XXI - Operative Procedures in the Management of Esophageal Disease | General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

> Table of Contents > Volume II > The Esophagus > Section XXIV - Malignant Lesions of the Esophagus > Chapter 151 - Multimodality Therapy for Esophageal Cancer

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Chapter 151

Multimodality Therapy for Esophageal Cancer

Delia Radovich

David H. Ilson

As reported by Jemal and colleagues (2003), the nearly 14,000 patients who are diagnosed with esophageal cancer annually in the United States have a 5-year survival rate of less than 10%. Although the survival rate is better for patients with stages I and II disease who have a complete surgical resection, most patients present with locally advanced or lymph node positive disease and have a poor prognosis. Half of all patients have distant metastases at diagnosis and can be treated only with palliative chemotherapy.

Because the majority of patients die of their disease even after potentially curative surgery or radiotherapy, the treatment of esophageal cancer has evolved to include multimodality therapy. Concurrent chemotherapy and radiation is now the standard of care in the nonsurgical management of locally advanced disease, and there is an increasing use of combined chemoradiation in the neoadjuvant (preoperative) setting. In addition, newer targeted therapies are being investigated in an effort to improve response rates while maintaining acceptable levels of treatment-related toxicity.

OVERVIEW

In the United States, esophageal cancer is a relatively uncommon malignancy, with an annual incidence of approximately 5 in 100,000. Elsewhere in the world, in Northern China for example, the incidence is as high as 100 in 100,000. Two cell types, adenocarcinoma and squamous cell cancer, account for approximately 98% of all esophageal malignancies. Small cell carcinomas constitute another 1%, while leiomyosarcomas, lymphomas, Kaposi's sarcomas, and melanomas account for the remainder of cases.

In the past, squamous cell carcinomas were the most common cell type worldwide. Although this is still the case in some countries, it is no longer true in North America and Europe. During the past two decades, adenocarcinoma has overtaken squamous cell esophageal carcinoma as the most prevalent cell type, and it now constitutes approximately 60% of the new cases seen annually in the United States. Theories about this shift implicate obesity, as well as the decline in gastric infection with Helicobacter pylori, as described by Mayne and Navarro (2002) and Richter and colleagues (1998), both of which may predispose to gastroesophageal reflux disease. This chronic reflux may lead to Barrett's esophagus, a setting in which adenocarcinomas frequently arise. Still, a direct correlation has not been established. For squamous cell carcinomas, tobacco and alcohol use have long been associated with increased risk, and the effects of these exposures are known to be multiplicative. However, the treatment options for both squamous cell carcinomas and adenocarcinomas currently remain the same.

APPROACHES TO TREATMENT

For locoregional disease, surgery remains the mainstay of treatment. In a large surgical review, Muller and coauthors (1990) found a 5-year overall survival rate of only 10%, but Hulscher and co-workers (2002) recently reported 5-year survival rates as high as 30% to 40% with surgical resection alone. Primary radiation therapy also has been used for local tumor control, though less successfully. In one large series reported by Earlam and Cunha-Melo (1980b), the 3-year survival after radiotherapy alone was only 6%. For metastatic disease, chemotherapy alone has moderate activity but is not curative.

Given the activity of all three modalities, numerous studies have combined them in distinct preoperative strategies, also called neoadjuvant therapy. Multimodality approaches have included chemotherapy followed by surgery, radiation followed by surgery, and concurrent chemotherapy and radiation (chemoradiation) followed by surgery, in an effort to improve the dismal prognosis of this aggressive cancer.

The results of these studies have been mixed, and their combined outcomes have failed to elevate any of these preoperative strategies to a clear standard for resectable esophageal carcinoma. However, numerous trials using neoadjuvant treatment, especially concurrent chemotherapy and radiation, have demonstrated a trend toward improved survival over surgery alone. Many clinicians now treat locoregional disease

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with preoperative multimodality therapy with the hope of improved outcomes.

CHEMOTHERAPY

Although several chemotherapeutic agents have modest antitumor activity in esophageal cancer, the duration of response to both single agents and combination regimens is brief, generally 4 to 6 months. In the palliative setting, this approach may be considered appropriate treatment. However, chemotherapy is rarely used alone with curative intent.

The activity of single-agent drugs in esophageal carcinoma is summarized in Table 151-1. Commonly used drugs include cisplatin, 5-fluorouracil, and mitomycin, with single-agent response rates ranging from 10% to 25%. Newer agents include paclitaxel, vinorelbine (Navelbine), and irinotecan, with response rates of 15% to 30%. Sandler and colleagues (2000) found gemcitabine to be inactive in a recent phase II trial. Despite the variable response rates reported for some single agents, the confidence limits overlap across trials in most cases.

Table 151-1. Activity of Single Agents in Esophageal Cancer

Single Agent	Cell Type	Pts	% Response	References
Antibiotics
Bleomycin	Squamous	80	15	Buonadonna and Monfardini (1977); Clinical (1970); Kolaric et al. (1976); Ravry et al. (1985); Stephens (1973); Tancini et al. (1974); Yagoda and Young (1972)
Mitomycin	Squamous	58	26	Desai et al. (1969); Engstrom et al. (1983); Whittington and Close (1970)
Doxorubicin	Squamous	38	18	Ezdinli et al. (1980); Kolaric et al. (1977)
Antimetabolites
5-Fluorouracil	Squamous	25	15	Ezdinli et al. (1980)
5-Fluorouracil	Squamous + adenocarcinoma	13	85	Lokich et al. (1987)
Gemcitabine	Squamous + adenocarcinoma	17	0	Sandler et al. (2000)
Methotrexate	Squamous	65	35	Advani et al. (1985); Ezdinli et al. (1980)
Plant alkaloids
Vindesine	Squamous	86	22	Bedikian et al. (1979); Bezwoda et al. (1984); Kelsen et al. (1979); Popkin and Byrne (1983)
Navelbine	Squamous	30	20	Conroy et al. (1996)
Heavy metals
Cisplatin	Squamous	152	28	Davis et al. (1980); Murthy et al. (1990); Panettiere et al. (1981, 1984); Ravry et al. (1985)
Cisplatin	Adenocarcinoma	12	8	Ajani et al. (1984)
Carboplatin	Squamous	59	5	Mannell and Winters (1989); Queisser et al. (1990); Sternberg et al. (1985)
Carboplatin	Adenocarcinoma	11	9	Einzig et al. (1985)
Taxanes
Paclitaxel (1-hr)	Squamous + adenocarcinoma	58	14.5	Kelsen et al. (2000)
Paclitaxel (24-hr)	Squamous	18	28	Ajani et al. (1994)
Paclitaxel (24-hr)	Adenocarcinoma	32	34	Ajani et al. (1994)
Paclitaxel (96-hr)	Squamous + adenocarcinoma	14	0	Xiao et al. (1998)
Docetaxel	Adenocarcinoma	18	28	Einzig et al. (1996)
Docetaxel	Squamous + adenocarcinoma	46	20.8	Ohtsu et al. (2002)
Topoisomerase inhibitors
Etoposide	Squamous + adenocarcinoma	27	0	Coonley et al. (1983); Kelsen et al. (1983)
Etoposide	Squamous	26	19	Harstrick et al. (1992)

