Quality of life of adult cancer survivors enrolled in Humanitas Research Hospital's survivorship care model.

INTRODUCTION: Clinicians should address the different health needs of cancer survivors (CS). We investigated concerns about physical/psychosocial symptoms and quality of life (QoL) of CS enrolled in our survivorship program. Our primary aim is to describe the CS population and their quality of life, considering both physical and psychosocial issues, with the intent to identify some possible association with the most frequently observed variables. METHODS: Adult patients, after ≥ 5 years from achieving complete hematologic or solid tumor remission, were included. The self-administered questionnaire used in the survey was based on the "Cancer Survivors Survey of Needs" (Mayo Clinic). RESULTS: We analyzed data from 191 CS. The median age was 63 years (53 years at diagnosis), and 70% of patients were females. A total of 93 patients (49%) reported a quality of life (QoL) score > 2. The most common psychosocial symptom concerns were fear of relapse (53%), genetic counseling (43%), living with uncertainty (35%), defining a new sense of normal (31%), and managing stress (28%). Females are more at risk to develop the following concerns compared with males: pain (40% vs 21%), sleep disturbance (54% vs 30%), weight gain (42% vs 21%), osteoporosis (41% vs 11%), body changes (45% vs 13%), hair or skincare issues (42% vs 16%), hot flashes (40% vs 11%), fear of recurrence (74% vs 54%), and living with a sense of uncertainty (53% vs 29%). Younger patients reported a higher score (> 2) for physical and psychological concerns compared with older patients. CONCLUSION: In this study, differences in physical and psychological symptoms/stressors among women and younger patients were identified. Female and younger patients appear to report physical and psychosocial concerns more frequently than other subgroups of patients. These observations should be validated and deepened in larger, prospective studies and considered during the long-term follow-up of these subgroups of patients.

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient's follow-up.

Methylation of tumor suppressor genes is among the most frequent alterations in patients with malignant pleural mesothelioma (MPM). The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15(INK4B), p16(INK4A), RASSF1A and NORE1A in MPM. Samples of 79 MPM patients were analyzed using a methylation-specific PCR method. Associations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined. The analysis documented methylation in 30 cases (38%). The methylation frequency for individual genes was 19% for p15(INK4B) (n=15), 11.4% for p16(INK4A) (n=9), 20.2% for RASSF1A (n=16) and 5.1% for Nore1A (n=4). In the whole series methylation was associated to an increased proliferation index (P=0.05). In patients treated with extrapleural pneumonectomy, methylated MPM showed a trend to a poorer OS in comparison to unmethylated cases (median OS 16 months vs. 35 months, P=0.06, HR=2.01, 95% CI 0.95-4.30). In the overall population, methylation did not correlate to patient outcome but a trend to an improved survival was detectable in ummethylated MPM treated with extrapleural pneumonectomy. This result suggests the need to select homogeneously treated and staged patients with MPM to address whether their methylation profile may impact on patient's survival.

Pemetrexed single agent in previously treated non-small cell lung cancer: a multi-institutional observational study.

UNLABELLED: Several drugs have been approved for the treatment of patients affected by advanced non-small cell lung cancer (NSCLC) in progression after first line chemotherapy: Docetaxel, Pemetrexed and Erlotinib. Poor gain of survival has been demonstrated in randomised trials and patient characteristics predicting activity are poorly known yet. We evaluated the activity and toxicity of Pemetrexed, in a post-registration phase, to assess whether clinical benefits justify its employment in a second-line setting in routine clinical practice. PATIENTS AND METHODS: We collected data on patients with advanced NSCLC treated with Pemetrexed 500mg/m(2) every 21 days, after progression to prior chemotherapy. RESULTS: One hundred and sixty patients from 4 different Italian Institutions, treated with Pemetrexed, mostly as second-line therapy, were analysed. There was a predominance of males versus females, adenocarcinoma versus other histologies; the median age was 63.6 years. The toxicity profile was extremely mild and the response rate (11.2% patients in complete or partial response) was similar to previous reports from the literature. The median overall survival, 12 months, was better than previously reported. CONCLUSION: Improved efficacy and mild toxicity observed in this clinically relevant patient population confirms Pemetrexed as an interesting choice in second-line treatment of NSCLC. Patient characteristics alone are not able to predict response to Pemetrexed.

Herpes infections in breast cancer patients treated with adjuvant chemotherapy.

OBJECTIVE: There is little information on Herpes zoster infection in breast cancer patients as a complication during adjuvant chemotherapy. The aim of this study is to evaluate the incidence of Herpes zoster and simplex infections in this patients setting. METHODS: We analyzed 623 early-stage breast cancer patients in our Institute over a period of 7 years (1998-2005). Four-hundred and sixty-one patients were treated with anthracycline-based chemotherapy, 116 with CMF and 46 with taxane-containing regimens. RESULTS: Twelve (1.9%) developed herpes zoster; 9 patients, receiving anthracycline-based chemotherapy, two taxane-containing regimens, and one CMF regimen. Herpes zoster infection required treatment delay in 6 patients. Adjuvant chemotherapy was delayed for 1 week in 2 patients, while in 4 patients with more severe symptoms chemotherapy was delayed for 2 weeks. One patient, despite i.v. acyclovir, had severe postherpetic motor neuropathy with a permanent ambulation impairment, and chemotherapy was stopped. In our study, herpes zoster occurred in 55/1,000 cases/year. The reported incidence in the general population varies between 2.2 and 4.1 per 1,000 patients/year; therefore, the risk of developing herpes zoster in these patients may be 13- to 25-fold higher compared to the incidence in the general population. In addition, 13 of 623 patients developed herpes simplex. CONCLUSION: Our findings suggest that adjuvant chemotherapy can facilitate reactivation of herpes infection.

