Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.

BACKGROUND: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. METHODS: TRIBE2 was an open-label, phase 3, randomised study of patients aged 18-75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116. FINDINGS: Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3-4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). INTERPRETATION: Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. FUNDING: The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann-La Roche.

Phase II Study of Preoperative Treatment with External Radiotherapy Plus Panitumumab in Low-Risk, Locally Advanced Rectal Cancer (RaP Study/STAR-03).

BACKGROUND: Treatment with fluoropyrimidines and concomitant long-course external radiotherapy (RTE) is the standard of care in locally advanced rectal cancer (LARC) preoperative chemoradiation. A randomized phase II study (RaP/STAR-03) was conducted that aimed to evaluate the activity and safety of the monoclonal antibody anti-epidermal growth factor receptor panitumumab as a single agent in combination with radiotherapy in low-risk LARC preoperative treatment. MATERIALS AND METHODS: Patients had adenocarcinoma of the mid-low rectum, cT3N- or cT2-T3N+, KRAS wild-type status, and negative circumferential radial margin. Panitumumab was administered concomitant to RTE. Rectal surgery was performed 6-8 weeks after the end of preoperative treatment. The adjuvant chemotherapy regimen was FOLFOX. The primary endpoint was the pathologic complete response (pCR) rate. The sample size was calculated using Simon's two-stage design. A pCR of 16% was considered to qualify the experimental treatment for further testing. RESULTS: Ninety-eight patients were enrolled in 13 Italian centers from October 2012 to October 2015. Three panitumumab infusions were administered in 92 (93.4%) patients. The RTE compliance was median dose 50.4 Gy; ≥28 fractions in 82 (83.7%) patients. Surgical treatment was performed in 92 (93.9%) patients, and no severe intraoperative complications were observed. A pCR was observed in 10 (10.9%) patients (95% confidence interval, 4.72%-17.07%). Pathological downstaging occurred in 45 (45.9%) patients. Grade 3 toxicities were observed in 22 (22.3%) patients, and the common adverse events were skin rash in 16 (16.3%) patients. No grade 4 toxicities were reported. CONCLUSION: The pCR rate (our primary endpoint), at only 10.9%, did not reach the specified level considered suitable for further testing. However, the analysis showed a good toxicity profile and compliance to concomitant administration of panitumumab and RTE in preoperative treatment of LARC. The pCR evaluation in all wild-type RAS is ongoing. IMPLICATIONS FOR PRACTICE: The aim of the RaP/STAR-03 study was to evaluate the activity and safety of monoclonal antibody anti-epidermal growth factor receptor (EGFR) panitumumab as a single agent without chemotherapy in low-risk, locally advanced rectal cancer (LARC) preoperative treatment. Nevertheless, the use of panitumumab in combination with radiotherapy in preoperative treatment in patients with KRAS wild type and low-risk LARC did not reach the pathologic complete response primary endpoint. This study showed a good toxicity profile and compliance to combination treatment. Further analysis of NRAS and BRAF on tissue and circulating levels of the EGFR ligands and vascular factors (soluble vascular endothelial growth factor, E-selectin) may provide insight on the potential molecular pathways involved in the anti-EGFR response.

Prognostic factors in 868 advanced gastric cancer patients treated with second-line chemotherapy in the real world.

BACKGROUND: Although second-line therapy is often considered for advanced gastric cancer patients, the optimal candidates are not well defined. METHODS: We retrospectively collected baseline parameters, tumour features, and treatment data for 868 advanced gastric cancer patients exposed to multiple treatment lines at 19 Italian centres. Cross-tables and chi-square tests were used to describe categorical features. To predict the impact of clinical variables on progression-free survival and overall survival, Kaplan-Meier and Cox regression analyses were performed. RESULTS: At the start of second-line therapy, median age was 64.8 years (25th-75th percentiles: 55.2-71.9 years). Overall, 43% of patients received single-agent chemotherapy, 47.4% a doublet, and 7.3% a triplet. Median second-line progression-free survival was 2.8 months (25th-75th percentiles: 1.8-5.2 months) and median second-line overall survival was 5.6 months (25th-75th percentiles: 2.9-10.0 months). Multivariate analysis showed that performance status, LDH level, neutrophils/lymphocytes ratio, and progression-free survival in the first-line therapy all impacted on prognosis. Based on these four prognostic factors, a prognostic index was constructed that divided patients into good, intermediate, and poor risk groups; median second-line overall survival for each group was 7.7, 4.5, and 2.0 months, respectively (log-rank p < 0.0001). CONCLUSIONS: Advanced gastric cancer patients with a favourable ECOG performance status, lower LDH levels, and a lower neutrophils/lymphocytes ratio at the start of second-line therapy seem to have better outcomes, regardless of age and intensity of treatment. A longer progression-free survival in the first-line therapy also had positive prognostic value. Our real-life study might help clinicians to identify the patients who may benefit most from a second-line therapy.

