Eur J Cardiothorac Surg 2001;19:880-886
© 2001 Elsevier Science NL
Pretreatment surgical lymph node staging predicts results of trimodality therapy in esophageal cancer
Xiaolong Jiao,
Mark J. Krasna,
Joshua Sonett,
Ziv Gamliel,
Mohan Suntharalingam,
Austin Doyle,
Bruce Greenwald
Department of Thoracic Surgery, University of Maryland Medical System, 22 South Greene Street, Baltimore, MD 21201, USA
Received 9 October 2000;
received in revised form 21 March 2001;
accepted 4 April 2001.
Corresponding author. Tel.: +1-410-328-6366; fax: +1-410-328-0693
e-mail: mkrasna{at}smail.umaryland.edu
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Abstract
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Objective: Prediction of responders to induction therapy in esophageal cancer (EC) patients is important. In this study, we evaluated the role of thoracoscopic/laparoscopic (Ts/Ls) staging in prediction of treatment response and survival in EC patients with trimodality treatment. Methods: Retrospective study of EC patients who had undergone Ts/Ls staging and received trimodality treatment at the University of Maryland Medical Center and the Baltimore Veterans Administration Hospitals from July, 1991 to December, 1999. Preoperative therapy consisted of concurrent chemotherapy (5-FU+cisplatinum) and radiotherapy. Results: Forty-four EC patients who underwent pretreatment Ts/Ls staging during the study period were able to complete concurrent chemoradiotherapy followed by surgical resection. There were 36 men and 8 women aged 40 to 77 (median age 62). Twenty-seven (61.4%) patients were found to have lymph node metastasis by surgical staging. Fourteen patients (31.8%) had a pathologic complete response. Patients with positive lymph nodes had a lower response rate than those with negative lymph nodes (14.8% vs. 58.8%, P=0.006). Other clinicopathologic features including gender, weight loss, clinical TNM stage, surgical T stage, and histology did not correlate with treatment response. Univariate analysis showed that weight loss and treatment response were important prognostic factors for disease-free survival (P=0.01 and P=0.02, respectively). Histology, surgical N stage and surgical TNM stage appeared to be associated with prognosis (P=0.067–0.097). Multivariate analysis revealed that only surgical N status and weight loss were significant prognostic factors (P=0.05, and P=0.006, respectively). Conclusions: Surgical Ts/Ls staging provides accurate evaluation of tumor spread in EC patients. Pretreatment N status was the single most important predictor of response to induction treatment as well as a reliable prognosticator of survival.
Key Words: Esophageal Cancer • Thoracoscopy • Laparoscopy • Trimodality treatment • Staging
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1. Introduction
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Esophageal cancer (EC) will afflict 12 300 new patients in the United States in 2000. Over 11 000 patients will die of this disease annually [1]. It continues to represent a significant therapeutic challenge. The results of single modality treatment for EC patients with locally advanced disease have been poor because of a high rate of local recurrence and distant metastasis. Multimodality treatment has been introduced to enhance both local and systemic control in order to improve survival. Although the results of these clinical trials remain controversial, most studies have shown that patients who had a response to induction therapy had better survival [2]. Unfortunately, thus far it has not been possible to predict a response to chemotherapy or chemoradiotherapy with any certainty before treatment. Thus those patients who will not benefit from the neoadjuvant therapy currently still suffer the unnecessary toxicity and treatment delay. The relationship between complete and partial responders to a variety and increasing numbers of potential molecular markers for tumor responsiveness has been studied in an attempt to find markers that can identify responders to combined therapy. Few reports have studied the correlation of pretreatment surgical pathological staging to treatment response and survival for this purpose.
At the University of Maryland, thoracoscopic and laparoscopic staging techniques (Ts/Ls) have been used for clinical evaluation in EC patients for more accurate staging. Our previous studies have demonstrated that Ts/Ls can determine lymph node involvement with an accuracy over 90% [3–5]. In this retrospective study, we reviewed a cohort of patients who have undergone surgical staging prior to trimodality treatment. The purpose is to determine the relationship of pretreatment minimally invasive surgical pathologic stage with treatment response and survival, and to find the prognostic factors that will improve patient selection for combined therapy.
