Lucio Buffoni

Stereotactic body radiation therapy for lung metastases

INTRODUCTION Stereotactic body radiation therapy (SBRT) has an emerging role in patients affected with pulmonary metastases. Purpose of this study was to evaluate efficacy and tolerability of SBRT in a cohort of patients treated between 2003 and 2009 at our institution. METHODS A total of 61 patients with oligometastatic lung tumors (single pulmonary nodules in 73.7%) were included in the study. SBRT was performed with a stereotactic body frame and a 3D-conformal technique. Fifty-one patients received 26 Gy in 1 fraction, 22 a dose of 45 Gy in 3 fractions and 3 a dose of 36 Gy in 4 fractions. Primary tumor was lung cancer in 45.7% of patients, colorectal cancer in 21.3% and a variety of other origins in 33%. The primary endpoint was local control, secondary endpoints were survival and toxicity. RESULTS After a median follow-up interval of 20.4 months, local control rates at 2 and 3 years were 89% and 83.5%, overall survival 66.5% and 52.5%, cancer-specific survival 75.4% and 67%, progression-free survival 32.4% and 22.3%. Tumor volume was significantly associated to survival, with highest rates in patients with single small tumors. Median survival time was 42.8 months, while median progression-free survival time was 11.9 months. Toxicity profiles were good, with just one case of grade III toxicity (pneumonitis). CONCLUSION This study shows that SBRT is an effective and safe local treatment option for patients with lung metastases. Definitive results are strictly correlated to clinical selection of patients.

IL-7 Up-Regulates TNF-α-Dependent Osteoclastogenesis in Patients Affected by Solid Tumor

Background Interleukin-7 (IL-7) is a potent regulator of lymphocyte development, which has also significant effects on bone; in fact it is a potent osteoclastogenic factor. Some human solid tumors produce high IL-7 levels, suggesting a potential IL-7 role on tumor development and progression. Methodology We studied 50 male patients affected by solid tumors, and their blood samples were collected at tumor diagnosis. PBMCs were isolated and cultured with/without IL-7 to study its influence on osteoclastogenesis. Serum and cell culture supernatant IL-7 levels were measured by ELISA. The quantitative analysis of IL-7 expression on T and B cells was performed by Real-Time PCR. Principal Findings Serum IL-7 levels were highest in osteolytic cancer patients, followed by cancer patients without bone lesions, and then healthy controls. We showed the IL-7 production in PBMC cultures and particularly in monocyte and B cell co-cultures. A quantitative analysis of IL-7 expression in T and B cells confirmed that B cells had a high IL-7 expression. In all cell culture conditions, IL-7 significantly increased osteoclastogenesis and an anti-IL-7 antibody inhibited it. We demonstrated that IL-7 supports OC formation by inducing the TNF-α production and low RANKL levels, which synergize in promoting osteoclastogenesis. Conclusions We demonstrated the presence of high serum IL-7 levels in patients with bone metastasis, suggesting the use of serum IL-7 level as a clinical marker of disease progression and of bone involvement. Moreover, we showed the capability of IL-7 to stimulate spontaneous osteoclastogenesis of bone metastatic patients and to induce osteoclastogenesis in cancer patients without bone involvement. These findings add further details to the disclosure of the mechanisms controlling bone metastasis in solid tumors.

Significance of the presence of microscopic vascular invasion after complete resection of Stage I-II pT1-T2N0 non-small cell lung cancer and its relation with T-Size categories: did the 2009 7th edition of the TNM staging system miss something?

Introduction: The aim of this study was to assess the significance of microscopic vascular invasion (MVI) in a population of resected patients with early-stage non-small cell lung cancer (NSCLC), along with an analysis of the effect of the combination of MVI and tumor size for the T-size categories T1a-T2b according to the 2009 7th edition of the tumor, node, metastasis (TNM) classification. Methods: From January 1993 to August 2008, 746 patients with pT1-T2N0 NSCLC received resection at our institution. MVI was ascertained using histopathological and immunohistochemical techniques. Results: MVI was observed in 257 patients (34%). Prevalence was higher in adenocarcinoma (ADK) than in squamous cell carcinoma (p = 0.002). A significant correlation was found between MVI and ADK (p = 0.03), increased tumor dimension (p = 0.05), and the presence of tumor-infiltrating lymphocytes (p = 0.02). The presence of MVI was associated with a reduced 5-year survival overall (p = 0.003) and in ADK (p = 0.0002). In a multivariate survival analysis, MVI was an indicator of poor survival overall (p = 0.003) and in ADK (p = 0.0005). In each T category (T1a-T2b) of the 2009 TNM staging system, survival of MVI+ patients was significantly lower than the corresponding MVI− patients; T1a and T1b MVI+ patients had a survival similar to MVI− T2 patients. Conclusions: The finding of MVI in pT1-T2N0 NSCLC is frequent. MVI correlates with adenocarcinoma histotype, increased tumor dimensions, and tumor-infiltrating lymphocytes. The presence of MVI is an independent negative prognostic factor. In our experience, MVI was a stronger prognostic indicator than T size in T1a-T2b categories according to the 2009 TNM staging system.

