Optimizing Treatment of Carcinoma of the Esophagus and Gastroesophageal Junction

UPDATE ON SURGICAL ONCOLOGY IN EUROPE

1055-3207/01 $15.00

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OPTIMIZING TREATMENT OF CARCINOMA OF THE ESOPHAGUS AND GASTROESOPHAGEAL JUNCTION Toni Lerut, MD, PhD, Willy Coosemans, MD, PhD, Paul De Leyn, MD, PhD, Dirk Van Raemdonck, MD, PhD, Philippe Nafteux, MD, and Johnny Moons, RN

Cancer of the esophagus currently ranks ninth in the list of the most common cancers in the world. Although the incidence of squamous cell carcinoma seems to remain stable or even to decrease in some countries, adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) had the fastest rising incidence of all carcinomas in the Western world during. the 1970s and 1980s. It is estimated now that the incidence of adenocarFinoma of the esophagus increased by 5%to 10%per year during the 1980~.'~, 68 Overall prognosis of patients presenting with carcinoma of the esophagus and GEJ, however, continues to be poor as most patients present with advanced disease.59Indeed dysphagia, the main symptom, does not become apparent until about two thirds of the lumen has become obliterated. As a result the majority of patients have locoregional or distant lymph node metastasis and organ metastasis at the time of diagnosis. According to data from literature up to 80%of the patients have positive lymph nodes at the time of surgery.' Postsurgical locoregional recurrence is attributed to lymph node involvement in approximately 40% of cases.38Undoubtly lymph node involvement is the most important prognostic index in cancer of the esopaghus and GEJ with a dramatic negative impact on cure rate in patients with positive lymph nodes.' A second strong prognostic indicator besides lymph node involvement is the completeness of resection33(the Ro resection according to From the Department of Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium

SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 1 0 . NUMBER 4 . OCTOBER 2001

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LERUT et a1

the International Union Against Cancer-Tumor Node Metastasis classifi~ation).'~ The chances of achieving a complete tumor resection depend on the tumor location and the extent of tumor into surrounding tissues. Because of the absence of a serosa especially in the upper third and midesophagus, carcinoma often spreads into surrounding vital structures (e.g., pars membranacea of trachea and adventitia of the aorta) at the time of diagnosis. Surgical resection has been the mainstay of treatment over the past decades but systemic and local recurrences are common even after complete resection. Multimodality neoadjuvant and adjuvant regimens therefore are used increasingly in the management of these difficult tumors. But the reported results often are conflicting, revealing numerous shortcomings or unanswered questions. Optimizing treatment of cancer of the esophagus and GEJ remains a challenging task and has to come from a more precise and individualized strategy for each patient. Such a therapeutic strategy is to be based on the precise location and staging of the tumor, an indepth knowledge of relevant prognostic and risk factors for each individual patient, and awareness of potential benefits and side effects of different therapeutic options individually or when used in combination. OPTIMIZING STAGING Occasionally medical history and clinical examination may reveal presence of distant metastasis (e.g., lymph node involvement) in the cervical region. But mostly, staging has to rely on technical examinations. Today a wide variety of investigative techniques are available: barium swallow, endoscopy, biopsy, computed tomography (CT), MR imaging, ultrasound, echoendoscopy (EUS), positron emission tomography, staging laparoscopy,thoracoscopy, and bronchoscopy. CT of the chest and abdomen and EUS have become the most useful and most widely used methods to assess locoregional extent of the tumor and lymph nodes and possible presence of organ metastasis. Both methods, however, have their limitations. CT images are considered to have an accuracy of approximately 80%for assessment of aortic invasion. Suspicion of tracheobronchial invasion is based on displacement or distortion of the posterior wall of either trachea or bronchi with 75%to 90% accuracy. Prospective comparative studies have questioned seriously the value CT because the T factor was overestimated in many cases.34In - .of .iiy an anaiysls Rosch of 367 paiients wi?;hesop!7=~n~!-z-.-:nn--f ---h racy in staging the T and N parameters was 58% and 54%, re~pectively.~~ As far as M parameters are concerned a prospective study on the value of CT by Watt et a1 on 90 patients with cancer of the esophagus and GEJ indicated a sensitivity of 56% for liver metastasis and 22% for peritoneal carcinomat~sis.~~ The introduction of spiral CT certainly offers better possibilities in detecting smaller nodules in lung and liver but sensitivity in detecting lymph nodes remains low. In a prospective study assessing the value of LLy,b..A

