Annals of Oncology Advance Access originally published online on October 3, 2008
Annals of Oncology 2009 20(2):231-238; doi:10.1093/annonc/mdn622
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gastrointestinal tumors |
Histological type of esophageal cancer might affect response to neo-adjuvant radiochemotherapy and subsequent prognosis
1 Department of General-, Visceral- and Cancer Surgery, University of Cologne
2 Institute of Pathology, University of Cologne, Cologne
3 Institute of Pathology, University of Düsseldorf, Düsseldorf
4 Department of Radiation Oncology, University of Cologne, Cologne, Germany
* Correspondence to: Prof. E. Bollschweiler, Klinik und Poliklinik für Allgemein-, Visceral- und Tumorchirurgie, der Universität zu Köln, Kerpener Str. 62, 50937 Köln, Germany. Tel: +49-221-478 6273; Fax: +49-221-478 5076; E-mail: elfriede.bollschweiler{at}uk-koeln.de
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abstract |
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Background: This study investigates response and prognosis after neo-adjuvant chemoradiation (CTx/RTx) in patients with advanced esophageal carcinoma, according to histological type.
Patients and methods: Patients with uT3 carcinoma of the esophagus treated with curative-intention esophagectomy from 1997 until 2006 were included in this retrospective analysis. Patients receiving preoperative CTx/RTx (5-fluorouracil, cisplatin, 36 Gy) were compared with those with primary surgery for pT3 tumors. Therapy response after CTx/RTx was evaluated using ‘Cologne Regression Grade’ (minor response: 
10% vital residual tumor cells (VRTCs), major response: <10% VRTC or pathologic complete response). Prognosis was evaluated for adenocarcinoma (AC) and squamous cell carcinoma (SCC).
Results: Of 297 patients, 52% were SCC and 48% AC. In all, 192 patients underwent CTx/RTx, 100 (65%) SCC and 92 (64%) AC (nonsignificant). In SCC group 51% and in AC group 29% achieved major response (P < 0.01). Patients with major response had a 2-year survival rate (2y-SR) of 78% versus those with minor response or without CTx/RTx, with a 2y-SR of 45% (P = 0.001). Examining patients with major response exclusively, the prognosis of AC (2y-SR 85%) is better than that of SCC (2y-SR 54%) (P < 0.01).
Conclusion: This retrospective study concludes that in esophageal tumors, response to and prognosis after neo-adjuvant CTx/RTx vary according to histology.
Key words: adenocarcinoma squamous cell carcinoma, esophageal cancer, lymph node metastases, neo-adjuvant chemoradiation, prognosis
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introduction |
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Topabstractintroductionpatients and methodsresultsdiscussionconclusionreferences |
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Increasingly, neo-adjuvant therapies are the standard of care in the treatment of advanced esophageal carcinoma [1]. A number of meta-analyses have been published investigating the effects of preoperative chemo- or radiochemotherapy compared with surgery alone [2–6]. Studies with neo-adjuvant chemotherapy plus surgery compared with surgery alone did not demonstrate a survival benefit for patients receiving neo-adjuvant therapy [2, 7]. In contrast, neo-adjuvant chemoradiation plus surgery improved 3-year survival and reduced local–regional cancer recurrence. CTx/RTx was associated with a lower rate of esophageal resection, but a higher rate of complete (R0) resection. There was a (nonsignificant) trend toward increased treatment mortality after neo-adjuvant chemoradiation [4]. Similar results have been found by other authors [3, 5, 6]. In these reviews, no differentiation of histological tumor type [squamous cell carcinoma (SCC) or adenocarcinoma (AC)] was made.
Radiation therapy plays an important role in the treatment of esophageal SCC and is used for both definitive treatment and the neo-adjuvant approach [8]. On the other hand, for patients with AC of the esophagus or the gastroesophageal junction and stomach, the clinical benefit of radiation remains a contentious issue. Surgical resection still plays the decisive role in the treatment of these tumor entities.
