MULTIMODALITY THERAPY FOR ADENOCARCINOMA OF THE ESOPHAGUS

THE COLUMNAR-LINED ESOPHAGUS

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MULTIMODALITY THERAPY FOR ADENOCARCINOMA OF THE ESOPHAGUS David Kelsen, MD

ADJUVANTTHERAPYOFESOPHAGEALCANCER

Adenocarcinoma of the esophagus is rapidly increasing in incidence in the Western world. In both North America and Western Europe, a marked shift in the epidemiologic profile of this disease has occurred. In the past, the vast majority of patients with esophageal cancer were found to have epidermoid carcinoma. These patients frequently abused tobacco or alcohol, had multiple comorbid medical conditions, and were often elderly. Over the last 10 to 15 years, a rapid increase in the number of patients having adenocarcinoma of the esophagus has been noted. In contrast to those with epidermoid carcinoma, these patients are predominantly young white men between the ages of 35 and 55 who much less frequently smoke or drink. Many have few or no comorbid medical conditions, are quite fit, and are able to tolerate aggressive combined modality therapy. This article focuses on the adenocarcinoma subgroup of patients, although identical therapeutic approaches are being studied in appropriate patients with epidermoid carcinomas. Premalignant Lesions

As has been indicated in other articles of this issue, there is intense interest in discovering the cause or causes of the rapid increase in adenocarcinoma, which is particularly targeted on a subgroup of Western populations. Several large-scale epidemiologic trials are underway in the United States to understand better the reasons why young white men in particular are at risk for this disease. There is a clear association between Barrett’s esophagus and the risk of From the Gastrointestinal Oncology Service, Department of Medicine, Memorial SloanKettering Cancer Center, Cornell University Medical College, New York, New York

GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 3 * SEPTEMBER 1997

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developing adenocarcinoma. From the therapeutic point of view, and as indicated later, prevention and early diagnosis are high-priority goals in the treatment of esophageal cancer. Although prevention may remain an elusive goal, until the causes of adenocarcinoma and Barrett’s esophagus are defined, periodic endoscopy may identify patients at high risk for the unsuspected presence of adenocarcinoma. Two studies indicate that patients with known Barrett’s esophagus who have severe dysplasia and who undergo esophagectomy are frequently found to have unsuspected invasive adenocarcinoma. The analogy is similar to that of patients with ulcerative colitis who are found to have areas of severe dysplasia, with a subsequent finding of unsuspected adenocarcinoma. Putnam and colleaguesI6 studied 19 patients who underwent esophagectomy for severe dysplasia in Barrett’s esophagus. In none of these patients was adenocarcinoma suspected before surgery. All underwent esophagectomy either by transthoracic or by transhiatal approach. The operative mortality was 5%. Seventy-four percent of patients (14 of 19) were found to have invasive cancer; the majority had earlystage (0-1) disease. At the time of the report, 16 patients remained alive and disease-free (84%). Similar results were found in a study by Heitmiller and coworkers.’ These data strongly suggest that prophylactic esophagectomy is an appropriate treatment option for patients with Barrett’s esophagus who are found to have severe dysplasia. There are no data currently available that prophylactic esophagectomy is appropriate for the vast majority of newly diagnosed patients with Barrett’s esophagus. These topics are discussed in more detail elsewhere in this issue. Treatment of Established Disease

Two approaches of potentially curative therapy are currently available for patients with biopsy-proven adenocarcinoma of the esophagus who have disease clinically limited to the local regional area (T1-T3, N,,,M,, stages I through 111). Surgery alone is one option. Radiation therapy as a single modality has been supplanted (most clearly for patients with epidermoid carcinoma) by a combination of radiation and concurrent chemotherapy. The use of combined modality therapy, including systemic chemotherapy in addition to a local modality (either surgery or radiation), is an attractive concept for patients with esophageal cancer because the disease has both a high distant failure rate and a significant risk for local recurrence. In addition, 40% to 50% of patients present with such extensive local regional tumor (with or without metastasis) that resection is impossible. This article reviews the reasons for the use of neoadjuvant and postoperative adjuvant therapy for adenocarcinomas of the esophagus and summarizes the results of trials involving these approaches, with a focus on those performed during the last 5 years. Earlier studies have been reviewed in detail elsewhere.’O Failure Pattern

