1. BACKGROUND
Despite therapy, most patients diagnosed with esophageal cancer in 2004 will die from their disease. Surgery and radia- tion have been the historical treatments of choice for esophageal cancer. However, in an effort to improve outcome, combination therapies have emerged with concurrent chemoradiotherapy, neoadjuvant chemotherapy and chemoradiotherapy, and adju- vant chemotherapy and chemoradiotherapy. Strong proponents for specific individual therapeutic approaches exist, as does controversy because no optimal treatment plan for esophageal cancer has clearly emerged.
Therapy also continues to evolve with the development of new chemotherapeutic agents and chemotherapy combina- tions. Future work will hopefully reduce the morbidity of ther- apy and increase survival in patients treated with esophageal cancer.
2. INTRODUCTION
Esophageal cancer is a relatively uncommon cancer in the United States. Of the estimated 1,368,030 new cases of cancer that were diagnosed in the United States in 2004, only 14,250 of these were esophagus cancer. This represents only 1% of all cancers. Still esophagus cancer is a lethal disease with an esti- mated 13,300 deaths occurring in 2004 (1). Over the last cen- tury, various surgical, radiotherapeutic, and chemotherapeutic options have evolved to treat esophageal cancer for cure and relief of symptoms.
From: Endoscopic Oncology: Gastrointestinal Endoscopy and Cancer Management. Edited by: D. O. Faigel and M. L. Kochman © Humana Press, Totowa, NJ
8 Esophageal Cancer Therapy
Surgery, Radiation, and Chemotherapy
J
OHNM. H
OLLAND,
MD ANDC
HRISTOPHERA. C
ANNING,
MDCONTENTS
BACKGROUND
INTRODUCTION
SURGERY FORESOPHAGUSCANCER
DEFINITIVERADIATIONALONE FORESOPHAGUSCANCER
CARCINOMA OF THECERVICALESOPHAGUS
PALLIATIVETHERAPY FORESOPHAGUSCANCER: SURGERY ANDRADIATION
CHEMOTHERAPY FORESOPHAGEALCANCER
FUTUREDIRECTIONS
REFERENCES
85
3. SURGERY FOR ESOPHAGUS CANCER 3.1. HISTORICAL PERSPECTIVE
In 1871, Theodor Billroth pioneered surgical therapy for the cervical esophagus by performing experimental resections in dogs. He performed the first resection of the cervical esophagus on a human in 1872. The distal esophagus was first successfully resected in the early 1900s through an abdominal route.
The development of improved ventilatory support and positive pressure anesthesia made possible a transthoracic approach to resection of the intrathoracic esophagus. Patients undergoing this procedure in its early days had a very high mortality rate, most commonly from pneumothoraces. Franz Torek performed the first successful transthoracic esophageal excision in 1913. He excised a mid-esophageal carcinoma by a left thoracotomy. Torek had planned to perform an esophageal reconstruction but the patient refused. Instead, the cervical esophagostomy and gastrostomy were connected by an exter- nal rubber tube that allowed the patient to swallow liquids and semiliquid food. This 67-yr-old patient lived without recur- rence for 13 yr.
Still, mortality from this transthoracic procedure continued to be very high for the next two decades, largely owing to sep- sis caused by intrathoracic anastomotic failure. Surgical results began to improve after 1938 when multi-stage operations were abandoned in favor of single-stage procedures. Adams and Phemister performed a successful one-stage resection of a tho- racic esophageal cancer with an intrathoracic esophago- gastrostomy. Marshall in the United States and Oksawa in Japan also performed single stage transthoracic esophagectomies with reconstruction in the 1930s. With the improvement in pre- operative and postoperative care, better anesthetic techniques,
diaphragm as well as the superior retroperitoneal lymph nodes.
Skinner has long been a proponent of this surgical procedure (4). He has argued that this procedure improves outcome. In a retrospective review of 128 patients, with 78 patients undergo- ing en bloc resection and 50 undergoing “standard” resection, Altorki and Skinner report a 4-yr survival of 34.5% and median survival of 27 mo after en bloc resection compared with 11%
and 12 mo, respectively, after standard surgery (p= 0.007).
Improved outcoume is felt to be related to the more extensive nodal resection seen in the en bloc surgery (5). In a more recent review of en bloc resection for esophageal cancer performed on 111 patients, Altorki and Skinner report 5-yr survival rates of 78, 72, 0, 39, and 27% for stages I, IIA, IIB, III, and IV, respec- tively. Node-negative patients have a 5-yr survival of 75%.
Lymph node-positive patients have a 5-yr survival of 26%.
Overall local recurrence rate is only 8% (6). Demonstrating the controversies that exist in surgery for esophagus cancer, others have argued that such aggressive surgery does not improve sur- vival and may be associated with increased peri-operative mor- bidity and mortality, especially in less experience hands.
Transthoracic esophagectomy using a right-sided thoraco- tomy is often used for midthoracic esophageal tumors. The thoracic incision is usually made in the fifth intercostal space.
The stomach is anastomosed either to the upper thoracic esophageal remnant or to the cervical esophagus. An abdominal incision may be used to mobilize the stomach (Fig. 1). The right-sided approach is preferred for mid to upper esophageal tumors to avoid the aortic arch.
The Ivor Lewis esophagectomy involves separate incisions for the right thoracotomy and laparotomy. Transthoracic resec- tion using a left thoracotomy is utilized for tumors of the lower half of the esophagus or tumors of the gastroesophageal junc- tion (GEJ) (Fig. 2) (7). Transhiatal esophagectomy has been performed as an alternative procedure avoiding the morbidities seen with thoracotomy. This approach uses a combination of cervical and abdominal incisions to obtain access to and mobi- lize the esophagus and stomach (Fig. 3). The thoracic esopha- gus is freed via blunt manual dissection with the surgeon’s hand coming up into the mediastinum from the abdominal inci- sion. The stomach is pulled up into the chest with anastomosis in the neck. Extensive mediastinal exploration is not possible with the transhiatal approach, but there is less pulmonary mor- bidity because the procedure omits thoracotomy.