*L-*

:<:LLcn n . ~

A.V----,m

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PET scan against CT and EUS Flamen et alZ6found a sensitivity of only 22% for CT for lymph node detection. Magnetic resonance gives similar information to that obtained by CT concerning tumor extent and involvement of surrounding structures48 and is therefore not considered as a tool for routine investigation. Diagnostic accuracy of EUS is superior to CT but is more operator dependent. EUS is limited by its inability to evaluate nodules distant from the esophageal wall or behind air-filled structures (e.g., trachea). EUS is especially valuable in assessing the transmural extent of the tumor provided the tumor can be passed, which may be the case in T, and T, tumors in up 6% to 37% of patients.", *'' 87, 98 Moreover conventional EUS is not able to discriminate between TI, and Tlb, which may be of therapeutic relevance. The recent introduction of miniaturized EUS probes has increased the rate of tumors that can be passed and therefore successfully assessed. EUS examination with high frequency probes (20 MHz) allows one to evaluate more accurately the different layers of the esophageal wall. The addition of vital staining methods2' and photosensiti~ers~~ is helpful in increasing the accuracy in detecting early carcinoma. As for the lymph node involvement EUS accuracy varies between 69% and 88% (Table 1). In the prospective study by Flamen et alZ6EUS accuracy was 85%, sensitivity 63%, and specificity 88%. EUS sensitivity was lowest for regional and distant lymph node metastasis, specificity lowest for local lymph node involvement. To overcome the difficulties in differentiating between benign and malignant nodes, EUS-guided biopsy was used by Hunerbein et a136in 50 patients with upper gastrointestinal tract lesions (pancreatic tumors (n = 26), submucosal (n = 5) or stenotic tumors of the esophagus (n = 4), and mediastinal lesions (n = 15)). Fine needle biopsy guided by EUS was successful in 44 patients. The sensitivity and specificity of EUS-guided biopsy were 88%and loo%, respectively. Further refinement in staging can be obtained by the use of ultrasonographic evaluation and fine needle cytology of the cervical lymph nodes, which are known to be frequently involved (up to 30% in carci~ ~ , ~et~ investigated 174 patients using noma of the e s ~ p h a g u s ) .Doldi a 7.7 or 10 MHz transducer. Eighteen (10.3%)patients were found to have metastatic cervical nodes at ultrasonographic examination. In 17 (94.4%),

Table 1. DIAGNOSTIC ACCURACY OF ENDOSCOPIC ULTRASONOGRAPHY FOR T AND N PARAMETERS IN PATIENTS WITH ESOPHAGEAL CARCINOMA

No. Patients

Accuracy T Parameter (%)

Accuracy N Parameter (%)

866

LERUT et a1

diagnosis was confirmed by fine needle biopsy, confirming a high sensitivity and diagnostic specificity. A most recent acquisition in staging is PET scan using 18-fluorodeoxy glucose (FDG). Kole et aP4 studied 26 patients. The primary tumor was visualized in 96%.Nodal status was correctly assessed and distant metastases were found in eight patients. Flamen et alZ6studied 74 patients. PET scan had a higher accuracy in detecting stage IV disease as compared with the combined use of CT and EUS (82%versus 64%, P = 0.004) mainly by the virtue of a superior sensitivity (74% versus 47%, respectively). PET upstaged correctly 15%from Mo to MI disease that otherwise would not have been recognized by other staging methods. In another study Lerut et aP2 compared the value of PET versus CT-EUS for staging of lymph nodes. Forty two patients entered the study. The gold standard consisted exclusively of histology from sampled lymph nodes either obtained by extensive two-field or three-field lyrnphadenectomies (n = 38) or from guided biopsies of suspected lymph nodes only detected by PET scan (n = 4). The accuracy for distant lymph node metastasis (M+Ly) was significantly higher for PET compared with the combined use of CT-EUS (86%versus 62%,P = 0,0094). This was based on a higher specificity (90% versus 69%, P = 0.0412) and higher sensitivity (77% versus 46%, P = not significant) of PET. Five patients were correctly upstaged from N1, stage to a MfLystage and six patients were correctly downstaged from a M+Ly stage to a NO-1-2 stage. (Table 2). Only one patient was downstaged falsely. It was concluded that PET improves the clinical staging of lymph node (LN) involvement based on increased detection of distant LN metastases and a superior specificity as compared with the conventional imaging modalities. In recent years numerous studies have addressed the molecular biology of cancer of the esophagus and GEJ (i.e., the mechanisms underlying the deregulation of cell proliferation, cell differentiation, and cell death [apoptosisl). Such mechanisms include mutations in oncogenes and tumor suppressor genes (e.g., p53), ploidy and aneuploidy, growth