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2. Patients and methods
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From July 1991 to June 1999, 103 patients underwent non-invasive staging examinations including CT/MRI/EUS as well as minimally invasive staging technique using Ts/Ls to determine their potential eligibility for trimodality treatment in the University of Maryland Medical System and the Baltimore Veterans Administration Hospitals. Patients found to have evidence of metastatic disease, history of previous malignancy treated less than 5 years ago, histology other than adenocarcinoma or squamous cell carcinoma, or stage I disease were not considered to be candidates for trimodality therapy. Eligible patients had to have an Eastern Cooperative Oncology Group performance status [6] of 0 (fully active, able to carry on all predisease performance without restriction), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) or 2 (ambulatory and capable of all selfcare but unable to carry out any work activities, up and about more than 50% of waking hours) as well as adequate hematologic, renal and hepatic functions. Among 103 patients who underwent Ts/Ls staging, 59 patients were found to be potential candidates for trimodality therapy. Forty-four of these 59 patients were able to complete trimodality treatment. Fifteen patients were not able to receive trimodality treatment (four patients developed distant metastasis before surgery, three patients experienced grade 3–4 induction treatment toxicity which prevented them from surgery, one patient had T4 disease invading the aorta, two patients just finished induction treatment, waiting for surgery, and five patients refused surgery after chemoradiotherapy).
2.1. Clinical evaluation
All patients underwent a routine history and physical examination, non-invasive staging using PA and lateral chest X-ray, computerized tomographic scanning (CT) and esophageal ultrasound (EUS). Bone scans were only ordered if clinically indicated. Those patients with CT evidence of disease extension into surrounding structures underwent a MRI in order to evaluate local invasion into adjacent organs. When non-invasive staging was unequivocal for evidence of aortic or airway invasion or presence of visceral metastases, patients were not considered to be surgical candidates and were excluded from further study. Those patients with upper thoracic level primary tumors underwent bronchoscopy at the time of surgical staging. All patients also had an esophagogastroduodenoscopy (EGD) with attempt at esophageal ultrasound (EUS). Patients were assigned a clinical T stage based on the current AJCC staging criteria utilizing depth of penetration as determined either radiographically or by ultrasound [7]. Lymph node involvement was noted according to size criteria on CT as well as any EUS evidence of pathologically appearing nodes. Clinical involvement of the celiac axis was not a contraindication to inclusion in this regimen.
2.2. Surgical staging
Thoracoscopic and laparoscopic staging were performed using a previously described technique [8]. Routine biopsy of lymph node levels 4, 7, 8 and 9 (right side) or 5, 6, 7, 8, 9 (left side) were performed. Any other suspicious nodal region identified by clinical evaluation or during the operation was also sampled and labelled according to the esophageal cancer lymph node map. After nodal sampling was performed, the esophagus was examined for evidence of disease extension through the wall (T3) or into surrounding organs (T4). If no visible esophageal disease was noted, the patients was classified as T1–2 based on CT or EUS findings. Laparoscopic staging was performed at the same sitting. The surface of the liver was inspected and any gross abnormalities were biopsied. Lymph node levels 16, 17, or 20 were sampled routinely. Feeding jejunostomies and medi-ports were placed at the same sitting when indicated.
2.3. Induction therapy
Preoperative therapy consisted of concurrent chemotherapy and radiation therapy. External beam radiation was delivered with a 6–18 millivolt linear accelerator to a total dose of 50.4 Gy, given at 1.8 Gy per fraction daily, 5 days per week. The initial treatment fields were arranged according to the surgical assessment of the primary tumor and the pathologic status of the regional lymph nodes. Lateral margins were 2 cm around the gross tumor volume as defined surgically, endoscopically and by CT scan with 5 cm margins proximally and distally. Regional lymph node changes including mediastinum and celiac axis were only covered if proven to be involved at the time of surgical staging.
