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Right arrow Esophagus - cancer

Eur J Cardiothorac Surg 2003;24:631-637
© 2003 Elsevier Science NL

Tumor response to induction chemoradiation: influence on survival after esophagectomy

Jessica S. Donington, Daniel L. Miller*, Mark S. Allen, Claude Deschamps, Francis C. Nichols, III, Peter C. Pairolero

Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, Rochester, MN, USA

Received 24 October 2002; received in revised form 21 May 2003; accepted 3 June 2003.

* Corresponding author. Section of Thoracic Surgery, Emory University Clinic, 1365 Clifton Road NE, Atlanta, GA 30322, USA. Tel.: +1-404-778-3755; fax: +1-404-778-4346
e-mail: daniel_miller{at}emoryhealthcare.org


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Clinical findings
 4. Results
 5. Discussion
 Appendix A. Conference...
 References
 
Objective: Preoperative chemoradiation is becoming standard of care for locally advanced esophageal cancer. The objective of this study was to determine if the degree of pathologic response to preoperative chemoradiation could predict survival and recurrence after resection in patients with adenocarcinoma of the distal esophagus. Methods: Between January 1998 and December 2001, 366 patients underwent esophagectomy for adenocarcinoma of the esophagus; 108 (30%) had induction chemoradiation prior to surgery. The records of these 108 patients were reviewed. Results: Histologic examination of the resected specimens documented complete pathologic response (CR) in 24 patients (22%) and residual tumor (RT) in 84 (78%). Operative mortality was 3.7%. Follow-up was complete in all patients and ranged from 1 to 46 months (median, 11 months). Three-year survival for patients with CR was 64% as compared to 34% for patients with RT (P=0.17). Median survival for patients with CR has not yet been reached; however, median survival for patients with RT was 19 months. Three-year cancer free survival for patients with CR was 57% compared to 30% for patients with RT (P=0.03). While median survival free of recurrence for patients with CR has not yet been reached, median survival free of recurrence for patients with RT was 9 months. Conclusion: Complete pathologic response to induction chemoradiation is associated with improved early overall and disease-free survival following esophagectomy for adenocarcinoma of the distal esophagus. Because recurrent cancer still develops in many of these patients, even after complete pathologic response, the search for the optimal treatment continues.

Key Words: Esophageal cancer • Neoadjuvant chemoradiation • Esophagectomy • Pathology


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Clinical findings
 4. Results
 5. Discussion
 Appendix A. Conference...
 References
 
Esophagectomy remains the standard of care for patients with clinically resectable esophageal carcinoma [1]. Unfortunately, long-term survival of patients with locally advanced disease is less than 25% [2]. To improve survival, treatment options have been developed which combine surgery with preoperative chemotherapy and/or radiation therapy. These treatment protocols have resulted in significant tumor response with a complete pathologic response (CR) occurring in up to 17–51% of patients (Table 1) [3–12]. Many of these initial CR occurred in patients with squamous cell carcinoma [3–6], but more recent reviews have reported similar rates for patients with adenocarcinoma [7–12]. Nonetheless, recurrence is frequent and long-term survival remains poor. The purpose of this review is to evaluate the effectiveness of preoperative chemoradiation in downstaging adenocarcinoma of the distal esophagus and to determine if the degree of pathologic response correlates with the pattern of recurrence and long-term survival after esophageal resection.


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  		Table 1. CR rates and survival after trimodality therapy

 

   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Clinical findings
 4. Results
 5. Discussion
 Appendix A. Conference...
 References
 
All patients who underwent esophagectomy for esophageal cancer at the Mayo Clinic in Rochester, MN, from January 1998 through December 2001 were retrospectively reviewed. Four hundred twenty-one patients were identified; 366 (87%) of whom had adenocarcinoma of the distal esophagus. Of these 366 patients, 108 (30%) underwent preoperative chemoradiation and these patients form the basis for this review.

