Preliminary efficacy of [90Y]DOTA-biotin-avidin radiotherapy against non-muscle invasive bladder cancer.

PURPOSE: Bladder cancer represents 3% of all new cancer diagnoses per year. We propose intravesical radionuclide therapy using the ß-emitter 90Y linked to DOTA-biotin-avidin ([90Y]DBA) to deliver short-range radiation against non-muscle invasive bladder cancer (NMIBC). MATERIAL AND METHODS: Image-guided biodistribution of intravesical DBA was investigated in an animal model by radiolabeling DBA with the 68Ga and dynamic microPET imaging following intravesical infusion of [68Ga]DBA for up to 4 h and post-necropsy γ-counting of organs. The antitumor activity of [90Y]DBA was investigated using an orthotopic MB49 murine bladder cancer model. Mice were injected with luciferase-expressing MB49 cells and treated via intravesical administration with 9.2 MBq of [90Y]DBA or unlabeled DBA 3 days after the tumor implantation. Bioluminescence imaging was conducted after tumor implantation to monitor the bladder tumor growth. In addition, we investigated the effects of [90Y]DBA radiation on urothelial histology with immunohistochemistry analysis of bladder morphology. RESULTS: Our results demonstrated that DBA is contained in the bladder for up to 4 h after intravesical infusion. A single dose of [90Y]DBA radiation treatment significantly reduced growth of MB49 bladder carcinoma. Attaching 90Y-DOTA-biotin to avidin prevents its re-absorption into the blood and distribution throughout the rest of the body. Furthermore, immunohistochemistry demonstrated that [90Y]DBA radiation treatment did not cause short-term damage to urothelium at day 10, which appeared similar to the normal urothelium of healthy mice. CONCLUSION: Our data demonstrates the potential of intravesical [90Y]DBA as a treatment for non-muscle invasive bladder cancer.

50 Patients with Malignant Mesothelioma of Both the Pleura and Peritoneum: A Single-Institution Experience.

BACKGROUND: The most common sites of malignant mesothelioma are the pleura and peritoneum, but little is known about the incidence, prognosis, or treatment of patients with disease in both cavities. Previous series suggest that multimodality treatment improves overall survival for pleural or peritoneal disease, but studies typically exclude patients with disease in both cavities. Despite limitations, this investigation is the only study to broadly examine outcomes for patients with malignant mesothelioma in both the pleural and peritoneal cavities. METHODS: This study retrospectively examined 50 patients with both pleural and peritoneal mesothelioma treated with the intent to prolong survival. The primary end point was overall survival from the initial operative intervention. RESULTS: The median overall survival was 33.9 months from the initial intervention. Female gender and intraperitoneal dwell chemotherapy were independent predictors of overall survival. Within 1 year after the initial diagnosis, second-cavity disease was diagnosed in 52% of the patients. The median time to the second-cavity diagnosis for those with a diagnosis 1 year after the initial diagnosis was 30 months. CONCLUSIONS: Well-selected patients with both pleural and peritoneal mesothelioma have a survival benefit over palliative treatment that is comparable with that seen in single-cavity disease. The presence of disease in both cavities is not a contraindication to multimodality treatment aimed at prolonging survival, whether the disease is diagnosed synchronously or metachronously. Patients with an initial diagnosis of single cavity disease are at the highest risk for identification of second-cavity disease within the first year after diagnosis.

Two-Stage Cytoreductive Surgery and Intraperitoneal Chemotherapy for Diffuse Malignant Peritoneal Mesothelioma: Predictors of Overall Survival in an Intention-to-Treat Series.

PURPOSE: Cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy is standard of care for diffuse malignant peritoneal mesothelioma (DMPM), but there is variability among institutions in the administration of adjuvant chemotherapy. Characterization of the largest series of DMPM patients treated at a single institution and identification of the demographic, disease, and treatment factors associated with overall survival were sought. PATIENTS AND METHODS: All DMPM patients who underwent initial cytoreductive surgery with the intention to undergo intraperitoneal chemotherapy and a second-look operation from 1995 to 2016 at our institution were retrospectively reviewed. The primary endpoint was overall survival. RESULTS: A total of 204 DMPM patients underwent initial cytoreduction. Median overall survival was 32 months from initial cytoreduction. Independent baseline prognostic factors of improved overall survival were female sex, age < 60 years, and epithelioid histology. Independent treatment factors associated with improved overall survival were attempted resection at initial operation, residual disease < 0.5 cm at the end of the initial operation, and dwell intraperitoneal chemotherapy. CONCLUSIONS: Cytoreductive surgery with intraoperative and dwell intraperitoneal chemotherapy is a feasible approach for DMPM. Expanded access to these therapies may offer benefit to a larger population of patients. Demographic and operative parameters associated with overall survival in this large cohort are consistent with previous reports. In the context of this treatment protocol, dwell intraperitoneal chemotherapy is associated with longer overall survival.