Gefitinib (ZD1839): therapy in selected patients with non-small cell lung cancer (NSCLC)?

PURPOSE To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP). PATIENTS AND METHODS A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed. RESULTS In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers. CONCLUSIONS In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.

DNA repair gene expression level in peripheral blood and tumour tissue from non-small cell lung cancer and head and neck squamous cell cancer patients

BACKGROUND The nucleotide excision repair pathway is crucial for cellular DNA integrity and the ERCC1 helicase is also potentially involved in resistance to platinum-based chemotherapy, and high levels of ERCC1 mRNA in tumours have been associated with cisplatin resistance in different human cancers. The aim of this work was to investigate the correlation between DNA repair gene expression levels in tumour tissue, normal tissue and peripheral blood samples from patients with two common human cancers, non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (HNSCC), to test if blood gene expression could be a proxy for tumour tissue gene expression to predict response to platinum-based chemotherapy. METHODS Using RT-qPCR we determined ERCC1, ERCC2, ERCC4, XPA, XPC, XRCC1, XRCC3, APEX, OGG1, MGMT mRNA levels in fresh NSCLC, normal lung and HNSCC tissue, as well as blood, from NSCLC and HNSCC patients who were treated surgically. RESULTS Target gene expression in NSCLC and HNSCC tissue was higher than in blood. A statistically significant correlation (p<0.05) was found between target gene mRNA expression in tumour tissue and blood, in particular ERCC1, MGMT, XPC, XRCC1 and XRCC3 in NSCLC and APEX, ERCC1, ERCC2, ERCC4, XRCC1 and XRCC3 in HNSCC. CONCLUSIONS The existence of a significant correlation between blood and tumour tissue expression of some genes of clinical interest, such as ERCC1 in NSCLC and HNSCC, could allow the introduction in clinical practice of a simple test that would measure mRNA levels of DNA repair genes in peripheral blood samples instead of tissue samples to determine prognostic and predictive factors in NSCLC and HNSCC patients.

Postoperative Radiotherapy for Patients With Completely Resected Pathologic N2 Non-Small- Cell Lung Cancer: A Retrospective Analysis

BACKGROUND Adjuvant radiotherapy in non-small-cell lung cancer (NSCLC) is still controversial. The purpose of this retrospective study was to evaluate the role of postoperative radiotherapy (PORT) in terms of local control and survival in pathologic N2 NSCLC. PATIENTS AND METHODS From January 2003 to December 2008, 66 patients with pathologic N2 NSCLC received PORT. Mediastinal lymph node metastases were classified into single (12 patients) or multiple (54 patients) stations. All patients received conformal radiation therapy, with a median total dose of 50.4 Gy. Target volumes included the bronchial stump, ipsilateral hilum, all pathologically involved lymph node regions, and all the lymph nodes between 2 noncontiguous pathologic nodal stations. The pattern of failure was considered as locoregional or systemic, or a combination of both. Locoregional failure was defined as in field or out of field. RESULTS Median follow-up time was 34.9 months (range 3.5-62.8 months). Local control was 80% at 12 months, 77.2% at both 24 and 36 months, and 72.1% at 60 months. The pattern of failure was locoregional in 3 patients (1 out of field and 2 in field) and systemic in 25 patients, with 12 patients presenting both locoregional and distant disease. Overall survival at 12, 36, and 60 months was 77%, 44%, and 37%, respectively. Median survival time was 34 months. The number of pathologically involved lymph node stations was a prognostic factor for local control (P = .05), cancer-specific survival (CSS) (P = .04), and disease-free survival (DFS) (P = .04). CONCLUSION Despite the limitations of the present study, mainly represented by its retrospective nature, our data support the role of PORT in terms of locoregional control and overall survival benefit; the number of involved mediastinal lymph nodes represents a significant prognostic factor in patients with pathologic N2 NSCLC.