Selecting patients for gastrectomy in metastatic esophago-gastric cancer: clinics and pathology are not enough.

AIM: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. PATIENTS & METHODS: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. RESULTS: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p < 0.001), as well as preserved performance status and benefit from first-line chemotherapy. None of the investigated clinico-pathological variables identified preferable candidates for surgery (all p > 0.05). CONCLUSION: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.

[Sequential inhibition of angiogenesis in metastatic colorectal cancer: activity and efficacy of aflibercept]. / Inibizione sequenziale dell'angiogenesi nel carcinoma del colon-retto metastatico: attività ed efficacia di aflibercept in un caso clinico.

We report a case of a young adult affected by an adenocarcinoma of the ascending colon with synchronous, unresectable liver metastases, diagnosed on April, 2011. The patient received a first-line of bio-chemotherapy with standard folfox regimen in association with bevacizumab. Deriving from which a good partial remission of the disease with its conversion to operability; so he underwent a right hemicolectomy with liver metastasectomy. Eleven months after radical surgery, the patient experimented an intrahepatic progression of the tumour, so he started a second-line therapy with FOLFIRI regimen plus aflibercept. Six months later than the beginning of the treatment he underwent a second liver metastasectomy. He subsequently received further twelve months of the same regimen. The patient is still alive forty-six months later than the diagnosis of the disease, expressing a good performance status and he's on fourth-line chemotherapy due to a relapse of its tumour.

Translational challenges from the 2014 Gastrointestinal Cancers Symposium: toward a true tailored therapy through effective research.

Gastrointestinal Cancers Symposium 2014, San Francisco, CA, USA, 16-18 January 2014. The Gastrointestinal Cancers Symposium represents an indisputable occasion for sharing results and research opportunities for investigators around the globe. Across the years along with clinical trials presentations the meeting increasingly acquired a distinct role as a scientific arena for translational research. Also, this year the need for predictive markers for first-generation targeted agents and research about novel biologically driven therapeutic options characterized most of the studies presented. We focus here on reports from the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium indicating an opportunity for biological selection of either the pharmacological target or the patient population in order to enhance clinical outcome.

Discontinuation of bevacizumab and FOLFIRI administered up to a maximum of 12 cycles as first-line therapy for metastatic colorectal cancer: a retrospective Italian study.

BACKGROUND: Bevacizumab significantly improves progression-free survival (PFS) and overall survival (OS) when added to chemotherapy for metastatic colorectal cancer (mCRC). The hypothesis that bevacizumab discontinuation could lead to an angiogenesis flare and eventually to an accelerated tumor progression has not been confirmed in a recent large pooled analysis. Therefore the optimal duration of bevacizumab still remains undefined. PATIENTS AND METHODS: PFS and OS were retrospectively analyzed in patients with previously untreated mCRC who received bevacizumab 5 mg/Kg and standard FOLFIRI regimen (leucovorin, infusional fluorouracil and irinotecan) up to a maximum of 12 cycles. RESULTS: Data from 209 patients were collected and analyzed. The median follow-up was 24 months. Fifty-five (26.3%) patients received at least 6 administrations and 114 (54.5%) received a maximum of 12 administrations of bevacizumab. Median exposure to bevacizumab was 148 days (4.9 months). Median PFS and OS were 10.7 months [95% confidence interval (CI) 9.2-12.2 months] and 31.6 months (95% CI 25.8-37.3 months), respectively. Overall objective response rate was 49.8% (95% CI 42.9-56.6) and the disease control rate 81.8%. Approximately 65% and 30% of patients received some form of second- and third-line therapy, respectively. The toxicity profile of bevacizumab was consistent with that documented in previous trials. CONCLUSIONS: In this retrospective analysis remarkably long PFS and OS were obtained with a first-line therapy duration limited to a maximum of 12 cycles. Our data does not support a decreased PFS or increased mortality after discontinuation of bevacizumab in mCRC patients.