Recurrence of Optimally Treated Malignant Peritoneal Mesothelioma with Cytoreduction and Heated Intraperitoneal Chemotherapy.

BACKGROUND: The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients. METHODS: We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan-Meier method. RESULTS: Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16-3.38). CONCLUSIONS: Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.

PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma.

Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.

Approach to offering remote support to mesothelioma patients: the mesothelioma survivor project.

BACKGROUND: From the moment of diagnosis, malignant mesothelioma (MM) decreases health-related quality of life (QOL) in patients and their caregivers. In addition to symptoms of disease, aggressive treatments such as surgery, radiation, and chemotherapy can cause extreme side effects-chemotherapy specifically is associated with chronic fatigue, unremitting nausea, vomiting, and systemic pain. These side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care. METHODS: The platform for the support group was remote, consisting of online and telephone domains. Participants would utilize both online and phone systems during sessions held once a week for a total of six weeks. Sessions were guided and kept closed, available only to those affected by mesothelioma. Follow-up information and session summaries were provided online after support meetings. RESULTS: Using a 0-5 Likert Scale, consistent attendees reported support groups as very helpful. Irregular attendees had mixed feelings ranging from extremely helpful to neutral. Eighty per cent of attendees participated in support groups prior to this project. CONCLUSIONS: Active participation in a guided and closed support group allowed participants to share their experiences and concerns about their diagnoses comfortably, supporting transition beyond active-treatment. Online space gave participants a place to provide more reflective responses outside the main dialogue of support sessions.

Genome-wide analysis of abdominal and pleural malignant mesothelioma with DNA arrays reveals both common and distinct regions of copy number alteration.

Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosal cavities. Pleural space is the most common site, accounting for about 80% of cases, while peritoneum makes up the majority of the remaining 20%. While histologically similar, tumors from these sites are epidemiologically and clinically distinct and their attribution to asbestos exposure differs. We compared DNA array-based findings from 48 epithelioid peritoneal MMs and 41 epithelioid pleural MMs to identify similarities and differences in copy number alterations (CNAs). Losses in 3p (BAP1 gene), 9p (CDKN2A) and 22q (NF2) were seen in tumors from both tumor sites, although CDKN2A and NF2 losses were seen at a higher rate in pleural disease (p<0.01). Overall, regions of copy number gain were more common in peritoneal MM, whereas losses were more common in pleural MM, with regions of loss containing known tumor suppressor genes and regions of gain encompassing genes encoding receptor tyrosine kinase pathway members. Cases with known asbestos causation (n = 32 ) were compared with those linked to radiation exposure (n = 9 ). Deletions in 6q, 14q, 17p and 22q, and gain of 17q were seen in asbestos-associated but not radiation-related cases. As reported in post-radiation sarcoma, gains outnumbered losses in radiation-associated MM. The patterns of genomic imbalances suggest overlapping and distinct molecular pathways in MM of the pleura and peritoneum, and that differences in causation (i.e., asbestos vs. radiation) may account for some of these site-dependent differences.

Prognostic significance of morphological growth patterns and mitotic index of epithelioid malignant peritoneal mesothelioma.

AIMS: The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has been recently reported, but similar data are lacking for peritoneal mesotheliomas. The aim of this study was to investigate possible relationships between histological growth patterns of epithelioid peritoneal mesotheliomas, clinicopathological features, and patient outcome. METHODS AND RESULTS: Eighty-four cases of chemotherapy-naive epithelioid peritoneal mesothelioma were classified into tubulopapillary, micropapillary, papillary, tubular, solid and trabecular growth patterns. Pathological features such as depth of invasion, lymphocytic host response, mitotic count, nuclear grade, lymphovascular invasion, lymph node metastasis and stromal desmoplasia were analysed. The most common histological patterns were solid (n = 37, 44%), tubulopapillary (n = 24, 29%), and micropapillary (n = 11, 13%). The overall median survival was 36 months. Patients with solid mesothelioma had shorter overall survival (median, 29 months) than patients with tubulopapillary and micropapillary growth patterns (median, 51 and 53 months, respectively; P = 0.053). A high mitotic index (>5 in 50 high-power fields) was found to be associated with poor survival (P < 0.03). A moderate to severe lymphocytic host response was associated with longer median survival (P = 0.13). CONCLUSIONS: Our study highlights the prognostic importance of the solid growth pattern among diffuse epithelioid peritoneal mesotheliomas, and reaffirms mitotic index as a predictor of overall survival.

Clinical utility of 18F-FDG positron emission tomography in malignant peritoneal mesothelioma.