Gastric cancer: The times they are a-changin'.

Gastric cancer is the third leading cause of cancer death worldwide. Even though during these last decades gastric cancer incidence decreased in Western countries, it remains endemic and with a high incidence in Eastern countries. The survival in advanced and metastatic stage of gastric cancer is still very poor. Recently the Cancer Genoma Atlas Research Network identified four subtypes with different molecular profiles to classify gastric cancer in order to offer the optimal targeted therapies for pre-selected patients. Indeed, the key point is still the selection of patients for the right treatment, on basis of molecular tumor characterization. Since chemotherapy reached a plateau of efficacy for gastric cancer, the combination between cytotoxic therapy and biological agents gets a better prognosis and decreases chemotherapeutic toxicity. Currently, Trastuzumab in combination with platinum and fluorouracil is the only approved targeted therapy in the first line for c-erbB2 positive patients, whereas Ramucirumab is the only approved targeted agent for patients with metastatic gastric cancer. New perspectives for an effective treatment derived from the immunotherapeutic strategies. Here, we report an overview on gastric cancer treatments, with particular attention to recent advances in targeted therapies and in immunotherapeutic approach.

Surgery in cerebral metastases: are numbers so important?

BACKGROUND The prognosis of cerebral metastases (MTS) is linked to progression of both systemic and local disease. The importance of MTS resection has been already pointed out. The observation of a high mortality for not-neurological causes confirms that the modern treatments allow a significant control of the disease within the nervous system. Nevertheless, management difficulties increase with multiple lesions and in these cases the role of surgery has still to be defined. MATERIALS AND METHODS We collected the clinical data of patients operated in two centers for cerebral MTS from lung carcinoma during 8 years. Patient selection for surgery followed definite criteria; the limit for multiple MTS was three. We analyzed the functional and survival outcomes of the cohort. RESULTS AND CONCLUSIONS Our series included 242 patients: 105 had multiple MTS. Statistical analysis did not show significant differences in mean survival and outcomes between patients with single and multiple lesions. The decease occurred for neurological causes in 15.7% of cases. The selection of candidates for surgery requires several considerations and entails the success rate of this treatment. In patients with the multiple lesions who fulfilled the selection criteria we observed a nevertheless satisfying success after the operation. Our results imply that surgery may be applied also in selected patients with more diffuse intracranial disease. A pre-operative accurate patient selection is related to acceptable quality-of-life following the operation even in cases of multiple MTS.

Neoadjuvant chemo-radiotherapy for locally advanced esophageal cancer: a monocentric study

AIMS AND BACKGROUND Multimodal therapy is a keystone of care in advanced esophageal cancer. Although neoadjuvant chemoradiotherapy is known to provide a survival advantage in selected cases, reliable prognostic and response predictive factors remain elusive. We report the outcome in a series of esophageal cancer patients treated at our center and the results of a retrospective analysis of epidermal growth factor receptor (EGFR) expression and EGFR/HER2 gene copy numbers taken as possible prognostic and predictive factors. METHODS AND STUDY DESIGN Between 2001 and 2009, a total of 40 consecutive patients (34 men and 6 women; median age, 59 years) were treated for esophageal cancer. TREATMENT cisplatin, 80 mg/m² day 1, and 5-fluorouracil, 800 mg/m²/24 h on days 1-5, every 21 days, concomitant with 3D-conformal radiotherapy (54-59.4 in 30-33 fractions) for three up to four cycles. Surgery was performed in eligible patients 6-8 weeks after chemoradiation. EGFR expression and EGFR/HER2 amplification and gene copy number were studied by immunohistochemical analysis and fluorescence in situ hybridization, respectively. RESULTS Acceptable toxicity following chemoradiation was recorded, with G3-G4 hematological toxicity in 20% of patients and G3-G4 dysphagia in less than 10%; 14 (35%) patients achieved complete response and 19 (48%) partial response; 18 underwent surgery after chemoradiation, of which 8 (20%) achieved pathologic complete response. The median survival was 29 months (95% CI, 25.7-32.1): 42 months for the resected and 20 for the unresected patients. EGFR and HER2 analysis in 28 patients showed that 89% had immunohistochemical EGFR expression, with 5 cases of EGFR and 10 of HER2 gene gain without a significant difference in response rate and survival in these patient subgroups. CONCLUSIONS Our results suggest a better outcome in patients who underwent surgery after chemoradiation. A larger sample size is necessary to clarify the role of EGFR and HER2 gene gain in predict response and survival.

