Ann Thorac Surg 2005;80:1176-1183
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Induction Chemoradiotherapy for Squamous Cell Carcinoma of the Thoracic Esophagus: Impact of Increased Dosage on Long-Term Results
Giovanni de Manzoni, MD
a
,
*
,
Corrado Pedrazzani, MD
a
,
Ernesto Laterza, MD
a
,
Felice Pasini, MD
b
,
Antonio Grandinetti, MD
c
,
Marco Bernini, MD
a
,
Andrea Ruzzenente, MD
a
,
Germana Zerman, MD
a
,
Anna Tomezzoli, MD
d
,
Claudio Cordiano, MD
a
a First Department of General Surgery, University of Verona
b Division of Medical Oncology, University of Verona
c Division of Radiation Oncology, Borgo Trento Hospital, Verona, Italy
d Division of Pathology, Borgo Trento Hospital, Verona, Italy
Accepted for publication February 14, 2005.
* Address reprint requests to Prof de Manzoni, 1a Chirurgia Clinicizzata, Ospedale di Borgo Trento, Piazzale Stefani, 1, 37126 Verona, Italy (Email: chirurgia.urgenza{at}univr.it; nadaffona{at}intrefree.it).
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Abstract
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BACKGROUND: This study analyzed the impact on long-term results of an increase in the dosage of an induction chemoradiotherapy protocol for squamous cell carcinoma (SCC) of the thoracic esophagus.
METHODS: Two groups were considered among 177 patients who underwent preoperative chemoradiotherapy for SCC of the thoracic esophagus. Group A includes 111 patients (from 1987 to 1995) who were submitted to cisplatin and 5-fluorouracil (two cycles) and radiotherapy (3,000 cGy). Group B includes 66 patients (from 1995 to 2002) in which the doses were raised both in terms of chemotherapy (three cycles) and radiotherapy (5,000 cGy).
RESULTS: The induction treatment was completed in most of the patients (92.1%) with an acceptable treatment-related mortality (2.6%). Surgery was accomplished in 148 patients; 78.4% and 92.4% in groups A and B, respectively (p = 0.015). The postoperative in-hospital mortality was 8.8%. Tumor resection was possible in 91.8% with a better R0-resection rate for group B (83.9%; p = 0.004). Responders represented 34.9% of the patients with 20.1% of "complete" responses (29.5% in group B; p = 0.018). The overall 5-year survival rate was improved in group B (30.2%; p = 0.017), and when survival analysis was restricted to responders (70.1%; p = 0.027).
CONCLUSIONS: No differences in feasibility and complication rate were observed during the two study periods. A higher rate of R0-resections was achieved in group B. The increased dosage led to an increased rate of complete responses and to an improved overall 5-year survival.
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Introduction
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Surgery is considered the mainstay of therapy for clinically resectable squamous cell carcinoma (SCC) of the thoracic esophagus. Nevertheless, in spite of the improvement in operative and perioperative care with a decreased early mortality and morbidity [1, 2], there has not been a significant change in long-term survival during the last three decades [3, 4]. Therefore, attempts have been made to ameliorate the outcome of surgical resection by adding preoperative chemoradiotherapy in order to control micrometastatic systemic disease, to raise potentially curative resections (R0), and to reduce locoregional and systemic recurrences.
There is increasing evidence that esophageal SCC responds to a combination of chemotherapy regimens based on cisplatin (CDDP) and 5-fluorouracil (5-FU) plus radiotherapy [5–7]. However, it is not yet clear which is the most appropriate therapeutic regimen and if the downstaging and the long-term results are dose related. In a previous experience, we described our long-term results in the treatment of SCC of the thoracic esophagus preoperatively treated with chemoradiotherapy [8, 9]. Since February 1995 the doses of this protocol regimen have been raised both in terms of chemotherapy (three versus two cycles of CDDP and 5-FU) and radiotherapy (5,000 versus 3,000 cGy). The aim of the present study was to analyze our experience on neoadjuvant treatment of SCC with special reference to patients' compliance, associated downstaging, and long-term survival, and to compare the results of the two described regimen protocols.
