Influence of radiotherapy technique and dose on patterns of failure for mesothelioma patients after extrapleural pneumonectomy

PURPOSE: Extrapleural pneumonectomy (EPP) is an effective treatment of malignant pleural mesothelioma. We compared the outcomes after moderate-dose hemithoracic radiotherapy (MDRT) and high-dose hemithoracic RT (HDRT) after EPP for malignant pleural mesothelioma. METHODS AND MATERIALS: Between July 1994 and April 2004, 39 patients underwent EPP and adjuvant RT at Dana-Farber Cancer Institute/Brigham and Women's Hospital. Between 1994 and 2002, MDRT, including 30 Gy to the hemithorax, 40 Gy to the mediastinum, and boosts to positive margins or nodes to 54 Gy, was given, generally with concurrent chemotherapy. In 2003, HDRT to 54 Gy with a matched photon/electron technique was given, with sequential chemotherapy. RESULTS: A total of 39 patients underwent RT after EPP. The median age was 59 years (range, 44-77). The histologic type was epithelial in 25 patients (64%) and mixed or sarcomatoid in 14 patients (36%). Of the 39 patients, 24 underwent MDRT and 15 (39%) HDRT. The median follow-up was 23 months (range, 6-71). The median overall survival was 19 months (95% confidence interval, 14-24). The median time to distant failure (DF) and local failure (LF) was 20 months (95% confidence interval, 14-26) and 26 months (95% confidence interval, 16-36), respectively. On univariate and multivariate analyses, only a mixed histologic type was predictive of inferior DF (p <0.006) and overall survival (p <0.004). The RT technique was not predictive of LF, DF, or overall survival. The LF rate was 50% (12 of 24) after MDRT and 27% (4 of 15) after HDRT (p = NS). Four patients who had undergone HDRT were alive and without evidence of disease at the last follow-up. CONCLUSIONS: High-dose hemithoracic RT appears to limit in-field LF compared with MDRT. However, DF remains a significant challenge, with one-half of our patients experiencing DF.     

Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.

PURPOSE: To investigate neoadjuvant chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy with or without radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had MPM with clinical stage T1-3, N0-2, M0 disease considered to be completely resectable and a WHO performance status of 0 to 2. Neoadjuvant chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1 and gemcitabine 1,000 mg/m2 on days 1, 8, and 15, given every 28 days. Surgery had to consist of a complete extrapleural pneumonectomy, including resection of pericardium and diaphragm. Postoperative radiotherapy was to be considered for all patients. RESULTS: Nineteen patients with MPM were included in this pilot study. According to the European Organization for Research and Treatment of Cancer prognostic score, two patients were in the good prognosis group, and 17 patients were in the poor prognosis group. The response rate to neoadjuvant chemotherapy was 32%. The major toxicity was thrombocytopenia. Extrapleural pneumonectomy was performed in 16 patients with no perioperative mortality. Major surgical complications occurred in six patients, and all were treated successfully. Thirteen patients received postoperative radiotherapy. The median survival time was 23 months. Two patients remain alive and free of disease 41 and 38 months after initiation of therapy. CONCLUSION: For patients with potentially operable MPM, the availability of active and well-tolerated chemotherapy regimens, the fact that extrapleural pneumonectomy can be safely performed after neoadjuvant chemotherapy in an experienced center, and the promising results regarding survival in our pilot study warrant further investigation of the role of neoadjuvant chemotherapy in a multimodality strategy.     

Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.

BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.     

Considerations for post-operative radiotherapy to the hemithorax following extrapleural pneumonectomy in malignant pleural mesothelioma

With growing interest in evaluating extrapleural pneumonectomy (EPP) and post-operative in selected patients with early stage malignant pleural mesothelioma, it is essential that clinical trials should be conducted using a clear and reproducible radiotherapy protocol. The considerations which have determined the policy of radiotherapy planning and treatment delivery for patients with mesothelioma in The Netherlands are given. As well as general considerations such as patient selection, target volume and critical organ delineation, a dose-fractionation scheme, constraints relating to normal tissue, treatment planning, the type of external beam equipment, treatment verification and radiation toxicity and scoring are all taken into account.     

Safety and efficacy of resistance training in germ cell cancer patients undergoing chemotherapy: a randomized controlled trial

Background:

Bleomycin–etoposid–cisplatin (BEP) chemotherapy is curative in most patients with disseminated germ cell cancer (GCC) but also associated with toxic actions and dysfunction in non-targeted tissues. We investigated changes in muscle function during BEP and the safety and efficacy of resistance training to modulate these changes.