Since its introduction in 1980, cisplatin has become a major building block in combination chemotherapy regimens for esophageal cancer. In contrast, carboplatin has shown a disappointingly low 0% to 9% response rate in both squamous cell carcinoma, as reported by Mannell and Winters (1989) and by Queisser (1990) and Sternberg (1985) and their colleagues, and adenocarcinoma, as described by Einzig and associates (1985). The newer platinum analogue oxaliplatin has been evaluated in recent combination chemotherapy trials, but not as a single agent in gastric or esophageal cancer.

Based on work done in breast and ovarian cancer, paclitaxel has been administered in various schedules, including infusions of 96 hours, 24 hours, 3 hours, and 1 hour. The initial phase II trial of 24-hour paclitaxel, reported by Ajani and colleagues (1994), showed an overall response rate of 32%, with similar responses in both adenocarcinoma and squamous cell carcinoma. One-hour, weekly paclitaxel has shown significant antitumor activity, with greater total dose delivery and lesser neutropenic toxicity than more protracted infusions. This schedule was recently evaluated in a national, multicenter trial reported by Kelsen and associates (2000)

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and was associated with a 17% response rate in 41 previously untreated patients. There are no studies comparing paclitaxel and docetaxel. However, in a recent Japanese phase II trial reported by Ohtsu and colleagues (2002), docetaxel had a response rate in the 20% to 25% range in patients with metastatic disease. Enzinger and co-workers (2000) and Lin and Hecht (2000) evaluated irinotecan, a topoisomerase II inhibitor, in two recent phase II trials in esophageal and gastroesophageal cancer, with a response rate of 15%.

Given the modest activity of single agents in esophageal cancer, combination chemotherapy (frequently using cisplatin-based regimens) has been extensively studied (Table 151-2). In metastatic disease, cisplatin-containing regimens have shown 25% to 35% activity in squamous carcinoma. In locoregional disease, response rates as high as 45% to 75% have been reported. Disappointingly, these responses have been no more durable than those of single agents.

Table 151-2. Activity of Combination Chemotherapy in Esophageal Cancer

Agents	Cell Type	Pts	% Response	References
Cis/etop	Squamous	15	20	Burton et al. (1986)
	Squamous	65	48	Kok et al. (1996)
	Adenocarcinoma	27	48	Spiridonidis et al. (1996)
Cis/etop/doxo	Adenocarcinoma	25	52	Ajani et al. (1991)
Cis vs. cis/5FU	Squamous	89	11 vs. 36	Bleiberg et al. (1991)
Cis/5FU	Squamous	238	49	Ajani et al. (1992); Bleiberg et al. (1991); Charlois et al. (1992); De Besi et al. (1986); Hilgenberg et al. (1988); Kies et al. (1987); Vignoud et al. (1990)
Cis/5FU/mitomycin	Squamous	33	61	Iop et al. (1996)
Cis/5FU/doxo	Squamous	21	33	Gisselbrecht et al. (1983)
Cis/5FU/etop	Squamous	20	65	Preusser et al. (1988)
Cis/5FU/etop	Adenocarcinoma	35	49	Ajani et al. (1990)
Cis/5FU/etop/doxo	Squamous	24	71	Bedikian et al. (1987)
Cis/5FU/vindesine	Squamous	32	53	Spielmann et al. (1987)
Cis/5FU/leuc	Squamous	56	42.8	Hayashi et al. (1992); Zaniboni et al. (1987)
Cis/5FU/leuc/etop	Squamous	38	58	Wilke et al. (1992)
5FU/leuc	Squamous	35	17	Alberts et al. (1992)
Cis/paclitaxel/5FU	Squamous + adeno	60	48	Ilson et al. (1998)
Cis/paclitaxel/5FU	Squamous	17	71	Garcia-Alfonso et al. (1998)
Cis/paclitaxel	Squamous + adeno	32	44	Ilson et al. (2000)
Cis/paclitaxel	Squamous + adeno	20	55	Petrasch et al. (1998)
Cis/paclitaxel	Squamous + adeno	59	52	van der Gaast et al. (1999)
Carbo/paclitaxel	Squamous + adeno	31	58	Gaast et al. (2002)
Cis/irinotecan	Squamous + adeno	35	57	Ilson et al. (1999)
Epirubicin/cis/5FU	Squamous	21	57	Andreyev et al. (1995)
ECF vs. FAMTX	Adenocarcinoma	274 (total)	45 ECF; 21 FAMTX	Webb et al. (1997)
ELF vs. FUP vs. FAMTX	Adenocarcinoma (gastric)	245 (total)	9 ELF; 20 FUP;12 FAMTX	Vanhoefer et al. (2000)
MCF vs. ECF	Squamous + adeno	580 (total)	44.1 MCF; 42.4 ECF	Ross et al. (2002)
Adeno, adenocarcinoma; carbo, carboplatin; cis, cisplatin; ECF, epirubicin, cisplatin, and 5-fluorouracil; ELF, etoposide, leucovorin, and 5-fluorouracil; etop, etoposide; doxo, doxorubicin; FAMTX, 5-fluorouracil, doxorubicin, and methotrexate; 5-FU, 5-fluorouracil; FUP, 5-fluorouracil and cisplatin; leuc, leucovorin; MCF, mitomycin, cisplatin, and 5-fluorouracil.

