Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress.

Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer 1 (BRCA1) and p53 binding protein 1 (53BP1). This ubiquitin signaling regulates pathway choice for repair of DNA double-strand breaks (DSB), toxic lesions whose frequency increases during tumorigenesis. Recruitment of 53BP1 curbs DNA end resection, thereby limiting homologous recombination (HR) and directing DSB repair toward error-prone non-homologous end joining (NHEJ). Under cancer-associated ubiquitin starvation conditions reflecting endogenous or treatment-evoked proteotoxic stress, the ubiquitin-dependent accrual of 53BP1 and BRCA1 at the DNA damage sites is attenuated or lost. Challenging this current paradigm, here we identified diverse human cancer cell lines that display 53BP1 recruitment to DSB sites even under proteasome inhibitor-induced proteotoxic stress, that is, under substantial depletion of free ubiquitin. We show that central to this unexpected phenotype is overabundance of RNF168 that enables more efficient exploitation of the residual-free ubiquitin. Cells with elevated RNF168 are more resistant to combined treatment by ionizing radiation and proteasome inhibition, suggesting that such aberrant RNF168-mediated signaling might reflect adaptation to chronic proteotoxic and genotoxic stresses experienced by tumor cells. Moreover, the overabundant RNF168 and the ensuing unorthodox recruitment patterns of 53BP1, RIF1 and REV7 (monitored on laser micro-irradiation-induced DNA damage) shift the DSB repair balance from HR toward NHEJ, a scenario accompanied by enhanced chromosomal instability/micronuclei formation and sensitivity under replication stress-inducing treatments with camptothecin or poly(ADP-ribose) polymerase (PARP) inhibitor. Overall, our data suggest that the deregulated RNF168/53BP1 pathway could promote tumorigenesis by selecting for a more robust, better stress-adapted cancer cell phenotype, through altered DNA repair, fueling genomic instability and tumor heterogeneity. Apart from providing insights into cancer (patho)biology, the elevated RNF168, documented here also by immunohistochemistry on human clinical tumor specimens, may impact responses to standard-of-care and some emerging targeted cancer therapies.

Esophageal carcinoma advances in treatment results for locally advanced disease: review.

The treatment results of patients with locally advanced esophageal carcinomas have evolved since the publication of the first trial of concurrent mitomycin C and 5-fluorouracil with radiotherapy (RT) in 1983. Subsequent studies refined and improved on the concurrent chemotherapy (chemo) with administration of cisplatin and 5-fluorouracil infusion (PF). Chemo (PF) before surgery improved overall survival (OS) in those patients in most of the randomized trials and in meta-analyses. Two courses of PF concurrent with irradiation followed by additional two courses of PF were superior to RT alone without surgery for both groups. Concurrent chemoradiotherapy followed by surgery was found to have statistically improved OS as compared with surgery only in randomized trials and meta-analyses. In most of these studies, it was found that those patients with pathologic complete response to the initial treatment(s) did better than those who had no improvement at all. Current treatment outcome for these diseases is disappointing; newer strategies including induction chemo with the optimal combination, proper dosage of each drug, and proper number of courses before concurrent chemoradiotherapy; improvement in RT; and immunotherapy with or without subsequent surgery are exciting and definitely need to be investigated in prospective randomized trial(s).

A multi-analyte serum test for the detection of non-small cell lung cancer.

BACKGROUND: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. METHODS: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. RESULTS: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. CONCLUSIONS: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various 'high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions.

A 74-year-old man with an enlarging pleural-based mass that was not a mesothelioma.

Soft tissue sarcomas of the chest wall, also known as primary malignant mesenchymal tumors, may be mistaken for a malignant mesothelioma because of their histologic similarities. Reports of primary pleural sarcomas are exceedingly uncommon. We present an unusual case of a primary pleural sarcoma with unique clinical and histological features not previously seen in any other subtype of pulmonary sarcoma.

A phase I/II trial of induction chemotherapy with carboplatin and gemcitabine followed by concurrent vinorelbine and paclitaxel with chest radiation in patients with stage III non-small cell lung cancer.