Methods:

Thirty GCC patients were randomly assigned to resistance training (resistance training group (INT), n=15) or usual care (CON, n=15) during 9 weeks of BEP therapy. Resistance training consisted of thrice weekly sessions of four exercises, 3–4 sets/exercise of 10–15 repetitions at 12–15 repetition maximum load. The primary endpoint was muscle fibre size, assessed in muscle biopsies from musculus vastus lateralis. Secondary endpoints were fibre phenotype composition, body composition, strength, blood biochemistry and patient-reported endpoints. Healthy age-matched subjects (REF, n=19) performed the same RT-programme for comparison purposes.

Results:

Muscle fibre size decreased by −322 μm² (95% confidence interval (CI): −899 to 255; P=0.473) in the CON-group and increased by +206 μm² (95% CI: −384 to 796; P=0.257) in the INT-group (adjusted mean difference (AMD), +625 μm², 95% CI: −253 to 1503, P=0.149). Mean differences in type II fibre size (AMD, +823 μm², P=0.09) and lean mass (AMD, +1.49 kg, P=0.07) in favour of the INT-group approached significance. The REF-group improved all muscular endpoints and had significantly superior changes compared with the INT-group (P<0.05).

Conclusions:

BEP was associated with significant reduction in lean mass and strength and trends toward unfavourable changes in muscle fibre size and phenotype composition. Resistance training was safe and attenuated dysfunction in selected endpoints, but BEP blunted several positive adaptations observed in healthy controls. Thus, our study does not support the general application of resistance training in this setting but larger-scaled trials are required to confirm this finding.     

Prognostic values of preoperative C-reactive protein,albumin, and neutrophil ratios in patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy

IntroductionA preoperative validation system for predicting the clinical outcome of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is required, as EPP for MPM is one of the most invasive operation types. Recently, several inflammatory and nutritional parameters, such as C-reactive protein (CRP) and albumin, have been re-focused on as useful prognostic factors for several types of cancer; however, few of these reports involved MPM.MethodsAs a retrospective study, clinicopathological characteristics and preoperative inflammatory and nutritional parameters were calculated in consecutive patients with MPM who underwent EPP. The prognostic value of the variables was examined using Cox regression, and the candidate preoperative parameters were entered into a multivariate model to determine their independent effects.ResultsOf the 61 eligible cases, the CRP/albumin ratio (CAR) was associated with histology, and the CRP index multiplied by the neutrophil ratio (C-NR index) was associated with histology and pathological stage. Patients with CAR >0.125 had a significantly poor survival outcome, and patients with a C-NR index >0.58 also had a significantly poor prognosis. Multivariate analysis showed that age, histology, CRP, albumin, CAR, and C-NR index were independent predictors of 5-year overall survival.ConclusionOur results demonstrated that the CAR and C-NR indices are promising preoperative predictive parameters for the clinical outcomes of EPP in patients with MPM.     

Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series

Background and purpose

To evaluate survival, locoregional control and toxicity in a series of 56 mesothelioma patients treated from May 2005 to May 2010 with post-operative radiotherapy after extrapleural pneumonectomy (EPP) in three Italian Institutions (Brescia, Florence, and Modena).

Material and methods

Fifty-six patients treated with adjuvant radiotherapy (RT) after EPP were analyzed. Four patients were treated with 3DCRT, 50 with IMRT and two with helical tomotherapy. Forty-five to 50 Gy in 25 fractions were given to the affected hemithorax and to ipsilateral mediastinum, with a simultaneous integrated boost to the sites of microscopically involved margins up to 60 Gy in 20/56 cases.

Results

Three year locoregional control (LRC), distant metastasis free (DMF), disease free (DF), disease specific (DSS) and overall survival (OS) rates are 90%, 66%, 57%, 62%, and 60%, respectively.

Conclusion

Postoperative RT with modern techniques is an effective method to obtain excellent local control and cure rates in mesothelioma patients submitted to EPP.     

Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation

PURPOSE: New insight into the extent of the target volume for the postoperative irradiation of malignant pleural mesothelioma as determined during surgery has indicated that standard conformal radiotherapy (IMRT) is not sufficient for curative treatment. We describe a novel technique for implementing intensity-modulated radiotherapy (IMRT) to deliver higher doses to treat the full extent of these complex target volumes. METHODS AND MATERIALS: After extrapleural pneumonectomy, 7 patients underwent simulation, treatment planning, and treatment with IMRT to the involved hemithorax and adjacent abdomen. The target volumes encompassed the entire operative bed, including the ipsilateral mediastinum, anterior pleural reflection, and ipsilateral pericardium and the insertion of the diaphragm and crura. These were extensively marked during surgery with radiopaque markers to facilitate target delineation. RESULTS: Setup uncertainty and respiratory-dependent motion were found to be small. Coverage of the planning target volume was very good, with the crus of the diaphragm the most difficult volume to irradiate. The radiation doses to normal structures were acceptable. CONCLUSION: IMRT for treatment of malignant mesothelioma after extrapleural pneumonectomy results in more potentially curative doses to large, complex target volumes with acceptable doses to normal tissues.     