The combination of cisplatin and continuous-infusion 5-fluorouracil has been studied extensively, with toxicity consisting primarily of mucositis and myelosuppression. Despite the common use of this regimen in the community, only a single phase II trial, reported by Bleiberg and associates (1997), has compared cisplatin with the combination regimen; this study did not show a statistically significant survival benefit. In addition, the combination group had 16% treatment-related deaths, compared with no deaths in the cisplatin arm.

Randomized trials have compared numerous other drug combinations to cisplatin and 5-fluorouracil, and phase II trials have studied the addition of other agents to the regimen. To date, no consistent improvement in response rates has been demonstrated by adding either etoposide or leucovorin to cisplatin and 5-fluorouracil. In a randomized trial, Webb and colleagues (1997) compared epirubicin, cisplatin, and 5-fluorouracil (ECF) to 5-fluorouracil, doxorubicin, and methotrexate (FAMTX). The ECF arm achieved

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superior median survival (8.9 months versus 5.7 months), antitumor response (45% versus 21%), and quality of life compared with FAMTX.

In a subsequent trial in gastric and gastroesophageal cancer, Vanhoefer and coauthors (2000) again compared FAMTX with two other regimens: cisplatin and 5-fluorouracil (by 5-day infusion), and ELF (etoposide, leucovorin, and bolus 5-fluorouracil). All treatments in this trial, including cisplatin/ 5-fluorouracil, resulted in response rates of less than 10% to 20% and median survival of less than 8 months. The authors questioned the adoption of 5-fluorouracil and cisplatin as the standard of care, given the equivalence in response and survival to other combination regimens.

A recent prospective randomized trial in the United Kingdom reported by Ross and co-workers (2002) compared a combination of mitomycin, cisplatin, and 5-fluorouracil administered by protracted continuous infusion to ECF, also by protracted infusion, in previously untreated patients with advanced esophageal cancer. The study reported no significant differences in overall response rate or median survival, but found that quality of life was superior with ECF. The equivalent response rates and outcomes that were seen after the addition of a third agent (either mitomycin or epirubicin) to 5-fluorouracil and cisplatin have led some to question whether either regimen offers any advantage over the conventional two-drug standard.

Gaast (2002), one of us (DHI) (1998, 2000), and Polee (2002a, 2000b) and respective associates all describe other trials that combined paclitaxel with cisplatin, both with and without 5-fluorouracil. Response rates ranged from 43% to 48% but were associated with significant neurotoxicity and myelosuppression. Mauer and colleagues (2002) at the University of Chicago assessed the activity of a combination of 5-fluorouracil, leucovorin, and oxaliplatin given every 2 weeks in advanced carcinoma of the esophagus and gastric cardia. The phase II study recently reported a 48% response rate, including one complete response, among 29 patients.

Newer agents, including the camptothecins, have undergone screening in metastatic disease and currently are being investigated in combined-modality trials. Irinotecan has shown promise in combinations with mitomycin, 5-fluorouracil, or cisplatin, with response rates ranging from 30% to 65%, as described by Baker (2001), Gold (2001), and Pozzo (2001) and their co-workers.

In a phase II study of irinotecan and cisplatin, given weekly for 4 weeks with 2 weeks' rest, one of us (DHI) and associates (1999) reported an overall response rate of 57%. A phase III trial is planned in the United States comparing this regimen with ECF. Another phase III trial is planned to expand on results of a randomized phase II trial described by Pozzo and co-workers (2001) that compared irinotecan/5-fluorouracil (by continuous infusion) with irinotecan/cisplatin in gastroesophageal cancer. The phase II trial suggested superior survival for the 5-fluorouracil/irinotecan combination. This will be compared with 5-fluorouracil/cisplatin in the phase III study.

A combination of irinotecan, mitomycin, and cisplatin was also investigated recently by Slater and colleagues (2002) in gastroesophageal and pancreatic cancer. The overall response rate for both cancer types was 42%, but the regimen was highly toxic, with significant rates of hospitalization and treatment-related death.

NEOADJUVANT (PREOPERATIVE) CHEMOTHERAPY

Despite the short-lived responses using chemotherapy alone in advanced disease, preoperative chemotherapy is associated with many potential benefits, as outlined by Harris and Mastrangelo (1991). In theory, this approach has the potential to assess future tumor response to chemotherapy and direct the possible use of chemotherapy postoperatively or in the metastatic setting. Chemotherapy may downstage the primary tumor, thereby increasing resection rates, and treat micrometastatic disease that is undetectable at diagnosis.

Kok and colleagues (1997) reported a small randomized phase III trial using cisplatin in combination with etoposide, which showed a survival advantage with preoperative chemotherapy over surgery alone. Between 1990 and 1996, 148 patients with squamous cell carcinomas were randomized to either surgery alone or chemotherapy (cisplatin and etoposide) plus surgery. A significant improvement in median survival in the group receiving chemotherapy plus surgery was reported: 18.5 months versus 11 months for patients who had surgery alone (p = 0.002).

However, a large intergroup North American phase III trial, reported by Kelsen and co-workers (1998), failed to show a survival benefit for preoperative cisplatin and 5-fluorouracil plus surgery compared with surgery alone in 440 patients. The trial enrolled patients from 123 U.S. institutions between 1990 and 1995. Both adenocarcinoma and squamous cell carcinoma were included, with no differences in outcome between the cell types. Patients in the combined-modality therapy arm received three cycles of cisplatin and 5-fluorouracil preoperatively and two cycles postoperatively. Eighty-three percent of patients completed at least two chemotherapy cycles preoperatively, but only 52% of patients actually received the postoperative chemotherapy. Pathologic complete responses were seen in only 2.5% of patients receiving preoperative chemotherapy, and there was no improvement in the curative resection rate: 62% for the chemotherapy patients versus 59% for those who had surgery alone. At a median follow-up of 55.4 months, the median survival was not significantly different in the two groups. Overall survival at 1 year was 59% for the preoperative chemotherapy group and 60% for the surgery group. At 2 years, survival was 35% and 37%, respectively; at 3 years, it was 23% and 25%. The 5-year overall survival of patients with or without chemotherapy was 20%. The addition of chemotherapy did not change the rate of recurrence either locally or at distant sites.

