Oesophageal cancer treatment: Studies, strategies and facts

Annals of Oncology 9: 951-962, 1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands.

Review Oesophageal cancer treatment: Studies, strategies and facts A.Wobst,1 R. A. Audisio,1 M. Colleoni2 & J. G. Geraghty1 Departments of Surgery, 2Medical Oncology, European Institute of Oncology, Milan, Italy

by surgery has accumulated in recent years, and confirmatory trials are presently ongoing. A pathological complete response Esophageal cancer is among the ten most frequent cancers in to chemoradiotherapy has been identified to significantly enthe world. Once diagnosis is established prognosis is poor with hance survival. Among the strategies to achieve higher response five-year survival rates below 10%. Over the last few years, the rates, variations in the administration of the most commonly evidence - base for treatment of oesophageal cancer has used drugs rather than higher drug and radiation dosages seem changed with the publication of several important articles in promising. Occult lymphatic spread has been recognised as a thisfield.This article reviews these and other relevant publica- major source of recurrence and has been successfully targeted tions with focus on current evidence which holds potential for by threefieldsurgical dissection and extendedfieldradiotherapy. In search of the optimal treatment for patients with oesoan improvement in survival in oesophageal cancer patients. Prevention and early detection represent the mainstay in the phageal cancer, a variety of different tracks are being pursued. ongoing struggle to improve prognosis, which is most strin- This review outlines and analyses current treatment approaches gently linked to tumor stage. Other efforts have been dedicated and investigates how recent advances may impact on patient to optimise surgical treatment, radiotherapy and chemotherapy management. and to discover the most efficient combinations of these treatment modalities. Strong but not unanimous evidence in favour Key words: Barrett's oesophagus, multimodality treatment, of a multimodality approach with chemoradiotherapy followed oesophageal cancer Summary

studies is limited by differences in tumor staging before treatment. Furthermore diagnostic precision varies Esophageal cancer is among the 10 most frequent can- (sometimes relying on esophagogastroscopy only, somecers in the world [1]. Incidence varies widely from over times involving EUS and CT) and different staging sys130/100000 in endemic regions (Linxian/China, Kaza- tems are used. Patient selection (resectable vs. unresectkhistan [2, 3]) to around 4/100000 among western pop- able, poor vs. excellent performance status), treatment ulations [4]. goals (curative vs. palliative), treatment specifics and Once diagnosis is established, the prognosis is poor. follow-up times of clinical studies vary, thus rendering Five-year survival rates for all patients lie below 10% [99] transparency of present esophageal cancer treatment and around 20% for surgically treated patients [5]. Tu- difficult. mor stage, lymph node spread and response to preoperThis article provides a comprehensive overview of the ative treatment have been identified as relevant prognos- status quo of esophageal cancer treatment analysing the tic markers. Histologic subtype is most frequently of results of clinical trials and studies involving chemosquamous cell origin although a dramatic and yet un- therapy, radiotherapy and surgery. explained increase in the incidence of adenocarcinoma of the esophagus has been seen in recent years [6, 7]. Since a survival advantage in favour of the adeno cell Staging type [8] did not reach statistical significance in the majority of clinical studies [9, 10] both histologic sub- Today the identical TNM staging systems of the UICC types will subsequently be discussed jointly. (since 1987, [11, 98]) and AJCC (since 1992, [12]) and Only slight improvements in five-year survival rates the slightly modified version of the Japanese Research have been seen in the last 10 years despite improvement Society for Esophageal Diseases (1987, Figure 1) are in surgical technique and perioperative mortality. Con- most commonly used for esophageal cancer. Clinical sequently a multimodal therapy approach and extended and pathological staging follow the same parameters. lymphadenectomy were introduced aimed at obtaining In older studies the former AJCC version for clinical higher cure rates with less recurrence from occult metas- staging (1978) can be found which differs substantially tases. Unfortunately comparability of clinical trials and and as such may confound comparisons between studies Introduction