SCC and AC of the esophagus are assumed to have differing biological behavior and this influences treatment choices. Some authors have classified AC as a primarily systemic disease [9, 10]. They propose different treatment approaches for each tumor entity, especially when neo-adjuvant therapy strategies are discussed [11]. In studies comparing the effectiveness of neo-adjuvant radiochemotherapy with that of surgery alone for esophageal cancer, the investigators generally include either SCC patients alone or both histological types. Very few groups have investigated patients with AC exclusively. In the first such study, treatment was not carried out using current standards of optimal fractionation and dosage and yet neo-adjuvant radiochemotherapy still achieved a complete response (CR) rate of 25% [12]. Gebski et al. [13] analyzed the treatment effects by tumor type, showing more benefits of radiochemotherapy in patients with AC compared with SCC. Randomized studies like the MAGIC trial [14] and the SWOG trial [15] have given new impetus to the debate regarding the value of chemotherapy and radiotherapy in these patients.
The aim of the current retrospective study was to analyze response and prognosis after neo-adjuvant radiochemotherapy, comparing patients with advanced SCC and AC of the esophagus.
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patients and methods |
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patients
In all, 523 patients with esophageal cancer were treated at the Department of Surgery between 1 January 1997 and 31 December 2006. Sixty-four patients received nonsurgical palliative treatment due to advanced disease or functional inoperability. A total of 459 patients were treated with surgical resection. Of these, 297 patients had uT3 or uT4 tumors according to endosonography (154 SCC and 143 AC) and were included in the study. Written informed consent was obtained from all patients.
staging
Tumor–node–metastasis (TNM) staging was carried out according to the criteria of the International Union Against Cancer [16]. Clinical staging was on the basis of the results from barium swallow examination, endoscopy, endoscopic ultrasound, and computed tomography (CT) of chest and abdomen (4 mm sections). Endoscopy and endoscopic ultrasound were carried out in a standardized manner for all patients.
therapy
Treatment of choice was subtotal en bloc esophagectomy using a right transthoracic approach including two-field lymphadenectomy of mediastinal and abdominal lymph nodes [17]. In 34 cases, a transhiatal subtotal esophagectomy was carried out because of poor physical condition or special situations [18]. The specimens were removed en bloc, including the lymph nodes. To ensure primary tumor integrity, the lymph nodes were dissected partially in the operating theater and partially by pathologists according to a standardized protocol. The examined lymph nodes were documented according to the sixth edition of the TNM classification [16]. The median number of examined lymph nodes was 27 (minimum 2 to maximum 58) for SCC and 28 (minimum 11 to maximum 74) for AC (difference not significant).
Standard reconstruction for patients receiving transthoracic esophagectomy was done by stomach interposition with high intrathoracic esophagogastrostomy [17]. After January 2004, laparoscopic mobilization of the stomach including the cardia and preparation of the gastric conduit was done with esophagectomy and reconstruction by gastric pull-up and intrathoracic esophagogastrostomy in a two-time setting (see [19]). Two patients underwent esophagogastrectomy, with colon interposition. The R0 resection rate was 93% (n = 276); R1, n = 20 and R2, n = 1.
Locally advanced tumors (uT2–4) were included in this study unless documented systemic metastases or bronchoscopically proven invasion of the tracheobronchial tree was present. Preoperative risk factors of all patients were monitored with standardized criteria: a composite risk score to evaluate the pulmonary, cardiovascular, hepatic, renal, and endocrine function as well as the general health status of patients using objective and subjective parameters [20, 21]. Patients with higher risk received no preoperative therapy (risk score >21 points according to risk analysis). Limits for neo-adjuvant chemoradiation were set for ages 75 years or younger, and creatinine clearance at least 60 ml/min. Patients with liver cirrhosis were also excluded. Patients with previous malignancies were disallowed, with the exception of surgically cured basal cell skin cancer and carcinoma in situ of the cervix.