BACKGROUND: The purpose of this study was to determine the utility of 18F-FDG-PET for evaluating the presence and the extent of malignant peritoneal mesothelioma (MPM), for disease surveillance/recurrence detection and for evaluating response to therapy. METHODS: We retrospectively analyzed clinical and imaging data of 60 MPM patients (34 women and 26 men, mean age 53.6 y, range 18-80 y) who had multiple 18F-FDG-PET/CT or PET scans (18F-FDG scans) at various stages of the disease. RESULTS: Eleven patients had baseline pretreatment scans and all 11 scans showed 18F-FDG avid diffuse, nodular or mixed disease distribution patterns characteristic of MPM. Four patients out of eleven had an early post-treatment 18F-FDG scan (<6 months) and all scans were accurate in determining response to treatment. Forty-nine patients with a history of treated MPM without baseline scans had multiple disease surveillance 18F-FDG scans. Their initial 18F-FDG scans had an accuracy of 82% and positive predictive value of 83% and negative predictive value of 80% for the detection of disease presence and disease-free state, respectively. For fifteen patients with a true negative 18F-FDG scan, a second follow-up scan accurately detected disease recurrence or absence of recurrence in all cases. Metastatic or remote nodal disease was more common in the biphasic histopathologic subtype group while pleural disease was predominantly seen in the epithelial MPM group. No relationship was found between the uptake pattern and the histopathologic subtype. CONCLUSION: 18F-FDG-PET is a valuable imaging modality in the pre-surgical evaluation and management of MPM and further prospective studies are warranted.

Quantitative X-ray computed tomography peritoneography in malignant peritoneal mesothelioma patients receiving intraperitoneal chemotherapy.

BACKGROUND: Intraperitoneal chemotherapy is used to treat peritoneal surface-spreading malignancies. We sought to determine whether volume and surface area of the intraperitoneal chemotherapy compartments are associated with overall survival and posttreatment glomerular filtration rate (GFR) in malignant peritoneal mesothelioma (MPM) patients. METHODS: Thirty-eight MPM patients underwent X-ray computed tomography peritoneograms during outpatient intraperitoneal chemotherapy. We calculated volume and surface area of contrast-filled compartments by semiautomated computer algorithm. We tested whether these were associated with overall survival and posttreatment GFR. RESULTS: Decreased likelihood of mortality was associated with larger surface areas (p = 0.0201) and smaller contrast-filled compartment volumes (p = 0.0341), controlling for age, sex, histologic subtype, and presence of residual disease >0.5 cm postoperatively. Larger volumes were associated with higher posttreatment GFR, controlling for pretreatment GFR, body surface area, surface area, and the interaction between body surface area and volume (p = 0.0167). DISCUSSION: Computed tomography peritoneography is an appropriate modality to assess for maldistribution of intraperitoneal chemotherapy. In addition to identifying catheter failure and frank loculation, quantitative analysis of the contrast-filled compartment's surface area and volume may predict overall survival and cisplatin-induced nephrotoxicity. Prospective studies should be undertaken to confirm and extend these findings to other diseases, including advanced ovarian carcinoma.

Body surface area predicts plasma oxaliplatin and pharmacokinetic advantage in hyperthermic intraoperative intraperitoneal chemotherapy.

BACKGROUND: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface-spreading malignancies to maximize local drug concentrations while minimizing systemic effects. The pharmacokinetic advantage of HIPEC is defined as the intraperitoneal to intravascular ratio of drug concentrations. We hypothesized that body surface area (BSA) would correlate with the pharmacokinetic advantage of HIPEC. Because oxaliplatin is administered in 5 % dextrose, we hypothesized that BSA would correlate with glycemia. METHODS: We collected blood and peritoneal perfusate samples from ten patients undergoing HIPEC with a BSA-based dose of 250 mg/m(2) oxaliplatin, and measured drug concentrations by inductively coupled plasma mass spectrophotometry. We monitored blood glucose for 24 h postoperatively. Areas under concentration-time curves (AUC) were calculated by trapezoidal rule. Pharmacokinetic advantage was calculated by (AUC[peritoneal fluid]/AUC[plasma]). We used linear regression to test for statistical significance. RESULTS: Higher BSA was associated with lower plasma oxaliplatin AUC (p = 0.0075) and with a greater pharmacokinetic advantage (p = 0.0198) over the 60-minute duration of HIPEC. No statistically significant relationships were found between BSA and blood glucose AUC or peak blood glucose levels. CONCLUSIONS: Higher BSA is correlated with lower plasma drug levels and greater pharmacokinetic advantage in HIPEC, likely because of increased circulating blood volume with inadequate time for equilibration. Plasma glucose levels after oxaliplatin HIPEC were not clearly related to BSA.

A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma.

INTRODUCTION: Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM. METHODS: Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months. RESULTS: 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients. CONCLUSION: This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.