952 Stage II

AJCC 1992-1997 UICC 1987-1997 Primary tumor (T) Minimum requirements to asess the primary TX tumor cannot be seen No evidence of primary tumor TO Tis Preinvasive carcinoma (carcinoma m situ) Tl Tumor invades into but not beyond the submucosa T2 Tumor invades into but not beyond the muscularis propria T3 Tumor invades into the adventitia T4 Tumor invades contiguous structures Regional lymph nodes (N) Cervical esophagus (cervical and supraclavicular lymph nodes) NX Regional lymph nodes cannot be assessed NO No demonstrable metastasis to regional lymph nodes Nl Regional lymph nodes contain metastatic tumor Thoracic esophagus (nodes in the thorax, not those of the cervical, supraclavicular, or abdominal areas) NX Regional lymph nodes cannot be assessed NO No nodal involvement Nl Nodal involvement Distant metastasis (M) MX Distant metastases cannot be assessed MO No evidence of distant metastasis Ml Distant metastasis present Stage grouping Stage 0 Tis, NO, MO Stage 1 T1,NO, MO Stage IIA T2, NO, MO T3, NO, MO Stage I IB T l / 2 , N1,MO Stage III T3/4, N1,MO Stage IV AnyT, any N, Ml AJCC 1978 Primary tumor (T) TO No demonstrable tumor Carcinoma in situ TIS Tl Tumor involves 5 cm or less of esophageal lenth No obstruction nor complete circumferential involvement No extraesophageal spread T2 Tumor involves more than 5 cm of esophagus Produces obstruction with circumferential involvement of the esophagus No extraesophageal spread Tumor with extension outside the esophagus T3 Involvement of mediastinal structures Regional lymph nodes (N) Cervical esophagus (cervical and supraclavicular nodes) NO No nodal involvement Nl Unilateral involvement N2 Bilateral involvement N3 Fixed nodes Thoracic esophagus (nodes in the thorax, not those of the cervical, supraclavicular or abdominal areas) NO No nodal involvement Nl Nodal involvement Distal metastases (M) MO No metastases Ml Distant metastases. Cancer of thoracic esophagus with cervical, supraclavicular, or abdominal lymph node involvement is classified as M1 Stage grouping for esophageal cancer Stage I T1,NO, MO Figure 1. TNM staging for esophageal cancer.

Stage III

T1,N1/2,MO T2, NO/1/2, MO AnyT3, Any Ml

Japanese Research Society for Esophageal Diseases (1987) Primary tumor (T) TX Primary tumor cannot be assessed TO No evidence of primary tumor Tis Carcinoma in situ Tumor invades lamina propna or submucosa Tl T2 Tumor invades muscularis propria T3 Tumor invades adventitia T4 Tumor invades adjacent structures Regional lymph nodes (N) a NX Regional lymph nodes cannot be assessed NO No regional node metastases Nl Regional lymph node metastases Distant metastasis (M) MX Presence of distant metastases cannot be assessed No distant metastasis MO Distant metastasis Ml Distant lymph node metastasis Ml LYM Stage grouping Tis, NO, MO Stage 0 Stage I T1.N0.M0 Stage IIA T2, NO, MO T3, NO, MO Stage I IB T1,N1,MO T2, N1,MO Stage III T3, N1,MO T4, N0/1.M0 Stage IV AnyT, any N, Ml LYM AnyT, any N, Ml a

The regional nodes are, for the cervical oesophagus, the cervical nodes including supraclavicular nodes and, for the intrathoracic eosophagus, the mediastinal and perigastric nodes excluding the coeliac nodes. Figure 1 Continued.

or metaanalyses. Whittington et al. [13] applied Dukes' classification of colorectal cancer to esophageal cancer and Yamada and Kobayashi used the term 'early cancer' for stages 0 and I [14]. Even when studies using the same staging system are compared, diagnostic accuracy varies (e.g., CTand endosonography instead of chest X-ray only). A common standard of preoperative diagnosis and staging would thus be most desireable and should become a requirement for all clinical trials and studies. As the prognostic value of local tumor extent and lymph node metastases are well recognised, thoracic CT and endosonography should be included in the preoperative staging process whenever possible.

Prevention

The impact of therapy on overall survival in oesophageal cancer has improved only marginally during the last two decades (10%-15%, five-year survival up to 1988 and about 15%—20% in recent studies). Since prognosis is significantly better for early tumour stages (over 70%, five-year survival for tumours stage I and II compared

953 Table I. Improved surgical results for esophageal resection in metaanlysis covering the decade from 1980-1990 [32] versus an older metaanalysis covering the previous decade 1970-1980 [31]. Reference

No. of papers

No. of patients

Resections (%)

Mortality (%)

Survival (%) One year

Two years

Earlam, 1980 [31]

122

83783

22

16

13

7

Mueller, 1993 [32]