PURPOSE: We designed a phase I/II trial in order to evaluate the efficacy and tolerability of induction carboplatin and gemcitabine and the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of subsequent chemoradiotherapy with weekly vinorelbine and paclitaxel in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients had pathologically confirmed N2-N3 stage NSCLC, adequate end-organ function, and ECOG performance status 0-2. Carboplatin was administered at an AUC of 5 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days, for two cycles, followed by weekly vinorelbine 10-15 mg/m2 and paclitaxel 50 mg/m2 and conventional chest radiotherapy up to 66 Gy. Patients with resectable disease underwent thoracotomy after 40-45 Gy. RESULTS: Thirty-nine eligible patients were enrolled; 17 had stage IIIB NSCLC. Grade 3 esophagitis developed in 4/5 patients on the second dose level of chemoradiotherapy (i.e. vinorelbine 15 mg/m2) and was considered dose-limiting. Of 34 patients treated at the maximum tolerated dose (i.e. vinorelbine 10 mg/m2), 2 patients (6%) had pneumonitis >grade 2 and 3 (9%), esophagitis >grade 2. Induction chemotherapy was well tolerated with only one patient developing >grade 2 non-hematologic toxicity (nausea). Forty-one percent of patients had an objective response after induction chemotherapy and 51% after chemoradiotherapy. Nineteen patients, 16 of whom had stage IIIA, underwent surgical resection. The pathologic complete response rate was 16% (42% in the mediastinal lymph nodes). With a median follow-up of 31 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 23 and 34%, respectively, and the median OS was 25 months. CONCLUSIONS: We identified a well-tolerated and active chemoradiotherapy regimen. Survival results are promising and the addition of a biologic agent to this regimen is of interest.

Critical factors for patient management.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer.

BACKGROUND: Lymph node metastases are the most significant prognostic factor in localized non-small cell lung cancer (NSCLC). Nodal micrometastases may not be detected. Identification of the first nodal drainage site (sentinel node) may improve detection of metastatic nodes. We performed intraoperative Technetium 99m sentinel lymph node (SN) mapping in patients with resectable NSCLC. METHODS: Fifty-two patients (31 men, 21 women) with resectable suspected NSCLC were enrolled. At thoracotomy, the primary tumor was injected with 2 mCi Tc-99. After dissection, scintographic readings of both the primary tumor and lymph nodes were obtained with a handheld gamma counter. Resection with mediastinal node dissection was performed and findings were correlated with histologic examination. RESULTS: Seven of the 52 patients did not have NSCLC (5 benign lesions, and 2 metastatic tumors) and were excluded. Forty-five patients had NSCLC completely resected. Mean time from injection of the radionucleide to identification of sentinel nodes was 63 minutes (range 23 to 170). Thirty-seven patients (82%) had a SN identified; 12 (32%) had metastatic disease. 35 of the 37 SNs (94%) were classified as true positive with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement. Two inaccurately identified SNs were encountered (5%). SNs were mediastinal (N2) in 8 patients (22%). CONCLUSIONS: Intraoperative SN mapping with Tc-99 is an accurate way to identify the first site of potential nodal metastases of NSCLC. This method may improve the precision of pathologic staging and limit the need for mediastinal node dissection in selected patients.

Continuous paravertebral extrapleural infusion for post-thoracotomy pain management.

BACKGROUND: Continuous thoracic epidural analgesia is considered by many the gold standard for post-thoracotomy pain control but is associated with its own complications. In this study we compare continuous paravertebral extrapleural to epidural infusion for post-thoracotomy pain control. METHODS: In a prospective fashion, 50 patients were randomized to receive either paravertebral or epidural infusion for post-thoracotomy pain control. The anesthesia department placed epidurals, and the operative surgeon placed unilateral paravertebral catheters. Patients were evaluated for analgesic efficacy and postoperative complications. RESULTS: We found that both methods of analgesia provide adequate postoperative pain control. Epidural infusion demonstrated an improved efficacy early in the postoperative course but provided statistically similar analgesia to paravertebral by postoperative day 2. Neither group demonstrated a greater number of pain-related complications. Narcotic-induced complications such as pruritus, nausea/vomiting, and postural hypotension/mental status changes/respiratory depression were seen with statistically similar frequency in both epidural and paravertebral arms. Urinary retention, however, was noted to be significantly more frequent in patients with epidural catheters. Drug toxicity was not observed with either epidural or paravertebral infusion. CONCLUSIONS: We recommend continuous paravertebral infusion as an improved method of post-thoracotomy analgesia that can be placed and managed by the surgeon.

