Richard H. Feins

Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial

BACKGROUND Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. METHODS Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. FINDINGS 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. INTERPRETATION Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. FUNDING National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

National Trends in Esophageal Surgery—Are Outcomes as Good as We Believe?

IntroductionPositive volume–outcome relationships in esophagectomy have prompted support for regionalization of care; however, outcomes have not recently been analyzed. This study examines national trends in provision of esophagectomy and reassesses the volume–outcome relationship in light of changing practice patterns and training paradigms.MethodsThe Nationwide Inpatient Sample was queried from 1998 to 2006. Quantification of patients’ comorbidities was made using the Charlson Index. Using logistic regression modeling, institutions’ annual case volumes were correlated with risk-adjusted outcomes over time, as well as presence or absence of fellowship and residency training programs.ResultsA nationwide total of 57,676 esophagectomies were recorded. In-hospital unadjusted mortality fell from 12% to 7%. Adjusting for comorbidities, greater esophagectomy volume was associated with improvements in the incidence of most measured complications, though mortality increased once greater than 100 cases were performed. Hospitals supporting fellowship training or a surgical residency program did not have higher rates of mortality or total complications.ConclusionsThe current national mortality rate of 7% following esophagectomy is higher than is reported in most contemporary case series. A greater annual esophagectomy volume improves outcomes, but only up to a point. Current training paradigms are safe.

The effects of low-dose radiation on neointimal hyperplasia

PURPOSE We sought to determine whether low-dose radiation can inhibit neointimal hyperplasia immediately after balloon injury to the common carotid artery and to assess the extent of endothelial regeneration after treatment. METHODS Sprague-Dawley rats were subjected to balloon injury to the common carotid artery. Immediately after injury rats were treated with a single dose of iridium 192 radiation at 5 gy, 10 gy, and 15 gy or received no radiation (control). Three weeks after injury and treatment, vessels were harvested and compartment areas were measured on fixed specimens. Scanning and transmission electron microscopy, along with Evans blue dye uptake into injured vessels, was used to assess the effect radiation had on endothelial regeneration. RESULTS Rats receiving radiation at all three doses demonstrated no intimal thickening when compared with rats that were not treated (at 5 Gy 0.01 +/- 0.01 mm2; at 10 Gy 0.02 +/- 0.01 mm2; at 15 Gy 0.05 +/- 0.02 mm2; with balloon injury/no radiation 0.12 +/- 0.02 mm2; p < 0.01). In addition, the groups that were irradiated had no medial thickening when compared with control rats (at 5 Gy 0.22 +/- 0.02 mm2; at 10 Gy 0.21 +/- 0.02 mm2; at 15 Gy 0.22 +/- 0.07 mm2; with balloon injury/no radiation 0.37 +/- 0.03 mm2; p < 0.01). Endothelial regeneration, evaluated by transmission and scanning electron micrographs along with uptake of Evans blue dye, was significantly greater in animals that received radiation compared with controls. CONCLUSIONS Low-dose radiation prevents the occurrence of neointimal hyperplasia after balloon injury and may have a future role in vascular grafting.