Recently, laparoscopic and thoracoscopic approaches have been utilized to resect malignant esophageal disease attempt- ing to limit operative and peri-operative morbidity (8). The use of a particular surgical technique depends on several factors including tumor location, the functional status of the patient (especially pulmonary function) and even individual surgeon expertise and preference. The use of thoracotomy clearly increases postoperative pulmonary morbidity. The best loca- tion for the surgical anastomosis is somewhat controversial.
Some feel anastomosis within the chest is associated with increased morbidity/mortality from mediastinitis caused by anastomotic leak. Walther actually randomized 83 patients to undergo esophagogastric anastomosis either in the neck (41 patients) or in the chest (42 patients). These authors found greater availability of antibiotics and increasing surgical expe-
rience, the success rate with transthoracic esophagectomies continued to improve.
In 1946, Ivor Lewis described a new approach for cancers of the mid-esophagus. His technique used both a right thoracotomy incision and a laparotomy incision to approach mid-esophageal tumors. This allowed direct visualization for lymph node dis- section and complete resection and staging of the tumor. This operation, with some minor technical refinements, is still com- monly employed today.
Another commonly utilized approach is the transhiatal esophagectomy. This technique was innovated by Denk in 1913 in animal experiments. It was first performed success- fully in a human in 1936 by Turner. In this procedure, the inci- sions are made in the neck and abdomen (2). The stomach is pulled up and anastomosed with the cervical esophagus. More recently, Orringer has become a major advocate for this tech- nique and has reported his experience in 583 patients (3).
Historically, some surgeons have advocated more extensive surgical resections, such as the so-called “en bloc” resection.
Recently, there has been interest in performing esophagectomy using less invasive techniques such as video assisted thoraco- scopic surgery or laparoscopy.
3.2. SURGICAL TECHNIQUES
Many different surgical techniques have been developed to resect esophageal cancers. Several common surgical approaches are listed in Table 1. Radical or en bloc resection involves removal of the esophagus with 10 cm proximal and distal mar- gins if possible as well as total resection of periesophageal tis- sues including the vascular and lymphatic supply. This includes removal of the pleura, part of the pericardium, the thoracic duct, and the azygous vein in the chest, and, for tumors of the distal esophagus, resection of the spleen, part of the stomach, and
Table 1
Comparison of Surgical Techniques for Resection of Esophageal Cancer
Technique Advantages Disadvantages
Transhiatal Avoids the morbidity Difficult to perform a esophagectomy of a thoracotomy, full thoracic
less pulmonary lymphadenectomy, morbidity, poor visualization of extrathoracic the midthoracic anastamosis dissection Ivor Lewis Allows direct Toxicity of
(transthoracic) visualization of thoracotomy, greater esophagectomy the thoracic pulmonary morbidity
esophagus and full lymphadenectomy
Esophagectomy Good exposure of Same disadvantages as via left lower esophagus Ivor Lewis technique thoracotomy
Thoracoscopic Less invasive, may be Unproven as an esophagectomy less morbid with oncological surgery,
quicker recovery lower morbidity is controversial En-bloc More comprehensive Invasive, controversy
esophagectomy cancer surgery regarding improved outcomes, increased morbidity
no difference in 5-yr survival (29 vs 30%) or anastomotic leak rate (1.8% overall). Furthermore, there was no difference in the anastomotic diameter on endoscopic follow-up or any dif- ference in body weight development between the two anasto- motic sites (9).
The specific type of surgery to resect esophageal carcinoma is controversial with strong proponents for particular techniques.
Hulscher et al. (10) compared extended transthoracic resection with limited transhiatal resection for adenocarcinoma of the esophagus. This study randomized 220 patients with tumors of the mid-to-distal esophagus or adenocarcinoma of the gastric car- dia. Transthoracic esophagectomy included an extended “en bloc”
lymph node dissection. Surgery was performed at Dutch academic centers performing at least 50 esophagectomies per year.
Transhiatal resection was associated with less morbidity and cost less than transthoracic resection. Patients undergoing transhiatal resection had fewer pulmonary complications (27 vs 57%) and chylous leakage (2 vs 10%). Transhiatal resection patients also had shorter durations of mechanical ventilation and shorter stays in the ICU. In-hospital mortality was 2% after transhiatal resec- tion compared with 4% after extended transthoracic resection (p
= 0.45). At a median follow-up of 4.7 yr, there is a trend, although not significant, toward improved overall 5-yr survival (39 vs 27%) in the group undergoing transthoracic esophagectomy.
Transthoracic esophagectomy was associated with a 56%
increased cost: $45,034.40 vs $28,901.70 for transhiatal surgery.
The authors estimate a cost of $50,414.40 per “quality-adjusted life span” when using the extended transthoracic approach.
3.3. OUTCOMES AFTER SURGERY ALONE
Surgical resection of esophageal cancer is curative for patients with disease limited to the mucosa and submucosa with- out spread to regional lymph nodes. King reports a 5-yr survival rate of 86% after Ivor Lewis esophagogastrectomy for stage I disease (11). Unfortunately, such lesions are uncommon, accounting for only 7–10% of esophageal cancers (12). In the United States, patients are generally diagnosed with more advanced-stage disease. As stage increases, 5-yr survival rates fall after esophagectomy: 34% for stage II, 15% for stage III. In an early review of outcome following surgical resection of esophageal squamous cell carcinomas, Earlam finds a dismal 5-yr survival rate of only 10% with only 39 of 100 patients resectable and only 4 alive at 5 yr (13). These results may seem unduly pessimistic; still, even in academic centers with signifi- cant esophageal cancer surgery experience, most report overall 5-yr survival rates of only 22–39% (10,12).