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Material and Methods
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Study Population
The study includes 177 patients, consecutively observed at the First Department of General Surgery, University of Verona, Verona, Italy, between January 1987 and December 2002, who underwent preoperative radiochemotherapy for SCC of the thoracic esophagus. Two periods were considered: the first period includes 111 patients treated between January 1987 and January 1995 (group A), while the later includes 66 patients observed between February 1995 and December 2002 (group B). Patients' characteristics are shown in Table 1 , and except for a higher male to female ratio in group A (p = 0.012), they were well-balanced for the two groups. In the same period 37 patients were operated on without having induction therapy because they did not match the inclusion criteria.
Inclusion Criteria
The inclusion and exclusion criteria were unchanged for the two groups and were previously specified in detail [9]. Briefly, the most important inclusion criteria were the following: histologically proven SCC, a Karnofsky performance status greater than 60, possibility of follow-up, and informed consent of the patient. The most important exclusion criteria were location in the cervical esophagus and/or hypopharynx, presence of tracheoesophageal fistula, presence of systemic metastases, and history of secondary malignancy. The limit age was 70 years old for group A, while it was raised to 75 years old in group B.
Staging Work-Up
The staging work-up included barium swallow, esophagogastroscopy with biopsy, tracheobroncoscopy, endoscopic ultrasonography, thoracoabdominal computed tomography, and cervical ultrasonography. The same investigations were performed at restaging, after the end of preoperative treatment, to assess the response to induction therapy and the actual operability of the patients. The average time of restaging was 1–2 weeks from the completion of chemoradiotherapy for group A and it was delayed to 2–3 weeks for group B.
Treatment Plan
In group A, the chemotherapy consisted of two courses of CDDP and 5-FU. The 5-FU was administered intravenously in doses of 1,000 mg/m2 per day on days 1–4 and 29–32, CDDP in doses of 100 mg/m2 on days 1 and 29. Radiotherapy started concurrently the first day of chemotherapy. Parallels opposing portals were used to deliver a total midpalmar dose of 3,000 cGy with a daily fraction of 200 cGy. The radiation field covered the primary tumor with margins of at least 5.5 cm above and below the lesion. In group B, the treatment was powered; three courses of CDDP and 5-FU. The 5-FU was administered intravenously in doses of 1,000 mg/m2 per day on days 1–4, 22–25, and 53–56, and CDDP in doses of 100 mg/m2 on days 1, 22, and 53. Radiotherapy was initiated on day 22 concurrent with the second course of chemotherapy and administered with the same technique increasing the total dose to 5,000 cGy.
Surgical Technique
Surgery was scheduled at least 3 weeks after the end of the treatment in group A while it was deferred for 4 to 5 weeks in group B. The principal aim of surgery was the complete resection of the tumor. The surgical technique was generally chosen according to the site of the tumor [9]. For tumors of the lower third of the esophagus, the preferred procedure was a subtotal esophagectomy with a right intrathoracic esophagogastrostomy (Ivor-Lewis procedure). In the case of tumors located in the middle or upper third, an esophagectomy with cervical esophagogastrostomy was performed via the right thoracic, abdominal, and cervical route. The esophageal resection was combined with a mediastinal and upper abdominal lymphadenectomy in all cases. A cervical lymphadenectomy was carried out only in cases with clinical or radiologic evidence of lymph node metastasis. Transhiatal esophageal resection was reserved for palliative resection cases or high-risk patients.
Staging
Tumors were staged according to the clinical (cTNM) and pathologic classification (pTNM) of the International Union Against Cancer [10]. The response to the treatment was evaluated on the resected specimen, taking into consideration the amount of tumor present at the histologic examination. Complete response was defined as the full disappearance of the tumor (pT0N0) and patients in which no viable tumor was present at histologic examination were defined as complete responders. Complete responders and patients with tumors limited to the mucosa or submucosa (pT1) and/or residual microfoci of tumor cells at the site of the primary (minimal residual disease [MRD]) with histologically negative lymph nodes (pN0) were regarded as responders. All other patients were regarded as nonresponders.
Follow-Up
After discharge from hospital all patients were followed up after 4 months and at 6-month intervals until their death or the time of study. None of the patients was lost to follow-up with an overall median period for the surviving patients of 70.4 months (range, 14–117 months). The median follow-up period was 74.0 months (range, 32–117 months) for group A while it was 65.3 months (range, 14–97 months) for group B (p = 0.116).