Cardiopulmonary bypass simulation at the Boot Camp

OBJECTIVE At Boot Camp, we evaluated a modular approach to skills mastery related to cardiopulmonary bypass and crisis scenarios. METHODS With 32 first-year cardiothoracic surgery residents divided into 4 groups, 4 consecutive hours were devoted to cardiopulmonary bypass skills by using a perfused nonbeating heart model, computer-controlled CPB simulator, and perfused beating heart simulator. Based on the cardiopulmonary bypass simulator, each resident was assessed by using a checklist rating score on cardiopulmonary bypass management and 1 crisis scenario. An overall cardiopulmonary bypass score was determined. Economy of time and thought was assessed (1 = unnecessary/disorganized to 5 = maximum economy). At the end of the session, residents completed a written examination. Residents rated the sessions on cannulation skills, cardiopulmonary bypass knowledge, and cardiopulmonary bypass emergency and crisis scenarios on a 5-point scale (5 = very helpful to 1 = not helpful). RESULTS Thirty residents completed cardiopulmonary bypass simulator exercises. For initiation and termination of cardiopulmonary bypass, most residents performed the tasks and sequence correctly. Some elements were not performed correctly. For instance, 3 residents did not verify the activated clotting time before cardiopulmonary bypass initiation. Four residents demonstrated inadequate communication with the perfusionist, including lack of assertiveness and unclear commands. In crisis scenarios management of massive air embolism (n = 8) was challenging and resulted in the most errors; poor venous drainage and high arterial line pressure scenarios were managed with fewer errors. For the protamine reaction scenario, all residents (n = 7) identified the problem, but in 3 cases heparin was not redosed before resuming cardiopulmonary bypass for right ventricular failure. The score for economy of time and thought was 3.83 ± 0.6 (range, 3-5). The score of the written examination was 90.0 ± 11.3 (range, 60-100), which did not correlate with the overall cardiopulmonary bypass score of 91.4 ± 7.1 (range, 80-100; r = 0.07). The session on acquiring aortic cannulation skills was rated 4.92, that for cardiopulmonary bypass knowledge was rated 4.96, and that for cardiopulmonary bypass crisis scenarios was rated 4.96. CONCLUSIONS This Boot Camp session introduced residents early in their training to aortic cannulation, principles and management of cardiopulmonary bypass, and crisis management. Based on a modular approach, technical skills and knowledge of cardiopulmonary bypass can be acquired and assessed by using simulations, but further work with more comprehensive educational modules and practice will accelerate the path to mastery of these critical skills.

Thoracoscopic laser bullectomy: A prospective study with three-month results

One hundred forty-one patients were prospectively enrolled in a study of contact-tip laser bullectomy at four institutions. Ninety-one have had both preoperative and postoperative testing at 3 months. Nonsmoking patients with disabling dyspnea at less than 50 yards and with a forced expiratory volume in 1 second of 35% or less were enrolled. Testing included formal pulmonary function tests, arterial blood gasses, computed tomographic scans, ventilation/perfusion scans, echocardiograms, electrocardiograms, 6-minute walk testing, transdiaphragmatic pressures, and quality of life and dyspnea index questionnaires. A modest 16% improvement was noted in forced expiratory volume in 1 second (0.69 to 0.80 L), and there was a 29% improvement in 6-minute walk distances (655.2 to 846.3 feet). Oxygen use was completely discontinued in 16%. Risk factors for mortality included age, 6-minute walk distances, low diffusing capacity for carbon monoxide, high carbon dioxide tension, and high base excess. Minor improvement was judged from the dyspnea index and the Medical Outcome Study Short Form-36. Preoperative predictors of good outcome included heterogeneous disease, lack of carbon dioxide retention, and no emaciation (weight < 40 kg). Comparison of our results with those in the literature suggests that the improvement seen with the contact neodymium:yttrium-aluminum-garnet laser is not as good as that provided by the stapled techniques for volume reduction.

Effects of photodynamic therapy on xenografts of human mesothelioma and rat mammary carcinoma in nude mice.

We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate- and fluence-dependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.

Photodynamic therapy for human malignant mesothelioma in the nude mouse

Photodynamic therapy (PDT) utilizes a photoactivatable preparation, Photofrin II, which selectively localizes in cancerous tissue and produces substances toxic to that tissue when activated by light. Whether PDT would be able to selectively destroy human malignant mesothelioma was investigated by using a human-derived malignant mesothelioma tumor subcutaneously implanted in nude mice. Human malignant mesothelioma was grown subcutaneously to a size of 0.2-0.4 cm3. Selective retention of Photofrin II was studied by measuring light-induced inhibition of cytochrome c oxidase activity in tumor, heart, and lung. Photofrin II was retained in greater quantities in tumor than in heart or lung at 24 hr after injection. Using laser light at 630 nm under varying conditions, tumor growth was measured every 2 days following PDT for 18 days. All PDT regimens were successful in destroying malignant mesothelioma. Photofrin II at 5 mg/kg was superior to 2 mg/kg (P less than 0.005), light delivered at 50 mW/cm2 x 2 hr was superior to that delivered at 200 mW/cm2 x 30 min (P less than 0.05), and a total fluence of 180 J/cm2 was equivalent to 360 J/cm2 in affecting tumor growth. Ten of 12 mice treated at 50 mW/cm2 became tumor-free and remained so for 30 days following treatment. We concluded that PDT was effective against human malignant mesothelioma in a nude mouse model without adversely affecting the animal. A role for PDT in treating patients with malignant mesothelioma may exist.