3.4. ADJUVANT THERAPY FOR ESOPHAGUS CANCER Given the relatively poor results using surgery alone to treat carcinoma of the esophagus, it is reasonable to consider com- bining other cancer modalities to try to improve outcome.
3.4.1. Adjuvant Radiation Alone for Esophagus Cancer:
Pre-Operative Radiation
There have been five randomized trials evaluating the bene- fit of pre-operative radiation in resectable esophageal cancer (14–18). Most patients in these studies had squamous cell his- tology. Pre-operative radiation therapy was not shown to improve respectability. Gignoux did show a decrease in local Fig. 1. Transthoracic esophagectomy through a right-sided thoracotomy. (Reproduced with permission from ref.7.)
failure rate with the addition of 33 Gy pre-operative radiation:
67% after surgery alone vs 46% after combined therapy (15).
Nygaard reported an improvement in overall survival in patients receiving pre-operative radiation (18). These results are tem- pered by the fact that this was a four-arm study: pre-operative chemotherapy, pre-operative radiation, pre-operative chemora- diation, or surgery alone. Three-year survival was significantly higher in the “pooled” groups receiving pre-operative radio- therapy with or without chemotherapy: 18 vs 5% (p= 0.009).
In this series, 48 patients received pre-operative radiation alone and had a 20% survival rate at 3 yr. Still, this apparent benefit did not reach statistical significance for the pre-operative radia- tion alone arm. Arnott reported the results of a meta-analysis evaluating pre-operative radiotherapy in esophagus cancer from the Oesophageal Cancer Collaborative Group (19). This analy- sis of five randomized trials included 1147 patients. With a median follow-up of 9 yr, hazard ratio analysis “suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 yr and 4% at 5 yr.” This apparent benefit, though, did not reach statistical significance (p= 0.062).
The authors, therefore, concluded that “there was no clear evi- dence that pre-operative radiotherapy improves the survival of patients with potentially resectable esophageal cancer.” If such a benefit did exist, it would be “modest with an absolute improve- ment in survival of around 3–4%.” The authors concluded:
“pre-operative radiotherapy cannot currently be routinely rec- ommended outside of controlled clinical trials.”
3.4.2. Adjuvant Radiation Alone for Esophagus Cancer:
Postoperative Radiation
There have been two randomized trials evaluating post- operative radiation for esophagus cancer. Teniere reported the outcome of a French study of 221 patients with resected squamous cell carcinoma of the mid-to-distal esophagus (20). Patients were randomized to undergo surgical resec- tion followed by 45–55 Gy or surgery alone. Postoperative radiation did not improve survival: 5-yr survival was 19%.
Locoregional failure was decreased after radiation (30–15%) but this benefit was only significant in lymph node negative patients (35 vs 10%). Fok and colleagues evaluated 130 patients with both squamous and adenocarcinoma histologies (21). This study evaluated postoperative radiation in patients undergoing both curative and palliative resections.
Postoperative radiotherapy was associated with increased com- plications of the intrathoracic stomach including four deaths from bleeding ulcers. The overall median survival was actually decreased in those patients receiving postoperative radiation:
8.7 vs 15.2 mo (p= 0.02). Radiotherapy did decrease intratho- racic recurrence with a particular benefit seen in patients with residual tumor having a decreased risk of dying from obstruc- tion of the tracheobronchial tree (7 vs 33%, p= 0.03). The Fig. 2. Transthoracic esophagectomy through a left-sided thoracotomy. (Reproduced with permission from ref. 7.)
3.4.4. Postoperative Chemotherapy
There is little data regarding the use of postoperative chemotherapy alone for esophageal cancer. The Japan Clinical Oncology Group performed a multicenter randomized trial evaluating two cycles of adjuvant cisplatin and 5-FU after transthoracic esophagectomy with lymphadenectomy in 242 patients with squamous cell histology (25). Most patients (75%) received both full cycles of chemotherapy. Five-year disease-free survival was improved with the addition of chemotherapy: 55 vs 45% (p= 0.037). This benefit was most pronounced in the lymph node positive patients: 5-yr disease- free survival 52 vs 38% (p= 0.041). Overall survival after chemotherapy was 61% compared with 52% after surgery alone but this failed to reach statistical significance (p= 0.13).
3.4.5. Pre-Operative Chemoradiation
The concept of combining radiation with radiosensitizing chemotherapy before surgical resection now dates back over 20 yr. Leichman and colleagues at Wayne State University treated 21 patients with squamous cell carcinoma with two cycles of cisplatin and 5-FU combined with 30 Gy external beam radia- tion (26). Of these patients, 15 (71%) underwent resection and 7 of the 15 (47%) had no viable tumor in the resected speci- men. Overall median survival was 18 mo; 24 mo in those with a complete pathological response. This approach was associ- ated with a peri-operative mortality rate of 27%. Because of this work, several phase III studies have been completed with conflicting results making this treatment approach one of the most controversial in cancer care. Le Prise combined low-dose radiation (20 Gy) with two cycles of cisplatin and 5-FU and compared pre-operative chemoradiation with surgery alone for Fig. 3. Transhiatal esophagectomy. (Reproduced with permission from
ref.7.)
authors concluded that postoperative radiotherapy should be limited to those patients with residual mediastinal tumor after resection in an attempt to reduce recurrent disease obstructing the airway. Accordingly, postoperative radiation has generally been reserved for those patients left with positive surgical mar- gins or gross residual tumor after resection.
3.4.3. Pre-Operative Chemotherapy
Three randomized studies give conflicting results regarding the benefit of pre-operative chemotherapy. Kelsen reported the results of a multi-institutional United States Intergroup trial involving 440 patients (22). Patients randomized to chemotherapy received three cycles of cisplatin and 5-FU before surgery followed by two more cycles after resection. With a median follow-up of 55.4 mo, there was no difference in survival: 16.1 mo after surgery alone vs 14.9 mo after surgery and peri-operative chemotherapy. Three-year survival rate was 26% after surgery alone vs 23% after chemotherapy plus surgery. The addition of chemotherapy did not improve resectability but it also did not increase operative morbidity or mortality. Chemotherapy did not affect locoregional or distant recurrence rates.