One hundred and ninety-two patients (65%) received preoperative radiochemotherapy according to a standardized protocol, which is described in detail elsewhere [22]. Patients with uT2 tumors were offered this treatment protocol when CT showed a tumor mass compatible with a T3 category while endoscopic ultrasound showed complete invasion of the muscularis propria without clear invasion of the adventitia (so-called ‘near T-3 categories’). Cisplatin (20 mg/m2/day) was administered as a short-term infusion on days 1–5 and 5-fluorouracil (5-FU) (1000 mg/m2/day) as a continuous infusion over 24 hours on days 1–5. Radiation therapy was administered by linear accelerators with 10–15 MV photons. Radiation therapy was planned to encompass the tumor volume with 5 cm cephalocaudal margins and 2 cm radial margins, and the planning target volume included enlarged regional nodes based on CT evaluation and endoscopic ultrasound. Radiation was delivered in daily fractions of 1.8 Gy (days 1–5, 8–12, 15–19, and 22–26) to a total dose of 36 Gy using a multiple field technique. Surgical resection was carried out 4–5 weeks following completion of chemoradiation, after clinical restaging.
The control group consisted of 105 patients with resected esophageal cancer who were staged as pT3 tumor but received no preoperative chemoradiation. The reasons for primary surgical resection were exclusion criteria for chemoradiation like comorbidity, age, lack of patient consent, etc.
pathology
Histopathologic examination of all resected specimens consisted of thorough evaluations of tumor stage, residual tumor (R) category, grading, and number of examined and involved lymph nodes.
The lymph nodes were counted and the maximum diameter of each node was measured with a slide gauge. A series of sections from each node was selected and stained with hematoxylin and eosin as well as with periodic acid-Schiff. All dissected lymph nodes were microscopically analyzed for metastatic disease. The ratio of the number of involved to examined regional lymph nodes was termed the ‘lymph node ratio’ [18]. The ratio of 0.2 was used as a cut-off point to differentiate advanced lymph node infiltration [23]. According to the sixth edition of the TNM classification for tumors of the lower thoracic esophagus, metastasis in the celiac lymph node group (LNG 9) was classified as M1a and in other nonregional locations as M1b [16]. After neo-adjuvant therapy, the pathological assessment is difficult because of possible tumor regression. Thus, such a classification is identified with the prefix ‘y’ to indicate decreased reliability compared with the pTNM classification after surgery alone.
histopathologic response classification
The degree of histomorphologic regression was classified into four categories (Cologne Regression Grade): grade I >50% vital residual tumor cells (VRTCs), grade II 10%–50% VRTC, grade III nearly complete response with <10% VRTC, and grade IV CR [22, 24]. This analysis was carried out by two independent staff pathologists who were blinded to all other clinical data. Due to prognostic implications, regression grades III and IV were classified as major histomorphologic response compared with grades I and II, which constituted minor histopathologic response. Histopathologic tumor regression is the most significant independent prognostic indicator [22].
statistics
Beginning in 1997, data were collected prospectively according to a standardized protocol. The median, with the lower (LQ) and upper (UQ) quartiles, was used for descriptive statistics. Chi-square statistics were calculated for frequencies of factors with a significance level of P < 0.05.
The median follow-up time was calculated using the time between the date of surgery and the date for patients reaching the end point and the time between surgery and the date of censoring for censored patients [25]. The median follow-up time of the patients was 4.5 years (range 1.0–11.2 years).
Kaplan–Meier plots were used to describe survival distribution [26]. The log-rank test was used to evaluate for survival differences [27]. For multiple comparisons, the Holm–Sidak method was used. In addition, 95% confidence intervals (CIs) for the different survival curves were calculated. Postoperative mortality was not included in the calculation of prognosis. The 30-day postoperative mortality was 3.0%. The multivariate analysis of survival used Cox regression analysis to identify independent prognostic variables. The level of significance was set to P < 0.05.
All statistical analyses were carried out using the statistic program SPSS for Windows version 15.0. For graphic presentation of the results, MedCalc version 9.3 was used.
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results |
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In all, 297 patients were included in the study. Gender distribution was 235 (79%) males and 62 females. The median age was 61 years: the youngest patient was 21 and the oldest 81 years old. Table 1 compares the demographics and tumor characterization of the different histological types.
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response evaluation
In all, 192 of the patients with advanced esophageal carcinoma received preoperative chemoradiation. The frequency of neo-adjuvant therapy use did not differ according to histologic tumor type (Table 1). Patients with SCC showed significantly more frequent tumor size reduction characterized by ypT category than those with AC (Table 2). Comparing histomorphologic tumor regression, only one-third of 92 AC patients showed major histomorphologic response (CR or <10% vital tumor cells) after neo-adjuvant radiochemotherapy. In contrast,
50% of patients with SCC were major responders (P < 0.01) (Table 3).