Chemotherapy consisted of two cycles of 5-FU and Cisplatinum beginning on day 1–29. Administration of 5-FU was as a continuous infusion over 96 h for 1000 mg/m2 per day on day 1 through day 4 and day 29 through day 32. Cisplatinum was given as a single intravenous bolus of 100 mg/m2 on day 1 and day 29. Appropriate dose reductions were made for the second cycle if significant toxicity was encountered. All patients underwent restaging by non-invasive methods including CT and EGD 4 weeks after completion of induction therapy. This allowed for recovery from the acute toxicities associated with chemoradiation and for regression of the primary disease.
2.4. Surgical resection
Surgery was scheduled for 6 weeks after the completion of induction surgery. The routine surgical procedure was an Ivor–Lewis esophagectomy (right thoracotomy and laparotomy) including a regional lymph node dissection. Anastamosis was done at the neck for patients with lesions at or about 26 cm or above. Six patients underwent a transhiatal esophagectomy due to coexisting medical conditions. Esophagectomy specimens underwent routine pathologic assessment. Pathologic response was scored as either gross residual disease, microscopic evidence of residual disease of the esophagus or microscopic residual disease in the lymph nodes (pathologic partial response, PR), and no residual disease (pathologic complete response, CR).
2.5. Statistical analysis
All patients were followed until time of death with no patient lost to follow-up. Measurements of survival were taken from the onset of therapy. Overall, disease free and cause specific survivals were estimated with the Kaplan–Meier method. Differences between the curves were determined by the log rank test. Chi-square test or Fisher's exact test was used to compare treatment response and recurrence in different groups. Statistical analysis was performed with SPSS software.
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3. Results
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3.1. Clinical results of staging and surgical resection
Among 44 patients who had surgical staging and underwent trimodality treatment, 27 (61.4%) were found to have pathologic evidence of positive lymph node involvement by Ts/Ls. Four of these patients had positive lymph nodes in the mediastinum, 21 had positive lymph nodes in the celiac axis, and two had both positive mediastinal and celiac axis lymph nodes. Fifteen of the 23 patients with positive celiac axis lymph nodes had primary tumors that were located in the distal third of the esophagus, or gastroesophageal junction. Of five patients who were thought to have clinical T4 disease by noninvasive testing, three were found to have no evidence of direct invasion into adjacent structures by thoracoscopy and were actually staged T3. Only one patient proved to be T4, the other patient was not evaluated because of pleural adhesions. Of the 26 patients with positive lymph nodes by noninvasive staging, 17 had pathologically positive lymph nodes at surgical staging. Of 18 patients who were thought to have negative lymph nodes by noninvasive staging, ten were proved to be histologically positive at surgical staging. This correlated with a sensitivity and specificity of 63%, 47% and overall accuracy of 57% with noninvasive staging. (Table 1) There was no major morbidity or mortality associated with the surgical staging procedure.
The morbidity and mortality after surgical resection was 29.5% (13/44) and 6.8% (3/44) respectively. Cardiopulmonary complications occurred in seven patients which led to a fatal result in three patients (two patients died of pulmonary emboli, one patient died of ARDS). One patient had an anastomotic leak which sealed with conservative treatment. One patient developed a chylothorax requiring surgical repair. One patient suffered a stroke on postoperative day 2 which subsequently resolved. Anastamotic strictures developed in four patients (including the patient who had anastomotic leak) which improved after repeat EGD with dilatation.
3.2. Treatment response and survival
All patients were followed up. Twenty-eight patients have died (15 died of disease, 13 died of other non-malignant courses). 13 were alive free of disease, while three patients were alive with disease. The median follow-up time for the 16 living patients is 19.5 months. The overall median survival of the entire group was 35 months. The median disease-free survival was 32 months. The projected 3-year overall and disease-free survival was 46.2% and 40.8%, respectively.
