Green oncology: cultivating sustainability in medical oncology.

INTRODUCTION: Green oncology is a new conceptual and operational paradigm of oncology, which compared to the traditional biomedical model focused on the interest of a single patient and on its exclusive relationship with the doctor, represents a complex evolutionary step towards clinical activities that have to be eco-responsible of the potential current and future impact on the human, professional, structural, technological, and organizational environment, where they arise, as well as on the biosphere. DEFINITION: Green oncology works through ethical and managerial choices that incorporate, besides the traditional criteria of efficiency and effectiveness, the criterion of cultural, economic, environmental, and social sustainability as they are fair, livable, and possible to be realized.

The impact of new cancer drugs in real practice oncology: a monoinstitutional experience.

Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (e.g. value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. We have analyzed a total of 856 cancer patients were registered in the onco-AIFA for various drugs. The results have shown that 38.1% of patients have received only few drug administrations and their treatment was stopped within 4 or 12 weeks (depending on the type of the drug schedule). We have examined the reasons, why their treatment was immediately suspended.

Neurological syndrome after R-CHOP chemotherapy for a non-Hodgkin lymphoma: what is the diagnosis?

A 63-year-old man was admitted to our Oncology department for management of a follicular non-Hodgkin lymphoma, stage IV A FLIPI 5. The patient entered chemotherapy following the R-CHOP schedule, and a PET scan after three cycles showed partial remission. One week later he was admitted to our hospital after developing serious pain in his left arm resulting in an impaired function, right facial hemiplegia, and ophthalmoplegia. Neuroimaging studies and laboratory features were negative. Given his symptoms, we suspected Miller Fisher syndrome and the patient was administered high dose immunoglobulin, but showed no improvement. Finally, chemotherapy with methotrexate 3 g/mq was initiated, but his condition progressively worsened and the patient died 2 months later. We suggest that any patient with neurological symptoms who has received rituximab should undergo PCR analysis for all neurotropic viruses together with neurophysiological and neuroimaging studies.

Increased overall survival independent of RECIST response in metastatic breast cancer patients continuing trastuzumab treatment: evidence from a retrospective study.

Recent studies have reported the potential clinical utility for metastatic breast cancer (MBC) patients of continuing trastuzumab beyond progression. Based on those results, here the authors have examined the benefits of trastuzumab-continuation by specifically evaluating RECIST responses upon first line trastuzumab-treatment as a potential predictive marker for therapeutic effect of trastuzumab-continuation beyond metastatic disease progression. The authors carried out a retrospective analysis of 272 HER2 positive MBC patients under trastuzumab treatment at 22 different oncology Italian centers during the years of 2000 and 2001 who progressed under first line trastuzumab-treatment. The primary end point of the study was the survival from the date of first documented progression upon first line trastuzumab treatment of disease. Data analysis involved the use of matching on propensity score to balance variables between treated and untreated subjects and to reduce bias. Of the 272 HER2-positive MBC patients, 154 (56.6%) continued treatment. 79 (51.3%) of those 154 patients showed responses based on RECIST criteria during first-line trastuzumab-treatment. Of the 118 patients that suspended trastuzumab, RECIST responses had been observed in 44 (37.3%). Cox proportional hazards analysis of progressed patients, matched using propensity score, showed that discontinuation of trastuzumab at metastatic disease progression was a risk factor for significantly reduced overall survival in both responder (HR = 2.23; 95% CI = 1.03-4.82) and non-responder groups (HR = 3.53, 95% CI = 1.73-7.21), with no significant differences in the two estimated HRs (P-value of the likelihood-ratio test = 0.690). Continued trastuzumab treatment after disease progression has clinically and statistically significant effects in both RECIST responder and non-responder MBC patients.

Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors and new therapeutic perspectives in non small cell lung cancer.

EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinase inhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all patients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in about a half of patients. Uncontrolled activation of MET, another tyrosine kinase receptor, has been implicated in neoplastic invasive growth. MET is overexpressed, activated and sometimes mutated in NSCLC cell lines and tumor tissues. MET increased gene copy number has also been documented in NSCLC and has been studied as negative prognostic factor. It has also been found in about 20% of patients developing acquired resistance to TKIs inhibitors. In this group, it seems to display a new mechanism, which is able to mark tumor independence from EGFR signaling. The study of delayed resistance mechanisms could lead to the development of new therapeutic strategies. Different molecular alterations could be specifically targeted in order to extend disease control in this group of NSCLCs with distinct clinical and molecular features. EGFR irreversible inhibitors, MET inhibitors and dual EGFR/VEGFR inhibitors represent one of the most challenging issues in current clinical research. Ongoing clinical trials and future perspectives are discussed.

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience.