The failure pattern of a solid tumor (i.e., localized versus disseminated recurrence) is useful to aid in planning adjuvant therapy. Tumors that have a high local failure rate but rarely metastasize ( e g , low-grade sarcomas) may best be treated by resection with or without postoperative radiation therapy (either external beam or brachytherapy). Tumors highly likely to metastasize to distant organs may require systemic therapy early in the treatment plan. The use of

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MULTIMODALITY THERAPY FOR ADENOCARCINOMA OF THE ESOPHAGUS

Table 1. ESOPHAGEAL CANCER FAILURE PATTERN: AUTOPSY DATA ~

~

_

_

Site

Anderson3*

Bosch4

Mandard’V

Suaimachi‘Y

Patient number Local only (Yo) Distant only (%) Local + Distant (%) Tumor Sites (Yo) Local

79

82 27 7 50

111 75

303

9 2 82 91 52 47 73 20 17

77 20

61 31 23 74 9 16

13 33 27 57

Lung

Liver Lymph nodes

Adrenal Trachea-bronchus

28 61 12

33

-

-

-

‘Autopsy performed a median of 4 months from diagnosis. tAutopsy performed a median of 6.3 months from diagnosis. +Includes 7 patients with autopsy, 23 clinical first site of failure.

chemotherapy before or simultaneously with a local modality (also known as preoperative or primary chemotherapy) is a particularly attractive concept if complete resection of the primary tumor is difficult or impossible or if radiation alone is frequently unable to sterilize the target volume. Those factors are clearly the case for esophageal tumors. The failure pattern of esophageal cancer has been assessed by autopsies and (less reliably) by clinical methods, such as radiographs and physical examination. These data have been previously reported in detail.l0 Several autopsy studies are summarized in Table 1. The median duration of survival in two of these trials was brief, and in a third trial, approximately 25% of patients died in the immediate postoperative period. The finding of disseminated disease to lung, liver, and lymph nodes so soon after diagnosis is impressive. A substantial number of patients had residual local regional disease despite attempted resection. Esophageal cancer is a systemic disease in many patients even at the time of diagnosis. Combined modality therapy may influence the failure pattern. Gill and colleagues6studied recurrence in patients who had received cisplatin and fluorouracil plus radiation as definitive treatment or after surgery. In a group of 49 patients, most with adenocarcinoma, local regional failure was found in 20%. Distant recurrence was more common: 39 patients had metastases, usually to liver or lung. In a second study, Kavanagh and associates9 reviewed sites of failure in a group of 103 patients receiving potentially curative chemotherapy plus radiation. The most common sites of metastases were lung (28), liver (21), bone (13), lymph nodes (19), and brain (4). Local regional failure was also found in approximately one third of patients. Additional data from phase I11 trials is necessary to clarify how well combined modality treatment improves distant and local control. After operation alone, local regional failure is seen in at least 10% to 20% of patients with adenocarcinomas. Because these are clinical findings in symptomatic patients, the true local failure rate may be substantially higher. The use of positron-emission tomography scanning or other noninvasive procedures may in the next few years provide a better understanding of the true risk for local regional failure after operation. With combined modality therapy, the local failure rate may be decreased, as discussed subsequently. Distant failure remains a vexing problem.

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Table 2. NEOADJUVANT THERAPY OF CANCER: PROS AND CONS

Pros

Promote early tumor regression Improve chances of local control Tumor regression allows conservative local regional therapy (radiation therapyhrgery) Tumor response is a marker for subsequent chemotherapy

Cons

Promotes tumor cell resistance Delay local measures Uncertainty in local therapy (margins) I f tumor response, patient may refuse

local regional therapy ~

From Muggia FM,Gill I Primaty chemotherapy In DeVita W Jr, Hellman S, Rosenberg SA (eds) Cancer. Principles and Practice of Oncology Updates Philadelphia, JB Lippincott, 1990, pp 1-12, with permission.