An analysis of various prognostic factors was performed to identify potential predictors of response and survival. These factors included age, sex, race, weight loss, histology, clinical T stage, clincal N stage, Ts/Ls T stage, Ts/Ls N stage, Ts/Ls TNM stage, and response to therapy. There were no survival differences regarding the factors of age, sex, race and clinical T stage and N stage. The median disease-free survival for patients with squamous cell carcinoma was longer than that of patients with adenocarcinoma (42.0 vs. 13.9 months, P=0.067).
Fourteen (31.8%) patients achieved a pathologic complete response (CR). The median disease-free survival for these patients was 33.0 months, which was longer than that of patients with non-CR (19.0 months), however, the difference was not significant. When patients with partial response (PR) were included, the total response rate was 54.5% (24/44), and this group of patients who had a response to induction therapy enjoyed a longer median survival than patients who had no response (42.0 vs. 14.0, P=0.02) (Fig. 1). The complete pathologic response rate and median survival for the 27 patients who had positive lymph nodes by pretreatment surgical staging was 14.8% and 13.0 months, respectively, while it was 58.8% and 42 months respectively for patients without lymph node involvement (P=0.006, P=0.08, respectively). (Fig. 2) Patients in pretreatment TNM stage II group had a longer median survival compared to patients in pretreatment TNM stage III group (42.0 vs. 13.0 moths, P=0.09) (Fig. 3).
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Fig. 1. Patients with response to induction therapy (CR+PR) had a better survival than patients without response (P=0.02).
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Fig. 2. The median survival of patients without pretreatment lymph node metastasis tended to be longer than patients with pretreatment lymph node metastasis (42.0 vs. 13.0 months, P=0.08).
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Fig. 3. The median survival of patients with pretreatment stage II disease tended to be longer than patients with pretreatment stage III disease (33.0 vs. 13.0 months, P=0.097).
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Three of 17 patients with Ts/Ls N0 stage were found to be N1 stage at resection, while nine of 27 patients with N1 disease had persistent lymph node metastasis. The median survival of patients who had persistent or newly found lymph node metastasis at the time of resection was shorter than that of patients without lymph node metastasis at final pathologic diagnosis, however, the difference was not significant (19 vs. 33 months, P=0.37). Among patients with pretreatment N1 disease, those who were downstaged to N0 following induction therapy had a 3-year DFS of 44.2%, while no one survived over 2 years for those who had persistent N1 disease (Table 2). When the main variables of pretreatment surgical T stage and N stage, weight loss, histology, treatment response, final pathologic T stage and N stage were included in a Cox multivariate model, only pretreatment surgical pathologic N status and weight loss were the significant prognosticators (P=0.05, P=0.006, respectively).
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Table 2. Correlation of clinicalpathologic characteristics and pretreatment surgical stage with recurrence and disease free survival (DFS)
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3.3. Patterns of failure
Of the 44 patients, 18 developed tumor recurrences. Eleven patients had single or multiple distant metastases, one patient had local disease only and six patients had both local and systemic disease failures. The sites of distant failure included liver (eight patients), peritoneum (four patients), lung (three patients), brain (one patient), ocular metastases (one patient), and kidney (one patient). Eighteen patients with squamous cell carcinoma had no local recurrence during the follow-up period, while seven of 26 patients (26.9%) with adenocarcinoma developed local recurrence (P=0.017). No difference was found in distant recurrence rate for the different histologic types. When stratified by T factors, patients with T2 disease were found to have a higher risk of local and systemic recurrence, however four of the six (66.7%) patients with T2 stage of disease had pretreatment lymph node metastasis, thus they actually had a higher TNM stage. Other factors including N stage, TNM stage, treatment response, and final surgical pathological N stage did not affect the recurrence pattern (Table 2).
