Carolyn E. Reed

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.

Worldwide esophageal cancer collaboration.

The aim of this study is to report assemblage of a large multi-institutional international database of esophageal cancer patients, patient and tumor characteristics, and survival of patients undergoing esophagectomy alone and its correlates. Forty-eight institutions were approached and agreed to participate in a worldwide esophageal cancer collaboration (WECC), and 13 (Asia, 2; Europe, 2; North America, 9) submitted data as of July 1, 2007. These were used to construct a de-identified database of 7884 esophageal cancer patients who underwent esophagectomy. Four thousand six hundred and twenty-seven esophagectomy patients had no induction or adjuvant therapy. Mean age was 62 +/- 11 years, 77% were men, and 33% were Asian. Mean tumor length was 3.3 +/- 2.5 cm, and esophageal location was upper in 4.1%, middle in 27%, and lower in 69%. Histopathologic cell type was adenocarcinoma in 60% and squamous cell in 40%. Histologic grade was G1 in 32%, G2 in 33%, G3 in 35%, and G4 in 0.18%. pT classification was pTis in 7.3%, pT1 in 23%, pT2 in 16%, pT3 in 51%, and pT4 in 3.3%. pN classification was pN0 in 56% and pN1 in 44%. The number of lymph nodes positive for cancer was 1 in 12%, 2 in 8%, 3 in 5%, and >3 in 18%. Resection was R0 in 87%, R1 in 11%, and R2 in 3%. Overall survival was 78, 42, and 31% at 1, 5, and 10 years, respectively. Unlike single-institution studies, in this worldwide collaboration, survival progressively decreases and is distinctively stratified by all variables except region of the world. A worldwide esophageal cancer database has been assembled that overcomes problems of rarity of this cancer. It reveals that survival progressively (monotonically) decreased and was distinctively stratified by all variables except region of the world. Thus, it forms the basis for data-driven esophageal cancer staging. More centers are needed and encouraged to join WECC.

Endoscopic ultrasound with fine-needle aspiration in the Diagnosis and staging of lung cancer

BACKGROUND Esophageal endoscopic ultrasonographic (EUS) guidance for fine-needle aspiration (FNA) of mediastinal lymph nodes has been introduced only recently. The utility of EUS/FNA in diagnosing and staging bronchogenic carcinoma is unknown. METHODS After a thoracic computed tomographic scan, 27 patients with known or suspected lung cancer underwent EUS. Accessible abnormal mediastinal lymph nodes were aspirated under EUS guidance. Patients with positive cytologic studies did not undergo further testing, whereas the remaining patients underwent mediastinal exploration. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated for both chest computed tomography and EUS/FNA: RESULTS Twenty-two of 27 patients had mediastinal adenopathy by computed tomography scan. Sixteen patients had positive findings on EUS, 15 with positive FNA (10 non-small cell lung cancer; 5 small cell lung cancer) and 1 with T4 status. Fourteen patients with positive FNA had lymph nodes sampled at level 5, level 7, or both. Of 11 patients with negative EUS/FNA, 2 had positive findings at operation (sensitivity 89%). The diagnosis of lung cancer was established in 7 patients. CONCLUSIONS The results showed that EUS/FNA improves the accuracy of computed tomographic scan in the staging of lung cancer. By accessing lymph nodes at levels 5 and 7, EUS/FNA complements mediastinoscopy and is considered the staging modality of choice in these regions. Positive EUS/FNA can obviate the need for further invasive staging.

Optimum lymphadenectomy for esophageal cancer.

Objective:Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy. Summary Background Data:What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data. Methods:A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression. Results:For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4. Conclusions:Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and ≥7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and ≥30 for pT3/T4 is recommended.

Pulmonary complications after esophagectomy.

BACKGROUND Pulmonary complications are common in patients who have undergone esophagectomy. There are no good predictive variables for these complications. In addition, the role that preoperative treatment with chemotherapy and radiation may play in postoperative complications remains unclear. METHODS We performed a retrospective review of all patients who underwent esophagectomy by a single surgeon at our institution over a 6-year period. Data were analyzed for a correlation between patient risk factors and pulmonary complications, including mortality, prolonged mechanical ventilation, and hospital length of stay. RESULTS Complete data were available on 61 patients. Nearly all patients had some pulmonary abnormality (eg, pleural effusion), although most of these were clinically insignificant. Pneumonia was the most common clinically important complication, and 19.7% of patients required prolonged ventilatory support. Significant risk factors identified included impaired pulmonary function, especially for patients with forced expiratory volume in 1 second (FEV1) less than 65% of predicted, preoperative chemoradiotherapy, and age. CONCLUSIONS Impaired lung function is a significant risk factor for pulmonary complications after esophagectomy. Patients with FEV1 less than 65% of predicted appear to be at greatest risk. There also seems to be an associated risk of preoperative chemoradiotherapy for pulmonary complications after esophagectomy.

Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung

BACKGROUND Endoscopic ultrasound (EUS)-guided fine needle aspiration is a safe, cost-effective procedure that can confirm the presence of mediastinal lymph node metastases and mediastinal tumor invasion. We studied the accuracy of EUS in a large population of lung cancer patients with and without enlarged mediastinal lymph nodes on computed tomographic (CT) scan. METHODS From 1996 to 2000 all patients referred to our institution with lung tumors and no proven distant metastases were considered for EUS and surgical staging. Patients had endoscopic ultrasound with fine needle aspiration of abnormal appearing mediastinal lymph nodes and evaluation for mediastinal invasion of tumor (stage III or IV disease). Patients without confirmed stage III or IV disease had surgical staging. RESULTS Two hundred seventy-seven patients met the inclusion criteria, including 121 who had EUS. Endoscopic ultrasound and fine needle aspiration detected stage III or IV disease in 85 of 121 (70%). Among patients with enlarged lymph nodes on CT, 75 of 97 (77%) had stage III or IV disease detected by EUS. Among a small cohort of patients without enlarged mediastinal lymph nodes on CT, 10 of 24 (42%) had stage III or IV disease detected by EUS. For mediastinal lymph nodes only, the sensitivity of endoscopic ultrasound and CT was 87%. The specificity of EUS (100%) was superior to that of CT (32%) (p < 0.001). CONCLUSIONS Endoscopic ultrasound with fine needle aspiration identified and histologically confirmed mediastinal disease in more than two thirds of patients with carcinoma of the lung who have abnormal mediastinal CT scans. Although mediastinal disease was more likely in patients with an abnormal mediastinal CT, EUS also detected mediastinal disease in more than one third of patients with a normal mediastinal CT and deserves further study. Endoscopic ultrasound should be considered a first line method of presurgical evaluation of patients with tumors of the lung.

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

Esophageal Cancer Staging: Improved Accuracy by Endoscopic Ultrasound of Celiac Lymph Nodes

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.

Predictors of survival for esophageal cancer patients with and without celiac axis lymphadenopathy: impact of staging endosonography

BACKGROUND Clinical staging of esophageal cancer is required for optimal therapy but remains imprecise. Pathologic verification of involved lymph nodes could potentially direct treatment allocation. With the rising incidence of distal and gastroesophageal junction adenocarcinomas, assessment of the celiac axis lymph nodes (CLNs) becomes important because it is a common nodal drainage basin. Endoscopic ultrasound (EUS) permits evaluation of CLNs and biopsy by fine-needle aspiration. This study examined the usefulness of this staging tool. METHODS A consecutive series of 62 patients with esophageal cancer considered resectable by computed tomographic scan underwent EUS for T and N staging and were retrospectively studied. A CLN visualized by EUS as greater than 5 mm was considered positive. Fine-needle aspiration of the CLN was performed routinely. Endoscopic ultrasound and computed tomographic staging were compared on the basis of pathologic verification of CLNs. RESULTS It was possible to evaluate CLNs by EUS in 59 (95%) of 62 patients: positive in 19, negative in 40. In EUS-positive patients, fine-needle aspiration was positive in 15, falsely negative in 2, and not done in 2. By computed tomographic scan, CLNs were negative in 57 patients and positive in 2. The CLNs were positive in 23 of 54 patients eligible for CLN pathologic verification. All positive CLNs not identified by EUS (7 false-negative EUS) were microscopic foci in one or two nodes and were associated with T3 tumors. Sensitivity and specificity of EUS were 72% and 97%, respectively, compared with 8% and 100% for computed tomographic scan. When EUS identified CLNs, fine-needle aspiration confirmed positivity in 88% of cases. CONCLUSIONS Endoscopic ultrasound with fine-needle aspiration is useful in the detection and confirmation of CLN metastasis. In T3 tumors of the distal esophagus, a negative EUS result does not substantiate absence of CLN disease. Endoscopic ultrasound with fine-needle aspiration may be important in guiding treatment for patients with distal adenocarcinoma and documenting disease before neoadjuvant therapy.

CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer

BACKGROUND Esophageal cancer patients with M1a disease are reported to have poor survival. We hypothesized that patients with celiac lymph node metastases (CLN) identified by endoscopic ultrasonography (EUS) would predict a cohort with significantly worse survival postoperatively. Accurate preoperative identification of this group will facilitate future adjuvant studies. METHODS During the study period, 211 patients with esophageal cancer underwent EUS staging. Patients with evaluable celiac axis (n = 182) were included in this study. Survival of patients with and without CLNs was compared and the factors affecting overall survival were assessed. A subgroup analysis based on CLN status was performed in the subgroup of patients who underwent surgical procedures. RESULTS Follow-up data was available in 91.2% (166 of 182) of the patients. As staged by EUS, T1, T2, T3, and T4 tumors accounted for 9.3%, 11.5%, 56%, and 21% of the cases, respectively. At least one CLN was imaged by EUS in 40% (72 of 182). The 5-year survival in patients with CLNs detected by EUS was 13% (95% confidence interval, 5% to 21%) compared with 30% (95% confidence interval, 21% to 40%) in patients with no CLNs detected by EUS (p = 0.007). In the subgroup of patients who underwent surgical procedures (n = 68), patients with CLN involvement had worse survival compared with those who did not have malignant involvement of CLNs at the time of their operation (median survival 39.8 versus 13.8 months, p = 0.0008). In a Cox proportional model, adjusting for race and the type of therapy, patients with CLN involvement or advanced EUS American Joint Committee on Cancer stage were more likely to have worse survival (p < 0.05) CONCLUSIONS EUS base line findings correlate with long term survival in patients with esophageal cancer. Patients with M1a disease as identified by EUS had a significantly worse postoperative survival when compared with non-M1a patients. This cohort of patients will be ideal for the study of induction therapy since the effect of down staging can be assessed before operation.