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However, a larger European trial conducted by the Medical Research Council Oesophageal Cancer Working Group (2002) generated renewed interest in this preoperative strategy. From March 1992 to June 1998, the study randomized 802 patients (nearly double the number of patients in the North American intergroup trial) to surgery alone versus two cycles of cisplatin and 5-fluorouracil before surgery, and demonstrated a statistically significant survival advantage. Patients with any cell type of esophageal cancer were enrolled. Cisplatin was given by a 4-hour infusion, followed by continuous-infusion 5-fluorouracil (4 days, every 3 weeks). Treating physicians were permitted to add radiotherapy preoperatively, and 9% of patients received this (an equal percentage in each arm of the trial). The authors were careful to note that results were not altered when the 9% radiation group was excluded from analysis. At a relatively short median follow-up of only 2 years, the chemotherapy-treated group demonstrated a 3.5-month survival advantage over the group treated with surgery alone, 16.8 months versus 13.3 months (p = 0.004, confidence interval 0.67 0.93). Two-year survival in the group that received chemotherapy was 43%, compared with 34% in the surgery group. The curative resection rate was improved only marginally, from 55% to 60%, and the reported pathologic complete response rate was 4% in the group that had preoperative chemotherapy. In the group treated with surgery (with or without radiation), there was no evidence of tumor in 2% of the resected specimens. The study concluded that two cycles of cisplatin and 5-fluorouracil, given preoperatively 3 weeks apart, should be considered for patients with resectable cancer of the oesophagus. The larger sample size may have facilitated the detection of a small improvement with chemotherapy. However, the median follow-up time was short, and more mature follow-up is needed before this can be considered as a standard treatment option.

In summary, no significant improvement in overall survival has been consistently demonstrated using preoperative chemotherapy (Table 151-3). Coupled with a low pathologic complete response rate and borderline improvement in the resection rate, the use of preoperative chemotherapy remains controversial.

ADJUVANT (POSTOPERATIVE) CHEMOTHERAPY

Combined-modality therapy in esophageal carcinoma has long focused on preoperative strategies. The role of postoperative, or adjuvant therapy, has not been studied extensively, but to date appears to have a very limited role in treatment of esophageal carcinoma.

A controlled trial by the Japan Clinical Oncology Group reported by Ando and associates (1997) failed to show any survival benefit among 205 patients randomized to surgery alone (100 patients) or surgery followed by two courses of chemotherapy (105 patients) using cisplatin and vindesine. Five-year survival was 44.9% in the surgery-alone group and 48.1% in the surgery-plus-chemotherapy group. Pouliquen and colleagues (1996) describe a French trial in which patients were randomized postoperatively to cisplatin and 5-fluorouracil for 6 to 8 months or no additional therapy after surgery. The study found no difference in survival between the groups, with significantly more complications in the chemotherapy group.

RADIATION THERAPY

Through the 1980s, a common approach to the primary treatment of localized esophageal cancer was to use either radiation or surgery alone. Without any randomized studies to compare them, retrospective reviews of both modalities conducted by Earlam and Cunha-Melo (1980a, 1980b) found no significant survival difference at 5 years between the two strategies: 4% for surgery alone, and 6% for radiation therapy alone.

Combined-modality approaches using radiation followed by surgery, or chemotherapy followed by surgery, also were

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employed commonly. These treatment patterns prompted a prospective randomized controlled trial, reported by Kelsen and associates (1990), comparing preoperative radiation to preoperative chemotherapy in patients with operable esophageal cancer. Although there was no increase in operative morbidity or mortality for patients treated with preoperative chemotherapy or radiation compared with historical controls treated with surgery alone, there was also no additional treatment benefit.

Table 151-3. Results of Phase III Preoperative Chemotherapy Trials in Esophageal Cancer

Regimen	Cell Type	Pts	Survival	References
Cis/5FU + surgery	Squamous	27	10 months (median)	Schlag et al. (1992)
Surgery alone	Squamous	42	10 months (median)	Schlag et al. (1992)
Surgery alone	Squamous	41	9% at 3 years	Nygaard et al. (1992)
Cis/bleo + surgery		50	3% at 3 years
RT + surgery		48	21 % at 3 years
Cis/bleo/RT/surgery		47	17% at 3 years
Cis/5FU + surgery	Squamous + adeno	213	14.9 months (median); 35% at 2 years	Kelsen et al. (1998)
Surgery alone	Squamous + adeno	227	16.1 months (median); 37% at 2 years	Kelsen et al. (1998)
Cis/etop + surgery	Squamous	74	18.5 months	Kok et al. (1997)
Surgery alone	Squamous	74	11 months	Kok et al. (1997)
Adeno, adenocarcinoma; bleo, bleomycin; cis, cisplatin; etop, etoposide; 5FU, 5-fluorouracil; RT, radiotherapy.

Arnott and coauthors (1992) reported another randomized trial involving 176 patients, which also failed to identify a benefit for preoperative radiation. Median survival of the overall group was 8 months, and the 5-year survival was 13%. The study found no significant difference in the survival of the 90 patients who received preoperative radiation therapy and the 86 who had surgery alone.

A prospective, multicenter Scandinavian trial in esophageal cancer described by Nygaard and co-workers (1992) cited a benefit for preoperative treatment with radiation, but no additional benefit when it was combined with chemotherapy. The study randomized 186 patients with squamous cell esophageal carcinoma to four treatment groups: surgery alone; preoperative chemotherapy (cisplatin and bleomycin) followed by surgery; preoperative radiation (35 Gy) and surgery; or preoperative chemotherapy and radiation, followed by surgery. The 3-year overall survival was significantly higher in the pooled groups receiving radiation compared with the nonradiation groups. The results indicated an intermediate-term survival benefit for preoperative radiation, but found that the chemotherapy regimen did not influence survival.

However, the subsequent meta-analysis performed by Arnott and associates (2000) was unable to establish a significant benefit for preoperative radiation. With a median follow-up of 9 years, an analysis of more than 1,100 patients from five randomized trials suggested a survival advantage of 3% at 2 years and 4% at 5 years. This result was not statistically significant (p = 0.062).

POSTOPERATIVE (ADJUVANT) RADIATION

A multicenter French study, reported by Teniere and colleagues (1991), randomized 221 patients to surgery alone (119) versus surgery followed by radiation (102). Patients were stratified by nodal status: N₀ (no lymph nodes involved), N₁ (periesophageal lymph node metastases), and N₂ (distant lymph node metastases). The radiation group received a total dose of 45 to 55 Gy and was observed from 3 to 9 years. The trial found no survival benefit from radiation in any nodal group.

