Whitney Burrows

Radiation Therapy Oncology Group Protocol 02-29: A Phase II Trial of Neoadjuvant Therapy With Concurrent Chemotherapy and Full-Dose Radiation Therapy Followed by Surgical Resection and Consolidative Therapy for Locally Advanced Non-small Cell Carcinoma of the Lung

PURPOSE To evaluate mediastinal nodal clearance (MNC) rates after induction chemotherapy and concurrent, full-dose radiation therapy (RT) in a phase II trimodality trial (Radiation Therapy Oncology Group protocol 0229). PATIENTS AND METHODS Patients (n=57) with stage III non-small cell lung cancer (pathologically proven N2 or N3) were eligible. Induction chemotherapy consisted of weekly carboplatin (AUC = 2.0) and paclitaxel 50 mg/m(2). Concurrent RT was prescribed, with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to all gross disease. The mediastinum was pathologically reassessed after completion of chemoradiation. The primary endpoint of the study was MNC, with secondary endpoints of 2-year overall survival and postoperative morbidity/mortality. RESULTS The grade 3/4 toxicities included hematologic 35%, gastrointestinal 14%, and pulmonary 23%. Forty-three patients (75%) were evaluable for the primary endpoint. Twenty-seven patients achieved the primary endpoint of MNC (63%). Thirty-seven patients underwent resection. There was a 14% incidence of grade 3 postoperative pulmonary complications and 1 30-day, postoperative grade 5 toxicity (3%). With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression-free survival rate was 33%. The 2-year overall survival rate was 75% for those who achieved nodal clearance, 52% for those with residual nodal disease, and 23% for those who were not evaluable for the primary endpoint (P=.0002). CONCLUSIONS This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoradiation with full-dose RT to sterilize known mediastinal nodal disease.

The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH

Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown.

Comparison of acellular dermal matrix and synthetic mesh for lateral chest wall reconstruction in a rabbit model.

Background: Synthetic mesh is used for chest wall reconstruction, but infection or exposure can occur and necessitate removal. Human acellular dermal matrix (AlloDerm) has been used to reconstruct musculofascial defects in the trunk with low infection and herniation rates. AlloDerm may have advantages over synthetic mesh for chest wall reconstruction. This study compared outcomes and repair strengths of AlloDerm to expanded polytetrafluoroethylene mesh used for repair of rib cage defects. Methods: A 3 × 3-cm, full-thickness, lateral rib cage defect was created in each rabbit and repaired with expanded polytetrafluoroethylene (n = 8) or acellular dermal matrix (n = 9). At 4 weeks, the animals were euthanized and evaluated for lung herniation/dehiscence, strength of adhesions between the implant and intrapleural structures, and breaking strength of the implant materials and the implant-fascia interface. Tissue sections were analyzed with histologic and immunohistochemical staining to evaluate cellular infiltration and vascularization. Results: No herniation or dehiscence occurred with either material. The incidence and strength of adhesions was similar between materials. The mean breaking strength of the AlloDerm-fascia interface (14.5 ± 8.9 N) was greater than the expanded polytetrafluoroethylene–fascia interface (8.7 ± 4.4 N; p = 0.027) and similar to the rib-intercostal-rib interface of the contralateral native chest wall (14.0 ± 5.6 N). The AlloDerm grafts became infiltrated with cells and vascularized after implantation. Conclusions: AlloDerm used for chest wall reconstruction results in greater implant-defect interface strength than expanded polytetrafluoroethylene. The ability of AlloDerm to become vascularized and remodeled by autologous cells and to resist infection may be advantageous for chest wall reconstruction.