130

76911

21

8

56

35

to 0%, five-year survival in stage IV tumours), early detection and prevention have been identified as prime targets for the reduction of mortality from oesophageal cancer [15]. Detection of oesophageal carcinoma in western populations normally follows the onset of dysphagia or during surveillance of Barrett's oesophagus. To establish a routine screening program as used in China (in an endemic region with a high incidence of oesophageal carcinoma) would probably not be cost-effective among western populations due to the low incidence [16]. The greatest potential for lowering mortality from oesophageal cancer thus lies in its prevention. Reduction of risk factors (alcohol and tobacco consumption) remain issues of public health and awareness campaigns while the optimal surveillance and treatment for Barrett's oesophagus are important questions in surgical oncology. Barrett's oesophagus is a premalignant condition characterised by metaplasia of the squamous oesophageal epithelium to specialised columnar epithelium following reflux oesophagitis. Progression to dedifferentiation, dysplasia and carcinoma have been observed in the natural course of disease and not been halted by surgical or medical treatment for reflux oesophagitis [17, 18]. Oesophageal resection has been propagated for severe dysplasia and seems justified in the face of the known dysplasia-carcinoma sequence and the high percentage of occult carcinomas (up to 41%) following surgery for dysplasia [19, 20]. Care should be taken not to underestimate the longitudinal spread of dysplastic changes since, in a number of cases, development of carcinomas adjacent to previous resection sites for dysplasia have been found [17]. For patients who are unfit or unwilling to undergo surgery photodynamic therapy may be regarded as an alternative. Regression of dysplastic and metaplastic changes and reepithelialisation with squamous cell epithelium have been seen and an estimated five-year survival rate of 62% has been reported in seven patients despite the fact that stage I carcinoma was present [2123]. Problems with photodynamic therapy include superficial penetration of light (about 0.6 cm) which may not be sufficient to ablate an occult carcinoma. Three questions remain: Should patients with symptoms of oesophageal reflux be screened for Barrett's oesophagus? What is the optimal surveillance once Barrett's metaplasia is discovered? Which treatment should be preferred for severe dysplasia? About 18% of patients undergoing endoscopy for reflux oesophagitis have columnar metaplasia and of

Three years

Five years

25

20

3

these about 10%—12% will already demonstrate cancer [24]. Even when signs of Barrett's oesophagus are not evident during endoscopy, metaplasia may be demonstrated in biopsy specimens (18% in one series of 142 patients [25]). In this respect it seems justifiable to perform an endoscopy after failure of conventional treatment, presence of reflux for over five years or complications such as dysphagia/odynophagia or bleeding [26]. There is a broad consensus about the importance of endoscopic surveillance for Barrett's oesophagus once detected [16, 26-28]. Guidelines for surveillance recommended by the Working Party on Barrett's Oesophagus at the Ninth World Congress of Gastroenterology [29] include (i) biopsy every 18 to 24 months for Barrett's metaplasia without dysplasia, (ii) endoscopic surveillance of low grade dysplasia after 12 weeks of medical therapy with routine endoscopy every 12 months thereafter, and (iii) surveillance every six months for patients with high grade dysplasia who do not undergo surgical resection. A less differentiated model (not taking the grade of dysplasia into account) based on a computer cohort simulation to evaluate effectiveness and costeffectiveness of endoscopic surveillance is used by Provenzale et al. [16]. The authors suggest annual endoscopy for Barrett's oesophagus if patient survival alone is considered. An endoscopic control everyfiveyears, however, would be more cost-effective [16]. Surgical resection of Barrett's oesophagus with high grade dysplasia is proposed due to the inherent difficulties in excluding occult carcinoma at endoscopy [19, 20, 29, 30]. Photodynamic therapy has proven to be effective for regression of dysplastic changes and should be considered for all patients not undergoing surgery. A controlled clinical trial would certainly help to evaluate superiority of either of these treatment approaches. The data of present studies, regarding either treatment modality individually, do not allow comparative conclusions to be made.

Surgery Surgery has been the standard for oesophageal cancer treatment for the last 40 years. During this time span, operative mortality rate and one-, three- and five-year survival rates have improved substantially when results of two metaanalyses are compared covering the years 1970-1980 [31] and 1980-1990 [32] respectively (Table 1). Perioperative mortality has further decreased

954 Table 2. Chemoradiotherapy is superior to radiotherapy alone in a curative treatment approach. Reference

No. of

Survival

Treatment groups

patients Herskovic, 1992 [51]

A: 60 B:61

64 Gy 50 Gy + 5-FU + Cp

Iizuka, 1989 [57]

A:911 B:1235

50 Gy Surgery

Whittington, 1990 [13]a

A: 50 B:25 C:8 D: 19 E:9 F:26 G:8

Surgery 50-60 Gy 5-FU + M or FAM Surg. + rad. Surg. + chem. Chem. + rad. Surg. + chem. + rad.