BACKGROUND: The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients. METHODS: Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS=0-2, adequate organ function, measurable disease. Chemotherapy was gemcitabine 1000 mg/m(2) days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m(2) or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan. RESULTS: Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2). The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75). Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%). CONCLUSION: Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.

M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by CellSearch analysis.

PURPOSE: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment. EXPERIMENTAL DESIGN: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer. RESULTS: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings. CONCLUSIONS: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers.

A case of anaplastic thyroid cancer with long-term survival.

Anaplastic thyroid carcinoma (ATC) (less than 10% of all thyroid cancer) is a high-grade neoplasm, characterized by an aggressive clinical course and refractoriness to currently available local and systemic modalities of treatment. It is considered the most aggressive solid tumour, there is no adequate therapy for this disease and few patients with ATC live more than 1 year following diagnosis. We report herein an unusual case of ATC in a 59-year-old woman. She presented to our Institute in December 2004. She received many kinds of chemotherapeutical and multimodal treatment; we obtained a long period of localized disease (about two years) and an excellent response to therapy. She is still alive 58 months from diagnosis.

Management of primary and advanced breast cancer in older unfit patients (medical treatment).

Elderly women constitute a large group of breast cancer patients, and after multidimensional geriatric assessment (MGA) only a minor part of them are found in perfect health (=fit), while the remaining display one or more physical or functional limitations or familial/social problems and are therefore categorized as vulnerable or frail (=unfit). Although randomized trials have not produced modest evidence that surgery impacts on ultimate survival of elderly women with hormone-responsive tumors, there is a general consensus that age alone should not prevent surgical local treatment even in unfit women due to the limited morbidity of breast surgery and to the risk of local progression. Activity and safety of AIs appear comparable in elderly women compared to younger counterparts, although concomitant cardiovascular comorbidity and osteoporosis should be closely monitored. Of note, compliance to oral therapy in unfit women and possible interferences with concomitant medications are still poorly documented issues. With the exception of high-risk node positive and estrogen-receptor negative patients, administration of adjuvant chemotherapy for estrogen-receptor positive unfit patients is rarely recommended since the uncertain gain in relapse-free survival is exceeded by the increased risk of toxicity and competitive causes of death. Endocrine-responsive metastatic disease is managed with one or more lines of endocrine treatment as in younger patients. Single agent sequential chemotherapy regimens are to be preferred to combination regimens, which are usually more toxic with a limited survival gain even in younger patients. When and how dose reductions should be applied to unfit patients is highly controversial. Trastuzumab in association with chemotherapy can be administered to elderly patients presenting HER2 overexpressing tumors, although the risk of cardiac adverse events in unfit patients is largely unknown. Bevacizumab-based combinations increase the activity and also toxicity of taxane chemotherapy, and are not a preferred option.

When an interim analysis of randomized trial changes the practice in oncology: The lesson of adjuvant trastuzumab and the HERA trial.

About 30% of the randomized clinical trials are stopped early because of appearance of clear clinical benefit. Though interim analyses protect patients in case of significant imbalance between two treatment arms, conclusions drawn from truncated studies can be premature and should be viewed with caution. We report the lesson learnt from the Herceptin adjuvant (HERA) trial.

MASPIN's prognostic role in patients with advanced head and neck carcinoma treated with primary chemotherapy (carboplatin plus vinorelbine) and radiotherapy: preliminary evidence.

CONCLUSIONS: Our very preliminary results support the hypothesis that MASPIN expression in primary head and neck squamous cell carcinoma (HNSCC) may be a valuable parameter for predicting patients' responses to a treatment based on carboplatin plus vinorelbine combined with radiotherapy. OBJECTIVES: The roles of induction chemotherapy and combined chemoradiotherapy in the treatment of locally advanced unresectable HNSCCs have evolved rapidly. MASPIN has a unique tumour-suppressing activity. Experimental evidence has shown that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. We investigated the potential prognostic roles of MASPIN and p53 in a series of HNSCCs treated with carboplatin plus vinorelbine combined with radiotherapy. PATIENTS AND METHODS: Nineteen consecutive stage III or IV HNSCC patients were recruited. The treatment plan consisted of the administration of carboplatin on day 1 and vinorelbine on days 1 and 8. Four weeks later, carboplatin was administered concomitantly with radiation therapy. Expression of MASPIN and p53 was determined immunohistochemically in HNSCC diagnostic biopsies. RESULTS: A significant inverse relation was found between MASPIN expression and cN staging (p = 0.003). From a prognostic viewpoint, MASPIN expression was directly correlated with chemoradiotherapy response (p = 0.041). Moreover, the log-rank test showed a significant relationship between higher MASPIN expression and longer disease-free survival (p = 0.03), overall survival (p = 0.006) and disease-specific survival (p = 0.007).

When an interim analysis of randomized trial changes the practice in oncology: the lesson of adjuvant Trastuzumab and the HERA trial.