Totally implanted venous access devices implanted in the saphenous vein. Relation between the reservoir site and comfort/discomfort of the patients.

BACKGROUND: When a totally implantable venous access device (TIVAD) is implanted in the femoral or saphenous vein, the port can be placed in the abdominal wall, thigh, or anteroinferior thoracic wall. This study analyzed the relationship between the position of the port and patient comfort. METHODS: All patients who underwent TIVAD implantation from 1995 to 2011 were included in the study. Sex, age, indication for TIVAD implantation, contraindication for implantation in a vein draining into the superior vena cava, surgical technique, length of procedure, complications, difficulties recorded by nurses, and patient comfort or discomfort were recorded. RESULTS: The TIVAD was implanted in the saphenous vein in 6 of 581 patients (1.3%) who received a TIVAD, consisting of four male subjects and two female subjects aged 35 to 56 years (mean age: 47.3 years), who all underwent TIVAD implantation for the treatment of a solid tumor. The port was positioned in the anteroinferior thoracic wall in one patient, the abdominal wall in one patient, the anterior thigh in three patients, and the lateral thigh in one patient. The mean procedure duration was 52 minutes (range: 20-135 minutes). No immediate or early complications were recorded. The nurses had difficulty in puncturing the port in the abdominal wall. Patient comfort levels were high when the port was placed in the anterior thigh. CONCLUSION: The anterior thigh may be the most useful and comfortable position for the port of a TIVAD implanted in the inferior vena cava. Larger studies should be undertaken to confirm this.

Colorectal Cancer Heterogeneity and the Impact on Precision Medicine and Therapy Efficacy.

Novel targeted therapies for metastatic colorectal cancer are needed to personalize treatments by guiding specific biomarkers selected on the genetic profile of patients. RAS and BRAF inhibitors have been developed for patients who become unresponsive to standard therapies. Sotorasib and adagrasib showed promising results in phase I/II basket trial and a phase III trial was planned with a combination of these RAS inhibitors and anti-EGFR monoclonal antibodies. Encorafenib and binimetinib were administered in phase II clinical trials for BRAF mutated patients. Pembrolizumab is now recommended in patients exhibiting microsatellite instability. Larotrectinib and entrectinib showed a fast and durable response with few and reversible adverse events in cases with NTRK fusions. Trastuzumab and trastuzumab deruxtecan exhibited promising and durable activity in HER-2-positive patients. In this review, the reasons for an extension of the molecular profile of patients were assessed and placed in the context of the advancements in the understanding of genetics. We highlight the differential effect of new targeted therapies through an ever-deeper characterization of tumor tissue. An overview of ongoing clinical trials is also provided.

Out-of-pocket costs in gastrointestinal cancer patients: Lack of a perfectly framed problem contributing to financial toxicity.

Fighting cancer is an economically expensive challenge for both health care payers, and the patients and their families and the median costs for cancer care are rapidly increasing in the last decade. Although both direct and indirect costs of medical assistance have been a frequent source of distress and contention, however analysis of the non-medical expenses incurred directly by cancer patients has not received adequate attention. Developing a deeper understanding of so-called "out-of-pocket" costs may be necessary. Out-of-pocket costs for medical care range from 7 % to 11 % of medical costs for all payers. However, the range of out-of-pocket costs shows considerable variability in different studies. In this review, we reviewed available data concerning direct and indirect medical costs, including psychosocial ones.

Is G8 geriatric assessment tool useful in managing elderly patients with metastatic pancreatic carcinoma?