Combined Modality Therapy: Theoretical Rationale

The approach of neoadjuvant treatment has been supported by a variety of animal models. These data have been summarized in earlier reviews. Theoretical considerations using this approach have also been summarized by Muggia and Gill6(Table 2). The rationale for use of chemotherapy and concurrent radiation has been reviewed by Vokes?' For example, chemotherapy might delay regrowth of tumor cell subpopulations that may be sensitive to radiation, and this delay in regrowth may increase total cell kill when radiation is given. Chemotherapy may cause cell cycle synchronization, increasing the fraction of tumor cells in a radiation therapy-responsive phase. By killing cycling cells, additional tumors may be recruited from the Go phase (which is resistant to either radiation or chemotherapy). Radiation may be more effective as tumor masses decrease in size, resulting in improved oxygenation. Steel and Peckham18 proposed several additional mechanisms resulting in enhanced tumor cell kill by combined chemotherapy and radiation. Spatial cooperation implies a high degree of local regional tumor cell kill by radiation, whereas chemotherapy can be effective both locally and systemically. Spatial cooperation does not necessarily require that the two modalities be given simultaneously. Independent toxicity profiles may allow full doses of each modality to be given concurrently. Normal tissue protection is a theoretical goal, which could be achieved by either technical improvements in radiation (three-dimensional treatment planning) or the development of pharmacologic agents that protect normal tissue while leaving tumor vulnerable. These theoretical advantages have driven the large number of clinical trials of chemoradiation in solid tumors, including esophageal cancer. CLINICAL TRIALS USING COMBINED MODALITY THERAPY IN ESOPHAGEAL ADENOCARCINOMAS

Combined modality therapy for patients with clinically localized esophageal cancers has been extensively studied over the last 10 to 15 years. Although many of the earlier trials involve primarily patients with epidermoid cancers of the esophagus, more recent studies included a large percentage of patients with adenocarcinoma. Most recently, randomized phase I11 trials have been reported involving preoperative chemoradiation therapy followed by surgery versus sur-

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gery alone in studies limited to patients with adenocarcinoma. Broadly speaking, combined modality therapy for adenocarcinoma of the esophagus can be divided into three approaches: (1) chemotherapy given before a planned operation, (2) chemotherapy and concurrent radiation followed by a planned operation, or (3) chemotherapy and radiation without surgery. Preoperative radiation without chemotherapy has primarily been studied in epidermoid cancer, and results have been disappointing. This topic is not discussed further. There are limited data using postoperative chemotherapy without preoperative treatment (postoperative adjuvant chemotherapy) for patients with esophageal cancer, mostly with epidermoid tumors. PREOPERATIVE CHEMORADIATION

With this approach, patients having undergone an extent of disease evaluation indicating that tumor is limited to the local regional area begin therapy by receiving chemotherapy and concurrent radiation. An operation is planned to follow the completion of chemoradiation. The rationale behind this approach is that for many patients obtaining cancer-free radial margins can be difficult and local control issues are paramount. Further, chemotherapy may have a substantial impact on decreasing the risk of distant metastases as described by VokesZ1 and Steel and Peckman18 previously. A series of phase I1 trials investigating various chemotherapy combinations and a variety of radiation therapy treatment plans have been performed in patients with localized esophageal cancer. Although many earlier studies involved only patients with epidermoid cancer, more recent U.S. trials almost invariably include patients with adenocarcinoma. In recent series, furthermore, the latter histologic subtype often involves a majority of patients. These phase I1 trials have demonstrated that by using cisplatin containing combinations (such as cisplatin plus fluorouracil or cisplatin plus a vinca alkaloid and fluorouracil) and by using radiation doses of between 4000 and 6000 cGy, patient tolerance is acceptable. In comparison to historical controls, no increase in operative morbidity and mortality has been seen, once careful attention to detail (such as close monitoring of the FIO, during the perioperative period) is performed. Chemoradiation may frequently cause substantial esophagitis. In one phase I1 study performed at the University of Michigan, it was necessary to hospitalize patients throughout the preoperative p e r i ~ dA . ~similar approach was used in a phase I11 study at the same institution, which is described in more detail later. Phase I1 trials indicated acceptable tolerance, and preliminary data were encouraging for more modern chemotherapy regimens used with appropriate radiation therapy doses and schedules. These studies have led to more definitive phase I11 trials. Two phase I11 trials comparing preoperative chemoradiation to surgery alone in patients primarily with adenocarcinomas of the esophagus have been reported (Table 3). In a preliminary report from the University of Michigan,2O 100 patients were randomized to receive chemoradiation followed by transhiatal esophagectomy versus surgery alone. The treatment plan involved cisplatin plus fluorouracil and vinblastine chemotherapy plus 4000 cGy of radiation. The radiation dose and schedule used 150 cGy twice a day in 15 fractions. The two groups appeared to be well balanced for the usual prognostic factors. A strength of this trial was that the same surgery (transhiatal esophagectomy) was used in all patients. In a preliminary report, no difference in operability, resectability, or survival was noted.

