Timothy Winton

Induction Chemoradiation and Surgical Resection for Superior Sulcus Non–Small-Cell Lung Carcinomas: Long-Term Results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160)

PURPOSE Traditional treatment for superior sulcus non-small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. PATIENTS AND METHODS Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. RESULTS From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites. CONCLUSION This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.

Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer

PURPOSE p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. METHODS p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. RESULTS Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. CONCLUSION p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

Adenoid cystic carcinoma of the airway: Thirty-two-year experience

METHODS We have reviewed our experience in 38 patients with adenoid cystic carcinoma of the upper airway seen between 1963 and 1995. The mean age was 44.8 years (15 to 80 years) with a male/female ratio of 1:1.1. Thirty-two of the 38 patients were treated by resection and reconstruction (primary anastomosis 28; Marlex mesh prosthesis 4). Twenty-six of the 32 patients undergoing resection received adjuvant radiotherapy. Six patients with unresectable tumors were treated primarily with radiotherapy only. RESULTS Pathologic examination revealed local invasion beyond the wall of the trachea in all patients. In a majority, microscopic extension was found in submucosal and perineural lymphatics, well beyond the grossly visible or palpable limits of the tumor. Lymphatic metastases were relatively uncommon, occurring in only five of 32 (19%) patients undergoing resection. Metachronous hematogenous metastases occurred in 17 of 38 patients (44%). Thirteen of these 38 patients (33%) had pulmonary metastases. Sixteen of 32 resections were complete and potentially curative. There were two deaths within 30 days of operation. The mean survival in the 14 patients undergoing complete resection was 9.8 years (12 months to 29 years). Sixteen of 32 resections were incomplete (residual tumor at the airway margin on final pathologic examination), with one operative death occurring in this group. The mean survival in the 15 surviving patients was 7.5 years (4 months to 21 years). Six patients were treated with primary radiation only and had a mean survival of 6.2 years (2 months to 14.3 years). In the patients with pulmonary metastases, mean survival was 37 months (4 months to 7 years) from the time of diagnosis of the pulmonary metastasis until their death. CONCLUSION Adenoid cystic carcinoma of the upper airway is a rare tumor, which is locally invasive and frequently amenable to resection. Although late local recurrence after resection is a feature of this tumor (up to 29 years), excellent long-term palliation is commonly achieved after both complete and incomplete resection. There was a small difference in survival between patients having complete and incomplete resection. Long periods of control can be obtained with radiotherapy alone. The best results, in this series of patients, were obtained by resection. Adjuvant radiotherapy is assumed to favorably influence survival.

Class III β-Tubulin Expression and Benefit from Adjuvant Cisplatin/Vinorelbine Chemotherapy in Operable Non–Small Cell Lung Cancer: Analysis of NCIC JBR.10

Purpose: High class III β-tubulin (bTubIII) expression in advanced non–small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non–small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial. Experimental Design: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII “low” or “high” using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups. Results: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance. Conclusions: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.

