed. The nomogram was externally validated and its performance was evaluated by examining calibration (how close predictions were to the actual outcome) and discriminative ability (Harrell C index) both on developing (internal validation) and validating (external validation) sets. Results: Four variables were selected and included in the nomogram: PS (P < 0.0001), primary tumor resection (P = 0.027), LDH value (P = 0.0001) and peritoneal involvement (P = 0.081). In the developing set, the nomogram discriminative ability was high (C = 0.778), and was confirmed in the validating set (C = 0.778), where the overall outcome was better as a consequence of the enrichment in patients receiving regorafenib or TAS-102 (46% versus 34%; P < 0.0001). Conclusions: Our nomogram may be a useful tool to predict the probability of death within 12 weeks in patients with refractory mCRC. Based on four easy-to-collect variables, the 'Colon Life' nomogram and free app for smartphones may improve mCRC patients' selection for later-line therapies and assist researchers for the enrollment in clinical trials in this setting.

Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

PURPOSE: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C. METHODS: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. RESULTS: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8%) ARM A and 3 (10%) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0%, and thrombocytopenia, diarrhea and fatigue in 0/3% of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. CONCLUSIONS: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients.

BACKGROUND: The aim was to investigate the outcomes associated with venous thromboembolism (VTE) among irresectable pancreatic cancer patients. METHODS: This is a follow-up study of consecutive irresectable cancer patients, treated and followed up in clinical trials between December 2001 and December 2004 in order to evaluate the prognostic impact of symptomatic VTE on clinical outcomes, such as response to treatment, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 227 irresectable pancreatic cancer patients, with Eastern Cooperative Oncology Group performance status (ECOG-PS) < or = 2, 59 (26.0%) patients developed a VTE. A synchronous VTE occurred in 28 (12.3%) patients, while a VTE during chemotherapy was observed in 15 (6.6%) patients, and 16 (7.0%) patients experienced both events. Presence of synchronous VTE was associated with a higher probability of not responding to treatment (odds ratio 2.98, 95% CI 1.42-6.27, P = 0.004), but showed no effect on both PFS and OS at least at multivariate analysis. Occurrence of a VTE during chemotherapy showed a statistically significant effect on PFS (hazard ratio [HR] 2.59, 95% CI 1.69-3.97, P < 0.0001) and OS (HR 1.64, 95%CI 1.04-2.58, P = 0.032). CONCLUSIONS: Our data suggest that the occurrence of VTE may be associated with a reduced response rate and a shorter PFS and OS among patients with irresectable pancreatic cancer. In these patients the development of VTE may reflect the presence of a biologically more aggressive cancer that in turn leads to a worse prognosis.

The role of adjuvant chemotherapy in colon cancer.

Surgical resection of the primary and regional lymph nodes is still, at this time, the standard treatment of colon cancer. However, the risk of recurrence is still high in many patients. Efforts of the past decades have proved the role of systemic chemotherapy in the adjuvant setting in improving the curative rates. The combination of 5-fluorouracil (5-FU)and leucovorin (LV) remains the cornestorne of colon cancer chemotherapy worldwide. The addition of Oxaliplatin to infusional 5FU/LV has been shown to prolong significantly disease-free survival and capecitabine may be considered as an alternative to 5-FU/LV in the adjuvant therapy of stage III colon cancer. Novel molecular and biological-oriented agents are being studied, with promising date.

New strategies in colon cancer adjuvant therapy.

Adjuvant therapy in colorectal cancer has always been a controversy during years. Despite the fact that benefit of adjuvant therapy in stage III is clear, a more controversial question concerns efficacy in stage II. The introduction of new drugs in addition to standard regimens has some benefit, but also adds toxicity. Ongoing studies with novel targeted therapies will show their results in the next years. Other open questions include duration of therapy and whether there is a real possibility of selecting patients for treatment on the basis of prognostic factors.

Adjuvant treatment of colorectal cancer.

Colorectal cancer is one of the most frequent causes of cancer deaths. Survival for locoregional colorectal cancer is about 70% overall and 30-60% in stage III patients. Several randomized trials have shown that adjuvant chemotherapy can increase this survival rate. 5-Fluorouracil-based chemotherapy is strongly recommended in this context. There are still some questions about the setting in which patients should be treated as well as the optimal treatment. New data for different schedules and combinations are now available. Physicians have to choose between the different options now available to offer the best treatment to their patients. This Review analyses the current options for adjuvant therapy in colon and rectal cancer.

Feasibility study of colorectal cancer screening by immunochemical faecal occult blood testing: results in a northern Italian community.