Our standard neoadjuvant treatment protocol consists of concomitant external beam radiation and two cycles of chemotherapy. Radiation is administered in daily fractions of 180 cGy, 5 days a week, for a total dose of 5040 cGy. 5-Fluorouracil (5-FU) is administered as a continuous infusion over 96 h (1000 mg/m2 per day) on days 1 through 4 of radiation and on days 39 through 42. Cisplatin is administered as an intravenous (i.v.) bolus (75 mg/m2 per day) on the same days as 5-FU. Patients received i.v. hydration and odansetron with cisplatin infusion. Neoadjuvant therapy is followed by a 4–6-week recovery period prior to esophageal resection.

All patients were staged postsurgically according to the TNM classification of the American Joint Committee for Cancer Staging (AJCC) [13], and were stratified into two different groups according to the efficacy of neoadjuvant treatment. If viable cancer was not identified in the resected specimen (T0N0M0), the patient was regarded as having a pathologic complete response (CR). If any viable cancer was detected, the patient was considered as having residual tumor (RT).

The medical records were analyzed for preoperative factors (age, gender, comorbid conditions, Barrett's esophagus, symptoms, and time from symptoms to treatment), tumor factors (pretreatment clinical stage and postsurgical pathological stage), hospital course (need for mechanical ventilation, transfusion requirement, morbidity, operative mortality and length of hospitalization), tumor recurrence, and long-term survival.

Follow-up consisted of examinations every 3 months for the first 2 years and at 6-month intervals thereafter. Extensive tumor evaluation was initiated only if the patient had signs and symptoms suggestive of recurrence. Follow-up data was obtained from the medical records, tumor registry survey and telephone interviews.

Operative mortality included those patients who died within the first 30 days after operation and those who died later but during the same hospitalization. Survival was estimated by the Kaplan–Meier method using the date of the esophageal resection as the starting point and the date of death or last follow-up as the end point [14]. Patients with resected margins positive for cancer or metastatic disease found at time of resection were assigned a disease-free survival of zero time. The influence of variables on survival was analyzed using the log-rank test for discrete variables [15] and the proportional hazards model of Cox for continuous variables and multivariate models [16]. All statistical tests were two-sided with the threshold of significance set at P<0.05. All analyses were conducted using SAS software (SAS Institute Inc., Cary, NC). This retrospective review was approved by Mayo Foundation's Institutional Review Board.


   3. Clinical findings
Top
 Abstract
 1. Introduction
 2. Methods
 3. Clinical findings
4. Results
 5. Discussion
 Appendix A. Conference...
 References
 
There were 105 men and three women. Median age was 61 years and ranged from 36 to 81 years. All patients were initially clinically staged with thoracic and upper abdominal computed tomography and esophageal endoscopy; 93 patients (86%) underwent endoscopic ultrasound (EUS). Pretreatment patient parameters and tumor characteristics are outlined in Table 2.


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  		Table 2. Pretreatment patient and tumor characteristics

 
Seventy-four patients (69%) completed our standard neoadjuvant protocol (Table 3), while 75% completed the chemotherapy arm and 74% radiotherapy. Median time interval from completion of the neoadjuvant treatment to esophagectomy was 40 days with a range of 17–86 days. Median Eastern Cooperative Oncology Group (ECOG) performance status was 0 (range 0–1) in all patients prior to operation. An Ivor Lewis esophagectomy was performed in 96 patients (86%), an extended Ivor Lewis (combined thoracic, abdominal, and cervical incisions) in 12 (11%), transhiatal in two (2%) and thoracoabdominal in one (1%). Ten-centimeter proximal and distal resection margins were obtained whenever possible. All patients had regional lymphadenectomy (perigastric, celiac, and periesophageal) and either a pyloroplasty or pyloromyotomy. All esophageal anastomosis were hand sutured. Fifteen anastomoses were cervical; 60 of the 93 of the intrathoracic anastomoses (65%) were reinforced with either an omental or pleura flap. Fifteen patients (14%) underwent intraoperative radiation therapy. Operative variables are shown in Table 3.


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  		Table 3. Treatment

 

   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Clinical findings
 4. Results
5. Discussion
 Appendix A. Conference...
 References
 
Pathologic examination of resected specimens documented CR in 24 patients (22%) and RT in 84 (78%). No significant difference was observed between these groups in regards to pretreatment demographics, tumor characteristics (Table 2) or the neoadjuvant therapy received or completed (Table 3). Patients with a CR had a significantly longer time interval (median 48 days) from the completion of induction therapy to resection than patients with RT (median 38 days) (P=0.002) (Table 3).