Chemo-RT

=

Cisplatin-fluorouracilvinblastine

Cisplatin-fluorouracil

Chemotherapy

45 Gy/l5 fractions

40 Gy/l5 fractions 50 50

58

55

No. Patients

Chemotherapy combined with radiation therapy; NS = not stated

Surgery Chemo-RT Surgery Surgery Chemo-RT

Walsh”

UrbaZ0

Arm

Author

Radiation Therapy

75 75

100 100

(%)

Adenocarcinoma 96 84

NS NS

NS NS

Resectability

100 88

Operability

Table 3. PHASE Ill TRIALS OF CHEMORADIATION IN ADENOCARCINOMA OF THE ESOPHAGUS

NS

NS

4 9

Treatment Mortality (%)

18 mo 18 mo

16 mo

11 mo

Median Survival

36 41

26 57

(YO)

2-Year Survival

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Walsh and co-workers” have reported the results of a trial with a similar design (see Table 3). This single-institution study, performed in Ireland, assigned patients to receive preoperative chemotherapy and concurrent radiation or surgery alone. The dose and schedule of chemotherapy and radiation were different from that used in the University of Michigan trial. Fluorouracil was given as a 16-hour daily infusion from days 1 to 5. Cisplatin was given on day 7. A second course of chemotherapy identical to the first was given at week 6. Starting on day 1, 40 Gy external-beam radiation was given in 15 treatment fractions over 19 elapsed days. Each fraction involved 2.67 Gy of radiation. Most patients were treated by a two-field anteroposterior-posteroanterior technique. In this study, a highly significant survival advantage was seen for patients randomly assigned to preoperative chemoradiation compared to those undergoing surgery alone. With 3 years of follow-up, 26% of patients receiving chemoradiation survived, whereas only 6% of those randomized to surgery were still alive. These encouraging results will undergo further testing involving a substantially larger number of patients in an American Intergroup trial, which is currently in the advanced planning stage. CHEMOTHERAPY FOLLOWED BY PLANNED OPERATION

Phase I1 studies involving the use of chemotherapy alone before surgery (neoadjuvant chemotherapy) have also been reviewed in detail.1° Although there are no data currently available to indicate that for all patients one cisplatincontaining combination is markedly superior to another, it should be recognized that epidermoid carcinoma may be more responsive than adenocarcinoma. Although four relatively small-scale random assignment trials have been performed in patients with epidermoid carcinoma of the esophagus, currently there are no phase I11 data involving substantial numbers of patients with adenocarcinomas receiving chemotherapy followed by an operation versus an operation alone. A number of phase I1 trials involving cisplatin-based chemotherapy have been reported; these data have been extensively summarized elsewhere.l1 Phase I11 trials are summarized in Table 4. All of these studies indicate a high degree of tolerance for preoperative chemotherapy, with no significant increase in operative morbidity or mortality. Several have suggested down-staging in 30% to 50% of patients, with resection rates ranging from 60% to 80%. Although median durations and long-term survival data are encouraging, it should be recognized that the data to date are in single-arm phase I1 trials of highly selected patients or in small-scale phase I11 studies. To test more definitively the hypothesis that preoperative chemotherapy followed by surgery is better than surgery alone, several large-scale trials have been performed. In the United States, Intergroup 113, a study involving several large American cooperative cancer research groups, compared three cycles of cisplatin and fluorouracil followed by operation to operation alone. Responding patients who underwent resection were scheduled to receive two additional cycles of the same chemotherapy postoperatively. This study, which included more than 450 patients, was closed to accrual in December, 1995. The study is undergoing detailed analysis, and the results will be reported shortly. Similarly, in Europe, a large-scale study of preoperative chemotherapy with a similar treatment plan compared to surgery alone has been completed and is also being analyzed. A second European trial using a slightly different chemotherapy regimen of epirubicin, cisplatin, and a prolonged fluorouracil infusion is nearing its accrual goals.