A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10

7018 Background: In meta-analyses platinum based adjuvant chemotherapy using 2nd generation regimens increased cure rate by 5% in completely resected NSCLC. JBR.10 was undertaken to determine whether the 3rd generation regimen VIN/CIS prolonged survival in this clinical setting. METHODS Patients with completely resected stage 1 (T2N0) or stage 2 (excluding T3N0) NSCLC were stratified by nodal status (N0 vs. N1) and ras mutation status (present vs. absent vs. unknown) and randomised to receive 4 cycles of VIN (25mg/m2 weekly x 16 weeks) plus CIS (50mg/m2 days 1 and 8 q 4 weeks x 4) or follow up alone; VIN dose was reduced from 30mg/m2 shortly after the study started due to unacceptable toxicity. The endpoints of the study were survival (OS), recurrence-free survival (RFS), quality of life (QOL) and toxicity. RESULTS 482 patients were randomized between 1994 and 2001. PATIENTS age 61 years, 65% male, 51% PS 1, 53% N1, 24% ras mutation present. 45% of patients had T2N0, 40% T2N1 and 15% T1N1. 53% had adenocarcinoma. Grade 4 neutropenia, was common with febrile neutropenia in 7%, predominantly in patients receiving VIN 30mg/m2. The commonest non-hematologic toxicities for VIN/CIS patients were fatigue (77%), nausea (76%), anorexia (53%), vomiting (46%), sensory neuropathy (45%) and constipation (44%). Two patients died of drug-related toxicity [1 febrile neutropenia, 1 pulmonary fibrosis]. The most common cause of death was NSCLC (including 1 patient with 2nd primary NSCLC), while 3 patients died from toxicity related to later anti-cancer therapy, 9 patients died of other primary malignancies, and 21 from other causes. Overall survival was significantly prolonged for VIN/CIS patients (94 months vs. 73 months; HR 0.69, p=0.011), as was RFS (not reached vs. 46.7 months; HR 0.6, p 0.0003). 5-year survival for VIN/CIS patients was 69% compared to 54% for patients followed expectantly. 38 patients developed 2nd malignancies. CONCLUSIONS This is the first randomized clinical trial demonstrating that a 3rd generation platinum-based doublet prolongs OS and RFS after surgery in early stage NSCLC. [Table: see text].

Pleural complications in lung transplant recipients

Pleural complications occurred in 30 (22%) of 138 patients after 53 single and 91 double lung transplants between September 1986 and February 1993. These were defined for the purpose of this study as pneumothorax persisting beyond the first 14 postoperative days, recurrent pneumothorax, or any other pleural process that necessitated diagnostic or therapeutic intervention. Overall, a higher pleural complication rate was seen in double lung transplantation (25 of 30) than in single lung transplantation (5 of 30) with no differences noted in the frequency among preoperative diagnostic groups (p > 0.05). Pneumothorax was the most frequent complication, affecting 14 of 30 patients, with 6 of 14 cases occurring after transbronchial biopsy. All pneumothoraces in single (n = 4) and double lung transplantation (n = 10) resolved spontaneously or with chest tube thoracostomy. One patient required placement of a Clagett window after open lung biopsy and another required thoracotomy and pleural abrasion after transbronchial biopsy. Parapneumonic effusion was observed in 4 of 30 double lung transplantations with spontaneous resolution in all cases. Empyema affected 7 of 30 patients and occurred exclusively in the double lung transplant group. Sepsis developed in three of the patients with this complication and they subsequently died. The risk of empyema was independent of preoperative diagnosis (p > 0.05). Of interest, all patients with cystic fibrosis (n = 3) with complicating empyema had Pseudomonas cepacia in the pleural fluid. Other miscellaneous complications included subpleural hematoma, chylothorax, and hemothorax. The latter two necessitated thoracic duct and bronchial artery ligation, respectively. In summary, a significant proportion of lung transplant recipients will have pleural space complications. The vast majority of these will resolve spontaneously or with conservative procedures. These complications were not related to preoperative diagnosis nor associated with a significant prolongation of hospital stay (p > 0.05). Empyema is the only pleural space complication associated with increased patient mortality and, as such, is an important clinical marker for those at risk for sepsis and death.

Quality-of-Life Outcomes for Adjuvant Chemotherapy in Early-Stage Non–Small-Cell Lung Cancer: Results From a Randomized Trial, JBR.10