AIM: This paper aims to analyze the usefulness of the G8 geriatric oncology questionnaire in patients with advanced/metastatic pancreatic adenocarcinoma (aPAC) and its possible association with different clinical outcomes. METHODS: Patients age > 70 years were screened with the G8 tool and treated with intravenous nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 for 3 consecutive weeks followed by one-week rest as prescribed after clinical evaluation by treating oncologists. Patient's charts were evaluated for type and severity of toxicity, 2 cycle rate of completion, discontinuation rate, delays, dose reductions, and other outcomes response rates, progression-free, and overall survival. Sensitivity, specificity, and possible correlations were analyzed. RESULTS: Sensitivity and specificity of the G8 score for severe toxicity were respectively 55.9% and 50%. No association between all types of severe grade 3-4 toxicity, delays, or dose reductions, and the G8 score was present (p=0.622). ORR was 32.5% with no complete responses. Median PFS and OS were 4.5 months and 8.1 months, respectively. Correlation between G8 score and PFS was not statistically significant (p=0.0652). Correlation between G8 score and OS was statistically significant (p=0.0251). Although median survival of G8 fit patients was superior to that of G8 vulnerable patients (6.5 versus 4 months), the difference was not statistically different (p=0.1975). CONCLUSION: Clinical results in terms of response rate, survival outcomes, and side-effects were in the range reported by others. However, the G8 questionnaire is not a reliable diagnostic tool to predict the risk of severe toxicity, and clinical outcomes in older patients with aPAC.

An Italian study on treatment trends and outcomes of patients with stage III pancreatic adenocarcinoma in the gemcitabine era: is it time to change?

A series of 650 patients treated between 1997 and 2007 at 10 Italian centers was analyzed to assess treatment trends and efficacy in stage III pancreatic adenocarcinoma. Data on patient characteristics, treatment and outcomes were collected. The inclusion criteria were pathological diagnosis of stage III pancreatic adenocarcinoma; age more than 18 years, Eastern Cooperative Oncology Group performance status less than 3, and no past therapy. Most patients (95%) received up-front chemotherapy, which mainly consisted of gemcitabine alone (N=323), gemcitabine-based four-drug combinations (N=107), gemcitabine-platinum compound doublets (N=87), or intra-arterial gemcitabine-free triplets (N=57). The use of gemcitabine-platinum compound doublets increased over time (1997-2001: 2%; 2002-2007: 21%) whereas an inverse trend was observed for gemcitabine (71-61%). No overall survival (OS) difference was observed between patients enrolled in clinical trials and those not enrolled. The median and 1-year OS were 9.5 months and 35.5% for patients treated with gemcitabine; 8.9 months and 36.8% for those treated with gemcitabine-free intra-arterial triplets; 13.3 months and 55.8% for those treated with gemcitabine-platinating agent doublets; and 16.2 months and 62.6% for those treated with gemcitabine-based four-drug combinations. Moreover, the median and 1-year OS were 12.7 months and 51.4% in patients who underwent planned consolidation chemoradiation, and 8.4 months and 30.4% in patients who did not. The use of a strategy consisting of a gemcitabine-platinating agent containing chemotherapy followed by consolidation chemoradiation has been increasing over time and may represent a suitable choice in the therapeutic management of stage III pancreatic adenocarcinoma.

Bevacizumab in Combination With Either FOLFOX-4 or XELOX-2 in First-line Treatment of Patients With Metastatic Colorectal Cancer: A Multicenter Randomized Phase II Trial of the Gruppo Oncologico dell'Italia Meridionale (GOIM 2802).