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The median number of lymph node metastases (LNM) in all patients was 1 (LQ = 1; UQ = 2). The rate of pN0 cases differed significantly (P < 0.001) for patients without neo-adjuvant therapy (25% pN0), compared with those with minor response (39% ypN0) and with major response (71% ypN0). In addition, the number of LNM in pN1 cases differed according to therapeutic procedure and response rate (Figure 1). There were no differences between the two histologic types regarding the frequency of pN0/pN1 cases or ypN0/ypN1 cases for the different procedures (Table 4), but patients without RTx/CTx or those with minor response had significantly higher rates of LNM in AC tumors compared with SCC (Table 4).
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prognosis
The median survival time for all patients was 1.7 years (95% CI 1.3–2.1 years) and the 5-year survival rate was 23.4% (95% CI 17% to 30%). There was no significant difference in the survival of patients with esophageal AC (median survival 1.9 years, 95% CI 1.1–2.3 years) versus SCC (median survival 1.7 years, 95% CI 1.2–2.1 years). Patients with major response had significantly better prognosis, with a 2-year survival rate (2y-SR) of 78%, versus those with minor response or without CTx/RTx, with a 2y-SR of 45% (P = 0.001).
The univariate survival analysis for cases with R0 resection showed significant prognostic impact only for major response after neo-adjuvant therapy (Figure 2) and pN/pM category. In the multivariate analysis, only age, presence of lymph node metastasis, and distant metastasis were independent prognostic factors (Table 5).
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Analyzing both histologic types separately, the prognosis was not significantly different for SCC patients without neo-adjuvant therapy compared with those with minor or major responses (Figure 3). Only patients with path CR showed a relevant survival benefit compared with the other groups (Table 3). Of patients showing a major response, the prognosis of AC (2y-SR 85%) was better than that of SCC (2y-SR 54%). With multivariate analysis, the pN category was the only significant prognostic factor (P < 0.01). In contrast, AC patients with major response showed a 5-year survival rate of 71%, a significant improvement over those with minor response or without RTx/CTx (Table 3 and Figure 4). In addition, compared with surgery-only patients, major response (P = 0.001), as well as pN (P < 0.001) and pM (P < 0.001) categories, was significant in multivariate analysis.
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discussion |
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Topabstractintroductionpatients and methodsresultsdiscussionconclusionreferences |
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The results of this study confirm the findings of previous studies that the use of appropriate neo-adjuvant therapies in patients with esophageal carcinoma can lead to reductions in both tumor size and stage according to the pN category [3–6]. After induction therapy, SCCs showed significantly more frequent tumor regression (50% major response) than ACs (33% major response). This was true not only for major regression but also for the frequency of path CRs, which in this cohort was 22% of SCC and 7% of AC patients. This appears to confirm the prevailing opinion that AC responds less than SCC to radiation [28]. Geh et al. systematically reviewed the benefits of radiation as well as response rates from neo-adjuvant chemoradiation with 5-FU, including studies published between 1983 and 1997. Of 1012 patients included, only 367 had esophageal AC. Studies including SCC exclusively have shown an average CR rate of 25% and those with AC 17% [29]. Similar results have been reported from Ireland with a path CR of 19% for AC and 33% for SCC [30]. However, in many studies investigating the use of neo-adjuvant radiochemotherapy for esophageal carcinoma, no differentiation between histological tumor types and efficacy of treatment has been made.
The differences in histomorphologic response to treatment could be a result of the type of therapy for one and of the quality of pathologic findings for another. The review of Geh et al. reported a dose–response relationship between increasing protocol prescribed radiotherapy, 5-FU and cisplatin doses, and path CR. Another significant factor was radiotherapy treatment time [29]. This review showed that the probability of path CR improved with increasing doses of radiotherapy (P = 0.006), 5-FU (P = 0.003), and cisplatin (P = 0.018). In contrast, increasing radiotherapy treatment time (P = 0.035) and increasing median age (P = 0.019) reduced the probability of path CR. However, low dosage of radiation reduced the risks of postoperative morbidity and mortality. Our study protocol, with 36 Gy and one cycle chemotherapy (100 mg/m2 and 5000 mg/m2 5-FU), is in the median range of published study protocols [13, 29]. The advantage of the current study is that all patients were treated with the same protocol regardless of histologic tumor type, so that varying therapies could not affect the results.
