Alessandra Bearz

Pretreatment Quality of Life and Functional Status Assessment Significantly Predict Survival of Elderly Patients With Advanced Non—Small-Cell Lung Cancer Receiving Chemotherapy: A Prognostic Analysis of the Multicenter Italian Lung Cancer in the Elderly Study

PURPOSE To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy. PATIENTS AND METHODS Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. RESULTS Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. CONCLUSIONS Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study

PURPOSE Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. PATIENTS AND METHODS Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). RESULTS Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. CONCLUSION Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

PURPOSE This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. RESULTS A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. CONCLUSION Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial.

BACKGROUND An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. METHODS From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m(2), intravenously, every 21 days, or docetaxel 75 mg/m(2), intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. FINDINGS 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8-10·9) in the chemotherapy group and 7·7 months (5·9-10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08-2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77-1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group. INTERPRETATION Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. FUNDING Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer

Pain is a highly distressing symptom for patients with advanced cancer. WHO analgesic ladder is widely accepted as a guideline for its treatment. Our aim was to describe pain prevalence among patients diagnosed with advanced non-small-cell lung cancer (NSCLC), impact of pain on quality of life (QoL) and adequacy of pain management. Data of 1021 Italian patients enrolled in three randomised trials of chemotherapy for NSCLC were pooled. QoL was assessed by EORTC QLQ-C30 and LC-13. Analgesic consumption during the 3 weeks following QoL assessment was recorded. Adequacy of pain management was evaluated by the Pain Management Index (PMI). Some pain was reported by 74% of patients (42% mild, 24% moderate and 7% severe); 50% stated pain was affecting daily activities (30% a little, 16% quite a bit, 3% very much). Bone metastases strongly affected presence of pain. Mean global QoL linearly decreased from 64.9 to 36.4 from patients without pain to those with severe pain (P<0.001). According to PMI, 616 out of 752 patients reporting pain (82%) received inadequate analgesic treatment. Bone metastases were associated with improved adequacy and worst pain with reduced adequacy at multivariate analysis. In conclusion, pain is common in patients with advanced NSCLC, significantly affects QoL, and is frequently undertreated. We recommend that: (i) pain self-assessment should be part of oncological clinical practice; (ii) pain control should be a primary goal in clinical practice and in clinical trials; (iii) physicians should receive more training in pain management; (iv) analgesic treatment deserves greater attention in protocols of anticancer treatment.

Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial

BACKGROUND Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. METHODS In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. FINDINGS Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. INTERPRETATION These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. FUNDING Novartis Pharmaceuticals Corporation.

Cisplatin Plus Gemcitabine or Vinorelbine for Elderly Patients With Advanced Non–Small-Cell Lung Cancer: The MILES-2P Studies

PURPOSE Two phase I/II trials were done to evaluate the feasibility of cisplatin combined with gemcitabine or vinorelbine in elderly patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC who were older than 70 years of age and who had a performance status of 0 to 1 were eligible. Cisplatin was given on day 1 (a starting dose of 50 mg/m2 with increasing increments of 10 mg/m2 at each level) and gemcitabine (1,000 mg/m2) or vinorelbine (25 mg/m2) on days 1 and 8. Cycles were repeated every 21 days. A two-stage flexible optimal design was applied in the phase II study, and unacceptable toxicity was the primary end point. RESULTS Overall, 159 patients were enrolled: 38 in phase I and 121 in phase II studies. Cisplatin was feasible at 60 mg/m2 with gemcitabine and at 40 mg/m2 with vinorelbine. With the former combination, 50 of 60 (83.3%) patients were treated without unacceptable toxicity; objective responses were reported in 26 of 60 patients (43.5%; 95% CI, 30.6 to 56.8); median progression-free and overall survivals were 25.3 and 43.6 weeks, respectively. With the latter combination, 50 (82.0%) of 61 patients were treated without unacceptable toxicity; objective responses were reported in 22 of 61 patients (36.1%; 95% CI, 24.2 to 49.4); median progression-free and overall survivals were 21.1 and 33.1 weeks, respectively. CONCLUSION Both cisplatin (60 mg/m2) plus gemcitabine and cisplatin (40 mg/m2) plus vinorelbine are feasible and active in the treatment of elderly patients with advanced NSCLC. The former combination, which provides a higher dose of cisplatin, deserves comparison versus single-agent chemotherapy in this setting of patients.

Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer

UNLABELLED Brain metastases from Non-Small Cell Lung Cancer are usually associated with poor prognosis and up to now chemotherapy has shown a modest activity upon cerebral localizations. We investigated the role of Pemetrexed, a new, well tolerated multi-target antifolate, on brain metastases. PATIENTS AND METHODS We collected 39 patients with evidence of cerebral nervous system (CNS) localizations from Non-Small Cell Lung Cancer (NSCLC) before starting treatment with Pemetrexed as second-line or further-line therapy. RESULTS We confirmed the good tolerability of Pemetrexed even in that setting of patients and we reported a progressive disease (PD) in 12 patients (30.8%), a stable disease (SD) and partial response (PR) in 12 (30.8%) and 15 (38.4%) patients respectively, with an overall clinical benefit obtained in 69% of patients. The cerebral response to Pemetrexed was interesting with a cerebral radiological benefit obtained in 32 patients (82%), while 7 patients only showed brain progressive disease. Overall median survival was 10 months. All irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed, overall 22 patients, were included in one group, in order to avoid overlapping effects between brain radiotherapy and Pemetrexed over CNS localizations. Within that setting, we demonstrated an overall clinical benefit (SD+PR) and cerebral benefit in 63% and 68%, of patients respectively. Distribution of patients by overall response to Pemetrexed and CNS response was highly suggestive of activity of Pemetrexed on brain metastases. CONCLUSION We demonstrated the good tolerability of Pemetrexed even in patients with advanced NSCLC and brain metastases, and we found a very good overall response rate with evidence of activity on brain localizations.

Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials.

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m−2 and carboplatin AUC 5 mg ml−1 min−1 intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those ⩾70 years old. A total of 178 patients with an ECOG performance status of ⩽2 were included. Median age was 65 years (range 38–79), with 48 patients ⩾70 years (27%). Grade 3–4 haematological toxicity was slightly worse in ⩾70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

Solid pseudopapillary tumour of the pancreas.

Solid pseudopapillary tumour (Frantz’s tumour) is a rare benign or low-grade neoplasm of the pancreas with distinct clinicopathological features. The diagnosis may be difficult, but should be considered as a possibility in young women who present with a large abdominal mass involving the pancreas. In this report we describe the clinical and pathological characteristics of these lesions and discuss therapeutic options. A 27-year-old woman was admitted to our hospital in October 1999 with a 3-month history of mild asthenia, weight loss, and a feeling of heaviness localised to the left lumbar region. Routine laboratory analyses were all within the normal range; however, abdominal ultrasound revealed the presence of a mass in the superior abdomen, which was composed of high and low echoic areas. Computed tomography showed the mass to be solid, encapsulated, and about 9 cm in diameter (figure 1). It was composed of high and low density areas and was located close to the splenic hilum—above the pancreatic tail, behind the stomach, and between the spleen and the aorta (Albarran-Chatelin’s anatomosurgical quadrilateral). Nuclear magnetic resonance imaging revealed a posterior anastomosis between the mass drainage vessels and the diaphragmatic veins. The patient underwent a complete surgical resection of the tumour (enucleation) and a resection of the pancreatic tail. The spleen was removed because of vascular damage consisting of large patches of venous stasis and ischaemia which did not resolve over time or after application of warm, moist dressings. The pathological diagnosis was epithelial solid papillary cystic neoplasm with signs of incipient pseudocapsular invasion. Immunohistochemical studies established that the tumour cells were positive for cytokeratins and vimentin, and negative for S100 protein, CD34, chromogranin, neurone-specific enolase (NSE), and glial fibrillary acid protein. The postoperative course was uneventful and the patient was discharged from hospital on day 7 and referred to the Centro di Riferimento Oncologico di Aviano for counselling. No residual tumour or metastases were found with clinical imaging, so no adjuvant therapy was recommended. In November 2001, routine work-up identified no signs of tumour relapse. This case is a typical example of solid pseudopapillary tumour of the pancreas or Frantz’s tumour. The diagnostic imaging techniques used were effective in defining the location of the tumour, although a nonfunctioning neoplasm of the left adrenal gland was initially suspected. In 1959, Frantz 1