Mark J. Krasna

Phase III Trial of Trimodality Therapy With Cisplatin, Fluorouracil, Radiotherapy, and Surgery Compared With Surgery Alone for Esophageal Cancer: CALGB 9781

PURPOSE The primary treatment modality for patients with carcinoma of the esophagus or gastroesophageal junction has been surgery, although primary radiation therapy with concurrent chemotherapy produces similar results. As both have curative potential, there has been great interest in the use of trimodality therapy. To this end, we compared survival, response, and patterns of failure of trimodality therapy to esophagectomy alone in patients with nonmetastatic esophageal cancer. PATIENTS AND METHODS Four hundred seventy-five eligible patients were planned for enrollment. Patients were randomly assigned to either esophagectomy with node dissection alone or cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 concurrent with radiation therapy (50.4 Gy total: 1.8 Gy/fraction over 5.6 weeks) followed by esophagectomy with node dissection. RESULTS Fifty-six patients were enrolled between October 1997 and March 2000, when the trial was closed due to poor accrual. Thirty patients were randomly assigned to trimodality therapy and 26 were assigned to surgery alone. Patient and tumor characteristics were similar between groups. Treatment was generally well tolerated. Median follow-up was 6 years. An intent-to-treat analysis showed a median survival of 4.48 v 1.79 years in favor of trimodality therapy (exact stratified log-rank, P = .002). Five-year survival was 39% (95% CI, 21% to 57%) v 16% (95% CI, 5% to 33%) in favor of trimodality therapy. CONCLUSION The results from this trial reflect a long-term survival advantage with the use of chemoradiotherapy followed by surgery in the treatment of esophageal cancer, and support trimodality therapy as a standard of care for patients with this disease.

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

Patients with Barretts esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2′-deoxycytidine (Aza-C) treatment. Real-time RT–PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33–2.20), RUNX3 (OR 1.80, 95% CI 1.08–2.81), and HPP1 (OR 1.77, 95% CI 1.06–2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

An analysis of multiple staging management strategies for carcinoma of the esophagus: computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy

BACKGROUND This study compares the health care costs and effectiveness of multiple staging options for patients with esophageal cancer. Techniques studied included computed tomographic (CT) scan, endoscopic ultrasound with fine-needle aspiration biopsy (EUS-FNA), positron emission tomography (PET), thoracoscopy/laparoscopy, and combinations of these. METHODS A decision-analysis model was constructed to compare different staging strategies. Costs were derived from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases and from other Medicare reimbursement rates. Life expectancies were obtained from the 1973-1996 SEER database and adjusted for quality of life. Cost and effectiveness measures were discounted at 0% and 3% per year. Sensitivity and specificity measures were obtained from the published literature and a parallel prospective clinical trial, and all key variables were subjected to sensitivity analyses. RESULTS Under baseline assumptions, CT + EUS-FNA was the most inexpensive strategy and offered more quality-adjusted life-years, on average, than all other strategies with the exception of PET + EUS-FNA. The latter was slightly more effective but also more expensive. The marginal cost-effectiveness ratio for PET + EUS-FNA was

Global gene expression profiling in Barrett's esophagus and esophageal cancer: a comparative analysis using cDNA microarrays

60,544 per quality-adjusted life-year. These findings were robust and changed very little in all of the sensitivity analyses. CONCLUSIONS The combination of PET + EUS-FNA should be the recommended staging procedure for patients with esophageal cancer, unless resources are scarce or PET is unavailable. In these instances, CT + EUS-FNA can be considered the preferred strategy.

Superior sulcus (Pancoast) tumor: experience with 105 patients

In order to identify and contrast global gene expression profiles defining the premalignant syndrome, Barretts esophagus, as well as frank esophageal cancer, we utilized cDNA microarray technology in conjunction with bioinformatics tools. We hybridized microarrays, each containing 8000 cDNA clones, to RNAs extracted from 13 esophageal surgical or endoscopic biopsy specimens (seven Barretts metaplasias and six esophageal carcinomas). Hierarchical cluster analysis was performed on these results and displayed using a color-coded graphic representation (Treeview). The esophageal samples clustered naturally into two principal groups, each possessing unique global gene expression profiles. After retrieving histologic reports for these tissues, we found that one main cluster contained all seven Barretts samples, while the remaining principal cluster comprised the six esophageal cancers. The cancers also clustered according to histopathological subtype. Thus, squamous cell carcinomas (SCCAs) constituted one group, adenocarcinomas (ADCAs) clustered separately, and one signet-ring carcinoma was in its own cluster, distinct from the ADCA cluster. We conclude that cDNA microarrays and bioinformatics show promise in the classification of esophageal malignant and premalignant diseases, and that these methods can be applied to small biopsy samples.