Fok and associates (1993) described another randomized controlled study in Hong Kong that actually demonstrated increased mortality with postoperative radiation. The study stratified 130 patients who had surgery for esophageal cancer according to curative (60 patients) or palliative (70 patients) intent. Each group was then randomized equally to receive postoperative radiation or no additional therapy. The study found that postoperative radiation (without chemotherapy) conferred a significantly shorter survival than did no additional therapy: 8.7 months versus 15.2 months for the group that had surgery alone (p = 0.02). The difference was attributed to radiation-related death and early metastatic disease. Hence, the use of postoperative therapy was relegated largely to patients with residual tumor in the mediastinum after resection.

More recently, a large prospective Chinese study, reported by Xiao and colleagues (2003), also failed to detect an overall survival benefit among 495 patients randomized to surgery alone (275) versus surgery with adjuvant radiation (220). Five-year survival was 31.7% and 41.3% in the groups, respectively (p = 0.4474). A subgroup of stage III patients, however, did show a 5-year survival benefit, up from 13.1% in the surgery-only group to 35.1% in the group that received adjuvant radiation (p = 0.0027).

COMBINED CHEMOTHERAPY AND RADIATION

Herskovic and coauthors (1992) showed radiation as a single modality to be inferior to concurrent chemotherapy and radiation in a seminal phase III randomized U.S. Radiation Therapy Oncology Group (RTOG) trial (RTOG 85 01). This nonoperative study compared standard-fractionation radiation to radiation plus concurrent cisplatin and 5-fluorouracil. The trial was stopped when data from 121 patients showed a median survival of 8.9 months in radiation-treated patients and 12.5 months in the patients who received concurrent chemoradiation. At 2 years, survival in the radiation group was 10%, compared with 38% in the chemoradiation group (p < 0.001). These results were confirmed by Cooper and associates (1999) at long-term follow-up, in a study that reported overall 5-year survival for the combined-therapy arm at 26%. No patient randomized to radiation alone survived to 5 years. A subsequent, nonrandomized cohort that received combined therapy achieved 14% 5-year survival.

As a result of this study, combined chemoradiotherapy was established as the standard of care in the nonsurgical management of locally advanced esophageal cancer. Patients in the radiation arm of the RTOG study received 6,400 cGy over 7 weeks. Patients receiving concurrent chemotherapy and radiation actually received a lower total dose of radiation (5,000 cGy). In addition to the survival benefit, disease recurrence was significantly reduced by the addition of chemotherapy to radiation. At 1 year, recurrent disease was observed in 62% of the group that received radiation only, versus 44% in the combined-modality arm (p < 0.01). Distant recurrence rates were 38% and 22%, respectively (p < 0.005).

Smith and co-workers (1998) reported another prospective trial comparing chemoradiation using 5-fluorouracil and mitomycin with radiation alone, conducted by the Eastern Cooperative

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Oncology Group (ECOG) in patients with squamous cell carcinomas. All patients were given radiation to 40 Gy; the combined-therapy cohort received 5-fluorouracil (96-hour infusion) and mitomycin during radiation. Following this initial therapy, patients had either esophagectomy or additional radiation to a total of 60 Gy, at the discretion of the treating physician. Patients in the combined chemoradiation group who continued with radiation received an additional infusion of 5-fluorouracil. Results from the 131 patients treated revealed a statistically significant median survival advantage for the group receiving combined chemoradiation, regardless of whether they were referred for surgery: 14.8 months versus 9.2 months (p = 0.03). Two-year and 5-year survival rates were 12% and 7% in the radiation group, and 27% and 9% in the chemoradiation arm, with the survival benefit becoming less significant after 3 years. Forty-six patients underwent surgical resection (23 from each cohort), with 36 achieving negative margins. Seven of the 36 also had achieved complete pathologic responses, five of these after chemoradiation. Patients who were referred for surgery tended to have earlier-stage disease, better performance status, and smaller tumors than those who continued radiation, introducing a large component of selection bias and obscuring the contribution of surgery.

Alternative treatment strategies, such as the addition of induction cycles of chemotherapy before radiation or an increase in the total dose of radiation, also have been investigated in an effort to improve response rates. In a nonoperative chemoradiation study conducted by Minsky and coauthors (1999) with cisplatin and 5-fluorouracil, induction chemotherapy before chemoradiation did not appear to afford any additional benefit. The same authors (2002) report a subsequent study comparing a total radiation dose of 64.8 Gy with 50.4 Gy during concurrent therapy with cisplatin and 5-fluorouracil, which also failed to demonstrate superior results with the more intense regimen. This study confirmed 50.4 Gy as the standard radiation dose when given in combined therapy with 5-fluorouracil and cisplatin.

As one might anticipate, there is significant toxicity associated with combined-modality therapy, including neutropenia, mucositis, diarrhea, and esophagitis. Twenty percent of patients receiving combination chemoradiotherapy in the seminal RTOG trial experienced life-threatening toxicity, compared with only 3% of patients receiving radiation alone. Conventional regimens typically employ either cisplatin or mitomycin with 5-fluorouracil (by continuous infusion), with concurrent radiation ranging from 3,000 cGy to 6,000 cGy. The frequent nausea and esophagitis seen with these combinations has compelled some investigators to mandate placement of enteral feeding tubes in study patients and has underscored the need to find more tolerable regimens. To this end, various other combinations have been studied.

An intensive regimen of paclitaxel, 5-fluorouracil, and either cisplatin or carboplatin, given with hyperfractionated (twice-daily) radiation, was demonstrated by Wright and coauthors (1997) to be associated with prohibitive toxicity in one trial. However, paclitaxel, 5-fluorouracil (low-dose, continuous infusion), and carboplatin was shown by Meluch and associates (1999) to be more tolerable when given with standard-fractionation radiation. This trial reported an encouraging pathologic complete response rate of 46%. Safran and co-workers (2001) report that another trial using weekly paclitaxel and cisplatin with standard-fractionation radiation to 39.6 Gy found less esophagitis than expected, with only two patients requiring supplemental nutrition. After initial chemoradiation, patients who did not undergo surgery had additional chemoradiation to a total dose of 50.4 Gy. Overall survival at 2 years was 42%, with a pathologic complete response rate of 29%. In another phase II trial, Bains and colleagues (2002) added induction cycles of weekly 96-hour paclitaxel and cisplatin, with relief of dysphagia in 92% of patients prior to chemoradiation. Only 5% of patients required feeding tubes, and there was a suggestion of decreased esophagitis using a non-5-fluorouracil regimen. Of 33 patients with potentially curative resections, 26% had complete pathologic responses, and 12% had only microscopic residual disease. Weekly paclitaxel combined with low-dose continuous-infusion 5-fluorouracil was given in a recent preoperative trial by Ajani and associates (2001b), with acceptable toxicity and with pathologic complete responses in 27% of patients. Mauer and colleagues (2000) also reported a study of single-agent docetaxel combined with hyperfractionated radiation, with pathologic complete responses seen in 44% of patients.