Hospital mortality,

Significance

treatment related mortality (%)

Median

1

2

9 12.5

33 50

10 38

_

_

0.8

P < 0.001 Survival advantage forB

-

37 61

16 40

9 32

3 26

7.5 7.5

-

16 9 5 14 — 10 20

66 38 13 53 _ 49 77

35 5 0 32 — 15 37

21 0 0 18 — 14 10

3.7

NS

3

5

— _ -

A-F: treatment subgroups. Abbreviations: - data not available; NS - no significant difference. a Some survival results extrapolated from survival curves.

recently to around 6%-8% in the hands of experienced surgeons. The five-year survival rate however has remained around a grim 20%. A significant survival benefit has been shown for R0 resection (tumour completely removed) in comparison to Rl (tumour reaches resection margins microscopically) and R2 (tumour incompletely removed macroscopically) [33-36]. Since occult lymphatic spread has been found to be a major source of recurrence even after 'curative' resections [37-39], radical surgery including en-bloc resection and extended field lymphadenectomy has been propagated. In 1983 Skinner [40] reported betterfive-yearsurvival rates for patients operated with en-bloc resection than historic controls. Since then only one controlled clinical trial [41] has been performed demonstrating significantly higher five year survival rates for en-bloc oesophagectomy compared to transhiatal oesophagectomy. Although patient numbers were low in this study (n 69), the data give enough evidence to warrant further randomized controlled clinical trials taking surgical morbidity, mortality, tumour recurrence and survival into consideration. Extended field lymphadenectomy has been predominantly proposed and promoted by Japanese surgeons. Differences in radicality are reflected in the number of resected nodes which average 80 in Japanese series [42] versus 30 nodes in other series [43] and in the fields of lymphadenectomy which include abdominal, mediastinal and cervical groups in the former. Retrospective data are strongly in favour of three field lymphadenectomy compared to two field lymphadenectomy and the most convincing data have been presented by Isono in a Japanese nation-wide study on extended field dissection [44]. The 34% five-year survival of almost 1800 patients undergoing three field dissection was significantly higher than that of 27% for the 2800 patients undergoing two field dissection. There was no

difference in perioperative mortality (2.8% and 4.6%, respectively) but a high morbidity with laryngeal nerve injury in 20% and 14% of patients, respectively. The only controlled study on extended field lymphadenectomy by Kato et al. [45] showed a significant advantage for three field dissection in perioperative mortality and five-year survival. Results may have been biased though by patient selection in that older patients (average of four years) with higher tumour stages were present in the two field dissection group [46]. As with enbloc resection the data in favour of extended field lymphadenectomy are not conclusive but sufficient [44, 46-50] to recommend further controlled clinical trials. Although operative mortality and five-year survival thus have improved even in recent years (Skinner 22%, Isono 34%), long-term prognosis remains poor and alternative or integrated treatment options remain the key to an improvement in survival.

Radiotherapy

Radiotherapy traditionally has been one of the standard treatment arms of oesophageal cancer, either alone or in combination with surgery. Despite this fact there has not been one convincing study demonstrating the benefits of radiotherapy alone or in an adjuvant setting when compared with surgery alone. Radiotherapy alone has been proven to be inferior to radiotherapy plus chemotherapy with 5-FU and cisplatin in the phase III trial by Herskovic [51]. After two years the advantage of radiochemotherapy over radiotherapy already became so obvious (P < 0.001) that the trial was stopped (Table 2). Radiotherapy alone versus surgery alone can only indirectly be compared since there are no randomised clinical trials. The studies conducted by Whittington et

955 Table 3. No significant advantage for postoperative radiotherapy in randomized clinical trials. Reference

No. of patients

Treatment

Significance

Survival Median

One year

Two years

Three years

Fok, 1993 [53] a

A: 65 B:65

Surg. + 49-56 Gy Surgery

8.7 15.2

35 63

11 22

Teniere, 1991 [54]a

A: 102 B: 119

Surg. + 45-55 Gy Surgery

18 18

91 95

31 29

Zieren, 1995 [52]a

A: 35 B: 35

Surg. + 30 Gy Surgery

14 13

57 53

29 31

Five years NS 19 21

22 20

NS NS

A - F : treatment subgroups. Abbreviations: - data not available; NS - no significant difference. a Some survival results extrapolated from survival curves. Table 4. No significant survival advantage by adding neoadjuvant radiotherapy to surgery in randomised clinical trials. Reference

No. of patients

Treatment

Survival Median

One year

Three years

Five years

Hospital mortality, treatment related mortality (%)

Significance

Arnott, 1992 [55]a

A-67 B:62

Surg. + 20 Gy Surgery

12 14

50 52

18 32

9 30

14

NS

EORTC, 1985 [59]

A: 102 B: 106

Surg. + 33 Gy Surgery

11 11

45 45

-

16 10

-

NS

Lannois, 1991 [58]

A: 67 B:57

Surg. + 40 Gy Surgery

11 12

45 50

10 12

-

NS

_

A: 104 B: 102

Surg. + 40 Gy Surgery

-

-

-

35 30

5 6

NS

Mei, 1989 [56]

A - F : treatment subgroups. Abbreviations: - data not available; NS - no significant difference. a Some survival results extrapolated from survival curves.