Malignant bone tumors of the chest wall.

Malignant bone tumors constitute only 0.2% of all tumors. Bone sarcomas occur at a rate approximately one tenth that of sarcomas of the soft tissue. Malignant bone tumors of the chest wall and sternum are even more rare because most bone tumors occur in the long bones or joints. Because of the relative paucity of experience treating these malignancies, progress in successful therapies has been limited. Chondrosarcomas remain the most common bony malignant chest wall lesions and are discussed elsewhere in this issue. Other lesions in descending order of incidence include Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma, solitary plasmacytoma, and Askin tumors. This article reviews these remaining five malignant bony chest wall tumors, along with their symptoms, presentations, and current approaches to therapy.

Complications from induction regimens for thoracic malignancies. Perioperative considerations.

The treatment of locoregionally advanced non-small cell lung cancer is evolving rapidly, and we as surgeons should continue to take a prominent role, from the pretreatment evaluation phase, through reassessment after induction therapy and intraoperative decision making, to vigilant postoperative care. These are by far the most challenging thoracic oncologic patients to care for. The multidisciplinary team formula required for optimal results and mandates the leadership that we, as surgeons familiar with all facets of patient care, can provide.

Solitary pulmonary nodule: treatment options.

Several options are available to the physician to aid in the diagnosis and treatment of newly discovered solitary pulmonary nodules. The physician must take into account a number of factors before deciding on the best course of action. Nearly all patients with pulmonary nodules detected on chest radiographs will go on to have a CT scan to better delineate the lesion. The radiologic characteristics, along with significant findings from the patient's history and physical examination, will determine whether observation, biopsy, or resection is most appropriate. The growing experience with video-assisted thoracoscopic procedures has led to combined diagnostic and therapeutic procedures and, in many cases, the treatment of lung cancer in earlier stages.

Wedge resection versus lobectomy for stage I (T1 N0 M0) non-small-cell lung cancer.

BACKGROUND: The role of nonanatomic wedge resection in the management of stage I (T1 N0 M0) non-small-cell lung cancer continues to be debated against the present gold standard of care--anatomic lobectomy. METHODS: We analyzed the results of 219 consecutive patients with pathologic stage I (T1 N0 M0) non-small-cell lung cancer who underwent open wedge resection (n = 42), video-assisted wedge resection (n = 60), and lobectomy (n = 117) to assess morbidity, recurrence, and survival differences between these approaches. RESULTS: There were no differences among the three groups with regard to histologic tumor type. Analysis demonstrated the wedge resection groups to be significantly older and to have reduced pulmonary function despite a higher incidence of treatment for chronic obstructive pulmonary disease when compared with patients having lobectomy. The mean hospital stay was significantly less in the wedge resection groups. There were no operative deaths among patients having wedge resection; however, a 3% operative mortality occurred among patients having lobectomy (p = 0.20). Kaplan-Meier survival curves were nearly identical at 1 year (open wedge resection, 94%; video-assisted wedge resection, 95%; lobectomy, 91%). At 5 years survival was 58% for patients having open wedge resection, 65% for those having video-assisted wedge resection, and 70% for those having lobectomy. Log rank testing demonstrated significant differences between the survival curves during the 5-year period of study (p = 0.02). This difference was a result of a significantly greater non-cancer-related death rate by 5 years among patients having wedge resection (38% vs 18% for those having lobectomy; p = 0.014). CONCLUSION: Wedge resection, done by open thoracotomy or video-assisted techniques, appears to be a viable "compromise" surgical treatment of stage I (T1 N0 M0) non-small-cell lung cancer for patients with cardiopulmonary physiologic impairment. Because of the increased risk for local recurrence, anatomic lobectomy remains the surgical treatment of choice for patients with stage I non-small-cell lung cancer who have adequate physiologic reserve.

