From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR-Positive Non-Small Cell Lung Cancer (MOST Study).

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab.

Purpose: LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC).Experimental design: We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models.Results: In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56; P = 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64; P = 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.Conclusions: Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab. Clin Cancer Res; 23(13); 3316-24. ©2017 AACR.

Adjuvant treatment for elderly patients with colon cancer. An observational study.

BACKGROUND: Adjuvant 5-fluoruracil-based chemotherapy significantly reduces mortality in patients with stage II-III colon cancer, but is less prescribed with rising age. In this study we were interested in the pattern of adjuvant treatment and possible effects on survival among elderly patients. PATIENTS AND METHODS: From January to December 2004, 63 questionnaires on the management of stage II-III resected colon cancer patients aged over 70 years, collected from 10 Italian Centres, were retrospectively examined. Determinants of receipt of adjuvant chemotherapy and their relation to survival were considered. RESULTS: The proportion of elderly patients receiving adjuvant chemotherapy was 79.4%, distinct of age, gender, educational level and comorbidities. Grade 3-4 toxicities were the following: haematological in 4 (8.5.%) patients, mucositis in 4 (8.5%), diarrhoea in 2 (4.2%) and nausea in 1 (2.1%). The disease-free survival (DFS) and overall survival (OS) at two years were 79.9% and 95.6%, respectively. Due to the paucity of events, the impact of prognostic factors (patient's age and comorbidity, tumour stage and grade) on DFS and OS could not be assessed. CONCLUSION: An increasing proportion of elderly patients with colon cancer may be treated with a tolerability and OS similar to those observed in the younger population. Development of age-based guidelines and increased awareness of both physicians and patients through education is important to prevent undertreatment of those elderly patients who are eligible for chemotherapy.

Palliative treatment for elderly patients with colon cancer in ten Italian medical oncology units.

BACKGROUND: Palliative chemotherapy significantly reduces mortality in patients with stage IV colon cancer, but is less prescribed with rising age. In this paper, we highlight the pattern of palliative treatment and possible effects on survival among elderly patients. PATIENTS AND METHODS: From January to December 2004, 78 files on the management of stage IV colorectal cancer (CRC) patients over 70 years, collected from 10 Italian Centres, were retrospectively examined. Determinants of receipt of palliative chemotherapy and their relation to toxicity and survival were considered. RESULTS: The proportion of elderly patients receiving first-line palliative chemotherapy was 98.7% and it was evaluated according to age, gender, educational level and comorbidities; patients receiving second-line therapy comprised 47.4%, those receiving third-line therapy 14.1% and those treated with a fourth-line therapy totalled 2.6%. Forty-one percent of patients received best supportive care (BSC) alone. CONCLUSION: In Italy, a proportion of elderly patients with metastatic chemonaive CRC are usually treated with a tolerability and overall survival similar to those for the younger population. Among progressive patients after second-line therapy, 45.8% usually undergo third line therapy; the remaining 54.2% undergo BSC.

Colorectal cancer treatment in elderly patients: results of a retrospective analysis addressed to the chiefs of medical oncology units in Italy.

BACKGROUND: The aim of this retrospective analysis was to evaluate the differences of 1-year treatment and chemotherapy related-toxicity in elderly colorectal cancer (CRC) patients in different Italian medical oncology units. PATIENTS AND METHODS: An open questionnaire on the management of CRC patients over 70 years of age, from January to December 2004, was sent to Italian centres. One hundred and seventy-five files from 10 centres were analysed. Variables considered were age, gender, educational level, comorbidities and modality of therapy administration. RESULTS: In only a minority of units were there some staff specifically dedicated to the older patients in close cooperation with geriatricians and the Multidimensional Geriatric Assessment (MGA) was not routinely used (11.2%-16.8% of cases). Only 5.7% patients were routinely enrolled in a protocol. In total, 95 out of 175 (54.3%) of CRC underwent adjuvant chemotherapy and 80 out of 175 (45.7%) received palliative chemotherapy. Of the patients who underwent adjuvant chemotherapy, 75.6% immediately accepted postoperative treatment while 12.2% were initially dubious but subsequently agreed. Only 5.5 and 9.7% of these patients reported very bad or bad tolerability, respectively. At disease progression, 62.5% patients accepted chemotherapy instantly while 33.3% accepted subsequently. Only 1.3% cases reported very bad and 1.3% bad tolerability. CONCLUSION: In those units in which the problem of the elderly is actually recognised, CRC treatment is adequate, not influenced by age discrimination but inhomogeneous. In the future, standardizing treatment in different oncology units could prove to be beneficial to this population.