al. [13] and Iizuka [57] are retrospective, nonrandomized and without stratification for tumour stage. The survival advantage for the resected patients thus maybe due to selection bias and the results are largely descriptive only. The studies regarding adjuvant radiotherapy show no advantage over surgery alone and controlled clinical trials did not show any survival benefit for patients treated postoperatively with 30 Gy [52] or even 4956 Gy [53, 54] (Table 3). In a neoadjuvant setting, preoperative doses from 20 Gy [55] to 40 Gy [56] have been used (Table 4) without improving results. In a subanalysis of Mei et al. [56], taking pathologic response to radiation into account, there was a positive correlation between radiation response and survival. Radiation response was subdivided into three degrees according to tumour shrinkage and pathologic evaluation (degree III just showing remnants of degenerated cancer cells). 50% of patients demonstrating a degree III response were reported alive atfiveyears compared to only 33% with a lesser degree of response. According to the above mentioned data radiotherapy cannot be recommended as a single modality treatment nor as the only adjuvant therapy with surgery in a curative approach. Since responsive patients might benefit from adjuvant radiotherapy [56], and since lymph node

spread often involves cervical nodes which are not included in most radiation fields, extended radiation fields should be included as an additional arm in future studies. Chemotherapy

Chemotherapy in oesophageal cancer pursues two main goals (i) reduction of recurrence from occult lymphatic metastases with potential improvement of survival and (ii) possible tumour shrinkage with an increased resectability rate. These goals have thus far not been achieved (Table 5). In four prospective randomised trials, neither a survival benefit nor an increased resectability rate were found after preoperative [61, 62, 100] and pre- and postoperative [63] chemotherapy. On the contrary a higher mortality rate was evident in the early postoperative period [62] and after six months [61]. It should be noted that a significant survival benefit was seen in the subgroup of patients who had a pathological response to chemotherapy [62, 63]. The retrospective analysis by Wright et al. on 91 patients with adenocarcinoma of the oesophagus or gastroesophageal junction was the only study which yielded a

956 Table 5. No survival benefit with adjuvant chemotherapy compared to surgery alone in randomised clinical trials. Reference

No.

Treatment

Hospital

Survival

Significance

c

of pts

Median

One year

Three years

Five years

mortality, treatment related mortality (%)

Kelsen, 1997 [102]

A: 221 B:202

Surgery Surg. + Cp, 5-FU (pre + postop.)

16.8 16.1

62 62

_ -

_ -

_ -

Interim analysis; no advantage of adjuvant chemotherapy in resection rate, relapse free survival or overall surival after two years

Maipang, 1994 [61]

A: 22 B:24

Surgery Surg + Cp, Bleo.,Vinbl. (preop.)

17 17

86 57

36 31

-

8.7

NS

Pouliquen, 1996 [89]

A: 68 B: 52

Surgery (palliative) Surg. (palliative) + 5-FU and Cp (postop.)

14 -

58 52

20 20

8 2

Roth, 1988 [63]

A: 20 B: 19

Surgery Surgery + Cp,Vind., Bleo. (pre + postop.)

9 9

33 50

5 25

_ -

Schlag, 1992 [62]a

A: 27 B:42

Surgery Surg. + preop. 5-FU + Cp

10 10

37 39

-

-

14 24

Wright, 1994 [64]a

A: 91

Surgery

13

59

11

8

2

B: 16

Surg. + preop. 5-FU + Cp

20

57

42

20

C:22

Surg. + preop. EAP

-

94

60

0

10

5.1

No advantage of chemotherapy for survival and alimentation Significance higher complication rate NS

NS Suggested benefit for preoperative chemotherapy Over historic control, P = 0.04 for 5-FU + Cp P = 0.004 for EAP

A - F : treatment subgroups. Abbreviations: - data not available; NS - no significant difference. Drugs: 5-FU - 5-fluorouracil; Cp - cisplatin; Mi - mitomycin-C; Bleo - bleomycin; Etop - etoposide; Vinbl - vinblastin; Vind - vindesine; FAM - 5-fluorouracil, Mitomycin-C, doxorubicin; EAP - etoposide, cisplatin, adriamycin. a Some survival results extrapolated from survival curves.

significant survival benefit after adjuvant chemotherapy as compared to a surgical historic control [64]. Patient selection, however, was nonrandomised and any study relying on a comparison with historic controls has to take into account that increasing surgical experience on its own improves operative results. Chemotherapy as the only adjuvant treatment cannot be recommended outside clinical studies or trials. The major aim should be to find drug combinations with higher response rates than the presently used combinations of 5-FU and cisplatin. Multimodality therapy Approaches A broad consensus exists on the benefits of multimodality therapy for oesophageal cancer. Most present trials thus include combinations of chemotherapy, radiotherapy and surgery. The emphasis lies either on surgery with different schemes of adjuvant chemotherapy, radiotherapy