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Table 4. PHASE 111 TRIALS OF CHEMOTHERAPY PLUS SURGERY VERSUS SURGERY ALONE

No. Study Roth

Arm

CisplatinVLB-BL Surgery Shlag CisplatinFU Surgery Nygeard Cisplatin-BL Surgery RT3500cGy Cisplatin-RT Kok Cisplatin-BL VPI 6 Surgery Fong CisplatinFU Surgery

Resectable (%)

Medial Survival (mo)

Overall Survival

Patients’

Cell Type

Operable (%)

17

EP

89

35

9

25

19 29

EP

95 87

21 71

9 8

5 NS

EP

100 82 93 75 72 NS

77 58 69 54 66 81

9 NS NS NS NS 14.5

NS 3 9 21 17 NS

EP EP

NS NS

82 88

9.5 12.6

NS NS

NS

93

12.3

NS

40 50 41 48 47 48 49

EP

‘Total patients = 160. P = .017. VLB = Uniblastine; BL = bleornycin; FU = fluorouracil; RT = radiation therapy; VP16 side; Ep = epiderrnoid carcinoma; NS = not stated.

(“w

=

etopo-

CHEMOTHERAPY PLUS RADIATION THERAPY WITHOUT SURGERY

The third approach involves nonoperative therapy using chemotherapy plus radiotherapy without subsequent surgery. Two treatment plans have been studied. The first involves giving chemotherapy (usually for one to two cycles) before definitive radiotherapy (usually 50 to 60 Gy). The second uses concurrent chemotherapy and radiation therapy. Although most trials reported to date are single-arm, phase I1 pilot studies, involving fewer than 50 patients, several prospective, randomized studies are summarized next. Chemotherapy Plus Concurrent Radiation

As is the case for other techniques, phase I1 pilot studies have been previously reviewed. More recently, several prospective, random assignment trials have been completed. These test the hypothesis that systemic chemotherapy plus concurrent radiation is superior to radiation therapy alone. The Eastern Cooperative Oncology Group completed a trial of systemic therapy using mitomycin and fluorouracil plus concurrent radiation versus radiation a10ne.I~The study did allow patients to undergo surgery after completion of chemotherapy and 40 Gy of radiation or after 40 Gy of radiation alone at the discretion of the attending physician. The introduction of surgery in a nonrandomized fashion makes interpretation of the data more difficult. In a preliminary report, a survival advantage was noted for the chemotherapy-radiation therapy arm. In 1992, Herskovic and colleagues* reported the results of an important study comparing chemotherapy plus concurrent radiation to radiation alone; surgery was not part of the treatment plan. Most patients (85%) had epidermoid