Kok has reported in abstract form the results of a phase III Dutch trial evaluating neoadjuvant cisplatin and etoposide in 160 operable squamous cell tumors (23). After two cycles of chemotherapy, tumor response was evaluated. Patients with a
“major response” received two additional cycles of chemother- apy followed by transhiatal resection. Nonresponders proceeded directly to surgery. Those patients receiving pre-operative chemotherapy had improved median survival compared with patients undergoing surgery alone: 18.5 vs 11 mo (p= 0.002).
The largest randomized trial evaluating pre-operative chemotherapy for resectable esophagus cancer comes from the Medical Research Council Oesophageal Cancer Working Party (24). This study randomized 802 patients to surgery alone or two cycles of pre-operative cisplatin and 5-FU. Chemotherapy increased the percentage of complete resections (54 vs 60%, p < 0.0001) without increasing postoperative complications.
Overall survival was improved with the addition of chemother- apy. Median survival increased from 13.3 to 16.8 mo; 2-yr survival rates were 43% after chemotherapy plus surgery com- pared with 34% after surgery alone. These three randomized trials are summarized in Table 2.
Table 2
Randomized Trials Evaluating Pre-Operative Chemotherapy for Esophageal Cancer
Variable Kelson (22) Kok (23) MRC (35)
No. of patients 467 160 802
Histology 54% adeno 100% squamous 66% adeno Chemotheraphy Cycles: three Cycles: two; two Two 40d
regimen pre-op, two additional for cycles every post-op, given responders 3 wk
every 4 wk
Chemotherapy Cisplatin: Cisplatin: Cisplatin:
dose 100 mg/m2; 80 mg/m2; 80 mg/m2;
5-FU: Etoposide: 5-FU:
1000 mg/m2d 100 mg iv/d 1000 mg/m2 1+ 2; 200 mg continuous
po/d 3 + 5 inf × 4 d
Chemotherapy 62% More R0 60%
patients resection in
undergoing group receiving
complete chemo
resection (%)
Median survival 14.9 mo 18.5 mo 16.8 mo with
chemotherapy
Survival None 7.5 mo 3.5 mo
benefit
Increased No One toxic death No
morbidity after chemotherapy
86 patients with squamous cell histology (27). Therapy was well tolerated with operative mortality of 8.5% after combined therapy and 7% after surgery alone. Unfortunately, long-term survival was also unaffected by the addition of neoadjuvant chemotherapy. Both groups had a 47% survival rate at 1 yr.
Three-year survival was 19% in the multimodal group com- pared with 14% after surgery alone but this difference was not significant. Bosset reported another larger French trial of chemoradiation followed by surgery vs surgery alone for squa- mous cell tumors (28). Most of these patients had early-stage (T1T2N0) disease. Radiation was delivered in an unusual split- course manner: two 1-wk courses of 3.7 Gy × 5 separated from each other by a 2-wk break, thereby delivering a total dose of 37 Gy over 4 wk. Cisplatin (80 mg/m2) was administered 0–2 d before each round of radiation. Curative resection was more likely in the combined modality arm: 81 vs 69% (p= 0.017). A complete pathological response was seen in 26% with an addi- tional 18% having a “major pathological response.” Combined therapy was also associated with an increased postoperative mortality rate: 12.3 vs 3.6% (p= 0.012). With a median follow- up of 55 mo, the median survival is 18.6 mo for both treatment arms. There were fewer deaths from esophagus cancer in the combined arm (68 vs 86%, p= 0.002) but this benefit was lost owing to the increased postoperative mortality. The authors concluded: “Future efforts should aim to improve the efficacy of the treatment whereas reducing its toxicity.”
A relatively small, single-institution trial from St. James’
Hospital in Dublin, Ireland has had a significant impact on clin- ical practice, especially in the United States. Walsh and col- leagues compared esophagectomy alone with pre-operative chemoradiation with 5-FU and cisplatin during 1–6 wk com- bined with 40 Gy external beam radiation delivered over 3 wk beginning with the first dose of chemotherapy (29). This ran- domized trial included 113 patients with adenocarcinoma of the esophagus. Chemoradiation was well tolerated with a 13%
rate of grade 3/4 toxicity and no increase in the frequency or grade of postoperative complications. Pre-operative chemoradi- ation resulted in a 25% complete pathological response rate Fig. 4. Kaplan–Meier actuarial survival of patients with esophageal adenocarcinoma treated with pre-operative chemoradiation or surgery alone. (Reproduced with permission from ref. 29.)
Fig. 5. Actuarial survival after pre-operative chemoradiation vs sur- gery alone for carcinoma of the esophagus. (Reproduced with per- mission from ref. 30.)
and a decrease in pathological lymph node positivity: 42 vs 82% after surgery alone (p < 0.001). Survival was improved in the multimodality arm with a median survival of 16 vs 11 mo after surgery alone (p= 0.01). Three-year survival was also improved in patients receiving pre-operative chemoradiation:
32 vs 6% (p= 0.01) (Fig. 4). A criticism of this study has been the poorer-than-expected survival seen after surgery alone.
Based on encouraging results of a pilot study, Urba et al.
(30) designed a phase III trial comparing transhiatal esophagec- tomy alone with the same surgery after concurrent cisplatin, 5-FU and vinblastine chemotherapy combined with acceler- ated, hyperfractionated external beam irradiation (1.5 Gy BID to 45 Gy over 3 wk). One hundred patients were randomized:
25% had squamous histology, 75% had adenocarcinomas. With a median follow-up of 8.2 yr, there is no significant difference in median survival: 17.6 mo after surgery vs 16.9 mo after tri- modality therapy. Three-year survival appears to favor the com- bined therapy arm: 30 vs 16% but this difference did not reach statistical significance (p= 0.15) (Fig. 5). Criticism of this study has focused on whether it had adequate patient numbers. The study was powered to detect “a relatively large increase in median survival from 1 to 2.2 yr.”