Adding gemcitabine to paclitaxel/carboplatin combination increases survival in advanced non-small-cell lung cancer: results of a phase II-III study.

PURPOSE: Paclitaxel/carboplatin (PC) is one of the reference combinations in the treatment of non-small-cell lung cancer (NSCLC). No triplet novel agent combination has until now shown superiority over a two-drug combination for advanced NSCLC. We therefore conducted a clinical trial to test if paclitaxel/carboplatin/gemcitabine (PCG) increases overall survival (OS) and response rate (RR) over PC. METHODS: Stage IIIB patients not suitable for radical radiation treatment and stage IV chemotherapy-naive patients with measurable disease and performance status of 0 to 2 were randomly assigned to PC arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1/q21 days) or the PCG arm (paclitaxel 200 mg/m(2) and carboplatin area under the concentration-time curve 6 day 1, and gemcitabine 1,000 mg/m2 days 1 and 8 every 21 days). RESULTS: A total of 324 patients were randomly assigned to the two arms. The RR for PC arm and PCG arm were 20.2% and 43.6% [corrected] (P < .0001). The median time to the progression was 5.1 months in the PC group and 7.6 months in the PCG group (P = .012; hazard ratio [HR] 1.34; 95% CI: 1.06 to 1.72). Median OS was 8.3 months and 10.8 months (P = .032; HR 1.309; 95% CI: 1.03 to 1.67) in favor of the PCG arm. One-year survival was 34% (PC arm) and 45% (PCG arm; P = .032). Only hematologic toxicity (neutropenia, thrombocytopenia, and anemia) was significantly increased in the PCG arm and the experimental arm required more platelet and red blood cell transfusions, and more granulocyte colony-stimulating factor usage. No toxic/early deaths were observed. CONCLUSION: The PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced NSCLC patients.

Surgical outcome of lung cancer patients with carcinomatous pleuritis.

In sporadic though non-anecdotal series, long-term survival has been reported for patients operated on for lung cancer with secondary carcinomatous pleuritis. In a retrospective study, we review the outcomes of 24 surgical patients (20 treated with standard lung resection +/- pleurectomy and 4 with extended pleuropneumonectomy) out of 48 individuals affected by pleural spread before or at thoracotomy. We observed a 16.6% major complication rate with no operative mortality; 5-year and median survival were 20% and 21 months, respectively. Time of diagnostic (pre- vs intra/postoperative) or pattern (effusion vs dissemination) of pleural disease, and type of resection (standard vs extended) did not seem to influence the prognosis, while an adenocarcinoma histotype, completeness of excision and N(0-1) were favourable prognostic indicators. Since most (90%) of these IIIB stages are usually associated with N(2-3) and/or unresectable tumour, it would seem reasonable to employ neo-adjuvant treatment as the first approach, reserving surgical treatment to responders. Multicentre studies are necessary to better determine which subgroup of patients with malignant pleuritis can most benefit from surgical therapy.

Neoadjuvant docetaxel, cisplatin, 5-fluorouracil before concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck versus concomitant chemoradiotherapy: a phase II feasibility study.