INTRODUCTION: Biweekly schedule of XELOX-2 (capecitabine plus oxaliplatin) showed interesting results in first-line therapy of patients with metastatic colorectal cancer (mCRC). Bevacizumab plus FOLFOX-4 (oxaliplatin, folinic acid, and infusional 5-fluorouracil) is among standard first-line treatment options in this setting. We performed a phase II randomized trial in order to evaluate the activity of bevacizumab plus either FOLFOX-4 or XELOX-2 in first-line therapy of patients with mCRC. MATERIALS AND METHODS: Patients with mCRC were randomized, in a 1:2 ratio, to first-line bevacizumab plus either FOLFOX-4 (Arm A), as calibration arm, or XELOX-2 (Arm B), up to 12 cycles. Patients without progression were further randomized to maintenance bevacizumab alone or with the same induction fluoropyrimidine. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival, overall survival, and toxicity. The study design was formally non-comparative, but exploratory comparison was performed. RESULTS: Forty-five patients were randomized in arm A and 87 in arm B with an ORR of 55.6% versus 48.3% (P = .43), respectively. After a median follow-up of 47.2 months, progression-free survival was 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival was 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41), respectively. The main grade 3 to 4 toxicities (% A/B) were: neutropenia 15/3 and nausea 9/5. CONCLUSION: This exploratory analysis showed that biweekly XELOX-2 plus bevacizumab has a comparable ORR with FOLFOX-4 plus bevacizumab in patients with mCRC.

Management of patients with early-stage colon cancer: guidelines of the Italian Medical Oncology Association.

About 75% of colorectal cancers are diagnosed as early stage, in which radical surgery is achievable. In the last decade, in Italy, the overall incidence of colorectal cancer has remained stable, while mortality gradually decreased, which is attributable to early diagnosis and improved medical, surgical and locoregional treatments. The Italian Medical Oncology Association formulated guidelines to manage early-stage colon cancer, including screening, diagnosis, treatment and follow-up, which we herein present.

Reactions and countermeasures of medical oncologists towards the incoming COVID-19 pandemic: a WhatsApp messenger-based report from the Italian College of Chief Medical Oncologists.

BACKGROUND: This descriptive, unplanned investigation has been undertaken to report reactions, attitudes and countermeasures which have been put in place and implemented by medical oncology units facing the COVID-19 outbreak in Southern Italy. MATERIALS AND METHODS: Data have been retrospectively obtained from the time-related analysis of conversations via a WhatsApp messenger-based group chat between the medical directors belonging to the Italian College of Medical Oncology Directors. Overall number, intensity and time trend of conversations related to reactions during the 4 weeks of observation related to the crucial events which occurred between 24 February and 28 March, 2020 2020 are included. A sentiment analysis of conversations was also carried out. RESULTS: We report 956 conversations among 19 medical oncology units related to reactions to the crucial events, such as epidemic spread, Government ordinances and guidelines during the 4 weeks of observation. Data show significant awareness of problems linked to the COVID-19 spread among oncologists and rapid diffusion of countermeasures. Actions taken were correlated time wise to crucial events. A correlation between conversations and the volume of activity of oncology units was found. By analysing the sentiment analysis of raw data, positive emotions were reduced in percentage over the weeks. A significant increase in negative emotions was observed as the outbreak impacted on the healthcare system. CONCLUSION: In our experience, the WhatsApp instant-messaging system seems to be a useful tool to share news and reactions between medical oncologists to rapidly implement necessary health measures and answers to most cancer patients' needs and queries in the COVID-19 pandemic scenario.

Oxaliplatin-Based Chemotherapy in Patients with Metastatic Colorectal Cancer Aged at Least 75 Years: A Post-Hoc Subgroup Analysis of Three Phase II Trials.

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged at least 75 years was included in this study. Oxaliplatin was combined with capecitabine in two trials and with uracil-tegafur (UFT) plus folinic acid in the third trial. In one study, bevacizumab was also added to chemotherapy. The median age of patients was 77 years, and all had a good performance status (0 to 1). The observed overall response rate was 45%, comparable to younger patients (51%, p = 0.49). The estimated median progression-free survival (PFS) time and overall survival (OS) time were 8.7 and 19.3 months, respectively. These results did not significantly differ from those in younger patients (8.0 months for PFS (p = 0.58) and 19.7 months for OS (p = 0.94), respectively). The most common grade 3-4 adverse events included diarrhea (13%), fatigue (13%), peripheral neuropathy (10%), and neutropenia (7%). Moreover, the toxicity was never statistically different from that in younger patients. The efficacy of oxaliplatin-based combination was maintained in fit elderly patients ≥75 years.

Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer.

BACKGROUND: In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate. METHODS: We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti-EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebo-controlled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months. RESULTS: The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm. CONCLUSION: RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance setting.