Data Analysis
Survival was measured from the date of the beginning of the induction treatment to the date of death or most recent follow-up visit. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Both cancer-specific and noncancer-specific deaths were included in the analysis because the majority of patients died of cancer-related causes. Chemoradiotherapy-related deaths and postoperative deaths were included in the survival analysis. Multivariate analysis was performed by Cox regression model with the principal aim of verifying if the change in protocol regimen independently affected the prognosis. The model was built up by taking into account the following risk factors: age (greater than median versus median value or below), gender (female versus male), tumor location (lower and middle third versus upper), clinical TNM stage (stage I and IIa versus stage IIb and III) and schedule of chemoradiotherapy (group A versus group B). Clinical TNM stage was taken into account instead of pathological TNM stage because the pTNM stage is highly related to the level of response to the induction treatment. Clinical stage I and IIa were considered together because of the very small number of stage I tumors; clinical stage IIb and III for the small number of stage IIb. The stratification of prognosis by cTNM stage was preventively verified using the Kaplan-Meier method (p < 0.001). As prognosis is usually influenced by complete resection of the tumor (R0) another model was studied by adding R category. At last the analysis was restricted to patients with major response to the induction treatment (responders). The 
2 test was used for categorical data and the t test for continuous data (age and duration of symptoms). Analyses were performed using the Statistical Product and Service Solutions, SPSS 10.0 for Windows, 2000 (SPSS Inc, Chicago IL).
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Results
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Data on surgery and induction treatment for the two study periods are available in Table 2. The induction treatment was completed in the majority of the patients (92.1%). The causes of discontinuation were death in 3 cases, severe postchemotherapy toxicity in 9 cases, and voluntary withdrawal of the patient in 2 cases. The treatment-related morbidity and mortality were 36.2% (64/177) and 2.3% (4/177), respectively. No deaths (0/66) were observed in the later period of the study (p = 0.119).
After completion of induction treatment 148 patients underwent surgery (83.6%), while 29 patients did not. Among these, 4 died during or after (one case) the induction treatment, 7 showed neoplastic progression, 7 were judged not suitable for surgery, and 11 refused surgery.
Tumor resection was possible in 91.8% (136/148) of the patients, with a significantly higher rate of potentially curative resections (R0) in group B (83.9%, p = 0.004) (Table 2). The postoperative in-hospital mortality was 8.8% (13/148), with a decreased death rate of 6.6% (4/61) in the later period (p = 0.423).
For the 42 patients with pretreatment evidence of adjacent organ invasion (cT4), the resection rate was 73.8% (31/42). A R0 resection was achieved in a small percentage of cases; 32.1% (9/28) in group A and 28.6% (4/14) in group B (p = 0.813).
The pathologic tumor stage is shown in Table 3. Response to induction treatment was determined for all the 148 patients operated on and one autoptic study. A complete disappearance of the tumor (pT0N0) was revealed in 20.1% (30/149) of the cases; 12 patients in group A (13.6%) and 18 patients in group B (29.5%) (p = 0.018). Furthermore, the presence of microscopic clusters of neoplastic cells (MRD) or tumors limited to the mucosa or submucosa (pT1) without evidence of lymph nodal involvement was found in 14.8% (22/149). Hence, responders represented the 29.5% (26/88) of group A and the 42.6% (26/61) of group B (p = 0.100).
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Table 3. Pathologic TNM Stage and Type of Response to the Induction Treatment for the Operated Patients in Group A and Group B
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Among pretreatment cT4 tumors, 19 out of 42 (41.0%) showed a locoregional down-staging of the tumor. A complete response (pT0N0) was observed in 4 cases (9.5%), while isolated clusters of neoplastic cells (MRD) without evidence of lymph nodal involvement were present in one more case showing a responders rate of 11.9%.
Survival Analysis
Survival according to patients' characteristics is shown in Table 4. The overall median survival time for all the 177 patients was 17.0 months with 2-year and 5-year survival rates of 37.0% and 21.1%, respectively. When R0 resection was obtained the 5-year survival was 37.2% while the survival rate fell to zero at 32 months when residual tumor (R1-2) was observed (p < 0.001). In operated-on patients, a clear advantage in survival was observed for responders with respect to nonresponders with 5-year survival rates of 54.4% (median beyond the observation period) and 18.3% (median, 19.3 months) (p < 0.001), respectively. The outcome was even better for complete responders (pT0N0), where the 5-year survival rate was 75.4%.