PURPOSE: To determine the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) compared with the same CHT-RT regimen alone in locally advanced head-and-neck squamous cell carcinoma. METHODS AND MATERIALS: We treated 24 patients (20 men and 4 women) who had Stage III-IVM0 squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, or hypopharynx. The median patient age was 59 years (range, 41-73 years). The stage distribution was as follows: Stage II, 1 patient; Stage III, 6 patients; and Stage IV, 17; 18 patients had a performance status of 0 and 6 had a performance status of 1. None had undergone previous CHT or RT. Group 1 underwent three cycles of CHT (carboplatin area under the curve 1.5 on Days 1-4 and 5-fluorouracil 600 mg/m(2)/d continuous infusion for 96 h) starting on Days 1, 22, and 43 during RT (one daily fraction, 66-70 Gy within 33-35 fractions). Group 2 underwent three cycles of neoadjuvant TPF (docetaxel 75 mg/m(2), cisplatin 80 mg/m(2), 5-fluorouracil 800 mg/m(2)/d continuous infusion for 96 h) followed by the same CHT-RT regimen. RESULTS: After the first 16 patients, 8 in Group 1 and 8 in Group 2, the concomitant CHT-RT schedule was modified. The limiting toxicity observed during concomitant CHT-RT was similar in Groups 1 and 2, independent of neoadjuvant TPF administration. An excess of G3-G4 mucositis and other relevant toxicity that did not allowing completion of CHT-RT without interruption occurred in 44% of the patients. A reduction of at least one cycle of concurrent CHT was required in 31% of patients. On the basis of these data, the next 8 patients (Group 3) received three cycles of neoadjuvant TPF followed by two cycles only of CHT (cisplatin 20 mg/m(2) on Days 1-4 and 5-fluorouracil 800 mg/m(2)/d continuous infusion for 96 h) (PF) during Weeks 1 and 6 of the planned 7 weeks of RT. In Group 3, 25% of the patients developed World Health Organization G3-G4 mucositis. No World Health Organization hematologic G3-G4 toxicity was seen. RT interruption was required for 2 patients (25%). In 1 patient (12%), one cycle of CHT was omitted. During neoadjuvant TPF (Groups 2 and 3), the principal toxicities were G3-G4 neutropenia (37.5%) and G2 mucositis (44%). At the end of therapy, the CR rate was 62.5% for CHT-RT alone (Group 1) and 80% for neoadjuvant TPF followed by CHT-RT (Groups 2 and 3). CONCLUSION: Three cycles of neoadjuvant TPF followed by two cycles of PF during RT are feasible without limiting toxicity. Three cycles of TPF were well tolerated and did not compromise subsequent concomitant CHT-RT. A randomized multicenter Phase III study has been started with the aim of comparing two cycles of PF during RT as standard treatment vs. the experimental arm with three cycles of neoadjuvant TPF followed by two cycles of PF during RT.

Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study.

BACKGROUND: Malignant pleural mesothelioma (MPM) is increasing rapidly worldwide. Currently, pemetrexed plus cisplatin chemotherapy showed a survival advantage versus cisplatin alone. No impact on patient survival of surgery, radiotherapy, or their combination has been demonstrated. METHODS: Eight centers in northeastern Italy participated in a Phase II multicenter study. Chemotherapy was comprised of carboplatin area under the concentration-time curve 5 on Day 1 and gemcitabine 1000 mg/m(2) on Days 1, 8, and 15. This cycle was repeated every 4 weeks. RESULTS: Between July 1996 and September 2000, 50 patients were treated. Of the sample, 68% were males, 88% had a Eastern Cooperative Oncology Group performance status score of 0-1, 56% had Stage I-II disease, 68% had epithelioid histology, and 62% had no previous treatments. The delivered dose intensity of gemcitabine was 617 mg/m(2) per week, which was 82% of the planned dose (750 mg/m(2) per week). For carboplatin, the delivered dose intensity was 80 mg/m(2) per week. Overall, 44% of 15th day doses were omitted or reduced. Twenty-six percent of the patients had partial responses (95% confidence interval: 15-40%) and 24% had disease progression. None of the patients had complete responses. The median response duration was 55 weeks (range, 13-113 weeks). Patients had good clinical benefit. For example, 46% had improved dyspnea, 40% improved in weight, and 26% experienced pain reduction. Patients developed Grade 3-4 leukopenia during 18 cycles (11%) of chemotherapy. Grade 3-4 thrombocytopenia occurred more frequently, i.e., there were 24 episodes (15%) among 17 patients. Grade 3 anemia developed among patients during eight cycles (5%). None of the patients developed Grade 3-4 nonhematologic toxicity. The median survival of this sample of patients was 66 weeks with 53%, 30%, and 20% of patients alive at 1, 2, and 3 years, respectively. The median progression-free survival period was 40 weeks. CONCLUSIONS: The gemcitabine/carboplatin combination is a valid option in the treatment of MPM due to its acceptable toxicity profile, the good response rate, and the clinical benefit to patients. Minor adjustments in schedule (3-week cycles instead of 4-week cycles) would permit a more optimal treatment administration.