Various systems and classifications have been developed to evaluate histopathologic response. According to the World Health Organization (WHO), clinical response is graded as complete, partial (>50% tumor regression), minor/no change (<50% tumor regression), or progressive disease [31]. In an effort to evaluate response to neo-adjuvant therapy objectively, morphologic criteria have been defined for several cancers, including lung, [32] stomach [33], and esophagus [34, 35]. In the current study, we used the Cologne Regression Classification System [22, 24], a modified system based on Junker et al. [32], that also considers clinical response evaluation according to WHO [31]. This type of classification has been used by other authors [33, 36]. Wu et al. [37] evaluated the quality of grading for the extent of residual carcinoma after preoperative chemoradiation in esophageal and esophagogastric junction carcinoma and reported that interobserver variability, particularly for the determination of path CR, is very small.Similar results were reported by Chang et al. [38]. They reanalyzed archived tumor blocks of esophageal carcinoma classified by routine pathology as path CR. They concluded that inadequate pathologic examination is likely not a major factor in the suboptimal survival of patients with path CR. One can conclude, therefore, that interstudy comparisons of path CR rates are reliable.
Currently, it is less well recognized that patients with esophageal AC benefit from this neo-adjuvant therapy regimen. In a meta-analysis, Gebski compared patients with AC and SCC and found no difference in survival. The hazard ratio for all-cause mortality with neo-adjuvant radiochemotherapy versus surgery alone was 0.81, with similar results for different histological tumor types [13]. In the current study, there was no significant difference in the overall prognosis of AC and SCC patients. However, AC patients with a major histologic response to neo-adjuvant therapy had a significantly better prognosis than those with SCC. The 73% 5-year survival rate in this group barely differs from that in patients with early-detected tumors of the same histology [39, 40].
For SCC patients, only a path CR to neo-adjuvant therapy leads to improved prognosis. The reasons for the differing responses of AC and SCC to radiochemotherapy and their prognostic relevance can only be derived experimentally. It is recognized that SCC patients, due to etiologic factors i.e. increased alcohol and tobacco consumption, have increased risk of multiple primary tumors [41, 42]. For early-detected carcinomas as well, SCC patients have a worse prognosis than AC patients for otherwise similarly characterized tumors [43].
We compared the data of patients receiving neo-adjuvant therapy with that of patients treated with primary esophagectomy and histologically diagnosed as pT3 category. Surprisingly, the surgery-only patients had no worse prognosis than patients having a minor response to neo-adjuvant therapy. Of course, this comparison shows some selection bias. However, one can assume that the non-neo-adjuvant patients show more negative selection bias. In a population-based study evaluating neo-adjuvant therapy for esophageal carcinoma in Sweden, patients having a minor response to pretreatment had worse prognoses than patients treated with surgery alone [44].
Prospective studies with multivariate analysis considering previous medical history and age have shown that after primary surgery, histology of the tumor has no particular impact on prognosis [23]. For this reason, the differing prognoses for patients with path CR after neo-adjuvant radiochemotherapy can be attributed to that therapy. Rohatgi et al. reported comparable results in a study of 235 patients receiving neo-adjuvant radiochemotherapy. The majority of patients (82%) had esophageal AC. The authors analyzed survival as a function of histological type with adjustment of exit variables. In the SCC patient group, the prognosis after path CR was not significantly different than that of patients with minor response to neo-adjuvant radiochemotherapy. In contrast, AC patients with path CR had a significantly better survival rate than minor responders and a 5-year survival >60% [45].
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conclusion |
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This retrospective study concludes that patients with uT3 esophageal AC have less frequent complete or major response to neo-adjuvant therapy with 5-FU, cisplatin, and 36-Gy radiation compared with patients with esophageal SCC. However, AC patients showing major response have a markedly better prognosis than those with SCC. The reasons for this difference require further evaluation.
Received for publication May 4, 2008. Revision received August 5, 2008. Accepted for publication August 6, 2008.
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references |
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