Table 2. PREOPERATIVEASSESSMENT OF LYMPH NODE INVOLVEMENT CT+EUS*

FDG-PET

P-Value

Sensitivity NI-2 K

"'+iy

Specificity NI-2

M+L~ Accuracy N1-2

M+, -

-

-

-

CT+EUS = combined computed tomography (CT) and endoscopic ultrasound (EUS); FDG-PET = flourodeoxyglucose (FDG)-positron emission tomography (PET); NS = not significant. * EUS includes only patients in whom complete passage of the primary tumor was possible.

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f a c t ~ r , adhesion ' ~ ~ ~ ~ molecules (e.g., E-cadherin, CD44),73DNA repair, inbone marrow metasta~is:~and so forth. cidence of micrometa~tasis,?'~ Although the general framework is well defined the insights in the true sequence of genetic alterations remain fragmentary. As a result the data on prognostic impact from molecular biology are still controversial and not useful yet for staging purposes. PROBLEMS OF CURRENT CLINICAL STAGING METHODS Despite these improvements in staging a number of important questions with clinical relevance remain unsolved. Although CT scan, EUS, and PET scan have improved the accuracy of clinical staging of esophageal cancer over the last two decades, important problems remain to be solved. Classical staging techniques lead to overstaging in as many as 25% to 36% of patients9~'2~48~60~75 with the potential risk of denying these patients their chance for possibly curative surgery and exposing them to the risk of tumor progression during what might be an unnecessary induction therapy. A histologic proof (i.e., by EUS-guided fine needle aspiration, biopsy by laparoscopy, or thoracoscopy) is therefore required whenever imaging techniques suggest lymphatic or organ metastasis. Inadequate assessment of tumor depth remains a problem in some 20% of patients with superficial tumors. The inability to reliably assess the difference between TI, in Tlb tumors16 still makes patient selection for nonradical treatment modalities such as endoscopic mucosectomy or photodynamic therapy very difficult because Tlb tumors are found to have lymph node involvement in up to 50% of reported series.64This lymph node involvement usually is rather limited and more locoregional and thus these patients are better candidates for surgery with curative option. Current imaging techniques for lymph node assessment are unreliable for the estimation of the global number and mapping of positive nodes especially for nodes localized off the esophageal wall. Because the total number of involved nodes or data such as the ratio involved/total nodes and the localization of positive nodes with respect to the tumor may have important implications on prognosis, these aspects need a better preoperative assessment. As long as accurate staging can only be obtained by surgical radical lymphadenectomy, patient selection for multimodality treatments and the assessment of their outcome remains unreliable. Moreover many of these newer techniques are not available in many centers causing difficulties in comparing results of clinical staging on an international level. Staging laparoscopy and thoracoscopy have been shown to be superior to EUS mainly because of a better assessment of nodes with a diameter of less than 1 cm and its ability to stage obstructive tumors precluding the passage of an EUS probe.45,53,91 But the drawback is the costly and time consuming aspect with a specific morbidity and maybe the potential for port-site metastasis. Its use should be restricted to situations where a positive finding will have a direct therapeutic impact (i.e., a more accurate patient selection for multimodality treatment protocol^).^^