These studies have failed to conclusively answer the ques- tion about the role of neoadjuvant chemoradiation for resectable esophagus cancer. The single positive study included only ade- nocarcinoma. A subsequent Intergroup trial comparing surgery alone vs pre-operative cisplatin and 5-FU combined with 50.4 Gy hoped to enroll 620 patients. Unfortunately, this study closed prematurely when only 75 patients had been enrolled in the first 2.5 yr, leaving the role of neoadjuvant chemoradiation unsettled (31).
3.4.6. Postoperative Chemoradiation
There is little data on the use of combination chemotherapy together with radiation after resection of esophageal cancer.
There exists the general perception that these patients are too frail after surgery to tolerate the morbidity of such aggressive adjuvant therapy.
Noting that “neither postoperative radiotherapy nor chemo- therapy alone provide a survival benefit after curative esophagectomy for esophageal squamous cell carcinoma,”
Tachibana and colleagues devised a prospective randomized trial to compare postoperative chemotherapy with chemo- radiotherapy (32). Patients were randomized to receive cisplatin and 5-FU chemotherapy alone or together with 50 Gy to the mediastinum after surgery. The 5-yr survival rates were 50%
after chemoradiation vs 38% after chemotherapy alone but this was not significant (p= 0.97). Further, locoregional failure rate was not affected by mediastinal irradiation: 18 vs 17%.
The authors concluded: “postoperative radiotherapy adminis- tered concurrently with chemotherapy does not provide a sur- vival benefit compared with chemotherapy alone.”
Although generally remembered as a gastric cancer study, MacDonald et al. (33) compared chemoradiotherapy after sur- gery with surgery alone for both adenocarcinoma of the stomach and the GEJ. In this study, 556 patients with resected adeno- carcinomas of the stomach or GEJ were randomized to receive postoperative chemoradiation (5-FU and leucovorin and 45 Gy over 5 wk) or observation. Approximately 20% of the patients had tumors of the GEJ. Overall, the median survival was increased in those patients receiving adjuvant chemoradiation:
36 vs 27 mo(p= 0.005). Three-year survival rates were also increased after chemoradiation: 50 vs 41% (p= 0.005). Local recurrence rates appeared to be less after chemoradiation as well (19 vs 29%) but because documentation only recorded the site of first relapse, statistical assessment was not felt reli- able and potentially biased owing to a lack of complete report- ing of sites of failure. Although these numbers apply to the entire set of 556 patients, most with gastric cancer, the authors
“were unable to detect differences in the effects of treatment according to … location of the primary tumor.” Therefore, it may be reasonable to apply this data accrued from approx 100 patients to the generalmanagement of resectable adenocarci- nomas of the GEJ.
4. DEFINITIVE RADIATION ALONE FOR ESOPHAGUS CANCER
Radiation oncologists often complain that definitive radia- tion for esophageal cancer is limited only to the patients the surgeons do not want—either because the tumors are too locally advanced or the patients are felt too frail to tolerate surgery. Whether this is true or not, what is true is radiation therapy alone is rarely curative in the treatment of esophageal cancer. In his review of radiotherapy in the management of squamous cell carcinoma of the esophagus, the British sur- geon Earlam reported a 1-yr survival rate of 18% and a 5-yr survival of 6% after radiation (34). Interestingly, Earlam was a strong proponent of an MRC trial comparing surgery alone
with radiotherapy alone. This trial closed early because it failed to enroll patients (35).
Radiotherapy alone has been used for early-stage eso- phageal cancer including patients medically unfit for surgery.
Sykes reported on the use of “radical” radiation of 45–52.5 Gy in 15 or 16 fractions over 3 wk in 101 patients with tumors
“no longer” than 5 cm. In this series of relatively favorable tumors, the median survival was 15 mo; 3-yr survival was 25%; 5-yr survival was 17% (36). Okawa reported an overall 9% 5-yr survival rate for 288 patients with squamous cell car- cinomas treated with radiotherapy alone (37). Within this group, patients with tumors 5 cm long or less had a 17.7%
5-yr survival. Patients with stage I disease had a 20.2% 5-yr survival but this fell to 9.9% for patients with stage II disease.
Hyden reviewed a less optimistic experience at the University of Southern California (38). Here, 46 patients with inoperable esophagus cancer were treated with a combination of external beam radiation and endoluminal brachytherapy. Even with this combination radiation therapy, the 5-yr actuarial survival for 28 patients with stages I or II disease was only 12%. Maingon and colleagues have used high-dose rate (HDR) brachytherapy alone or in combination with external beam radiotherapy to treat either primary or recurrent superficial esophageal cancers (39). This series included eleven patients without invasion of the basal membrane (Tis) and 14 patients with tumors involv- ing the submucosa without spread into the muscle (T1).
Overall survival was 24% for Tis patients and 20% for T1 dis- ease. Those select patients treated with HDR brachytherapy alone had a survival rate of 43%. Complications included four patients with stenosis and one developing a fistula. Nemoto et al. (40) treated 78 select patients with superficial esophageal cancer using external beam radiotherapy alone. All patients had T1 biopsy-proven squamous cell carcinomas. Endoscopic ultrasound was used to confirm the depth of invasion in 34 patients. Patients undergoing endoscopic mucosal resection were excluded. Mean radiation dose was 65.5 Gy. Overall, the 5-yr survival was 45% with a local control rate of 66%. Late complications included esophageal stricture and radiation pneumonitis developing in two patients each.