Phase II Study of Tivantinib and Cetuximab in Patients With KRAS Wild-type Metastatic Colorectal Cancer With Acquired Resistance to EGFR Inhibitors and Emergence of MET Overexpression: Lesson Learned for Future Trials With EGFR/MET Dual Inhibition.

BACKGROUND: MET overexpression/amplification has been associated with resistance to anti- epidermal growth factor receptor therapies in patients with metastatic colorectal cancer (mCRC). Combining tivantinib, an inhibitor of the MET receptor tyrosine kinase, and cetuximab may be effective in patients with epidermal growth factor receptor-resistant MET-high mCRC. PATIENTS AND METHODS: This multicenter, single-arm, Simon 2-stage, phase II study enrolled patients with MET-high, KRAS wild-type mCRC, who were treated with ≥ 1 prior systemic therapy, with at least stable disease on the last treatment regimen containing cetuximab or panitumumab. Patients were enrolled if they presented tumor progression on cetuximab or panitumumab within 3 months before enrollment. Patients received tivantinib (360 mg twice daily) plus cetuximab (500 mg intravenously every 2 weeks). The primary endpoint was objective response rate; secondary endpoints included progression-free survival, overall survival, and safety. The treatment would be considered effective if ≥ 5 confirmed partial responses were observed among 41 patients. RESULTS: In total, 41 patients were evaluated, 4 patients (9.8%) achieved an objective response, the median progression-free survival was 2.6 months (95% confidence interval, 1.9-4.2 months), and the median overall survival was 9.2 months (95% confidence interval, 7.1-15.1 months). Among 13 patients with tested MET amplification, 2 responding patients had MET amplification compared with none of the nonresponding patients. The most common grade ≥ 3 treatment-emergent adverse events were neutropenia (14.6%), skin toxicity (12.2%), and fatigue (9.8%). CONCLUSION: Although the study did not meet its primary endpoint, efficacy results suggest some activity of the tested combination, with almost 10% of patients achieving objective response in a difficult-to-treat setting. Treatment-emergent adverse events were consistent with the known safety profile of tivantinib and cetuximab.

Italian survey on cetuximab-based therapy of elderly patients with metastatic colorectal cancer.

PURPOSE: There is no consensus on the use of cetuximab in elderly patients with metastatic colorectal cancer. To this end, a survey was carried in 17 Italian oncology centers. METHODS: The centers answered a 29-item questionnaire structured as follows: (i) demographic characteristics; (ii) medical history; (iii) assessment of RAS/BRAF mutations and DPD/UGT polymorphism before treatment; (iv) treatment schemes and side effects; (v) geriatric assessment and customization of treatment. RESULTS: One-third of patients are over 80 years old. The RAS/BRAF mutational status is not primarily evaluated by 17.6% of the centers, while DPD and UGT polymorphism is not evaluated by 82.4% and 76.5% of the centers. The most common therapeutic scheme is cetuximab/FOLFIRI and diarrhea is the main cause of suspension/reduction of treatment. The 70% of centers use systemic tetracyclines for skin toxicity. The 23.5% of the centers do not carry out any geriatric evaluation before the start of the therapy and those who perform it prefer the G8 (70.6%) and VES-13 (29.4%) scales. CONCLUSIONS: Greater efforts should be made to improve the evaluation of the patient both about mutational and genetic procedures with geriatric evaluation. As for cetuximab in elderly patients, randomized studies are needed to provide guidance to physicians.

Treatment of peritoneal carcinomatosis from colorectal cancer with cytoreductive surgery and perioperative intraperitoneal chemotherapy: state of the art and future prospects.

Peritoneal carcinomatosis (PC), a malignancy limited to the peritoneal surface, has a severe prognosis, but a new therapeutic approach has resulted in cure in some cases. The treatment consists of complete cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy or early postoperative intraperitoneal chemotherapy. At present, only about 25 centers in the United States offer this treatment, and only a few have treated more than 100 cases. This approach may be the most promising new therapy for PC from colorectal cancer but requires collaboration among medical oncologists, colorectal surgeons, and peritoneal surface malignancy treatment centers.