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4. Discussion
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In non-small cell lung cancer (NSCLC), patients with N2 disease (ipsilateral mediastinal lymph node metastasis) have a poor prognosis. Mediastinoscopy has been used to find mediastinal lymph node metastasis pretreatment. Patients who are found to have N2 disease are usually selected as candidates for multimodality treatment trials. The bias of treatment outcome which may result from the heterogeneity of patients with different prognosis is thus minimized in NSCLC. Lymph node metastasis is also an important independent poor prognosticator for EC patients [9–11]. However, many reports on trimodality therapy in EC patients include a wide variety of patient populations with different disease stages. In part, the lack of standard patient selection criteria is due to the inability to accurately assess the extent of disease with clinical evaluation according to the current AJCC staging system. CT and EUS are the most commonly used diagnostic modalities utilized in the staging of EC. These non-invasive staging methods usually overstage or understage EC due to the lack of pathological verification and direct visualization of the diseased esophagus. They are not able to distinguish a normal lymph node from a metastatic lymph node, inflammatory nodules from metastatic nodules, and T3 lesions abutting surrounding tissue versus T4 invasive lesions [12–15]. Compared to these non-invasive staging methods, Ts/Ls has the advantage of direct visualization of the thoracic and peritoneal cavities, which provides accurate information in differentiating T3 from T4 tumors, and in assessing distant metastatic disease such as liver metastasis. Furthermore, it provides direct biopsy access to suspicious lymph nodes. Ts/Ls staging in EC patients has been shown to be superior to other staging methods [16,17]. With accurate pretreatment staging by Ts/Ls, the true effect of induction therapy on patients with different stage of disease can be evaluated.
Similar to the results of the recent clinical trial by Law et al. [18], which showed that the earlier or more favorable stages of cancer were more likely to have response to preoperative chemotherapy, we found that patients with pretreatment positive lymph node metastasis had a lower treatment response, and tended to have a poorer survival. Patients with early stage (stage II) of disease or patients who had response to induction therapy had a longer survival than patients with advanced stage of disease (stage III) or patients without response. Among the main clinicopathological factors, only pretreatment surgical N status and weight loss were the most important prognosticators. These results, on one hand, suggest that pretreatment N status might be a predictor of treatment response and survival. On the other hand, the results underscored the limitations of current induction therapy, as only patients without lymph node metastasis are likely to have significant treatment response. This is also the group of patients who have a good prognosis after curative surgery alone in prior reports. Whether the survival benefit in this group of patients is due to the effect of induction therapy or because of the favorable early stage of disease remains unknown. An interesting finding in this study is that those patients with N1 disease who were downstaged to N0 had a 3-year survival of 44.4%, while no patients with persistent N1 disease survived over 2 years. Although the difference was not significant probably because of the small size of patient group, it indicated that induction therapy might have an impact on EC patients with N1 disease. Nevertheless, a more aggressive induction therapy regimen should be considered in these patients since the CR rate of current induction therapy in these patients was lower.
The doses of radiotherapy in most of the clinical trials on trimodality treatment in EC patients have varied from 35 to 45 GY [19]. Higher total dose or higher dose per fraction has been used to enhance the local control, however, the increased dose is generally associated with increased toxicity [20,21]. In order to safely escalate doses in the preoperative setting, we must search for strategies which will allow for maximizing dose delivery to area of known disease, while minimizing dose to surrounding sensitive, normal tissue. Surgical staging with regional lymph node assessment has allowed us to limit the field of irradiation therapy without sacrificing local control or response to therapy. Local failure rates seen in our patient group is similar to previous institutional reports with a low toxicity despite a higher dose of irradiation therapy used in our study. By utilizing the results of Ts/Ls lymph node staging, we have shown that higher irradiation therapy dose of 50.4 Gy can be safely delivered during the induction phase without increasing the postoperative complication rate.