Phase I/II Trial of Hyperfractionated Radiation and Chemotherapy Followed by Surgery in Stage III Lung Cancer

BACKGROUND We have previously demonstrated that high-dose chemoradiotherapy followed by resection for patients selected on the basis of mediastinal sterilization was feasible and resulted in excellent outcomes. This study was designed to determine the ability to intensify our prior approach utilizing hyperfractionated radiation and more aggressive consolidative chemotherapy. METHODS Patients with documented stage IIIA/B nonsmall-cell lung cancer, performance status 0 to 2, and adequate organ function were eligible. A phase I portion utilized escalating doses of carboplatin and vinorelbine, commencing with areas under the curve of 1 and 5 mg/m(2), respectively, and concurrent 69.6 Gy hyperfractionated radiotherapy. A phase II portion utilized the identical radiotherapy with carboplatin/vinorelbine at the maximum tolerated dose established in phase I. Patients for whom mediastinal nodal clearance was demonstrated underwent resection. All patients were to receive consolidation chemotherapy consisting of carboplatin/vinorelbine for three cycles, followed by docetaxel for three cycles. Prophylactic cranial irradiation was offered to patients after completion of therapy. RESULTS Forty-seven patients participated in the study (33 IIIA, 14 IIIB; 15 men, 32 women; median age, 56 years). The maximum tolerated dose for concurrent carboplatin/vinorelbine and hyperfractionated radiotherapy was established at areas under the curve of 1 and 10 mg/m(2), respectively. Twenty-eight patients completed trimodality treatment including surgery. Median survival time for the entire study cohort (n = 47) is 29.6 months, and it is 55.8 months for patients with mediastinal clearance who underwent resection (n = 28). CONCLUSIONS Surgical resection of locally advanced stage IIIA and IIIB nonsmall-cell lung cancer after induction hyperfractionated radiation and concurrent chemotherapy is safe and well tolerated. Whether this approach is superior to less aggressive therapy is uncertain and will require comparative studies.

Thoracoscopy/laparoscopy in the staging of esophageal cancer: Maryland experience.

Precise clinical staging of esophageal cancer before treatment is important. Thoracoscopic/laparoscopic (Ts/Ls) staging has been proposed as a promising staging method. This study was conducted to evaluate the potential benefits of Ts/Ls staging over conventional noninvasive clinical staging in patients with esophageal cancer. From 1991 to 1999, 111 patients with esophageal cancer underwent Ts/Ls staging by the University of Maryland Medical System. Pretreatment staging workup included computed tomography, magnetic resonance imaging, and esophageal ultrasonography, followed by Ts/Ls surgical staging. Thoracoscopy was successfully performed in 102 patients and was aborted in 4 patients because of pleural adhesions. Laparoscopy was successfully done in 76 patients and was aborted in 1 patient because of peritoneal adhesion. Sixty-seven patients had both Ts and Ls staging, whereas 35 patients and 9 patients, respectively, had only Ts or Ls staging. Thirteen of 19 patients with clinical T4 disease were downstaged to T3 disease, and 8 patients with clinical T3 disease were upstaged to T4 by Ts/Ls staging. No clinical T1–2 disease was found to be associated with local invasion (T4) by Ts/Ls. Forty-eight and 19 patients had mediastinal and celiac lymph node metastases clinically diagnosed, respectively. Nine (18.8%) and 12 (63.2%) of them were proved by Ts and Ls, respectively. An additional 5 and 16 patients were found to have unexpected mediastinal and celiac lymph node metastases, respectively, by Ts/Ls. Biopsy specimens of pleura, lung, or liver were obtained by Ts/Ls procedures in 17 patients because of suspicious findings of routine imaging studies or unexpected findings during the staging operation. Five patients were found to have distant metastasis, and the presence of metastases in others was excluded. The correlation between Ts/Ls staging and conventional noninvasive clinical staging in the diagnosis of T4 disease, mediastinal lymph node metastasis, celiac lymph node metastasis, and M1 disease was 18.8%, 14.5%, 25.5%, and 20.0%, respectively. Ts/Ls provides more accurate information for evaluating local invasion, lymph node metastasis, and distant metastasis. The poor correlation of staging diagnosis between Ts/Ls and conventional noninvasive clinical examinations suggests that the accuracy of current noninvasive clinical staging is questionable and needs to be improved.

Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: a phase 2 trial.

PurposeTo evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer. Patients and MethodsPatients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m2/wk) and cisplatin (25 mg/m2/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. ResultsForty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma. ConclusionPPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation.PURPOSE To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer. PATIENTS AND METHODS Patients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m(2)/wk) and cisplatin (25 mg/m(2)/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. RESULTS Forty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma. CONCLUSION PPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation.

Pneumonectomy for Lung Cancer After Preoperative Concurrent Chemotherapy and High-Dose Radiation

BACKGROUND We studied the clinical characteristics and outcomes of patients undergoing pneumonectomy after preoperative concurrent chemoradiation for non-small cell lung cancer. METHODS Clinical records of patients with non-small cell lung cancer who underwent pneumonectomy at our institution between 1995 and 2005 after preoperative concurrent chemoradiation were reviewed retrospectively. RESULTS Twenty-nine patients underwent pneumonectomy after preoperative concurrent chemoradiation. Of the 21 men and 8 women who were treated, 1 had stage IIB (T3N0M0) and the remainder had stage IIIA or IIIB non-small cell lung cancer. Mean patient age at surgery was 53.4 years. There were 15 right pneumonectomies, of which 2 were for pancoast tumors. All patients received concurrent preoperative chemoradiation. Mean total radiation dose was 61.1 Gy. All patients went on to have complete (R0) resection by pneumonectomy. Pathologic complete response was found in 16 patients (55.2%). All patients were discharged alive from the hospital after pneumonectomy. Median hospital length of stay was 5 days (mean 8.6). Ninety-day mortality after surgery was 3.4% (n = 1). Recurrences have been found in 11 patients (38%), including brain metastases (n = 6), bone metastases (n = 4), liver metastases (n = 2), and cervical lymph node metastases (n = 2). One patient had a contralateral new primary lung cancer develop 70 months after undergoing pneumonectomy. Estimated 5-year disease-free survival is 48%. Median survival time has not been reached. CONCLUSIONS Pneumonectomy can be performed safely after preoperative concurrent chemoradiation, even with high-dose radiation. The frequency of disease recurrence in the brain underscores the need to evaluate the role of prophylactic cranial radiation in non-small cell lung cancer.

Stratified Analysis of Clinical Outcomes in Thoracoscopic Sympathicotomy for Hyperhidrosis

BACKGROUND The primary goal of this study is to identify clinical variables associated with successful surgical treatment for hyperhidrosis and facial blushing. METHODS Six hundred eight thoracoscopic sympathicotomies were performed in 304 patients. Retrospective stratified analysis of patients after thoracoscopic sympathicotomy for hyperhidrosis or facial blushing and having completed follow-up of at least 6 months (n = 232) was performed. Preoperative and postoperative quality-of-life indices (range, 0 to 3) were used to measure impact of surgery, and comparisons were indexed to preoperative symptoms. Postoperative compensatory sweating was analyzed with respect to the level(s) of sympathetic chain division. RESULTS Thoracoscopic sympathicotomy was performed at level T2 alone in 5% of patients; levels T2 to T3 in 63% of patients; levels T3 to T4 in 3% of patients; levels T2 to T4 in 14% of patients; and more than three levels in 14% of patients. In hyperhidrosis patients, mean preoperative quality-of-life index was 2.0 and postoperative quality-of-life index was 0.4 (p < 0.001). Facial blushers had preoperative and postoperative quality-of-life index of 2.6 and 1.0, respectively. Significant compensatory sweating was seen in 33% patients overall and occurred in 29% of patients with palmar symptoms, 26% of axillary patients, and 42% of facial blushers. Significant compensatory sweating in relation to the level(s) of sympathetic chain division occurred in T2 alone, 45%; T2 to T3, 30%; T3 to T4, 14%; T2 to T4, 38%; and more than three levels, 49%. CONCLUSIONS Significant improvement in quality of life can result from surgery for hyperhidrosis. However, the incidence of postoperative compensatory sweating may be dependent on the level of sympathicotomy performed. The choice of sympathicotomy level(s) should be directed toward reducing the incidence of significant compensatory sweating while simultaneously ensuring relief of primary preoperative symptoms.