Overall, chemoradiation trials using paclitaxel in combination with other agents and at varying doses and schedules have demonstrated pathologic complete responses in 19% to 46% of patients, but no long-term survival data have been reported to date. A current nonsurgical RTOG trial is comparing a 96-hour paclitaxel/cisplatin combination to 5-fluorouracil/cisplatin with concurrent radiation. Patients with locally advanced esophageal cancer will receive a total dose of 5.040 cGy radiation in 180-cGy fractions.

Another combination that has shown significant efficacy and palliation of dysphagia is cisplatin and irinotecan. Based on encouraging results of a trial in metastatic esophageal cancer, reported by one of us (DHI) and colleagues (1999), the combination also has been explored in multimodality therapy. Induction cycles of chemotherapy were given prior to chemoradiation in a phase I chemoradiation trial, again with significant dysphagia relief, as noted by one of us (DHI) and co-workers (2003). Following chemoradiation, a complete response rate of 32% was demonstrated, with three pathologic complete responses in 10 patients who had subsequent surgery. A phase II study of the combined regimen is near completion. An upcoming phase II trial by the Cancer and Leukemia Group B (CALGB) will evaluate a regimen of irinotecan and cisplatin as both induction chemotherapy and combined therapy with radiation. ECOG also is conducting a randomized phase II trial comparing weekly 1-hour paclitaxel and cisplatin to weekly irinotecan and cisplatin, each as

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preoperative chemoradiation and as postoperative adjuvant chemotherapy.

Phase III Trials

Until recently, there were no prospective randomized trials comparing chemoradiation alone to chemoradiation followed by surgery. Bedenne and associates (2002) then reported results of a phase III trial comparing these two approaches with an end point of overall survival. Between 1993 and 2000, 445 eligible patients received induction chemoradiation with two cycles of cisplatin and 5-fluorouracil during radiation (either on a protracted schedule of 46 Gy over 4.5 weeks or as split courses of 15 Gy twice daily on days 1 to 5 and 22 to 26). After the initial induction phase, 259 patients who responded to chemoradiation and who remained eligible for resection were randomized to surgery or three additional cycles of chemoradiation. Results showed 40% 2-year overall survival among the patients who had additional chemoradiation without surgery, versus 34% for patients who were resected (p = 0.56). Median survival was 19.3 and 17.7 months, respectively. The trial was powered to detect a 15% survival benefit at 2 years. Though this goal was not met, the study concluded that continuation of chemoradiation could be considered as an alternative to surgery in patients who responded to chemoradiation. The authors stated that nonoperative therapy afforded patients comparable overall survival, lower early mortality, shorter hospital stay, and performance status that was at least equivalent after palliation for dysphagia. Sequential preoperative regimens of chemotherapy and radiation also have been investigated by Le Prise and co-workers (1994), and Nygaard and associates (1992), showing no clear benefit of this approach compared with surgery alone.

Results of combined chemoradiation trials have had far-reaching effects. The Patterns of Care Study, reported by Coia and coauthors (2000) reviewed records from 63 institutions for 400 patients whose treatment included radiation between 1992 and 1994. Follow-up was available for 395 patients. Fully three-quarters of the patients treated with radiation therapy also received chemotherapy, most of these (84%) as concurrent treatment. Thus, among patients treated with radiation, 63% were treated with combined chemoradiation. Chemoradiation without surgery (total radiation dose 50 Gy or higher) was given to 45% of patients included in the review. Preoperative and postoperative chemoradiation (total radiation dose greater than 40 Gy) was given to 9% and 5% of patients, respectively. Fluorouracil (63%), cisplatin (48%), and mitomycin (6.8%) were the drugs used most frequently. At 2 years, 44% of patients who did not undergo subsequent esophagectomy had locoregional recurrence, compared with 28.2% of those who underwent surgery (p = 0.0024). Patients resected after preoperative chemoradiation (to the specified doses) had improved survival at 2 years: 64% versus 39% for those treated with chemoradiation alone, although this difference did not reach statistical significance (p = 0.11). For those patients who received radiation alone, survival was only 20.6% at 2 years. Coupled with the 50% to 60% local failure rate of chemoradiation alone, a trend toward improved survival with trimodality therapy has sparked further investigations with chemoradiation as a preoperative strategy.

CHEMOTHERAPY, RADIATION, AND SURGERY

In recent trials, between 20% and 40% of patients who underwent esophagectomy after chemoradiation had achieved pathologic complete responses to the preoperative treatment, with nearly all trials showing a significant survival benefit for this subgroup of patients. The contribution of esophagectomy in this group remains unclear. On the other hand, for those with residual disease resected after chemoradiation, surgery may have conferred a survival benefit, as noted by Forastiere and co-workers (1993) and Leichman and colleagues (1984). Forastiere and associates (1993) conducted a single-arm prospective trial of 41 patients treated with chemoradiation followed by surgery with a median follow-up of 6.5 years. Thirty-six patients underwent potentially curative resection, and 10 of these (41%) achieved a pathologic complete response. The median survival for all 43 registered patients was 29 months; the 5-year survival was 34%. For patients who had a pathologic complete response, the median survival was 70 months, and 60% of these patients were alive at 5 years. Patients who had residual tumor in the resected esophagus experienced a median survival of 26 months, and 32% were alive at 5 years (p = 0.114 by the log-rank test and p = 0.04 by the Wilcoxon test). The authors concluded that the preoperative chemoradiation regimen appeared to double the 5-year survival, and that resection of residual tumor appeared to confer a survival benefit.