Patterns of failure after trimodality therapy for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma is uncommon, and presently, no standard treatment of this disease exists. The objective of our analysis was to study the patterns of failure for malignant pleural mesothelioma after trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and radiation therapy. METHODS: Between 1987 and 1993, 49 patients with malignant pleural mesothelioma underwent extrapleural pneumonectomy. There were two perioperative deaths, and 1 patient died 5 weeks after extrapleural pneumonectomy. Thirty-five of the surviving patients received adjuvant chemotherapy (32/35 received cyclophosphamide, doxorubicin, and cisplatin) followed by hemithorax radiation therapy. Ten patients received chemotherapy but no radiation therapy, and 1 patient received no adjuvant therapy. Median follow-up time for the 23 living patients from the date of operation was 18 months. RESULTS: Of the 46 evaluable patients, 25 had recurrence (54%), with a median time to first failure of 19 months (range, 5 to 51 months). The sites of first recurrence were local in 35% of patients, abdominal in 26%, the contralateral thorax in 17%, and other distant sites in 8%. (Some patients had recurrence in multiple sites simultaneously.) CONCLUSIONS: The most common site of failure after trimodality therapy was the ipsilateral hemithorax. Isolated distant failures were uncommon. Future strategies should investigate methods of enhancing local tumor control.

Small pulmonary lesions detected at CT: clinical importance.

PURPOSE: To evaluate the histopathologic findings of pulmonary nodules 1 cm or smaller detected at computed tomography (CT) that were removed at video-assisted thorascopic surgery. MATERIALS AND METHODS: Clinical, radiologic, and histopathologic findings were retrospectively reviewed in 64 patients (48 women, 16 men; aged 22-85 years) who underwent video-assisted thorascopic surgical resection of small pulmonary lesions present on CT scans. RESULTS: Sixty-four patients had a total of 65 lesions resected. Of the 64 patients, 37 (58%) patients had no known previous malignancy and 27 (42%) had previous malignancy. Overall, 58% (38 of 65 [95% confidence interval = 0.45, 0.73]) of these lesions were malignant. Among the patients without previous malignancy, 14 (38%) had lung carcinoma (10 [27%], primary bronchogenic carcinoma; four [11%], carcinoid). In patients with a previous malignancy, malignant lesions were diagnosed in 81% (22 of 27). This included seven (26%) patients with bronchogenic carcinoma as a second primary carcinoma. In patients without previous malignancy, benign lesions were diagnosed in 59% (22 of 37); in patients with previous malignancy, benign lesions were diagnosed in 18% (five of 27). CONCLUSION: A considerable number of the malignant lesions were primary bronchogenic carcinoma. In addition, diagnosis in patients with a previous malignancy other than suspected metastatic disease can substantially alter treatment. For these reasons, early biopsy with an acceptable technique for diagnosis of these lesions is recommended.

Video-assisted thoracic surgery in the elderly. A review of 307 cases.

STUDY OBJECTIVE: The objective of the study was to investigate the impact of video-assisted thoracic surgery (VATS) on age-related morbidity and mortality for thoracic surgical procedures. DESIGN: Prospective data were collected on 896 consecutive VATS procedures from July 1991 to June 1994. Daily in-hospital, postoperative data collection by a full-time thoracic surgical nurse and postdischarge follow-up in a thoracic surgery clinic at 1 and 6 weeks were done. PATIENTS: On 296 patients aged 65 or older, 307 procedures were performed. One hundred nine procedures were performed on patients between 65 and 69 years, 110 on patients between 70 and 74 years, 55 on patients between 75 and 79 years, and 33 on those between 80 and 90 years. MEASUREMENTS AND RESULTS: The population was divided into four cohorts of 5-year age spans for analysis. Comparison was made with Fisher's Exact Test. Overall, 61% of the 307 procedures were for pulmonary disease. There were 32 anatomic lung resections (VATS lobectomies or segmentectomies), 156 extra-anatomic lung resections (thoracoscopic wedge or bullectomy), 78 procedures for pleural disease (25%), 27 mediastinal dissections (9%), and 14 pericardial windows (5%). There was a trend toward a lower mean FEV1 with increasing age. There were 3 deaths; overall mortality was less than 1%. There were 4 conversions to open thoracotomy (1%). Complications occurred with 45 procedures (15% morbidity). Twenty-two operations (7%) were associated with major complications adding to the length of stay and 27 procedures (9%) had minor complications. Median length of stay after VATS was 4 days for patients aged 65 to 79 years and 5 days for those aged 80 to 90 years. Morbidity and mortality were unrelated to age. CONCLUSIONS: The 30-day operative mortality is superior to previous reports of standard thoracotomy. Morbidity is low and length of hospital stay appears improved. VATS techniques may be safer than open thoracotomy in the aged. Age alone should not be a contraindication to operative intervention.

Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients.

OBJECTIVE: The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND: Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS: From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Women's Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS: The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS: Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system.

Prospective analysis of pneumonectomy: risk factors for major morbidity and cardiac dysrhythmias.

BACKGROUND: Data were acquired prospectively on 136 consecutive patients undergoing pneumonectomy for cancer from 1988 to 1993, to define factors that increase the risk of major morbidity and postoperative cardiac dysrhythmias. METHODS: There were 81 patients (60%) with non-small cell lung cancer (standard pneumonectomy) and 55 patients (40%) with malignant pleural mesothelioma (extrapleural pneumonectomy). RESULTS: Four perioperative deaths occurred (3%) with no identifiable associated risk factors. Twenty-three patients (17%) had a major complication with an increase in the median length of stay from 7 to 11 days (p < 0.01). Age greater than 65 years, right-sided procedures, and dysrhythmias were associated with an increased risk of a major complication (p < 0.05). Thirty-two patients (24%) had supraventricular dysrhythmias, which occurred on postoperative days 1 to 2 (n = 8), 3 to 4 (n = 13), 5 to 6 (n = 6), and 7 to 12 (n = 5). The median length of stay increased from 8 to 11 days with dysrhythmias (p < 0.05). Factors associated with an increased risk of dysrhythmias included age greater than 65 years, intrapericardial or extrapleural pneumonectomy, right-sided procedure, and any major complication. CONCLUSIONS: Pneumonectomy can be performed safely in selected patients with cancer. Supraventricular dysrhythmia was the most common complication noted with a peak incidence at 3 to 4 days after resection.

An historical perspective of multi-modality treatment for resectable non-small cell lung cancer.

We examine the origins of surgical therapy, radiotherapy, and chemotherapy as they were applied to lung cancer in the mid-portion of this century. Surgical therapy for lung cancer started in the 1930s with pneumonectomies. The prognostic significance of nodal metastases was soon recognized, and surgical staging procedures became an important part of patient workup. Radical radiotherapy for potential cure of lung cancer began in the 1950s with megavoltage linear accelerators. The first application of chemotherapy for lung cancer was the use of nitrogen mustards in the 1940s. Single modality surgical therapy has become the treatment of choice for Stages I and II non-small cell lung cancer, but 50% of clinical Stage I patients die of recurrent disease, and 70% of those recur outside the chest. Biologic markers may identify high risk subgroups of Stage I and II patients who may benefit from adjuvant chemo- or radiotherapy. Within the last decade, several single and multi-institutional Phase II trials and two single institution Phase III trials have reported improved survival in Stage IIIA patients treated with cisplatin-based neoadjuvant chemotherapy prior to surgical resection. These trials have reported high response and resectability rates, but at a substantial toxicity. A new standard of care for Stage IIIA disease has not been conclusively established.

Thoracoscopic staging and surgical therapy for esophageal cancer.

Esophageal cancer continues to be a major health problem with an associated poor prognosis. New technology is being applied to the staging of this cancer. The new staging system requires assessment of depth of wall penetration and lymph node status prior to resection. To determine penetration and node status with a high degree of accuracy generally requires some combination of chemotherapy, magnetic resonance imaging, endoesophageal ultrasound, and/or surgical staging. Several variables need to be considered in planning the surgical approach to the patient with esophageal cancer: the intent of the surgeon to either cure or palliate, the anatomic location of the tumor, and the method of reconstruction. Surgery is optimal for localized esophageal cancer. Neoadjuvant chemoradiation has increased survival in specific subgroups. Phase 2 trials have shown the safety and efficacy of chemoradiation. Randomized multi-institutional trials are needed to verify the encouraging results of recent phase 2 trials.

Mesothelioma and radical multimodality therapy: who benefits?

The incidence of malignant pleural mesothelioma is increasing. Untreated, patients with this disease experience a rapid and horrendous clinical decline. Surgery plays a role in the diagnosis, staging, and treatment of this malignancy. Surgery, chemotherapy, and radiotherapy alone have been unable to achieve major improvements in survival for most patients. More recent phase II trials suggest that surgery, at one time a purely palliative approach, may have a potentially curative role when used in combination with chemotherapy and radiotherapy.