or combined chemoradiotherapy [66-72] or on chemoradiation with additional surgical resection for nonresponders [73-75, 88]. Thefacts Prospective randomised trials To date, Walsh et al. are the only group which have shown a significant survival benefit (P < 0.01) for a multimodality approach with preoperative radiochemotherapy (n - 58) over surgery alone (n = 55) for oesophageal adenocarcinoma in a prospective randomised trial. The three year survival rate of 6% in the surgery only group, however, compared very low to historical controls and preoperative staging has been questioned [101]. Bosset et al. {n = 297), Urba et al. (n = 100) and Le Prise et al. (« = 87) however did not find a significant advantage for adjuvant chemoradiation over surgery alone (Table 6). To the present day there are no available data on prospective randomised trials comparing chemoradiation only, surgery only and chemoradiation plus surgery.

957 Table 6. Significant survival advantage for multimodal therapy in one of four randomized clinical trials. No. of pts

Treatment

Bosset, 1997 [102,65] a

A: 134 B: 143

Le Prise, 1994 [66]

Reference

Survival

Hospital mortality. treatment related mortality (%)

Significance

4 12

No differences in overall survival, longer disease free survival and survival free of local disease for multimodal group

Median

One year

Two years

Three years

Five years

Surgery Surg. + Cp + 37 Gy (preop.)

18.6 18.6

74 77

48 44

36 33

25 25

A: 45 B:41

Surgery Surg. + Cp. 5-FU and 20 Gy (preop.)

10 10

47 47

_ -

14 19

7 8.5

NS

Urba, 1997 [67, 103]

A: 50 B:50

Surgery Cp,Vinbl, 5-FU + 45 Gy (preop.)

17.5 16.9

-

36 41

15 32

-

Survival advantage for pathologic CR (P < 0.01)

Walsh, 1996 [68]

A: 55 B:58

Surgery Surg. + preop. 5-FU, Cp, 40 Gy

11 16

44 52

26 37

6 32

6

Survival advantage for multimodal therapy (P < 0.01)

A - F : treatment subgroups. Abbreviations: - data not available; CR - complete response; NS - no significant difference. Drugs: 5-FU - 5-fluorouracil; Cp — cisplatin; Mi — mitomycin-C; Bleo - bleomycin; Etop - etoposide; Vinbl - vinblastin; Vind - vindesine, FAM — 5-fluorouracil, Mitomycin-C, doxorubicin; EAP — etoposide, cisplatin, adnamycin. a Some survival results extrapolated from survival curves.

Nonrandomised or retrospective studies If one examines the studies listed in Table 7, it becomes obvious that treatment approaches, histology and staging, follow up, mortality rates and conclusions are very heterogeneous. One recurrent observation is a significantly improved survival for the subgroup of patients with a complete remission after chemoradiation (Bates, Carey, Forastiere, Naunheim, Wolfe). A significant benefit for all patients treated with a multimodality approach versus surgery/radiotherapy alone was, however, demonstrated by three groups only (Naunheim, Vogel, Stewart). A survival benefit for resected patients after chemoradiation is seen in the studies by Bates, Carey (P < 0.001, n - 70) and Forastiere. In contrast, studies from Naunheim {P < 0.05, n=28), Stahl and de Pree have all questioned the need for surgery after chemoradiation. Survival figures vary widely between the different protocols. This is partly due to different pre-treatment stages and staging systems but also due to exclusion of perioperative deaths [77]. This precludes any meaningful interstudy analysis and leaves the observation of fiveyear survival rates of over 30% in four studies [71, 73, 75, 84] on one hand and a five-year survival of 60% for patients with complete remission after chemoradiotherapy[72,78]. A subanalysis regarding histologic tumour type showed a significant survival advantage for adenocarcinoma compared to squamous cell carcinoma among 68 patients in the study by Hoff et al. [74] but in contrast no differences among the 47 patients analysed by Naunheim et al. were described.

Trends and developments Different strategies to improve response to radiochemotherapy have been pursued and are under surveillance presently. Since the publication of the results of the RTOG [51] and ECOG [92] trials, radiochemotherapy involving a combination of cisplatin, 5-FU and external beam radiation has become the standard treatment for non-surgical patients and in an adjuvant treatment setting. In the search for improving results of radiochemotherapy, two strategies have been pursued (i) intensification of existing chemoradiotherapy schedules and (ii) evaluation of new drug combinations and radiation regimes. Toxicity limits intensification of the combined RTOG treatment arm as preliminary experience of the intergroup 0122 phase II trial shows. A treatment related mortality of 11% (compared to 2% for the RTOG trial) resulted from more aggressive chemotherapy (five instead of four days of 1000 mg/m2 5-FU with 75 mg/m2 cisplatin on day 1, 5 instead of four cycles of treatment and three cycles of full-dose immediately before radiotherapy) whilst simultaneously increasing radiotherapy from 50 Gy to 64 Gy [90]. In the area of new drug combinations, cytotoxic agents are either being added to the combination of 5-FU and cisplatin or are replacing one or both of them. Bleomycin has not been used in combination with radiotherapy due to the potentiation of pulmonary toxicity. Etoposide worsened prognosis when added to a combination of 5-FU, cisplatin and leucovorin [74] although clinical