There were four operative deaths (3.7%). All occurred in critically ill patients with prolonged intensive care unit (ICU) stays. Three of these deaths occurred from sepsis and one following myocardial infarction. Although all deaths occurred in the RT group, no significant difference in mortality was observed between the CR and RT groups (P=0.57). Complications occurred in 51 patients (47%). Atrial arrhythmias (25%) and respiratory (19%) (including pneumonia, respiratory failure, aspiration and adult respiratory distress syndrome) complications were the most frequent. Hospitalization ranged from 6 to 56 days (median 10 days). Intensive care admission, ventilatory requirements, complications and hospitalization were similar in both groups. Postoperative data are summarized in Table 4.


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  		Table 4. Hospital course

 
Follow-up was complete in all patients and ranged from 1 to 46 months (median 11 months). Median survival for all patients was 21 months. Overall 1-, 2- and 3-year survival was 70, 46 and 41%, respectively (Fig. 1) . The 1-, 2- and 3-year overall survival for the CR group was 73, 64 and 64%, respectively, compared to 69, 41 and 34%, respectively, for patients with RT (P=0.17) (Fig. 2) . Median overall survival for the CR patients has not been reached; however, median survival for patients with RT was 19 months.



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  		Fig. 1. Probability of survival (death from any cause) in 108 patients who underwent neoadjuvant chemoradiation followed by esophagectomy. Zero time on the abscissa represents the date of esophagectomy.

 


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  		Fig. 2. Probability of overall survival (death from any cause) in 24 patients with CR as compared to 84 patients with RT following neoadjuvant therapy and esophagectomy. Zero time on the abscissa represents the date of esophagectomy. CR, complete pathologic response; RT, residual tumor.

 
The median disease-free survival for all patients was 13 months. Overall 1-, 2- and 3-year disease-free survival for all patients was 52, 37 and 37%, respectively (Fig. 3) . A significant improvement in disease-free survival was observed in patients with CR. One-, 2- and 3-year disease-free survival for patients with CR was 76, 57 and 57%, respectively, compared to 44, 30, and 30%, respectively, for patients with RT (P=0.03) (Fig. 4) . Again the median disease-free survival has not yet been reached in the CR group, while the median disease-free survival for patients with RT was 9 months. Seventeen CR patients (71%) are alive and free of disease, while one (4%) is alive with tumor recurrence. The six remaining patients have died, four from tumor recurrence and two from unknown causes. In the RT group, 36 patients (43%) are alive and free of disease, 13 (14%) are alive with recurrent disease. Thirty-five (43%) patients have died; causes included cancer in 25, postoperative complications in four, respiratory failure and gastric bleeding in one each, and unknown in four.



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  		Fig. 3. Probability of disease-free survival (death from any cause) in 108 patients who underwent neoadjuvant chemoradiation followed by esophagectomy. Zero time on the abscissa represents the date of esophagectomy.

 


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  		Fig. 4. Probability of disease-free survival (death from any cause) in 24 patients with CR as compared to 84 patients with RT following neoadjuvant therapy and esophagectomy. Zero time on the abscissa represents the date of esophagectomy. CR, complete pathologic response; RT, residual tumor.

 
There was no difference in the pattern of recurrence between the two groups. The rate of local recurrence was extremely low in both groups. Patients with CR had a local recurrence rate of 5% compared to the patients with RT who had a rate of 7%. This difference was not statistically significant (P=0.48). The rate of distant recurrence was 5% for the CR patients and 20% for the patients with RT. Again, this difference was not statistically significant (P=0.39).


   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Clinical findings
 4. Results
 5. Discussion
Appendix A. Conference...
 References
 
Esophagectomy remains the standard treatment for patients with nonmetastatic esophageal carcinoma. In recent years, with improved surgical and anesthetic techniques, resection of carcinoma of the esophagus has become a much safer procedure. Despite these advances, however, the long-term prognosis for esophageal cancer remains poor [17]. As a result, many institutions have adopted neoadjuvant chemoradiation protocols in an attempt to improve survival following esophagectomy. Encouraging results from Phase II neoadjuvant trials have been published [7–9,11]. Unfortunately, the only two Phase III randomized trials completed have shown conflicting results [10,12], and currently no convincing data exist that demonstrate survival advantage with neoadjuvant therapy. A consistent finding in these reports is that patients with a significant histologic response to therapy appear to have improved survival after esophagectomy. All major series investigating the use of neoadjuvant therapy have a group of patients with no evidence of residual tumor (T0N0M0) in the resected specimens (Table 1).