Safety and efficacy of primary thromboprophylaxis in cancer patients

Cancer is often complicated by venous thromboembolism (VTE), a common and potentially fatal complication associated with poor prognosis in these patients. An increased incidence of VTE is being observed due to the advanced age of cancer patients, the thrombogenic effect of novel drugs and advances in the diagnosis of related complications. In this review, we look at five different risk groups of cancer patients with an increased probability of developing VTE, including hospitalized patients undergoing chemotherapy, patients undergoing a surgical procedure, ambulatory patients undergoing chemotherapy, patients with a central venous access and patients receiving antiangiogenic drugs or anticoagulant therapy due to previous chronic diseases. The aim of this review is to summarize the most important clinical evidence reported to date on the suitability of primary thromboprophylaxis to cancer patients. Recommendations have drawn up for each group based on current evidence and guidelines to facilitate decision-making in clinical practice.     

Safety and efficacy of radionuclide therapy with high-activity In-111 pentetreotide in patients with progressive neuroendocrine tumors

The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2-24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2-24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.     

Miliary mesothelioma: a new clinical and radiological presentation in mesothelioma patients with prolonged survival after trimodality therapy

Malignant pleural mesothelioma is usually a fatal disease and is considered a locally aggressive tumor. Consequently, distant metastases are very rare and a diffuse involvement of the lung is seldom reported. However, due to more efficient chemotherapy protocols and aggressive management strategies including induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation therapy, so called trimodality therapy, survival is prolonged in selected patients. Therefore, new presentations of the disease are appearing with new diagnostic and therapeutic challenges. Herein, we report two cases of treated mesothelioma patients who developed a miliary mesothelioma in the remaining lung 36 and 41 months after undergoing multimodal therapy. Diagnostic assessment and therapeutic strategy are discussed taking into account the different evolutions of each patient.     

Natural cytotoxicity in patients undergoing radiation therapy

Natural cytotoxicity against K562 target cells was measured in 51 adults with solid epithelial malignant tumors who were untreated, in 42 patients who were studied within 6 weeks following completion of radiotherapy (4,000-7,000 rads), and in 27 normal subjects. In both the radiated and the nonirradiated groups, mean cytotoxicity for patients with localized cancers was not significantly different from that of the normal controls, whereas mean cytotoxicity for patients with advanced cancers was significantly lower than that for normal controls and patients with localized disease. Twelve percent of nonirradiated patients and 13% of radiated patients with localized tumors, but 46% of nonirradiated patients and 44% of irradiated patients with advanced cancers, failed to exhibit normal NK activity. Mean cytotoxicity for irradiated patients was not significantly different from that of untreated patients. PBL from most patients showed enhanced cytotoxicity after preincubation of PBL with interferon (IFN alpha). Mean cytotoxicities for nonirradiated and irradiated patients after IFN alpha pretreatment of PBL were not significantly different. In both patient groups, IFN alpha-boosted killing was significantly less in patients with advanced disease than in patients with local tumors or normals. These results indicated that radiotherapy has no significant effect on spontaneous or IFN alpha-boosted natural cytotoxicity.     

The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer.

The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.     

Safety and efficacy of long-term oral anticoagulation in cancer patients

The course of long-term oral anticoagulation in 25 patients (186 patient-months) with cancer managed in an outpatient anticoagulation clinic was analyzed to determine the frequency of complications. Major and minor hemorrhagic complications occurred in 10.7% and 32% of treatment courses, respectively, for an incidence of 1.6% and 4.8%, respectively, per patient-month. Recurrent thromboembolism occurred in 14% of treatment courses. These results are better than previous reports in the literature, but worse than our overall anticoagulation clinic experience. Patients with cancer requiring anticoagulation are at a higher risk of hemorrhagic and thrombotic complications. Accordingly, we recommend that such patients be monitored closely, preferably by physicians experienced with such therapy, as in an anticoagulation clinic, to avoid an excessive degree of morbidity.     

Safety of bevacizumab in metastatic breast cancer patients undergoing surgery

BackgroundEvaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials.Patients and methodsThe incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6 weeks before elective surgery and to wait 28 days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy.ResultsIn AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n = 46, 2.2%), bevacizumab 7.5 mg/kg (n = 57, 1.8%) and bevacizumab 15 mg/kg (n = 52, 1.9%). Incidence of grade 3–4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively.ConclusionsSurgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to.