In 1997, Forastiere and colleagues reported a subsequent nonrandomized trial of chemoradiation followed by esophagectomy. Of 47 patients who underwent resection, 19 (40%) were shown to have had a pathologic complete response, whereas 28 (60%) had residual tumor in the resected pathology specimens. The median survival for all patients was 31.3 months. Again, patients who demonstrated complete pathologic response at surgery had substantially better median survival: 58 months versus 22.4 months for those who had residual disease. The 2-year survival was 78% for patients with a complete pathologic response versus 46% for those with residual tumor (p = 0.006).

Heath and associates (2002) evaluated complete responses to a similar but less intense regimen of continuous-infusion cisplatin and 5-fluorouracil with radiation to 44 Gy. This phase II study added postoperative therapy with paclitaxel and cisplatin. Forty-two patients were enrolled, and 39 proceeded to surgery after neoadjuvant chemoradiation. With a median follow-up of 30.2 months, the overall survival rate

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was 62%. Eleven patients (25%) demonstrated pathologic complete responses at resection. Once again, 2-year survival was significantly higher in the group of patients achieving complete response: 91% versus 51% in patients with residual disease (p = 0.03). Pilot studies looking at the addition of induction chemotherapy before chemoradiation also were conducted by Ajani and colleagues (2001a, 2001b), Bains and coauthors (2002), and Stuschke and associates (2000), with early promising results.

A trend toward improved survival with multimodality therapy appeared to be emerging, and clinical trials sought to identify a clear standard. At the time of this writing, there have been at least four randomized trials comparing surgery alone to combined chemotherapy and radiation followed by surgery (Table 151-4). A clear survival benefit was demonstrated by only one of the studies, with a second study demonstrating improved survival in patients who had a pathologic complete response to chemoradiation. However, all of these studies have sample sizes that are too small to show small improvements (5% to 15%) in overall survival.

Prolonged overall survival for patients receiving preoperative therapy was demonstrated in a prospective trial by Walsh and associates (1996) involving 113 patients with operable esophageal adenocarcinoma. The study accrued from 1990 to 1995 and randomized 58 patients to chemoradiation followed by surgery, and 55 to surgery alone. In the multimodality treatment arm, patients received two cycles of 5-fluorouracil (16-hour infusion for 5 days), followed by cisplatin (over 8 hours on day 7). The cycle was repeated during week 6. Radiotherapy was delivered 5 days a week for 3 weeks, beginning on day 1, for a total dose of 40 Gy. At the time of surgery, a pathologic complete response was demonstrated in 13 of 52 patients (25%). The chemoradiation group achieved a median survival of 16 months, versus 11 months for the surgery-alone group (p = 0.01). However, when data were analyzed by actual treatment received, the median survival for the multimodality arm was far superior: 32 months versus 11 months (p = 0.001). Similarly, while overall survival at 3 years was 32% for the multimodality arm versus 6% for the surgery arm (p = 0.01), an analysis based on actual treatment showed a marked survival benefit for the multimodality group at 3 years: 37% versus 7% (p = 0.006). However, it is important to note that the 6% overall survival seen in the surgery-only arm was much lower than the expected 20% seen in modern trials, raising questions about the validity of these findings.

Table 151-4. Results of Phase III Preoperative Chemoradiotherapy Trials in Esophageal Cancer

Regimen	Type	Patients	Survival	References
Surgery alone	Adenocarcinoma	55	11 months (median); 6% at 3 years	Walsh et al. (1996)
Pre-op cis/5FU + 40-Gy RT	Adenocarcinoma	52	16 months (median); 32% at 3 years	Walsh et al. (1996)
Surgery alone	Squamous	139	18.6 months (median)	Bosset et al. (1997)
Pre-op cis + 37-Gy RT	Squamous	143	18.6 months (median)	Bosset et al. (1997)
Surgery alone	Squamous and adenocarcinoma	50	17.6 months (median); 16% at 3 years	Urba et al. (2001)
Pre-op cis/5FU and vinblastine + 45-Gy RT	Squamous and adenocarcinoma	47	16.9 months (median); 30% at 3 years	Urba et al. (2001)
Surgery alone	Squamous and adenocarcinoma	205 total (both groups)	18.5 months (median)	Burmeister et al. (2002)
Pre-op cis/5FU + 35-Gy RT	Squamous and adenocarcinoma	205 total (both groups)	21.7 months (median)	Burmeister et al. (2002)
Cis, cisplatin; 5FU, 5-fluorouracil; RT, radiotherapy.

Other randomized trials failed to support these results. The European Organization for Research and Treatment of Cancer (EORTC) conducted a multicenter randomized trial of 282 patients with stage I and II squamous cancers, as reported by Bosset and coauthors (1997). A total of 275 underwent esophagectomy (137 surgery only, 138 combined-modality treatment). Patients who received preoperative chemoradiation (cisplatin and 3,700 cGy) had a longer disease-free survival, a lower rate of cancer-related deaths, and a higher frequency of curative resection (all p values < 0.05). In the combined-modality group, pathologic complete responses were seen in 29 (26%) of 112 patients, and pathologic major responses in 20 patients (18%). However, preoperative therapy failed to improve median survival, which was 18.6 months for both treatment groups. With a median follow-up of 55.2 months, there was also no significant difference in overall survival. A higher than expected operative mortality was observed in the combined-modality arm. Critics of the study argue that any potential treatment benefit in that group was obscured by the unusually high operative mortality rate.

Urba and co-workers (2001) reported a randomized study of 100 patients with squamous carcinoma or adenocarcinoma treated with surgery alone or with preoperative chemoradiation plus surgery. Fifty patients were randomized to surgery alone, and 50 received preoperative cisplatin (continuous infusion, days 1 to 5 and 17 to 21), 5-fluorouracil (continuous infusion, days 1 to 21), and vinblastine (bolus, days 1 to 4 and 17 to 20). Radiation was given during chemotherapy in fractions of 1.5 Gy twice daily, to a total dose of 4,500 cGy. This inpatient chemoradiation regimen resulted in severe toxicity, with 78% of patients experiencing grade 3 to 4 neutropenia, 50% developing neutropenic fever, and 63% requiring

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feeding-tube placement for nutritional support secondary to radiation esophagitis. With median follow-up of 8.2 years, median survival was similar in both groups: 16.9 months for the multimodality arm versus 17.6 months for the surgery arm. Improved survival was observed for the multimodality group at 3 years: 30% versus 16% (p = 0.15). The lack of statistical significance probably reflects the small number of patients entered in this study. However, this study did show that the patients who achieved a complete response to preoperative chemoradiation (as documented at time of resection) had improved survival compared with patients found to have residual tumor in resected tissue. Twenty-eight percent of the patients who received preoperative treatment had a complete pathologic response at surgery. Their median survival was an impressive 49.7 months, compared with 12 months for patients who had residual disease at the time of resection. At 1 and 3 years, survival rates for the multimodality group were 86% and 46%, respectively, compared with 52% and 19%, respectively, for the patients who had residual disease at resection (p = 0.01). These findings underscore the need to increase the pathologic complete response rate if overall survival is to be improved by preoperative treatment.