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cancer. The trial design involved radiation alone as the standard arm; the treatment plan was 5000 cGy with a boost of 1400 cGy (total dose of 6400 cGy) delivered over 6 weeks. Patients randomized to receive chemotherapy plus radiation were given a lower total dose of 5000 cGy over 5 weeks. The chemotherapy regimen was fluorouracil by continuous infusion at 1 g/m2/day for 4 consecutive days plus cisplatin 75 mg/m2 on day 1 of each fluorouracil course. At the initial report with a median follow-up of 18 months, a highly significant survival advantage for chemoradiation versus radiation alone was demonstrated. An update of this study published in abstract form showed that 30% of patients receiving chemoradiation were alive at 5 years compared to no patients randomized to receive radiation alone? Importantly, in this update, the distant failure rate for patients with adenocarcinoma was significantly higher than those for epidermoid cancer, again raising the questions as to whether or not cisplatin and fluorouracil chemotherapy was as effective for adenocarcinoma patients as it appears to be for epidermoid carcinoma patients. Toxicity of chemoradiotherapy was substantial with 64% of patients experiencing grade 3 or 4 toxicity. Treatment-related deaths were rare, however. Two phase I1 studies involving the use of induction chemotherapy therapy followed by chemoradiation (using the same dose and schedule of chemoradiation as that employed in the initial Radiation Therapy Oncology Group study) have been reported.14An unexpected increase in toxicity, including a treatmentrelated mortality of approximately lo%, has been seen in these trials. In the second study, reported only in abstract form, chemoradiation plus brachytherapy also had an unacceptable risk of toxi~ity.'~ Chemotherapy Followed by Radiation Therapy

Using this approach, in general, cisplatin-based multidrug chemotherapy has been employed, followed by standard dose radiation. Response to chemotherapy using this approach ranges from 20% to 60% with no evidence of additive toxicity. Most studies, however, have not involved postradiation chemotherapy. In addition, many have not analyzed failure patterns, so that the percentage of patients relapsing first in the radiation field is difficult to interpret. An attempt to use induction chemotherapy followed by chemoradiation encountered unacceptable toxicity as described earlier. CONCLUSIONS

Important progress has been made in the treatment of esophageal cancer. Studies show that combined modality therapy involving chemotherapy and concurrent radiation is superior to radiation alone, at least for patients with epidermoid cancer. Trials of chemotherapy plus surgery versus surgery alone will address a similar question in patients who have potentially resectable disease. Encouraging data showing superiority of chemoradiation preceding surgery versus surgery alone have been reported. Paclitaxel has been identified as an active drug in the treatment of this disease; this has increased the therapeutic armamentarium of medical oncologists.' Paclitaxel as a single agent causes objective regressions in approximately one third of patients both with adenocarcinoma and with epidermoid cancer. In follow-up trials, paclitaxel has been added to cisplatin and fluorouracil, a combination that appears to have a higher response rate than paclitaxel alone but with substantial toxicity. Newer studies

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involving paclitaxel and cisplatin without fluorouracil and paclitaxel plus radiation therapy (with or without the use of cisplatin) are now underway at several institutions. These trials will assess the possibility that the addition of this new agent will both improve local control and decrease distant failure rates. A number of other agents that have substantial activity in gastrointestinal malignancies will shortly begin trials in esophageal cancer, including irinotecan and gemcitabine. Thus, a fairly large number of avenues of clinical research have opened using new agents plus radiation therapy or new chemotherapeutic agents given in the preoperative setting. In addition, there is intense interest in the development of molecular data that will predict outcome. These studies, involving cytogenetic abnormalities, oncogene amplification, or oncogene expression, are all a high priority. Preliminary data suggest that thymidylate synthase messenger RNA levels predict outcome in patients receiving chemotherapy and that there is a difference between adenocarcinomas and epidermoid cell tumors.1ZHigher levels of thymidylate synthase messenger RNA were seen in patients with adenocarcinomas than those with epidermoid cancer. This finding may explain lower response rates to fluorouracil chemotherapy combinations in adenocarcinoma patients. P53 oncogene mutation has been assessed in the same population. Presence of a mutated P53 has also been correlated with resistance to chemotherapeutic agents. A high degree of correlation between elevated levels of thymidylate synthase messenger RNA and mutated P53 was seen, predicting lack of responsiveness. These types of studies are potentially of considerable importance in designing systemic chemotherapy treatment plans tailored to resistance characteristics of the individual patient. The identification of molecular markers of sensitivity or resistance is now being translated into prospective clinical trials. Finally, other new systemic agents, not based on their ability to kill cycling cells (cytotoxicity)but rather on their ability to prevent invasion and metastasis or to block the development of new blood vessels (antiangiogenesis agents) have also entered clinical trials. Matrix metalloproteinase inhibitors such as Marimastat and antiangiogenesis agents such as TNP470 have had preliminary study in patients with solid tumors. Tolerance has been identified, and efficacy trials are now underway. Preliminary data suggest that assays of patient tissue may allow targeting of specific molecular markers to guide therapy using these agents as well. Although still experimental, these approaches are entering phase I and I1 studies. Eventually, they too will be used in the adjuvant setting, testing the hypothesis that cytostatic agents alone or in combination with cytotoxic drugs will decrease the recurrence rate. ACKNOWLEDGMENTS The author gratefully acknowledges the expert assistance of Ann Martin and Adrienne Scodary in the preparation of the manuscript.