The comparison of the two treatment groups based on an intention to treat analysis showed a survival benefit for group B (Fig 1). The 5-year survival rate was 17.5% for the 111 patients of group A and 30.2% for the 66 patients of group B (p = 0.017). Also excluding treatment-related deaths a better outcome was observed in the later period (group A, 5-year survival: 19.1%, median: 17.3 months; group B, 5-year survival: 32.1%, median: 23.2 months) (p = 0.037). When the survival analysis was restricted to R0-resected patients a better survival was observed for group B, even though the difference was not statistically significant (group A, 5-year survival: 31.9%, median: 27.1 months; group B, 5-year survival: 43.0%, median: 38.3 months) (p = 0.310). Survival analysis limited to responders showed a better long-term prognosis for group B, where a 5-year survival rate of 70.1% was obtained (p = 0.027) (Fig 2). Prognosis was significantly better in group B even for complete responders (group A, 5-year survival: 34.1%, median: 27.1 months; group B, 5-year survival: 75.0%, median beyond the observation period) (p = 0.042). On the contrary, no survival advantage was gained when no major response was observed (p = 0.217) (Fig 3).
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Fig 1. Kaplan-Meier estimates of survival probability based on an intention to treat analysis are shown according to group A and group B.
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Fig 2. Kaplan-Meier estimates of survival probability for responders are shown according to group A and group B.
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Fig 3. Kaplan-Meier estimates of survival probability for nonresponders who underwent R0-resection are shown according to group A and group B.
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Multivariate Analysis
Cox regression model was aimed at verifying if the regimen of induction treatment used was an independent prognostic factor. When age, gender, level of tumor, and clinical TNM stage (cTNM) were considered in the model, low cTNM stage (p < 0.001) and higher doses of chemoradiotherapy (p = 0.022) resulted as favorable prognostic factors (Table 5). If R category (R0 versus R1-2 resection) was introduced the dose of chemoradiotherapy lost its importance (p < 0.291) and the complete removal of the tumor (R0) emerged as the most important prognostic factor (p < 0.001) (Table 5). As for univariate analysis and also at multivariate analysis , when only patients with a major response to the induction treatment (responders) were analyzed in the model the dosage of preoperative chemoradiotherapy regained its statistical relevance (relative risk [95% confidence interval] for group A with respect to group B: 3.042 [1.112–8.324) (p = 0.030).
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Table 5. Relative Risks of Death From SCC of the Thoracic Esophagus According to the Dosage of Induction Chemoradiotherapy; Relative Risks of Death after Introducing R Category
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Comment
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There is increasing evidence that SCC of the thoracic esophagus responds to a combination of chemotherapy and radiotherapy [5–7], although no definitive results on long-term prognosis are available in prospective controlled randomized trials [11–14]. Furthermore, confusion exists on the protocol regimen to use as different types of drugs and different dosages of radiotherapy were investigated [11–16]. The present study analyzed a single institution experience with the most commonly used chemotherapy regimen (CDDP and 5-FU) delivered concomitantly with radiotherapy in two treatment plans with different dosages.
No significant differences in feasibility and rate of complications were observed during the two study periods. Discontinuation of the induction treatment due to chemoradiotherapy toxicity and toxic death rate were comparable with the literature results (mean, 3%; range, 0–15%) [6]. Interestingly despite the increased dosage no treatment-related mortality was observed in the latest period of the study.
The operability improved significantly during the time of study (78.4% in group A and 92.4% in group B, p = 0.015) due to a variety of reasons: the aforementioned annulment of toxic deaths, a decrease in neoplastic progressions, and an improvement in the patient's care management. The resection rate of 92% for the two groups is among the highest reported in literature (mean, 74%; range, 50%–100%) [6]. It is of note that the high number of potentially curative resection (R0) achieved during the second period of our experience, with a rate of about 85%, is better than that obtained by surgical resection only (54%–78%) [17–21] or with the use of neoadjuvant chemotherapy (60%–79%) [17, 18, 22, 23].
The current postoperative complications rate in high-volume centers varies in a range of 30% to 50% with an in-hospital mortality that does not exceed 6% to 8% [1, 2, 4, 22–25]. Some reports showed an increase in postoperative morbidity and mortality in patients undergoing neoadjuvant treatments [14, 15, 26, 27], but we did not experience such an increase either after potentiating the multimodal treatment schedule (overall in-hospital mortality: 8.8%; group B in-hospital mortality: 6.6%).