4.1. ACCELERATED HYPERFRACTIONATED RADIOTHERAPY ALONE FOR ESOPHAGUS CANCER
During a fractionated course of radiotherapy, surviving cancer cells can continue to divide. In fact, radiobiologists and clinicians have observed tumor clonogens actually begin divid- ing at an increased rate during the course of radiotherapy. This
“accelerated repopulation” can occur around the fourth week of standard once-a-day fractionated radiotherapy (41). In an attempt to deal with this tumor regrowth, clinicians have attempted to shorten or accelerate the course of radiation.
Decreasing total treatment time by using hyperfractionated (more than one treatment per day) radiation may improve results when using radiation alone for esophagus cancer (42).
Institut Gustave Roussy has used this approach delivering 65 Gy over 4–5 wk (median treatment duration 32 d) for 88 patients ineligible for surgery. Of these patients, 64% did receive neoadjuvant chemotherapy before radiation. Three-year
cause-specific survival was 40, 22, and 6% for T1, T2, and T3 tumors, respectively. Grade 3 esophagitis was seen in 16%.
Late toxicity included esophageal stenosis in 8% and pul- monary fibrosis in 9% (43). Shi tested accelerated fractiona- tion in a small randomized study (44). Eighty-five patients with esophageal cancer were randomized to receive conventional once-a-day fractionation with 1.8 Gy delivered 5 d a week to a total dose of 68.4 Gy over 7–8 wk or late course-accelerated hyperfractionated (LCAF) radiation. This group received the same once-a-day radiation as the conventional group for the first two-thirds of the treatment (41.4 Gy/23 fractions over 4–5 wk). Accelerated hyperfractionation was then delivered as a boost to a reduced volume with 1.5 Gy fractions twice-a-day to 27 Gy. This delivered a total dose of 68.4 Gy as in the con- ventional arm but the LCAF therapy was completed sooner:
6.4 vs 7–8 wk. These authors found that the LCAF group achieved greater local control at 5 yr: 55 vs 21% (p= 0.003).
Five-year actuarial survival was 34% after LCAF compared with 15% after conventional fractionation, but this difference did not reach statistical significance. Acute morbidity was
“increased but acceptable.” Late toxicity at 5 yr after LCAF was “not increased.”
4.2. CONCURRENT CHEMOTHERAPY AND RADIATION
Radiation alone has been compared with radiation with con- current cisplatin and 5-FU chemotherapy in an Intergroup study enrolling 129 patients with carcinoma of the thoracic esopha- gus (45). Eighty-eight percent had squamous histology, 12%
had adenocarcinomas. The total radiation dose was 64 Gy for radiation alone and decreased to 50 Gy when delivered with concurrent chemotherapy. The chemotherapy consisted of cis- platin at 75 mg/m2on the first day with continuous infusion 5- FU at 1 gm/m2on days 1–4. Two cycles of chemotherapy were delivered with thoracic radiation during weeks 1 and 5. Two additional cycles were then delivered after radiation during weeks 8 and 11. Concurrent chemoradiation was morbid with 44% “severe” and 20% “life-threatening” side effects.
Hematological side effects were the most common: 33% severe, 13% life-threatening. Mucositis of the oral cavity, pharynx, and esophagus was severe in 26%, life-threatening in 13%.
Although chemoradiation was difficult, it also improved sur- vival. Median survival was increased from 8.9 mo after radia- tion alone to 12.5 mo after chemoradiation. Two-year survival was 38% after chemoradiation vs 10% after radiation alone. By 5 yr, 27% were alive after chemoradiation compared with no survivors after radiation alone (46). An additional group of 69 patients were treated with chemoradiation confirming these improved results with a median survival of 17.2 months and a 3-yr survival rate of 30%. Further long-term analysis found there were no further deaths from esophageal cancer in the chemoradiation arm after 8 yr with a 22% rate surviving “at least 8 yr” (47) (Fig. 6). Locoregional failure was decreased after concurrent chemoradiation but was still common. After completing chemoradiation, 27% had persistent disease and 16% suffered local failure as the first site of recurrence (43%
total). At 12 mo, 22% of the chemoradiation patients had devel- oped distant metastases compared with 38% after radiation alone. Late toxicity after chemoradiation was infrequent with no significant increase seen over radiation alone.
4.2.1. Concurrent Chemoradiation: Radiation Dose Escalation
Seeking to improve outcome in the use of chemoradiation for esophagus cancer and recognizing the greater than 40%
local failure rate seen with its prior chemoradiation regimen, the Radiation Therapy Oncology Group (RTOG) developed two studies evaluating the benefit of increasing local therapy by increasing the radiation dose. RTOG 9207 was a phase I/II trial adding endoluminal brachytherapy to boost the site of the tumor in addition to the 50 Gy external beam dose used in the prior trial. Here, patients could receive boost with either HDR brachytherapy with three fractions of 5 Gy each or low-dose rate brachytherapy with a single boost fraction of 20 Gy. This study enrolled 49 patients (92% squamous, 6% adenocarcino- mas). With a median follow-up of 29 mo, 3-yr survival was 29% but toxicity was felt to be unacceptably high with 6%
“life-threatening” strictures and 12% fistulas. The authors con- cluded with the following advice: “use caution in employing esophageal brachytherapy when used in conjunction with chemotherapy” (48). Finding that brachytherapy as a boost was associated with unacceptable morbidity, RTOG next tried to dose-escalate radiation by increasing external beam therapy.
RTOG 9405 randomized patients to receive either: 50.4 Gy with 1.8 Gy daily fractions or 64.8 Gy with 1.8 Gy fractions.
This phase III trial hoped to enroll 298 patients. However, the RTOG Data Monitoring Committee performed an interim analysis after enrollment of 230 patients (77% of the target number) and found “the survival associated with the assigned higher total dose (64.8 Gy) arm was worse than the control (50.4 Gy) arm” (49). Two-year survival in the higher dose arm was 31 vs 40% after the standard dose. The decrease in sur- vival was attributed to 11 treatment-related deaths in the high- dose arm compared with only two such deaths in the standard-dose arm. Interestingly, 7 of these 11 deaths occurred in patients receiving 50.4 Gy or less, and, therefore could not be attributed to the increased dose of radiation. Still, with these results RTOG was left to conclude “standard dose for patients receiving concurrent cisplatin/5-FU is 5040 cGy.”