Previously reported CR rates vary from 17 to 51% [3–12]. Our CR rate of 22% is consistent with these studies. Several factors are believed to contribute to the accuracy of the CR rate, including how thorough the specimen is examined by the pathologist and the timing of the pathologic examination in relation to the completion of therapy. The greater the number of histologic sections examined, the greater the likelihood of finding viable tumor cells. Also, Forastiere and associates have suggested that the ideal time to examine the specimen for the full effect of therapy is at 12 weeks following therapy [7]. However, the majority of patients reported, including our own, underwent esophageal resections at approximately 6 weeks following the completion of neoadjuvant therapy. This early tissue examination may underestimate the true CR rate. The RT patients in our review had a significantly shorter interval between therapy and resection than the CR patients. Some of the tumor cells in those specimens may have been non-viable and would have been deemed a CR if examined at a time further from the completion of the induction therapy.

Despite the problems of adequately defining CR, most studies associate CR with improved survival [3,6,7,9]. Our patients who had a CR had an overall three-year survival of 64% compared to 34% for those patients with RT. Although the trend toward improved survival was observed in our patients, the difference between the two groups was not statistically significant. However, with longer follow-up this difference will more than likely be significant. We also demonstrated a significant benefit in disease-free survival in patients with CR (57 vs. 31% at 3 years; P=0.03). The survival rate of 34% at 3 years in patients with RT compared favorably to reported survival in patients treated with either chemoradiation or surgery alone [2,17–21]. This suggests that even in the absence of CR, trimodality therapy may offer a potential benefit over surgery or chemoradiotherapy alone.

The pattern and rate of tumor recurrence did not appear affected by the degree of tumor response. Seventy-one percent of our patients with CR are currently free of tumor as compared to 47% of those patients with RT. While disease-free survival was improved in those patients with CR, we demonstrated no significant difference in the pattern of recurrence despite the fact that distant recurrence disease was less in the CR groups. Local recurrence was extremely low in both groups, 5% for CR and 7% for RT patients, respectively.

Some authors question the need for esophageal resection following neoadjuvant therapy, the philosophy being that CR is the key to survival and therefore surgery is unnecessary [18,19]. Our data reinforce the fact that surgery plays an important therapeutic role. First, it provides better local control (5–7%) than chemoradiation alone, which has a local recurrence rate of 45–48% [18–21]. In addition, we demonstrated meaningful survival benefit in patients with RT. Finally, no staging method currently exists, other than esophageal resection, to accurately determine which patients truly have a CR response after induction therapy [22,23].

This study focused on patients with adenocarcinoma of the distal esophagus, which is a different population than patients with squamous cell carcinomas. Our review reinforces the point that CR is a positive prognostic indicator for long-term survival following trimodality therapy. Therefore, strategies aimed at increasing the CR rates are needed to impact overall survival such as modification of radiation delivery and total dose and introduction of new chemotherapy modalities. Radiation doses greater than 4500 cGy have been shown to correlate with higher CR rates [24,25]. Eighty-five percent of our patients received radiation doses greater than 4500 cGy, which may have counted for the low local recurrence rate. This higher dose of radiation was not associated with an increase in operative morbidity or mortality. Exploration of agents such as taxanes and combinations of agents and new modalities of treatment are also essential in an attempt to improve CR rates and enhance long-term survival by decreasing the risk of systemic disease.

In summary, concurrent chemoradiotherapy followed by surgery appear to provide exceptional control of locally advanced disease. Complete pathologic response to induction chemoradiation is associated with improved early overall and disease-free survival following esophagectomy for adenocarcinoma of the distal esophagus. In order to prove this benefit a prospective randomized multi-center trial is warranted. Until a large prospective trial is completed and newer agents are developed for the treatment and prevention of systemic disease, esophagectomy remains the standard of care for patients with adenocarcinoma of the distal esophagus.