Utility of glucose transporter 1 in the distinction of benign and malignant thoracic and abdominal mesothelial lesions.

CONTEXT: Malignant mesothelioma, of either peritoneum or pleura, is an uncommon cancer. The diagnosis is often difficult to make, in part because of the overlapping morphology of reactive and malignant mesothelial cells. Glucose transporter 1 (GLUT-1) is a glucose transporter typically found on erythrocytes, which is aberrantly expressed in various carcinomas. It has recently been reported as specific and sensitive in discriminating malignant pleural mesothelioma from reactive hyperplasia. The application of GLUT-1 staining in peritoneal mesothelioma has not been fully explored. OBJECTIVE: To determine if GLUT-1 staining is helpful in distinguishing abdominal mesotheliomas from benign, reactive mesothelial lesions and to further study its utility in the thorax. DESIGN: Tissue microarrays containing 135 abdominal malignant mesotheliomas and 30 malignant pleural mesotheliomas were stained with an antibody to GLUT-1, as were 56 reactive mesothelial lesions. RESULTS: The overall sensitivity and specificity for GLUT-1 in mesothelioma was 53% and 98%, respectively. The sensitivity in epithelioid malignant mesothelioma was 49% and in sarcomatoid/biphasic malignant mesothelioma, 66%. In the thorax, the sensitivity was 50% and in the abdomen it was 54%. The positive predictive value of GLUT-1 immunoreactivity was 98% and the negative predictive value was 40%. CONCLUSION: Glucose transporter 1 staining of thoracic mesotheliomas showed high specificity but lower sensitivity than previously reported. Abdominal malignant mesotheliomas showed similar results. Because of low sensitivity, only positive staining is informative. In both sites, the utility of the stain was limited by nonspecific staining (eg, in necrotic areas) as well as bright labeling of erythrocytes and occasional lymphoid elements. Despite these limitations, GLUT-1 can help differentiate malignant mesothelioma from reactive benign mesothelium.

PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma.

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation-based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.

Adjuvant chemotherapy in 2011 for patients with soft-tissue sarcoma.

The mainstay of treatment for adults with soft-tissue sarcomas is wide surgical excision. Half of all patients with adequate local control of high-grade sarcomas develop distant metastases and, despite additional treatment, ultimately die from their disease. This daunting reality has resulted in a three-decade research effort to assess the efficacy of adjuvant therapy for adult soft-tissue sarcomas. The multitude of histopathological subtypes, each with its own biology and clinical behavior, and the rarity of adult soft-tissue sarcomas as a whole greatly complicate such an assessment. This Perspectives article examines data that support or refute the use of adjuvant chemotherapy in the treatment of soft-tissue sarcomas.

Phase II Study of Temozolomide and Thalidomide in Patients with Unresectable or Metastatic Leiomyosarcoma.

We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m(2)/day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7-28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.

Combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for the treatment of malignant peritoneal mesothelioma.

OBJECTIVE: We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma. METHODS: Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41 degrees C, and finally whole abdominal radiotherapy. RESULTS: The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%-81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4-71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71-110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70-106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity. CONCLUSION: Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.

Phase II trial of pemetrexed and gemcitabine in chemotherapy-naive malignant pleural mesothelioma.

PURPOSE: Pemetrexed and gemcitabine have single-agent activity in malignant pleural mesothelioma (MPM). The combination of pemetrexed/gemcitabine has not previously been studied in MPM to our knowledge. PATIENTS AND METHODS: Patients with histologic or cytologic diagnosis of MPM were included. Cohort 1 received gemcitabine 1,250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) on day 8, and cohort 2 received gemcitabine 1,250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) on day 1. Cycles were repeated every 21 days; all patients were supplemented with folic acid and vitamin B(12) and received dexamethasone. RESULTS: One hundred eight patients (cohort 1, n = 56; cohort 2, n = 52) with pleural mesothelioma were enrolled. Among assessable patients, response rate was 26.0% in cohort 1 and 17.1% in cohort 2. Median time to disease progression was 4.34 months for cohort 1 and 7.43 months for cohort 2. Median survival was 8.08 months for cohort 1 (1-year survival = 31.14%) and 10.12 months for cohort 2 (1-year survival = 45.80%). In cohorts 1 and 2, incidence of grade 4 neutropenia was 25.0% and 29.4%, grade 4 thrombocytopenia was 14.3% and 3.9%, grade 3 or 4 anemia was 5.4% and 5.9%, and grade 3 or 4 fatigue was 23.2% and 15.7%, respectively. CONCLUSION: The combination of pemetrexed and gemcitabine resulted in moderate clinical activity in MPM. However, the median survival times are similar to those with single-agent pemetrexed and inferior to outcomes observed with cisplatin in combination with an antifolate.