Biologic lung volume reduction in advanced upper lobe emphysema: phase 2 results.

BACKGROUND The evolution of therapy in 105 patients with superior sulcus (Pancoast) tumor over the past 42 years was reviewed. METHODS There were 82 men and 23 women aged 30 to 75 years. Tumor cell types were: squamous, 41 (39%); adenocarcinoma, 23 (21.9%); anaplastic, 14 (13.3%); undetermined, 12 (11.4%); mixed, 9 (8.7%); and large cell 6 (5.7%). Therapy was based on extent of disease and lymph node involvement. There were 5 treatment groups: I, preoperative radiation and operation (n = 28); II, operation and postoperative radiation (n = 16); III, radiation (n = 37); IV, preoperative chemotherapy, radiation, and operation (n = 11); and V, operation (n = 12). RESULTS The median survival for group I was 21.6 months; group II, 6.9 months; group III, 6 months; and group V, 36.7 months. Median survival for group IV has not yet been reached (estimated at 72% at 5 years). On univariate analysis, mediastinal lymph node involvement, Horner syndrome, TNM classification, and method of therapy affected survival. On multivariate regression analysis, only N2 and N3 disease and method of therapy were significant (p < 0.05). CONCLUSIONS The optimal treatment for superior sulcus tumor was preoperative radiation and operation. However, triple modality therapy, although promising, requires longer follow-up.

Combined thoracoscopic/laparoscopic staging of esophageal cancer

RATIONALE Biologic lung volume reduction (BioLVR) is a new endobronchial treatment for advanced emphysema that reduces lung volume through tissue remodeling. OBJECTIVES Assess the safety and therapeutic dose of BioLVR hydrogel in upper lobe predominant emphysema. METHODS Open-labeled, multicenter phase 2 dose-ranging studies were performed with BioLVR hydrogel administered to eight subsegmental sites (four in each upper lobe) involving: (1) low-dose treatment (n = 28) with 10 ml per site (LD); and (2) high-dose treatment (n = 22) with 20 ml per site (HD). Safety was assessed by the incidence of serious medical complications. Efficacy was assessed by change from baseline in pulmonary function tests, dyspnea score, 6-minute walk distance, and health-related quality of life. MEASUREMENTS AND MAIN RESULTS After treatment there were no deaths and four serious treatment-related complications. A reduction in residual volume to TLC ratio at 12 weeks (primary efficacy outcome) was achieved with both LD (-6.4 +/- 9.3%; P = 0.002) and HD (-5.5 +/- 9.4%; P = 0.028) treatments. Improvements in pulmonary function in HD (6 mo: DeltaFEV(1) = +15.6%; P = 0.002; DeltaFVC = +9.1%; P = 0.034) were greater than in LD patients (6 mo: DeltaFEV(1) = +6.7%; P = 0.021; DeltaFVC = +5.1%; P = 0.139). LD- and HD-treated groups both demonstrated improved symptom scores and health-related quality of life. CONCLUSIONS BioLVR improves physiology and functional outcomes up to 6 months with an acceptable safety profile in upper lobe predominant emphysema. Overall improvement was greater and responses more durable with 20 ml per site than 10 ml per site dosing. Clinical trial registered with www.clinicaltrials.gov (NCT 00435253 and NCT 00515164).