   Footnotes
 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Clinical findings
 4. Results
 5. Discussion
 Appendix A. Conference...
References
 
Dr O. Kshivets (Siauliai, Lithuania): The first question, do you have the surgery alone group for control? The second question is, you analyzed only adenocarcinoma. What about the squamous cell carcinoma? You have adenocarcinoma in 80%. The third question, do you try to perform adjuvant immunotherapy?

Dr Donington: I'm sorry, your first question was did we have a group that did not go to surgery?

Dr Kshivets: Surgery alone (for control).

Dr Donington: This was all patients who went to surgery. We did not include patients in this review who had started chemotherapy and didn't progress through surgery. As for squamous cells, we did not focus on squamous cells. As a referral center, the population of squamous cells we see has gotten so small that we felt it was more important to focus on adenocarcinoma, which is becoming such an aggressive disease which we see more and more frequently.

I'm sorry, your third question?

Dr Kshivets: Immunotherapy.

Dr Donington: Adjuvant therapy or immunotherapy?

Dr Kshivets: Adjuvant immunotherapy.

Dr Donington: We had no immunotherapy. We had none in our patients at all.

Dr W.S. Walker (Edinburgh, UK): Could I just clarify what the selection criteria were for the induction therapy?

Dr Donington: This was not a randomized trial. This was just a review of the Mayo experience. It took place over a 3-year period where the philosophy of the institution toward neoadjuvant therapy had changed. Also, many patients had come to us who had already been treated with induction therapy elsewhere. So there really was no inclusion criteria per se.

Dr D. Watson (Norwich, UK): You mentioned that you gave some on-table radiotherapy. Did I understand that correctly?

Dr Donington: Yes.

Dr Watson: Did you subgroup them to look at whether that made any difference in the survival curves?

Dr Donington: We did, and it did not. Five out of the 15 patients who received intraoperative radiation therapy were actually in the complete response group. So even though they had large, bulky tumors to start with and radiation therapy was always planned, some of those patients had responded to a point where they actually had no residual tumor and yet still received intraoperative radiation therapy.

Dr Watson: So my question is, what was the indication for perioperative radiotherapy?

Dr Donington: The indication is bulky disease on CT scan and EUS either before or after treatment. But again, this goes to show why we really don't know who to resect and not resect, and what is residual disease versus treatment effect. Many of these patients still had very impressive CT scans or EUS prior to surgery, and we really have no way of knowing who has bulky disease and who doesn't prior to surgical resection.

Dr A. Lerut (Leuven, Belgium): Since you had no inclusion criteria, can you say whether this regimen is indeed giving a benefit to your patients, whether you are improving results in particular in the group who were not complete responders? Are they not paying the price for those who are responders, because your median survival there was only 9 months, which I think is maybe a reflection that if they would have had primary surgery immediately, they would not have lost time and maybe would have done better overall.

Dr Donington: I think it's an excellent point. Actually, I think at the Mayo Clinic we haven't really made our decision on how we feel about induction therapy, and this study does not really say that we think induction therapy is a proven benefit for adenocarcinoma of the esophagus. All we're saying is that we found this select group of patients who benefit. And you may be right that other patients do pay the price for this group which benefits, and I think that that would require a controlled study where people are well-staged in order to determine if there truly is a benefit.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Clinical findings
 4. Results
 5. Discussion
 Appendix A. Conference...
 References
 

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  18. Coia L.R., Engstrom P.F., Paul A.R., Stafford P.M., Haines G.E. Long-term results of infusional 5-FU, mitomycin-C, and radiation as primary management of esophageal cancer. Int J Radiat Oncol Biol Phys 1991;20:29-36.[Medline]
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  20. Herskovic A., Martz K., Al-Sarraf A., Liechman L., Brendle J., Vaitikevicius V., Cooper J. Combined chemotherapy and radiotherapy compared to radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-1598.[Abstract]
  21. Al-Sarraf M., Martz K., Herskovic A., Liechman L., Brindle J., Vaitikevicius V., Cooper J. Progress report of combined preoperative chemoradiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997;15:277-284.[Abstract/Free Full Text]
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