Management of Stage IIIA Non-Small Cell Lung Cancer by Thoracic Surgeons in North America

BACKGROUND Stage IIIA(N2) non-small cell lung cancer is a heterogeneous spectrum ranging from microscopic lymph node metastases to bulky multistation nodal disease. While some favor surgical resection after neoadjuvant therapy, others favor definitive chemoradiation for treatment. Our aim was to determine practice patterns of thoracic surgeons. METHODS We invited 2,539 active surgeons identified on the Cardiothoracic Surgery Network as expressing interest in general thoracic surgery to participate in an anonymous Web-based survey. The participants evaluated clinical vignettes of a patient with single station N2 disease. RESULTS In all, 513 surgeons (20%) responded, with 222 (43%) in academic practice. For microscopic N2 disease, 84% (n=430) preferred neoadjuvant therapy followed by surgery. For grossly involved N2 disease, 62% (n=318) favored neoadjuvant therapy followed by surgery if N2 disease was downstaged. In patients with normal pulmonary function tests, requiring pneumonectomy, in the presence of bulky, single station N2 disease, there was less consensus: 32% (n=163) favored neoadjuvant therapy followed by lobectomy (less radical surgery than initially predicted) if feasible and N2 disease had downstaged, 30% (n=159) favored neoadjuvant therapy followed by pneumonectomy if N2 disease downstaged, 12% (n=60) would favor surgery regardless of N2 disease downstaging, and 22% (n=114) favored definitive chemoradiation. If the patient did not have adequate pulmonary function for pneumonectomy but could tolerate lobectomy, 50% favored neoadjuvant therapy followed by reassessment for lobectomy and 41% favored definitive chemoradiation. CONCLUSIONS There is no clear consensus on management of patients with stage IIIA lung cancer in the United States. Diversity of opinion is greatest in patients with more advanced lung cancer, and limited pulmonary function.

Pulmonary changes induced by combined mouse β-interferon (rMuIFN-β) and irradiation in normal mice - toxic versus protective effects

This study in normal mice was undertaken to investigate possible enhancement of pulmonary toxicity by interferon-beta (IFN-beta) combined with single doses of irradiation. A pharmacokinetic study preceded the toxicity study to determine the optimal route and timing of IFN administration. Graded single doses of radiation were combined with graded doses of IFN. Pulmonary toxicity was determined using endpoints of alveolar surfactant and procollagen in lung lavage fluid at 7 days, breathing frequency, lethality and histology. Increased lethality was seen when IFN was combined with irradiation at 12.5 Gy vs. irradiation alone. This occurred between 20 and 30 weeks post treatment with no increased breathing frequency or surfactant release, suggesting independent mechanisms of injury. Increased breathing frequency after 40 weeks, usually associated with fibrosis, was less pronounced for IFN treated vs. irradiation only controls. Ultrastructural studies at 72 weeks suggest reduced fibrosis in lungs of IFN treated vs. irradiation only controls. Supporting this was the finding that Procollagen III, a biosynthetic precursor of collagen, was increased in the lavage fluid at 7 days for all radiation doses but decreased with the addition of IFN at 12.5 and 15 Gy. Interferons can act either as sensitizers or radioprotectors, depending on the biological system and type of interferon. Our study suggests that while IFN-beta may increase the acute effects of radiation in the mouse lung, some protection from radiation-induced fibrosis, possibly related to alteration of immune mechanisms, may exist.

Doppler evaluation of the pedal arch

The association of a patent pedal arch with early distal bypass patency has recently been emphasized. Unfortunately, in many patients information about the pedal arch can only be obtained with intraoperative angiography. An 8 mHz Doppler probe was used to noninvasively evaluate the pedal arch in 62 patients with various degrees of vascular disease. The probe was placed in the first metatarsal space, and the presence of a Doppler signal was taken as evidence of a patent pedal arch. Digital pressure was then applied over each tibial artery at the malleolar level to determine each vessels communication with the pedal arch. Fifty-two patients were found to have patent pedal arches, while 10 did not. Preoperative hyperemic angiography or intraoperative arteriography was used to study the pedal arch in 22 of these patients. The arteriographic and Doppler findings were the same in 21 of 22 cases (96 percent accuracy). In the one case in which the results conflicted, the Doppler examination also gave information about which calf vessel contributed the most flow to the pedal arch. Preoperative Doppler evaluation of the foot combined with arteriography allows better selection of patients for distal bypass grafts.