Fig. 6. Long-term survival benefit of chemoradiation over radiation alone for esophagus cancer (log-rank test of randomized patients p < 0.001). Survival curve created using data from ref. 47.
4.2.2. Concurrent Chemoradiation: New Chemotherapy Combinations
Current phase II studies combining radiation with concur- rent chemotherapy tend to focus more on modification of the chemotherapeutic component rather than radiation. RTOG E-0113 adds paclitaxel to cisplatin and 5-FU. Ilson and colleagues have combined cisplatin with the topoisomerase I inhibitor irinotecan together with concurrent radiotherapy for locally advanced esophageal cancer (50).
4.3. CHEMORADIATION VS CHEMORADIATION PLUS SURGERY FOR LOCALLY ADVANCED ESOPHAGEAL
4.3.1. Cancer
The best therapy for locally advanced esophageal cancer is far from established. Two recent European phase III trials question the value of adding surgical resection after chemo- radiation for esophagus cancer. Bedenne reported the results of the French trial FFCD 9102 which evaluated induction chemoradiation with 5-FU and cisplatin combined with pro- tracted (46 Gy over 4.5 wk) or split-course (3 Gy × 5 on days 1–5 and 22–26 for a total dose of 30 Gy) (51). Patients experi- encing at least a partial response were then randomized to receive either surgical resection or more chemoradiation with three cycles of 5-FU and cisplatin with radiation (protracted 20 Gy or split-course 15 Gy). This study enrolled 455 patients to receive the induction chemotherapy but only 259 (57%) were randomized. Two-year survival rate was 34% after sur- gery vs 40% after chemoradiation (p= 0.56). Median survival was 17.7 mo after surgery compared with 19.3 mo after chemoradiation. The 3-mo death rate was higher after surgery (9 vs 1% [p= 0.002]) but the patients with chemoradiation alone had a significantly greater likelihood of ultimately need- ing stent placement or dilatation for recurrent dysphagia.
Interestingly, patients receiving continuous course radiother- apy needed less palliative intervention than those patients receiving the split-course radiotherapy.
At ASCO 2003, Stahl reported a similar German phase III study with induction chemoradiation (three cycles of 5-FU/
leucovorin/etoposide/cisplatin followed by concurrent cis- platin/etoposide plus 40 Gy) (52). A total of 177 patients with squamous histology were then randomized to receive either surgery via transthoracic esophagectomy with two-field lym- phadenectomy or more chemoradiation with cisplatin/etopo- side and radiation to doses “>60 Gy.” Treatment related mortality was 10% after surgery vs 3.5% after chemoradia- tion. There was a “strong trend” toward improved local con- trol after surgery. First site of tumor progression was observed locally in 64% after surgery compared with 81% after chemoradiation alone (p= 0.08). Still, there was no difference in median or 3-yr survival rate: 16 mo, 28% after surgery vs 15 mo, 20% after chemoradiation alone (log rank p= 0.22).
Nonresponders to induction chemoradiation appeared to ben- efit from “complete tumor resection” with a 3-yr survival of 35% compared with 11% for nonresponders continuing with more chemoradiation. These two European studies strongly question the benefit of adding surgery to chemoradiation for esophagus cancer.
5. CARCINOMA OF THE CERVICAL ESOPHAGUS Carcinoma of the cervical esophagus presents distinct prob- lems in management. The cervical esophagus begins below the cricopharyngeus muscle (just below the level of the cricoid cartilage) at about 15 cm and extends down to the thoracic inlet at approx 20 cm measured from the upper incisors. These tumors are almost always squamous cell tumors and are often difficult to distinguish from primary tumors that originate in the hypopharynx. In fact, the narrow cricopharyngeus muscle is all that separates the postcricoid area of the hypopharynx from the cervical esophagus.
Surgical resection of cervical esophagus cancer is exten- sive. Most patients require total laryngoesophagectomy. Para- tracheal lymphadenopathy is common and together with radial tumor growth, surgery often needs to include thyroidectomy and bilateral paratracheal lymph node dissection. Alimentary reconstruction may require gastric transposition or interposi- tion of bowel. Overall, results of therapy are disappointing.
Kakegawa reported outcome after surgical resection of 64 patients with cervical esophagus cancer (53). In this series, most patients underwent “visceral replacement” using the stomach. Twelve patients underwent cervical esophagectomy with 33% peri-operative mortality and a 5-yr survival rate of 16.7%. Most patients (81%) were resected with total esophagec- tomy and fared better with a 5.8% operative mortality and a 5-yr survival rate of 30%. Therefore, these authors recommended total esophagectomy with stomach replacement for cervical esophagus cancer. Peracchia et al. at the University of Padua have resected 169 patients with cervical esophagus cancer (54). Resection was complete in 85% and with palliative intent in 15%. Most patients (61%) underwent laryngopharyngo-total esophagectomy. Digestive tract reconstruction was with pharyngo-gastrostomy in 85 patients and pharyngo-colostomy in 16 patients. Operative mortality was 13–18%. Overall 5-yr actuarial survival, excluding operative mortality, was 15.8%.
Radiotherapy alone has also been used to treat carcinoma of the cervical esophagus. Mendenhall reported the University of Florida experience treating 34 patients (55). With a mini- mum follow-up of 2 yr, only 26% of these patients maintained local control. Five-year survival was only 14%.
Concurrent chemoradiation has also been used for cervical esophagus cancer. Iop and colleagues reported a small series of 23 patients treated with concurrent cisplatin, 5-FU and radi- ation using a combination of external beam radiotherapy and endoluminal brachytherapy to a mean dose of 60 Gy (56). With a short median follow-up of 14 mo, the actuarial 4-yr survival was estimated to be 30.4%. Locoregional failure as the first site of failure was also 30.4%. There were no toxic deaths;
acute and late toxicity were “moderate.” Two long-term survivors did develop stenosis requiring dilatation.