Outcomes after trimodality therapy for esophageal cancer: the impact of histology on failure patterns.

Objectives: This retrospective analysis of patients undergoing neoadjuvant chemoradiation followed by surgical resection was performed to determine if histology or pathologic response affected local-regional control (LRC), survival outcomes or patterns of failure. Methods: We performed a review of 164 patients who underwent neoadjuvant chemoradiation followed by surgical resection from 1992 to 2006 for esophageal cancer. Information on patient characteristics, pathologic response, failure patterns, and survival was collected. Survival was estimated by the Kaplan-Meier method, and Cox multivariable Regression model was used to analyze trends. Results: The median follow-up was 18 months and 27 months in surviving patients. The 3-year overall survival (OS) and LRC was 46% and 79%. The overall response for the entire cohort included a pathologic complete response (pCR) rate of 41.4%, 21.3% with microscopic residual disease (mRD) and 36.3% with gross residual disease (gRD). The 3-year OS of patients who achieved a pCR versus mRD versus gRD was 58%, 53%, and 29%. OS was significantly improved in patients with a pCR and mRD compared with gRD (P = 0.001). On multivariate analysis both pCR and mRD correlated with an improved OS. Squamous cell cancers (SCC) had a higher rate of pCR than adenocarcinomas (AC), 54% versus 34.8% (P = 0.01). The 3 year LRC for patients with SCC and AC was 100% and 71% (P = 0.03). Among SCC with recurrence, there were no local failures and all failed distantly (P = 0.001). Conclusions: Patients with microscopic residual disease following trimodality therapy had similar outcomes to patients achieving a pCR. Patients with SCC were more likely to achieve a pCR, and had a higher propensity to fail distantly when compared with patients with AC. This data should be considered in the design of future clinical trials.

Immunohistochemistry analysis of micrometastasis in pretreatment lymph nodes from patients with esophageal cancer.

BACKGROUND With recent advances in neoadjuvant therapy in esophageal cancer, pretreatment lymph node staging has become increasingly important in stratifying patients to appropriate treatment regimens and for prognostication. Immunohistochemical analysis (IHC) using epithelial markers has been shown to identify micrometastases in histologically negative lymph nodes. We performed this study to evaluate if IHC analysis in thoracoscopic/laparoscopic (Ts/Ls) pretreatment staging lymph nodes can reveal additional diagnostic information to routine histopathology. METHODS Specimens of 106 patients with esophageal cancer who had pretreatment Ts/Ls staging were retrospectively studied. Lymph node biopsies were obtained for IHC staining using cytokeratin (CK) of AE1/AE3. IHC staining for p53, an apoptosis protein associated with poor prognosis in esophageal cancer, was also performed. RESULTS 331 Ts/Ls staging lymph node biopsies were collected from 106 patients. A total of 15.4% (51/331) of the lymph nodes or 34.9% (37/106) of patients were found to have metastatic deposits by routine histology. All the histologically positive lymph nodes were CK positive. Among the remaining 280 histologically negative lymph nodes, 11(3.9%) were found to have micrometastasis by CK staining. Three patients (4.3%, 3/69) were upstaged from N0 to N1. They died of early recurrences after treatment. A total of 67.6% (25/37) of the patients with histologically positive lymph node were p53 positive. No histologically negative lymph node was found to be p53 positive in this series. CONCLUSIONS Immunohistochemical analysis for CK can detect micrometastatic involvement of lymph nodes that are missed on routine pathologic examination, and, therefore, can improve lymph node staging. Its clinical significance in esophageal cancer warrants further study.