About 30% of the randomized clinical trials are stopped early because of appearance of clear clinical benefit. Though interim analyses protect patients in case of significant imbalance between two treatment arms, conclusions drawn from truncated studies can be premature and should be viewed with caution. We report the lesson learnt from the Herceptin adjuvant (HERA) trial.

Adjuvant systemic chemotherapy with 5-fluorouracil and leucovorin in colon cancer: a monoinstitutional institutional experience.

The efficacy of adjuvant chemotherapy in colon cancer has been well established in clinical trials, yet data on its routinely clinical practice are few. Two hundred forty-one patients were treated with fluorouracil-based adjuvant therapy from 1996 to 2001 and 147 out of 241 patients consecutively treated was aged 65 years or more at the time of diagnosis. Kaplan-Meyer progression-free survival and overall survival of stage II and III patients were calculated, the same statistic analyses were done for elderly population. Three- and 5-year overall survivals were respectively 94.4% and 90.4%. The survival observed in our retrospective study reflects that reported in the chemotherapy arm of randomized clinical trials. As expected, stage II patients survival was better than that of stage III patients (p = 0.0019, log-rank test). The treatment was generally well tolerated and there was no therapy related death and no clinical immonotoxicological effects was observed also in elderly patients.

Neoadjuvant carboplatin and vinorelbine followed by chemoradiotherapy in locally advanced head and neck or oesophageal squamous cell carcinoma: a phase II study in elderly patients or patients with poor performance status.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of neo-adjuvant carboplatin and vinorelbine followed by concomitant chemoradiotherapy in patients > or =70 years of age or with Karnofsky performance status (PS) 70-80, diagnosed with locally advanced head and neck (H&N) or oesophageal carcinoma. PATIENTS AND METHODS: The treatment plan consisted of three courses of carboplatin AUC4 on day 1 and vinorelbine 25 mg/m2 on day 1 and 8, every 21 days, followed by chemoradiotherapy. Carboplatin 100 mg/m2 was delivered weekly for the duration of the radiation therapy (70 Gy, 2 Gy/daily). RESULTS: Thirty-five patients with an average age of 68 years (range 42-85, 16 patients > or =70 years) were treated. Twenty-seven patients (77.1%) responded to neo-adjuvant chemotherapy (2 complete and 25 partial responses). Haematological toxicity was grade 3-4 in 13 patients (37.2%), while gastrointestinal toxicity was grade 3-4 in 20 patients (57.1%). All the patients completed the chemoradiotherapy plan, with grade 4 mucositis plus febrile neutropenia in 3 patients (8.5%). Median time to progression (TTP) was 10.2 months, with 31.5% of patients being alive at two years. CONCLUSION: The regimen of neo-adjuvant carboplatin and vinorelbine followed by chemoradiotherapy is feasible and active in older (> or =70 years) or low PS (Karnofsky 70-80) patients, although toxicity is not negligible and long-term outcome remains poor.

FOLFOX4 in advanced colorectal cancer: a monoinstitutional experience.

AIMS AND BACKGROUND: Patients included in clinical trials are "selected", and they usually differ from those commonly treated. METHODS: From 1999 to 2004, in the Medical Oncology Department of Padua (Italy), 70 metastatic colorectal cancers were treated with FOLFOX4. RESULTS: Our results, compared with those of the registration trial (response rate, duration of response and progression-free survival) appeared lower; overall survival was improved. CONCLUSIONS: The number of therapeutic regimens more than their type influenced the results.

Stable disease in advanced colorectal cancer: therapeutic implications.

Colorectal cancer is one of the most common neoplasms in Western Countries and ranks second as a cause of death due to cancer. The overall mortality at 5 years is about 40%. Patients with resectable metastatic disease can be cured, but for those who cannot, treatment is purely palliative, and overall survival (OS) is from approximately 7 to 24 months. Infusional regimen with modulated 5Fluorouracil (5FU) gives an objective response rate (RR) of up to 30-40%. The addition of CPT11 or oxaliplatin to 5FU improves RR, time to progression (TTP) and OS with a stabilization of disease (SD) in 40-70% of cases and 20-40%, respectively. The concurrent utilization of selective biological agents as growth factor receptors acting at a molecular level and influencing the processes of tumor formation and growth, increases tumor cell apoptosis and inhibits tumor growth; as a result, the tumor regresses or is inhibited, with consequently prolonged OS and TTP. This paper examines the problem related to the treatment of metastatic colorectal cancer with SD. Current doubts regarding the continuation of one treatment until disease progression (PD) with a risk of toxicity, whether or not to use a less toxic "maintenance" therapy after a fairly aggressive "induction" therapy in "stabilized" responders, or whether to stop the treatment in the presence of a SD confirmed after at least two consecutive evaluations, are present.