AIM: Screening by means of faecal occult blood testing (FOBT) has proved to be effective in reducing colorectal cancer incidence and mortality. We performed a pilot screening for colorectal cancer by latex immunological FOBT in two municipalities of the region Valle d'Aosta, Italy, focusing on problems and obtaining indications for the feasibility and extension of the screening programme on a regional basis. METHODS: A total of 2961 subjects aged 50-74 years were invited by mail to perform a one-day immunochemical FOBT without any dietary restrictions and with a positive threshold put at 100 ng/ml. Patients with positive tests were then invited to undergo colonoscopy and double-contrast barium enema if colonoscopy was incomplete. RESULTS: A total of 1631 subjects performed the screening test with an overall compliance of 55.1%. Seventy-two subjects had a positive FOBT. Detection rates for cancer and adenomas were 1.8 per thousand and 16.6 per thousand, respectively. Positive predictive values (PPVs) for cancer and adenomas were 4.5% and 40.3%, respectively. CONCLUSIONS: Screening had an adequate attendance rate and the majority of the indicators were satisfactory. The use of a one-day quantitative latex FOBT with no dietary restrictions, automation of the analytical procedure, and a positive threshold of 100 ng/ml has shown that a programme based on this test is feasible in both organizational and attendance terms. On the basis of this experience, the extension of the screening on a regional basis is suggested.

A phase II study of weekly cisplatin, 6S-stereoisomer leucovorin and fluorouracil as first-line chemotherapy for elderly patients with advanced gastric cancer.

The incidence of gastric cancer (GC) increases significantly after the fifth decade and palliative chemotherapy is the ultimate treatment in the majority of patients. We investigated safety and efficacy of a weekly regimen with cisplatin, fluorouracil and leucovorin as first-line chemotherapy for elderly patients with advanced GC. Chemotherapy-naive patients older than 65 years were considered eligible for study entry. Frail elderly patients were identified and excluded according to the following criteria: age >85 years, dependence in one or more activities of daily living (activities of daily living and instrumental activities of daily living scales), three or more comorbid conditions, one or more geriatric syndromes. Chemotherapy consisted of 1-day per week administration of intravenous cisplatin 35 mg m(-2), 6S-stereoisomer leucovorin 250 mg m(-2) and fluorouracil 500 mg m(-2) (PLF). Patients were re-evaluated after eight weekly cycles and six additional weekly administrations were planned for patients without disease progression. A 5-day subcutaneous filgrastim (5 mug Kg(-1) day(-1), days +1-+5) was used after the first treatment delay for neutropenia and maintained thereafter. In the whole group, the best intention-to-treat overall response rate was 43% (95% CI: 30-56%). The time to disease progression and the median survival time were 5.3 and 8.6 months, respectively. Fatigue was the commonest nonhaematologic toxicity (71% of the patients). Filgrastim was used in 30 patients who showed grade II (20 patients) or grade III (10 patients) neutropenia. Neither grade IV toxicity nor toxic deaths were observed. The weekly PLF regimen resulted safe and effective in elderly patients with advanced GC. This outpatient regimen is based on old and low-cost drugs and it may represent an alternative to new and more expensive combinations.

New drugs and combinations in the palliative treatment of colon and rectal cancer.

Colorectal cancer (CRC) is a common disease. The overall survival has improved only marginally in recent decades despite advances in surgery and early detection. Potentially curative resection at disease presentation can be performed only in 70-80% of the patients, and overall survival at 5 years is less than 60%. Advanced disease is associated with a poor prognosis. Treatment for advanced colorectal cancer has nevertheless made progress in the last few years. Systemic chemotherapy doubles the survival of these patients compared to untreated controls. Chemotherapy has demonstrated effective palliation, improvement of quality of life (QoL) and symptom improvement in such patients. For nearly four decades, fluorouracil (5FU) has been the mainstay of treatment. New compounds active against colorectal cancer are now available. Several studies on this topic are ongoing.

The value of oxaliplatin in combination with continuous infusion +/- bolus 5-fluorouracil and levo-folinic acid in metastatic colorectal cancer progressing after 5FU-based chemotherapy: a GISCAD (Italian Group for the Study of Digestive Tract) cancer phase II trial.

AIMS AND BACKGROUND: The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) +/- bolus 5-fluorouracil (5FU) and levo-folinic acid (I-FA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. PATIENTS AND METHODS: We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 i.v. 2 h on day 1) + I-FA (100 mg/m2 i.v. 2 h on days 1 and 2) + 5FU i.v. bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 i.v. 2 h on day 1) + I-FA (250 mg/m2 i.v. 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 Cl 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With "de Gramont" as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. CONCLUSIONS: Treatment with L-OHP, CI +/- bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.