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LERUT et a1

OPTIMIZING THERAPY Surgery

A complete resection (Ro) is the goal of any surgery aiming for cure. With improvements in surgical technique and advances in perioperative care, postoperative hospital mortality and morbidity have substantially decreased over the last two or three decades. Anastomotic leaks occur in 5% to 10%but rarely result in fatal septic complications especially if anastomosis is performed in the neck. Peracchia in a multicentric survey among a number of European centers of high volume referrals reported a substantial decrease in mortality from 14.1%before the 1980s to 6.2% after 1990.70Today many centers report hospital mortality figures well below 5% by applying well-established risk criteria to excIude high risk patients from surgery.13 Much debate persist on extent of resection and lymphadenectomy. A number of authors consider lymph node involvement as a marker of systemic disease and for them the systematic removal of lymph nodes is believed to be of no benefit. Therefore, and to minimize surgical trauma, transhiatal esophagectomy is mostly preferred with a cervical esophagastrostomy to restore continuity. OrringeF7 reported a 5-year survival of 63% in patients with the tumor confined to the submucosa. For stage 111 and IV the survival dropped to 12% and 16%, respectively, after transhiatal esophagectomy. Vigneswaran et alg3using transhiatal esophagectomy reported an overall survival of 20.8%. Others believe that in patients with positive lymph nodes the natural course of the disease can be influenced positively by wide peritumoral resection and extensive lymphadenectomies, mostly using a transthoracic approach. Japanese authors have been adding bilateral cervical lymphadenectomy,' the so-called third field, in an attempt to further improve survival and cure rate. In many studies, however, the extent of esophagectomy and lymphadenectomy has been defined poorly. Only recently has an agreement on the anatomic classification of the different extents of lymphatic dissection for cancer of the thoracic esophagus been reached.28 Undoubtly more extended surgery has resulted in optimizing the accuracy of final staging of the disease. Akiyama studied the lymph node metastasis pattern in a series of 290 patients.' According to the location of the tumor (upper, middle, or distal third of the esophagus) cervical ? --A,. :-~ 1--------L ,.,.,... in 46.3%)2a,241n,2nd 27% while inlYlllrll V,i;i~ci::el:L :.:.== 3cz1: volvement of abdominal lymph nodes was 12.2%, 39.9%, and 74%, respectively. Moreover involvement of distant lymph nodes regardless of tumor location was unpredictable because of the high incidence of skip metastasis. The most important question to be answered is whether such more radical dissection really contributes to improvement of survival. Japanese authors have been focusing mostly on the value of two-field versus threefield dissection constantly reporting an advantage in favor of three-field -7--

--

llVUC

.T--

LIL

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lyrnphadenectomy whether comparing the results in relation to overall survival, nodal status, T status, or stage grouping.39,40,61,ss,97 Ud agawaE8 comparing three-field versus two-field lyrnphadenectomy reports 5-year survival rates of 100%versus 59% for stage I, 84%versus 58%for stage 11, 32%versus 24% for stage 111, and finally 25% versus 14%for stage IV disease. In the Western World the attention traditionally has been focusing more on two-field (i.e., mediastinal and superior abdominal compartment) lyrnphadenectomy versus more limited lymphadenectomy. Lerut et a151 compared in a retrospective study the results between patients who underwent a radical intervention with two-field lymphadenectomy and those who underwent less radical interventions. There was a statistically significant difference in favor to the more radical resection and lyrnphadenectomy (P = 0.002) with a one year survival of 90% and 72%; 2 years 81% and 46%; and at 5 years 48% and 41%. Repartition of TNM staging was the same in both groups. Similar results have been reported by different Western authors after two-field lymphad~nectomy.~~, 30, 78, In his European multicenter survey Peracchia reported an increase in 5-year survival from 17% before 1980 to 38.5% after 1990 in patients who underwent an l& resection with two-field lymphadenectomy. This figure clearly is superior to the figures generally reported after standard resection without lyrnphadenectomy and which are mostly below 25%70 (Figs. 1,2, and 3).

-

-+ Barrett

--a-

(n=63) GEJ (n=94) Esophagus (n-198) 58%

Years Figure 1. Overall survival after primary resection for carcinoma of the esophagus, gastroesophageal junction (GEJ), and Barrett.

-m-

Stage 1 (n=23)

---A-

Stage 2A+2B (n=46) Stage 3 (n=75)

- me--

Stage 4 (n=54)

Years Figure 2. Survival curves according to Tumor Node Metastasis (p) TNM (1987) staging in carcinoma of the esophagus.