The rate of response after induction chemoradiotherapy reported in the literature varies widely with a complete response rate of 8% to 56% (mean, 24%) [6]. In the present experience, the raised dosage of preoperative treatment led to an increased number of responders (29.5% in group A and 42.6% in group B, p = 0.100) with a statistically significant higher rate of complete responses (13.6% in group A and 29.5% in group B, p = 0.018).
The overall 5-year survival rate, based on an intention to treat analysis, was 21.1% considering the entire cohort with a better 5-year rate of 30.2% for the 66 patients of the later period (p = 0.017). As shown by many authors, potentially curative resection (R0) leads to better long-term survival. We achieved a 43.0% 5-year survival rate in group B, which is among the highest results reported in the literature (23%–49%) [4, 7, 14, 19–24, 28, 29].
Altorki and colleagues [29], Skinner [30], and others [20, 31, 32] reported 5-year survival rates very high after surgery alone using an en bloc esophagectomy (40%–49%). Nevertheless, we think that this might be due to slightly different surgical populations: (a) en bloc esophagectomy is usually reserved for tumors without adjacent structures invasion [20, 29] while we have more than 20% of patients with clinical T4 tumors; (b) a relatively high rate of early tumors (Tis and T1) was included in these experiences (21%–23%) [20, 29]; (c) en bloc esophagectomy is more frequently described for distal esophageal or gastroesophageal junction tumors, which are usually adenocarcinoma [20, 29, 31]; (d) node dissection of the upper mediastinum, frequently done in SCC, is more difficult because of the anatomic complexity in relation to important organs such as the trachea and recurrent laryngeal nerves [21].
Considering tumors with adjacent structures invasion (pT4), in spite of a considerable resection rate a dismal prognosis was observed in our experience (Table 4) and surgical resection does not seem to be justified by these long-term results. Controversies exist about the optimal treatment of clinical T4 tumors and many authors advocate the utility of definitive chemoradiotherapy [33, 34]. During the time of study every tumor was resected if feasible. This policy led us to obtain a 5-year survival rate of 4.8% for cT4 with a 5-year rate of 15.4% for cT4 with R0 resection (data not shown). This means that only low-risk patients with a significant response and a high probability of R0 resection can benefit from surgical resection.
Focusing on R0 patients, as already reported by the majority of papers on neoadjuvant treatment [6], responders showed a significantly better long-term survival compared to nonresponders (p < 0.001). The increase in chemoradiotherapy dosage showed it to significantly influence the prognosis when only responders were considered (Fig 2), while no benefit was observed for nonresponders of both groups (Fig 3). This supports the idea of Skinner [30], who believes that multimodal treatments have value only in those patients who respond to such treatment and that it is damaging in patients who do not. In order to continue and possibly improve the survival results gained in the responders group avoiding ineffective treatments for those who do n ot respond, the goal would be to find new successful schedules and to try to identify patients who will respond to multimodality treatments.
Finally, a consideration about the better results obtained in group B and the possible role of concomitant chemotherapy and radiation therapy has to be done. In group A patients, only one of two courses of chemotherapy was concomitant with radiation therapy, whereas in group B patients, two of three courses were administered along with radiation therapy. In addition to the increased dosage of each modality, the potential influence of 5-FU as a radiosensitizer could have played a role.
In conclusion, we have found the following. (1) No significant differences in feasibility and rate of complications were observed during the two study periods. Interestingly, in spite of the increased dosage no treatment-related mortality was observed in the latest period of the study. (2) A higher rate of potentially curative resection (R0) was achieved in group B. (3) The increased dosage of preoperative treatment led to an increased rate of histopathologic major responses with a statistically significant higher rate of complete responses. (4) The increase in chemoradiotherapy dosage led to an improved overall 5-year survival and (5) significantly influenced the prognosis when only responders were considered. (6) Also, in our experience, no survival benefit was obtained for nonresponders even with the increased chemoradiotherapy dosage.
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J. M. Piehler
Invited commentary
Ann. Thorac. Surg.,
October 1, 2005;
80(4):
1183 - 1184.
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Abstract
Introduction