958 Table 7. Multimodality treatment studies and trials (retrospective or nonrandomized). Reference

Stage

No. of pts

Treatment

FU

Median

Bates 1996

Primary lesion + /— periesophageal In, no mediast. or abd. In

35

Preop. 45 Gy + 5-FU, Cp + surgery

18

Burmeister 1995°

-

294

60 Gy, 5-FU + Cp (137 Datients'1. DreoD. 30-35 Gy, 5-FU + Cp + surgery [78], palliat. 30-35 Gy + 5-FU + Cp [79]

22

Carey 1993

UICCp Tl = 5 T2 = 19 T3 =25 T4 = 1 N+=20

A: 55

Surgery + 36 Gy + 5-FU + Cp postop. 5-FU + Cp preop.

18

22

B: 15

M

Survival One year

26

67

AJCC c 0 I 0 Ha 17 lib 9 III 14 IV

P 1 2 11 5 7 5

32

Surgery 5-FU, leucov preop. 51-66 Gy, HU, 5-FU postop.

22

20

Forastiere 1997 [89]a

Nst. MO and resect;

50

Preop. 5-FU, Cp and 44 Gy + surgery [47]

43

31

Forastiere 1993

Tl T2 T3 N+

42

Surgery 5-FU, Cp,Vinbl + 37,5^»5 Gy preop.

79

29

Ganem 1997 [87]

AJCCc I = 14 II = 2 9 III =45

88

5-FU + Cp + HU + 40 Gy + surg [41] + third cycle radiochemo [24]

42

18

Hoff 1993°

AJCCp I =8 Ha = 9 lib = 8 III = 13 IV = 6

68

Surgery + preop. 5-FU, Cp, Leucov, Etop., 3000 Gy

19

24

Iizuka (Jap. eso. one group) 1993

R0 I Ha lib III IV

A: 127 B: 126

Surgery + 50 Gy Surgery + Cp,Vind Postop.

80 90

Kitamura 1995

TNM I + 11 III + IV

A: 32

Bleo, Cp, 30 Gy, surg. + HCR Bleo, Cp, 30 Gy, surg.

68

Millikan 1995

AJCCp I =2 Ha =31 lib = 7 III =80 IV = 18

157

Surgery + adj. radiochemo (67 patients), adj. radiotherapy (24 patients), adj. chemotherapy (15 patients)

Naunheim 1995

AJCCp I =5 II = 5 III = 10

28

Preop. 5-FU,Cp. 3& 36 Gy + surgery (20 patients), or + add 5-FU, Cp 24-34 Gy (8 patients)

=4/4 = 17/17 = 1 = 56%/42%

=7 = 58 = 52 = 106 =30 c 21 24

p 45 42

B: 34

60 17

50

18

51 p

Significant longer survival (P < 0.05) and disease free survival (P < 0.01) with neg. pathology

Five years

53

41

52

43

43

19

Significant better freedom from dysphagia in surg. group (P < 0 003), better palliation with radiochemotherapy for females (P < 0.04)

34

31

47 c 7 p

Sgn. impr. surv. with resect. (P < 0 001), complete responders to chemo benefit (P < 0.01)

71c

2p

-

36

40 p

No sigificant difference for ad and sec for neg patholgy: median survival has not been reached; two-year survival 78%

34

24 p

Neg. patholog : - 70 months med. survival - Five-year survival 60%

58

48

12.5

42

72

Significance

Three years

38

78

CR

Two years

73

Ferguson 1995

RR

51

40

51 52

56

7.3

64 p 20 p

-

74 c 21 p

Survival adv. vor ad vs. sec; P < 0.05

NS

44 42

50

P < 0.05 for cytostatic benefit with HCR

40

24

40

34

21

28

20

7.6

-

Benefit for adj. therapy in node + pat. (P = 0.01, hospital death excluded survival figures)

Neg. path, with significant survival benefit (P < 0 05)

959 Table 7. Continued. Reference

No.