6. PALLIATIVE THERAPY FOR ESOPHAGUS CANCER: SURGERY AND RADIATION
Recognizing that all esophagus cancer patients are not good candidates for curative therapy, surgery still has a long- established history for providing effective palliation of dysphagia
with either bypass surgery or esophagectomy. Mannel per- formed bypass surgery on 124 patients with unresectable esophagus cancer (57). Peri-operative mortality was 11% and was increased in patients undergoing colonic bypass and patients with “large tumor load.” Of those surviving surgery, 89% could eat a “normal, unrestricted” diet on discharge and 82% of survivors had complete and durable dysphagia relief.
The most common complication was sepsis due to anastomotic leakage in the neck. Median survival after surgery was only 5 mo. Segalin et al. (58) reviewed their experience of surgery for palliation of advanced esophageal cancer. Resection was performed in 156 patients. Successful palliation was achieved in 78%: 41% were able to eat an unrestricted diet (scored as excellent) and 37% were able to eat a normal diet with occa- sional dysphagia (scored as good). In-hospital mortality was 9.6% with a median survival of 7.8 mo. Evaluating an addi- tional 49 patients treated with bypass surgery, excellent or good palliation was achieved in 71% of operative survivors.
In-hospital mortality was high at 20.2% with a median sur- vival of only 6.2 mo.
Surgery, therefore, can provide effective palliation to relieve dysphagia but at the cost of significant peri-operative mortality and morbidity in a patient population with a very limited expected length of survival.
Radiation alone or in combination with chemotherapy has also been used for palliation of advanced esophageal cancer.
Rosenberg has described the use of palliative radiation to relieve both dysphagia and pain in up to 80% (59). Wara reviewed the University of California, San Francisco experi- ence of radiation alone for 169 patients with squamous cell carcinoma of the esophagus (60). In this group of patients, 66% achieved “significant relief” of dysphagia for 2 mo or longer. Median length of survival was 7 mo. Similar palliative response rates were seen for tumors of the upper, middle, and lower esophagus. Coia evaluated swallowing function in 120 patients receiving concurrent chemoradiation (61). He found an improvement in dysphagia occurring by a median of 2 wk in 88%. There was no difference in dysphagia relief between patients with squamous cell or adenocarcinoma histologies.
Patients with distal third tumors had both earlier and greater frequency of initial dysphagia relief than patients with tumors of the upper two-thirds of the esophagus: 95 vs 79%. In patients with advanced disease treated with palliative intent, 91% had an initial improvement in swallowing and 67% had dysphagia relief until death.
Endoluminal brachytherapy can also be useful in palliation especially in recurrent tumors. Sharma has used HDR Iridium- 192 brachytherapy in 58 patients with advanced or recurrent esophageal carcinoma (62). Improvement in swallowing was seen in 48% with median “dysphagia-free survival” of 10 mo.
This benefit was at the expense of a 30% complication rate including strictures in 15%, ulceration in 10% and tracheoe- sophageal fistulas in 5%. Sur and colleagues have also used HDR brachytherapy as sole palliative therapy in 232 patients with inoperable advanced esophageal tumors. Patients received either 18 Gy in three fractions or 16 Gy in two fractions. The length of dysphagia-free survival for the entire group was 7.1
mo with an overall survival of 7.9 mo. There was no significant outcome difference (dysphagia relief or complication rate) between the two fractionation regimens (63). Using patient interviews, Stoller evaluated palliative outcome in a series of 82 patients and compared radiation alone (65%) with esophagec- tomy with reconstruction (35%). Level of palliation was based on scores for swallowing ability, sleep, leisure activity, and pain control in this nonrandomized study (64). The authors found no significant differences between surgery or radiation in ability to provide palliation.
Clearly, surgery and radiation remain viable options for pal- liation in esophageal cancer. Still, over the last 20 yr, there has been rapid development of other palliative tools beyond the scope of this chapter including esophageal stents, Nd-Yag thermal ablation laser and photodynamic therapy.
7. CHEMOTHERAPY FOR ESOPHAGEAL CANCER The use of chemotherapy combined with surgery and/or radiation for locoregional disease has been discussed. Still, as many as 50% of patients with esophagus cancer will present with metastatic disease. Further, most patients treated with curative intent will ultimately develop locoregionally recurrent or metastatic disease.
Most single agents of chemotherapy have response rates of 15–25% against esophagus cancer (Table 3) (65). The use of chemotherapy in this population is palliative with most patients receiving therapy living less than 1 yr. Any hoped for benefit from therapy, therefore, must be weighed against the potential morbidity of side effects in these patients with limited life spans.
Certainly patients with good performance status and limited weight loss are the best candidates for further therapy.
Combination chemotherapy generally has higher response rates but may have greater toxicity. In a randomized phase II trial, the combination of cisplatin plus continuous infusion 5-FU was com- pared with cisplatin alone (66). Ninety-two patients were ran- domized to receive cisplatin 100 mg/m2plus continuous infusion 5-FU 1000 mg/m2on days 1–5 or cisplatin alone with cycles
Table 3
Chemotherapeutic Agents Used for Esophageal Cancer:
Response Rates and Mechanisms of Action Agent Response rate (%) Mechanism of action
Bleomycin 15 Antibiotic
Mitomycin 35 Antibiotic
Methotrexate 13 Antimetabolite
5-FU 15–18 Antimetabolite
Cisplatin 19 DNA crosslink formation
Carboplatin 5 DNA crosslink formation
Paclitaxel 15–32 Prevents microtubule depolymerization
Docetaxel 33 Prevents microtubule
depolymerization Inrinotecan 15 Topoisomerase I inhibitor Vinorelbine 6–20 Prevents microtubule
assembly
Vindesine 22 Prevents microtubule
assembly