The most recent randomized trial, involving 256 patients at 25 institutions in three countries and reported by Burmeister and associates (2002), also failed to show a survival benefit with the addition of preoperative chemoradiation. Over a 70-month period, patients with squamous carcinoma or adenocarcinoma were randomized to surgery alone or to a neoadjuvant regimen of cisplatin, 5-fluorouracil, and radiation followed by surgery. Two hundred and five patients completed the intended treatment, including surgery. The pathologic complete response rate in the patients who received neoadjuvant treatment was 15.1%. The median overall survival in this arm was 21.7 months, compared with 18.5 months for the surgery arm (p = 0.38).

Prior to surgery, it is difficult to determine with certainty which patients will have a pathologic complete response to chemoradiation. Though endoscopy may not show evidence of residual disease, there is no guarantee that microscopic disease has been eradicated deep in lymph nodes or in the wall of the esophagus. Bedenne and associates' (2002) results and other studies have not yet answered the question regarding the role of surgery in the setting of an apparent complete response to chemoradiation. A phase II study under consideration by the RTOG may help provide an answer, because it will assign patients to two different treatment arms following chemoradiation. Those who demonstrate clinical complete responses to chemoradiation will be observed, whereas patients who demonstrate a partial response or persistent disease will be referred for surgery.

For now, it has been shown that combined chemotherapy and radiation is an active strategy that increases the pathologic complete response rate at resection and confers a survival benefit to the group of complete responders. Newer, less-toxic agents have been identified, decreasing the need for feeding-tube placement to help patients complete treatment. Current trials may guide the selective application of surgery, perhaps reserving it as a salvage regimen for those patients without a complete response to chemoradiation. Certainly for those patients with disease resistant to chemoradiation, surgery remains the only curative treatment.

NEW DIRECTIONS

Despite advances in the treatment of esophageal cancer with multimodality therapies, the prognosis for long-term survival remains poor. Many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors. Therefore, the focus of recent study has shifted toward testing newer agents that target specific molecular abnormalities known to occur in esophageal cancer.

Growth factor receptors, receptor-associated tyrosine kinases, tumor suppressor genes, angiogenesis regulators, cell-cycle regulatory factors, and markers of resistance to chemotherapy are all being actively investigated as therapeutic targets. Among these, agents that inhibit the epidermal growth factor (EGR) receptor pathway are already in clinical trials. Raben (2001) and Saltz (2001) and their co-workers reported trials using the monoclonal antibody C-225, which directly targets the EGF receptor and appears to have synergistic action with both radiation and cytotoxic drugs. Other new therapies inhibit this pathway at a different site, by binding the receptor's associated tyrosine kinase to interrupt intracellular signaling. Two of these agents [OSI-774, as reported by Hidalgo and associates (2001), and ZD-1839, described by Baslega (2002) and Herbst and their colleagues (2002) as well as by Lorusso (2003)] are being investigated, having shown promise in lung cancer and head and neck cancer trials.

Monoclonal antibodies that target the vascular endothelial growth factor pathway, such as bevacizumab, already have been investigated in phase II combination trials by Kabbinavar and associates (2003) and Miller (2003), with other trials under way in several different cancers. Schwartz and colleagues (2001) and Tan and associates (2002) also continue to explore in clinical trials the activity of flavopiridol, a cyclin-dependent kinase inhibitor, and bryostatin, which influences cell proliferation, metabolism, and signaling through modulation of protein kinase C.

The identification of molecular markers that may help predict increased response or resistance to current therapies also is receiving much attention. One such marker, thymidylate synthetase, is the target enzyme of 5-fluorouracil, as reported by Gonen (2003) and Kubota (2002) and their associates. Another possible predictor of response is ERCC-1, a gene involved in excision and repair of DNA that may affect response to cisplatin, as noted by Lord (2002) and Metzger (1998) and their colleagues. Rosell and co-workers (2002) are also studying other genetic markers that may predict response to chemotherapy. Candidate markers of response

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and resistance will need to be validated in prospective trials assessing their clinical utility.

Positron emission tomographic (PET) scanning may also provide a useful tool to assess patient response to combined-modality therapy. The degree of response detected by PET following chemoradiotherapy has been correlated with pathologic response at surgery and with patient survival by Downey and colleagues (2003) and by Flamen and associates (2000). In one trial of induction chemotherapy followed by surgery, Weber and coauthors (2001) found that response to PET performed early during induction chemotherapy was prognostic of subsequent pathologic response detected at surgery, and of survival. The use of PET to assess response to induction therapy may ultimately play a role in treatment selection during combined chemoradiation. For example, patients who do not appear to be responding to the initial cycles of induction chemotherapy based on PET scan assessment might be switched to a different chemotherapy regimen rather than being referred directly for surgical resection.

CONCLUSION

The treatment of esophageal cancer remains a great challenge to medical, surgical, and radiation oncologists. Although it is clear that patients with advanced disease can be palliated by chemotherapy, trials evaluating newer drugs, including the taxanes and irinotecan, may help identify more efficacious and tolerable systemic regimens that can be combined with other treatment modalities. Concurrent chemotherapy and radiation is now the standard of care in the treatment of nonoperable, localized disease. The use of preoperative chemoradiotherapy continues to be investigated, but appears to lead to improved overall survival in patients who had a complete pathologic response. Although surgery remains the standard curative treatment for early-stage disease, its role is being reexamined as a possible salvage therapy for patients refractory to chemoradiation. The identification of markers of response or resistance to therapy, the development of new, specifically targeted novel agents, and the use of sensitive metabolic imaging to assess response to therapy represent future directions for the improved treatment of esophageal cancer.

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