A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms

Unlike mediastinoscopy in lung cancer, there exists no standard minimally invasive test to stage esophageal cancer. If it were possible to obtain exact preoperative staging in esophageal cancer, patients could be separated prospectively to receive neoadjuvant therapy appropriately. We studied the feasibility and efficacy of thoracoscopic and laparoscopic lymph node staging in esophageal cancer. Thoracoscopic staging was performed in 45 patients with biopsy-proven carcinoma of the esophagus. Laparoscopic staging was done in the last 19 patients. Thoracoscopic staging was aborted in three patients because of adhesions. Thoracic lymph node stage was N0 in 39 patients and N1 in three; celiac lymph nodes were normal in 13 and diseased in six. Esophageal resection was performed in 30 patients after thoracoscopic staging; 17 of these underwent laparoscopic staging. Thoracoscopic staging showed N0 lymph node status in 28 patients and N1 in two patients. Two of the 28 patients (7%) with N0 disease were found at resection to have paraesophageal lymph node involvement (N1); thus the disease was understaged by thoracoscopic staging. Thoracoscopic staging was accurate in detecting the presence of diseased thoracic lymph nodes in 28 of 30 cases (93%). Laparoscopic staging detected normal celiac nodes in 12 patients and diseased lymph nodes in five patients. After esophagectomy, the final pathology report in the 12 patients with N0 disease was N0 in 11 and diseased lymph nodes in one patient. Thus laparoscopic staging was accurate in detecting lymph node metastases in 16 of 17 patients (94%). Thoracoscopic and laparoscopic staging are more accurate than existing staging methods. Six of 19 patients in whom laparoscopic staging was used had unsuspected celiac axis lymph node involvement that had been missed by standard noninvasive techniques. One of three patients with thoracic lymph nodes and three of six with celiac lymph nodes were downstaged after preoperative chemotherapy/radiotherapy. The role of thoracoscopy and laparoscopy in staging esophageal cancer should be further evaluated in a multiinstitutional trial.

Clinical significance of micrometastasis in lung and esophageal cancer: a new paradigm in thoracic oncology

BACKGROUND & AIMS Numerous gastrointestinal tumors, notably sporadic and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias, gastric cancers, and esophageal carcinomas, manifest microsatellite instability. Recently, a transforming growth factor beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in colorectal carcinomas showing instability. One hundred thirty-eight human neoplasms (61 UC-associated, 35 gastric, 26 esophageal, and 16 sporadic colorectal) were evaluated for this TGF-beta 1RII mutation. METHODS Whether instability was present at other chromosomal loci in these lesions was determined. In lesions manifesting or lacking instability, the TGF-beta 1RII coding region polydeoxyadenine (poly A) microsatellite tract was polymerase chain reaction amplified with 32P-labeled deoxycytidine triphosphate. Polymerase chain reaction products were electrophoresed on denaturing gels and exposed to radiographic film. RESULTS Three of 18 UC specimens with instability at other chromosomal loci (17%) showed TGF-beta 1RII poly A tract mutation, including 2 cancers and 1 dysplasia; moreover, 2% of UC specimens without instability (1 of 43) (1 cancer), 81% of unstable sporadic colorectal cancers (13 of 16), and none of the 61 stable or unstable gastric or esophageal cancers contained TGF-beta 1RII mutations. CONCLUSIONS Mutational inactivation of the poly A microsatellite tract within TGF-beta 1RII occurs early and in a subset of unstable UC neoplasms and commonly in sporadic colorectal cancers but may be rare in unstable gastric and esophageal tumors.

Hemodynamic effects of carbon dioxide insufflation during thoracoscopy

In the past decade, detection of micrometastatic disease in different clinical samples including pleural lavage, lymph node, bone marrow, and blood has become a rapidly growing area of interest in research of non-small cell lung cancer and esophageal cancer. The results of these studies support the concept that, just as in many other solid malignancies, systemic spread may happen at an early stage in non-small cell lung cancer and esophageal cancer. Such systemic spread is often occult (micrometastases) at the time of primary diagnosis, which may have adverse effects on survival. Improved staging can be expected with information on micrometastases, and a subgroup of patients who will benefit most from adjuvant therapy might be identified. Although reliable and standard methods need to be developed before detection of micrometastasis is incorporated in the routine clinical practice, we suggest that it be considered an important correlate in clinical trials in non-small cell lung cancer and esophageal cancer.