Stage

Treatment

FU

Survival

M

RR

CR

Significance

-

21 p

Adv. over historical control (25 patients, without staging) treated either surg. or with radioth. only (P < 0.005), no significant difference between ad and sec

of pts

Median

One year

Two years

Three years

Five years

Naunheim 1992

AJCCp 0 =8 I =5 Ha = 9 lib = 5 HI = 10 IV = 1

47

Preop. 5-FU, Cp, 30-60 Gy + surgery (38 patients), or + add. 5-FU. Cp, 20 Gy (7 patients)

23

23

71

47

40

4.3

Poplin 1994

AJCCc I—III

26

40-50 Gy + 5-FU, Cp + surgery (3 patients)

24

24

65

60

-

8.9

65 c

-

Poplin 1996

AJCCc I—III exclusion when cervical In +

32

50 Gy + 5-FU. Cp + surgery (9 patients)

-

20

59

31

-

6.3

44c

Severe morbidity (four treatment related death additional to the surgical deaths), not recommended

Stahl 1996"

LAEC UICCp T2 = 14 T3 = 4 8 T4 = 10

72

Folic acid, Etop, 5-FU, Cp and 40 Gy Preop. Definite radiochemo (60-66 Gy) Resected

22

17

70

36

33

55

55

Preop. Cp, 5-FU, Leucov, Etop and 30 Gy + surgery Surgery

_

Surgery Cp, 5-FU, 45 Gy preop.

-

A: 52 B: 12 C:48

Steward 1993

Vogel 1995

0 I Ha lib III IV

-neoad 0 2 1 4 8 1

Nst.

+neo 6 4 5 2 4 2

A: 24

B: 16

A: 98 B:44

-

_

42

37

26

66

37

24

8

33

15

6

16 28

32 65

-

11 36

8 36

21

-

33 p

Neg. path with 68% three-year survival

8

-

22 p

Significant survival benefit for neoadjuvant (P < 0.001) complete response not significant better

5

-

Retr. nonrand Significant better survival for node neg. (P < 0.04) and for multimodal therapy (P < 0.04)

A - F : treatment subgroups. Abbreviations: - data not available; c - clinical; CR - complete response; NS - no significant difference; p - pathological; RR - response rate. Drugs: 5-FU - 5-fluorouracil; Cp - cisplatin; Mi - mitomycin-C; Bleo - bleomycin; Etop - etoposide; Vinbl - vinblastin; Vind - vindesine; FAM - 5-fluorouracil, Mitomycin-C, doxorubicin; EAP - etoposide, cisplatin, adriamycin; HU - hydroxyurea; Leukov - leukovorin. Staging: AJCCc - American Joint Committee on Cancer, clinical; AJCCp - AJCC, pathological; UICC - Union against Cancer; Gund Gunderson modification of Astler-Coller staging for rectal cancer; LAEC — locally advanced esophageal cancer. Histology: ad — adenocarcinoma; sec - squamous-cell carcinoma. a Some survival results extrapolated from survival curves.

(74%) and pathological (21%) response rates were promising. Cytotoxic drugs under investigation in phase II clinical trials include paclitaxel, docetaxel, gemcitibin, vinorelbin, topotecan, LMB-7 and carboxyamidotriazol. A 32% clinical response rate for paclitaxel administered as a single agent has been demonstrated which increases to 44% in combination with 5-FU and cisplatin. Low toxicity (e.g., vinorelbin) and radiosensitising qualities (e.g., gemcitabine) are other advantages of new drug combinations. To optimise radiotherapy, the local tumour dose has been enhanced by increasing the amount of external beam radiation as demonstrated in the INT 0123 trial which replaced the RTOG 85-01 trial. The tumour dose was increased to 64.8 Gy in this study while chemotherapy remained the same. The trial started in 1994 and

accrual is still ongoing. Also by adding brachytherapy to external beam therapy, the local tumour dose can be increased. Toxicity due to the development of fistulas has limited [91] this approach, which at present cannot be recommended. A promising development involves the additional use of hyperthermia, which technically is difficult to perform but has led to a significant survival benefit (P < 0.05), when compared to chemoradiotherapy only [76] in 66 patients. Conclusions To optimise treatment and survival rates from oesophageal carcinoma three main aspects must be addressed. Firstly, the discovery and treatment of early stage dis-

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This work was supported by a 'Paolo Baffi' study grant for surgical oncology of the Fondazione per la Formazione Onologica. Note Summaries of a number of ongoing studies and clinical trials, among them three phase three randomised controlled trial for oesophageal carcinoma of surgery vs. surgery plus neoadjuvant chemoradiation can be found on the internet under the National Cancer Institute's PDQ Clinical Trial (http://cancernet.nci.nih.gov/cgi-bin/ cancerform?Diagnosis=Esophageal+cancer&Phase=alt&Modality= alt&Sponsorship=alt&Drugs=&Protocol+ID=&City=&State= &Country=).

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Received 25 July 1997; accepted 3 March 1998. Correspondence to: J. G. Geraghty, MD, PhD Professorial Department of Surgery Nottingham City Hospital Hucknall Road Nottingham NG5 1PB UK