Is There Room for Second-Line Treatment of Pleural Malignant Mesothelioma?

Malignant pleural mesothelioma (MPM) is characterized by a bad prognosis and modest activity of systemic treatment. Currently, there is no clear agreement on the clinical role of second-line chemotherapy in patients with MPM; nevertheless, early case study reports including some pretreated patients had provided evidence that additional responses are possible with the use of further chemotherapy1 after the failure of firstline treatment. Unfortunately, the evidence supporting the efficacy of second-line treatment in this setting is globally weak. A randomized phase 3 trial, enrolling 243 patients, compared pemetrexed plus best supportive care vs best supportive care alone in patients previously treated with a first-line regimen not including pemetrexed. When this study was published, however, the use of pemetrexed in combination with cisplatin had been already accepted as standard first-line treatment. The study showed a statistically significant increase in objective response rate, disease control rate, and time to progression for pemetrexed, but without significant benefit in overall survival.2 Whether the benefit in other end points, in the absence of difference in survival, could be considered sufficient to recommend second-line pemetrexed for clinical practice is debatable. In any case, the trial recruited patients who were pemetrexed naive, which greatly reduces the current applicability of these results, with pemetrexed being part of first-line treatment in the majority of patients now. Can we consider the external validity of these results useful for clinical practice? Probably not. Even when we consider the shift from pemetrexed to other chemotherapy drugs, like vinorelbine, their use as second-line treatment is based on small, nonrandomized series. Following previous experience in the firstline setting,3 weekly vinorelbine was tested within a single-center phase 2 open-label study in 63 patients with previous exposure to chemotherapy. Like all the single-arm trials, the results obtained in this series of patients are at strong risk of being conditioned by selection bias: median interval between the end of the firstline chemotherapy and the start of the weekly secondline vinorelbine was 6 months, most patients had a good performance status, all were classified as low risk according to the European Organization for Research and Treatment of Cancer prognostic score, and median age of this highly selected population was 59 years. A total of 10 partial responses (16%) were observed, and a further 43 patients (68%) had stable disease defined as no evidence of progression for 6 months. Median overall survival was 9.6 months. However, can we trust in the reproducibility of these results in unselected patients, with a shorter treatment-free interval, older age, and worse performance status? Probably not. Similarly, rechallenge with platinum-pemetrexed chemotherapy is sometimes considered in patients who have obtained a long progression-free interval, but the evidence supporting this strategy is again weak. This strategy is probably more supported by the analogy with the rechallenge in other solid tumors where platinumbased therapy is used, rather than by data specifically produced in patients with MPM. In this specific setting, the rechallenge has been explored by Ceresoli et al,4 describing the outcome of patients who had obtained prolonged progression-free survival (PFS) (greater than 3 months) with the previous first-line treatment. Thirtyone patients were included in the study, but there was heterogeneity in the treatment adopted: 15 patients had a rechallenge with single-agent pemetrexed alone, while 16 had a real rechallenge with both drugs. One patient experienced a complete response, whereas a partial response was achieved in 5 patients, producing a modest overall objective response rate of 19%, and an overall disease control rate of 48%. Is this evidence sufficient to consider rechallenge with pemetrexed-based chemotherapy as a second-line treatment option in patients with MPM? Probably not. Considering this absence of robust evidence supporting the use of second-line treatment in clinical practice, what is the position of existing guidelines? National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines seem to support the use of secondline treatment. In fact, although specifying that limited data are available to guide the choice, NCCN guidelines state that “second-line chemotherapy options include pemetrexed (if not administered as first-line therapy), vinorelbine, or gemcitabine, and data suggest that rechallenging with pemetrexed is effective if patients had a good response to first-line pemetrexed.”5 Moving from the United States to Europe, current guidelines of the European Society of Medical Oncology, published in 2015, state that, given the absence of standard secondline or further-line therapy, it is recommended that patients who are in good clinical condition at disease progression after first-line treatment should be enrolled into clinical trials.6 There is no explicit recommendation for patients outside the opportunity of clinical trials, although the statement that “single agent vinorelbine has shown useful activity in phase II trials” implies that, although not standard, second-line treatment can be considered in clinical practice. Italian experts participating in the Third Italian Consensus Conference for MPM stated that, in patients progressing after a first-line pemetrexedbased regimen, there is no standard second-line therapy, and patients should be encouraged to participate in cliniVIEWPOINT