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4. Bosch A, Frias Z, Caldwell WL, et a1 Autopsy findings in carcinoma of the esophagus. Acta Radio1 Oncol 18:103-335, 1979 5. Forastiere AA, Orringer MB, Perez-Tamayo C, et al: Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: Final report. J Clin Oncol 11:1118-1123, 1993 6. Gill PG, Denham JW, Jamieson GG, et al: Patterns of treatment failure and prognostic factors associated with the treatment of esophageal carcinoma with chemotherapy and radiotherapy either as sole treatment or followed by surgery. J Clin Oncol 10:10371043, 1992 7. Heitmiller RF, Redmond JM, Hamilton SR Barrett esophagus with high grade dysplasia: An indication for prophylactic esophagectomy [abstr]. Sixth World Congress of the International Society for Diseases of the Esophagus, Milan, Italy, 1995, p 228 8. Herskovic A, Martz K, Al-Sarraf M, et a1 Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus [see comments]. N Engl J Med 3261593-1598, 1992 9. Kavanagh B, Anscher M, Leopold K, et al: Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990. Int J Radiat Oncol Biol Phys 24:633-642, 1992 10. Kelsen DP: Adjuvant therapy of upper gastrointestinal tract cancers. Semin Oncol 22582-599, 1995 11. Kelsen D, Ajani J, Ilson D, et al: A phase I1 trial of paclitaxel (Taxol) in advanced esophageal cancer: Preliminary report. Semin Oncol 21:44-48, 1994 12. Lenz HJ, Leichman C, Danenberg P, et al: Thymidylate synthase (TS) gene expression predicts response of primary gastric cancer (GC) to 5-fluorouracil (5FU)-leucovorin (LV)-cisplatin (DDP) [meeting abstr]. Proc Annu Meet Am SOCClin Oncol 12:A585, 1993 13. Mandard AM, Chasle J, Marnay J, et al: Autopsy findings in 111 cases of esophageal cancer. Cancer 48:329-335, 1981 14. Minsky BD, Neuberg D, Kelsen DP, et al: Neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus: A preliminary analysis of the phase I1 intergroup trial 0122. J Clin Oncoll4149-155,1996 15. Muggia Fh4, Gill I: Primary chemotherapy. In DeVita VT Jr, Hellman S, Rosenberg SA (eds):Cancer: Principles and Practice of Oncology Updates. Philadelphia, JB Lippincott, 1990, pp 1-12 16. Putnam JB, Soysal 0, Roth JA, et al: Results of esophagectomy for severe dysplasia in Barrett’s esophagus [abstr]. Sixth World Congress of the International Society for Diseases of the Esophagus, 1995, p 168 17. Sischy B, Ryan L, Haller D, et al: Interim report of EST 1282 phase 111 protocol for the evaluation of combined modalities in the treatment of patients with carcinoma of the esophagus, stage I and I1 [abstr]. Proc Am SOCClin Oncol 9:105, 1990 18. Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys 5235-91, 1979 19. Sugimachi K, Inokuchi K, Kuwano H, et al: Patterns of recurrence after curative resection for carcinoma of the thoracic part of the esophagus. Surg Gynecol Obstet 157537-540, 1983 20. Urba S, Orringer M, Turrisi A, et a1 A randomized trial comparing transhiatal esophagectomy (THE) to preoperative concurrent chemoradiation followed by esophagectomy in locoregional esophageal carcinoma [abstr]. Proc Am SOCClin Oncol 14199, 1995 21. Vokes EE: Interactions of chemotherapy and radiation. Semin Oncol 20:70-79, 1993 22. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335462-467,1996

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