PURPOSE Adjuvant chemotherapy for early stage non-small-cell lung cancer (NSCLC) is now the standard of care, but there is little information regarding its impact on quality of life (QOL). We report the QOL results of JBR.10, a North American, intergroup, randomized trial of adjuvant cisplatin and vinorelbine compared with observation in patients who have completely resected, stages IB to II NSCLC. PATIENTS AND METHODS QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline and at weeks 5 and 9 for those who received chemotherapy and at follow-up months 3, 6, 9, 12, 18, 24, 30 and 36. A 10-point change in QOL scores from baseline was considered clinically significant. RESULTS Four hundred eighty-two patients were randomly assigned on JBR.10. A total of 173 patients (82% of the expected) in the observation arm and 186 (85% of expected) in the chemotherapy arm completed baseline QOL assessments. The two groups were comparable, with low global QOL scores and significant symptom burden, especially pain and fatigue, after thoracotomy. Changes in QOL during chemotherapy were relatively modest; fatigue, nausea, and vomiting worsened, but there was a reduction in pain and no change in global QOL. Patients in the observation arm showed considerable improvements in QOL by 3 months. QOL, except for symptoms of sensory neuropathy and hearing loss, in those treated with chemotherapy returned to baseline by 9 months. CONCLUSION The findings of this trial indicate that the negative effects of adjuvant chemotherapy on QOL appear to be temporary, and that improvements (with a return to baseline function) are likely in most patients.

Effects of presurgical exercise training on quality of life in patients undergoing lung resection for suspected malignancy: a pilot study.

The aim of this study was to explore the effects of presurgical exercise training on quality of life (QOL) in patients with malignant lung lesions. Using a single-group prospective design, patients were enrolled in supervised aerobic exercise training for the duration of surgical wait time (mean 59.7 days). Participants completed assessments of cardiorespiratory fitness (peak oxygen consumption) and QOL using the Functional Assessment of Cancer Therapy-Lung scales, including the trial outcome index (TOI) and the lung cancer subscale (LCS) at baseline, immediately presurgery, and postsurgery (mean, 57 days). 9 participants provided complete data. Repeated-measures analysis indicated a significant effect for time on TOI (P = .006) and LCS (P = .009). Paired analysis revealed that QOL was unchanged after exercise training (ie, baseline to presurgery), but there were significant and clinically meaningful declines from presurgery to postsurgery in the LCS (−3.6, P = .021) and TOI (−8.3, P = .018). Change in peak oxygen consumption from presurgery to postsurgery was significantly associated with change in the LCS (r = 0.70, P = .036) and TOI (r = 0.70, P = .035). Exercise training did not improve QOL from baseline to presurgery. Significant declines in QOL after surgery seem to be related to declines in cardiorespiratory fitness. A randomized controlled trial is needed to further investigate these relationships.

Lung transplantation in patients over the age of 50.

It is common to assign an upper age limit for potential lung transplant recipients. The influence of age on LTX outcome is, however not, documented. A review of our first 103 LTXs, 51 single LTXs and 52 double LTXs, includes 31 recipients aged 50–63 years (mean 55.3± 3.9); 19 received single LTX, and 12 received double LTX. Indications for LTX in those aged greater than 50 included proportionately more patients with emphysema and interstitial lung disease. Actuarial survivals in those aged less than 50 at 12, 36, and 60 months were 68%, 60%, and 55%, and in those aged greater than 50 was 70%, 61%, and 61%, respectively. The causes of death reflect a tendency of younger patients to die from graft rejection and older patients to die from sepsis. Acute rejection more than 6 weeks posttransplant and chronic rejection were less frequent in older patients (P<0.05). The 6-minute walk and modified Bruce protocol tests, the incidence of CMV pneumonitis, and the late post-LTX renal function were not related to age. In conclusion, in carefully selected candidates in their sixth and seventh decades, LTX is an acceptable operation for end-stage lung disease. The tendency of older patients to a lower incidence of late allograft rejection (acute or chronic) may reflect decreased immunological responsiveness with age.

Simultaneous single-lung transplantation and lung volume reduction

We report our experience with 2 cases of simultaneous single-lung transplantation and lung volume reduction for emphysema. The lung volume reduction was undertaken electively in an attempt to improve overall lung function above that to be expected from single-lung transplantation alone. There were no postoperative problems related to the addition of lung volume reduction. The pulmonary function at 3 months was greater than that seen in a retrospective group of bilateral lung transplants previously reported from our institution.