In recent years, many reports of clinical trials of multimodality treatment showed significant downstaging, however, few prospectively compared pretreatment staging to post-treatment staging. Random assignment without stratification for stage can cause a bias in either arm of these studies. Since repeat EGD, CT or EUS fails to adequately predict extent of disease, or of downstaging, more precise evaluation is necessary to determine the benefits of induction therapy among patient groups. Ts/Ls staging can meet this need by providing more accurate pretreatment surgical pathological staging information. Such information is helpful in selection of patients who may benefit from trimodality treatment, and it also allows safe escalation of irradiation therapy dosage by including the involved lymph node area only. Systemic failure still remains the primary cause of death in all patients after receiving trimodality therapy, which suggests the need of more aggressive treatment regimens or better treatment strategies.
A recently trial by Kelsen et al. [22] showed no improvement in survival or local control when comparing neoadjuvant chemotherapy to surgery alone in EC patients. This result again, highlights the controversies in multimodality treatment studies in EC patients. We believe that randomized trials with accurate pretreatment staging are essential for evaluation of the true effects of different treatment modalities. Preoperative minimally invasive surgical staging in EC patients may be used for this purpose much as the successful application of mediastinoscopy in preoperative staging for lung cancer. Such staging in EC may separate advanced disease from early local disease. Patients may be stratified into groups with similar prognosis, which allows a comparison analysis with minimal patients selection bias. Only in this way, can we answer the questions whether multimodality treatment is over surgery alone, and which patients may benefit from it.
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Footnotes
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Presented at the 14th Annual Meeting of the European Association for Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.
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Appendix A. Conference discussion
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Dr A. Lerut (Leuven, Belgium): In fact, if I look through your data, the real message in my mind is that in the N1 patients, that is 85% of the patients, there was no advantage because they were mostly nonresponders. The chemotherapy, therefore, has been useless whilst losing some precious time that you could have used for maybe a curative surgical option. In the responder group, mostly the N0 patients, that's where with primary surgery you would expect a 60% or more 5-year survival, which you didn't reach with your induction therapy. There, too, your induction therapy was of little value, if any at all. All this questions indeed the value of induction therapy and also the efforts that you are making with the patients going through two operations with in between induction chemoradiation with the morbidity that you showed. I think that in fact you are overtreating with chemoradiation in a protocol like yours and that we need to zoom in on the patients who really need induction therapy i.e. patients with multiple lymph node metastases in different compartments; the abdomen, the chest, and the neck. That's why we have been using PET scan, which is highly specific and which could reveal, especially in the neck, a number of patients with positive lymph nodes. we would consider those patients as good candidates for induction therapy. so my question is, did you have any experience with PET scan, and, if so, could you compare it with the results of your staging procedure and see whether you can get any gain from the PET scan rather than from invasive staging methods?
Dr Jiao: When we looked back to the medical literature, it's true that most of the studies show that patients with early stage disease are more likely to have a response to induction therapy. I agree that those patients actually are candidates for surgery in our minds. The important result of our study is that patients with N1-disease who were downstaged to N0 tended to have a better survival than nonresponders. So with surgical staging we can select those patients who are more likely to have response to induction therapy and those who are candidates maybe for future, more aggressive induction therapy or new treatment strategies just as you are suggesting. Regarding your question on PET scan, yes, we now have included PET scanning in our staging algorithm in our study, but so far we just have a few patients.
Dr V.V. Sokolov (Kiev, Ukraine): I have two questions. The first question is, did you compare results of multimodality treatment of adenocarcinoma and squamous cell carcinoma of the esophagus? The second question is, what is your procedure of choice in cancer of the midthoracic esophagus?
Dr Jiao: Regarding your first question, actually we did. There is no significant difference regarding response rate and survival for these two groups of patients. These data are included in our manuscript.
For your second question, at the university of Maryland, the Ivor–Lewis esophagectomy was the routine procedure, but according to my personal experience, I usually do left thoracotomy and transphrenectomy for those patients with lower esophageal cancer and cancer of the gastric cardia. For middle and upper esophageal cancer we prefer a right thoracotomy followed by laparotomy and neck approach (modified McKeown).
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Abstract
1. Introduction