Neoadjuvant Chemoradiotherapy with Volumetric-modulated Arc Therapy for Medium-distal Oesophageal and Gastro-oesophageal Junction Carcinoma.

AIM: to appraise the role of volumetric-modulated arc therapy (VMAT) in the neoadjuvant chemoradiotherapy management of advanced medium and distal oesophageal cancer in terms of toxicity and response to treatment. PATIENTS AND METHODS: Thirty patients were treated according to the neoadjuvant chemoradiation followed by surgery versus surgery-alone trial scheme with VMAT radiation therapy. Patients presented mainly T3-T4 stage (80%) and N1-2 (96.6%) disease. The chemotherapy scheme consisted of 3-5 cycles, while a radiotherapy course of 41.4 Gy in 23 fractions was administered to all patients. RESULTS: The median age of patients was 65 years, and there was a predominance of males (80%), smokers or ex-smokers (90%) and modest alcohol habit (80% negative). Primary tumor localisation was in the medium and distal third of the oesophagus in 57% of the cases, the rest being in the gastro-oesophageal junction. Modest toxicity profiles were observed, with limited incidence of grade 2-3 events. Partial or complete response was observed in more than 90% of the cases (radiological/metabolic) and was confirmed after surgical intervention (67% partial or complete and 27% stable response). Tumor down-staging was recorded in 67% of patients and nodal down-staging in 50%. CONCLUSION: VMAT was applied in the context of neoadjuvant chemoradiotherapy for the treatment of medium and distal oesophageal carcinoma with satisfactory results in terms of tolerance and toxicity.

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.

Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.

BACKGROUND: Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. METHODS: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. RESULTS: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. CONCLUSIONS: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.

EGFR tyrosine kinase inhibitors: a therapy for a few, for the majority or for all non-small cell lung cancer patients?

The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.

Is gemcitabine cost effective in cancer treatment?

Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monotherapy or in association with other cytotoxic compounds, in pancreatic, ovarian, breast, bladder and non-small-cell lung cancer. The drug has an acceptable toxicity profile with myelosuppression being the most common adverse event. Pharmacoeconomic assessments have been performed in order to determine whether gemcitabine is a cost effective cancer treatment. Several cost analyses have investigated gemcitabine in association with cisplatin in the treatment of non-small-cell lung cancer, indicating that the combination is cost effective when compared with either old- or new-generation platinum-based treatments. Results in other malignancies are not corroborated by the same quality of evidence, therefore more extensive analyses are warranted. Overall, available data indicate that accurate selection of patients and careful cost analyses should be included in the development of new anticancer drugs for an appropriate use of limited healthcare resources.

Phase II trial of alternating intravenous and oral vinorelbine in combination with cisplatin in advanced non-small cell lung cancer.

Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Several platinum-based doublets have been tested in phase II/III trials with equivalent results in terms of tumour response and survival. Our study was designed to evaluate activity, tolerability and convenience of alternating intravenous (i.v.) and oral vinorelbine in combination with cisplatin in advanced NSCLC. Forty chemo-naive patients with stage IV or relapsed unresectable disease and good performance status were enrolled to receive i.v. cisplatin 40 mg/m(2) on days 1 and 2 plus i.v. vinorelbine 25 mg/m(2) on day 1, every 3 weeks. Oral vinorelbine 60 mg/m(2) was given at home on day 5, without checking of blood cell count. A total of 175 treatment cycles were delivered. The overall response rate was 30% (one complete, 11 partial responses). Median time to progression and overall survival were 5 and 10 months, respectively. The main toxicity was haematological, with grade 3-4 neutropenia observed in 75% of patients, without febrile neutropenia. Non-haematological toxicity was mild. This schedule of cisplatin and vinorelbine treatment showed a good toxicity profile and an efficacy similar to other standard regimens. Oral vinorelbine could be administered safely at home on day 5.

The efficacy of hybrid chemotherapy with intravenous oxaliplatin and folinic acid and intra-hepatic infusion of 5-fluorouracil in patients with colorectal liver metastases: a phase II study.

Intra-arterial chemotherapy in patients with liver metastases from colorectal cancer has some limitations such as hepatic toxicity and extra-hepatic progression. With the aim of overcoming these limitations, a phase II trial was designed to assess the efficacy and tolerability of a hybrid chemotherapy regimen with systemic infusion of oxaliplatin and folinic acid associated with intra-arterial 5-fluorouracil. Thirty-nine patients with colorectal liver metastases were recruited. The median age was 59 years, 30 patients (77%) had synchronous metastases, and half of the patients were chemo-naive. A total of 313 chemotherapy cycles were administered (median number 8). Treatment was well tolerated and hepatic toxicity negligible. Out of 34 evaluable patients an ORR of 41%. was observed. Eight patients (21%) underwent radical liver surgery. The median time to progression (TTP) was 10 months (range 2-63) and the median overall survival (OS) 21 months (range 6-63). Extra-hepatic progression was observed in six patients. Our results suggest that this regimen is active even if technical complications are frequent. Our aim to reduce hepatic toxicity and extra-hepatic progression was reached.

Unexpected low efficacy of stealth liposomal doxorubicin (Caelyx) and vinorelbine in metastatic breast cancer.

In this phase II study, 23 patients with metastatic breast cancer were treated with a combination of Caelyx (40 mg/m2 on day 1) and vinorelbine (20 mg/m2 on days 1 and 8) every 4 weeks. According to the statistical design, enrollment was closed after the first stage due to the low response rate observed (four partial remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3-4 neutropenia was not negligible. Our study does not support the development of this combination in advanced breast cancer.