90%

90%

-+- Stage l(n=13) Stage ll (n=13)

---fr-- Stage Ill (n=28) ---+-Stage lV (n=40)

28% 1

U

.

U

1

28%

1

Y

Y

Years Postoperatively

U

Y

P < .005

Figure 3. Survival curves according to pTNM (1987) staging in carcinoma of the GEJ.

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Experience with three-field lymphadenectomy in the Western World is rather limited but from our own experience and others it becomes clear that adding the third field is not only changing final staging but also resulting in improving prolonged tumor-free s u r ~ i v a l .A~ recent , ~ ~ analysis has been made in our institution on the results of patients operated between 1996 and 1999 for adenocarcinoma of the distal third of the esophagus (Type I), adenocarcinoma of the GEJ (Type II), and adenocarcinoma of the subcardia (Type 111). The best results are obtained in adenocarcinoma of the distal third with a 4-year survival probability of 57.3% in R, resection. The worst results are seen in tumors of the subcardia because almost all patients were in advanced stage of the disease at the time of treatment (Figs. 4-7). It is interesting to note that in Ro resection with adenocarcinoma of the GEJ three-field lymphadenectomy showed a clear advantage (P = 0.028) (Fig. 8) over two-field lymphadenectomy in patients with a follow-up of at least three years. None of these patients received either chemo- or radiotherapy pre- and postoperatively. In the group of three-field patients three patients were in stage 111,, five in stage IV (M+Ly). In the group of two-field patients one patient was in stage I,,, six in stage 111,, one in stage IIIb, and 4 in stage IVb (M+Ly). From all the data coming from these reports on more extensive lymphadenectomies it seems that the lymph node ratio between involved and all removed lymph nodes is constituting a strong prognostic factor and a

Months

Figure 4. Overall cancer specific survival curves after Ro, R,, R, resection in adenocarcinoma of the distal third (Type I), GEJ (Type II), and subcardia (Type 111) 1996-1999.

-

-Distal

113 OVERALL (n =90)

oistal 113 R 0 (n = 82)

- - u - Distal 113 R 1 (n = 6) ~

0

12

24

36

48

Months

Figure 5. Survival curves after Ro, R1, RP resection in distal third (Type I) adenocarcinoma 1996-1 999. TNM 1997.

Months

Figure 6. K.U. Leuven. Survival curves after Ro, R1, R2 resection in adenocarcinoma of the GEJ (Type 11). TNM 1997.

872

CARCINOMA OF THE ESOPHAGUS AND GASTROESOPHAGEAL JUNCTION

I

873

S u b c a r d i a OVERALL (n = 21)

-1, 0

12

24

36

48

Months Figure 7. K.U. Leuven. Survival curves after Ro, R1, R, resection in adenocarcinoma of the subcardia (Type Ill). TNM 1997.

Figure 8. Adenocarcinoma of the GEJ (Type 11) 1996-1 997. Survival curves after three-field versus two-field resections with a minimum follow-up of 3 years.

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LERUT et a1

ratio of more 20% seems to equal very poor survival.74And thus only patients with a limited number of involved nodes may benefit from (extensive) surgery. Unfortunately for the time being the only way to have an exact idea about this lymph node ratio is to extensively remove all lymph nodes for final pathologic examination. The major drawback on the subject of lymphadenectomy is the lack of definitive evidence from randomized trials. Only one randomized study by Kato et a14' compares the value of two-field versus three-field lymphadenectomy. In this study the 5-year survival after three-field dissection was 48.7% versus 33.7%for two-field. A criticism of this study was the difference in patient characteristics between groups.'O There is also controversy about the optimal route and extent of resection for adenocarcinoma of the distal esophagus and GEJ. This controversy is mainly fuelled by different opinions regarding lymph node involvement. According to Siewert lymph flow in carcinoma of the distal esophagus and GEJ is mainly directed downwards towards the lymphatic nodes around the coeliac axis. In his analysis lymph node metastases were rarely found in the paratracheal, subcarinal, or midthoracic paraesophageal lymph nodes. As a result the Munich group using a wide incision in the diaphragm favors a radical transhiatal lymphadenectomy and en bloc lymphadenectomy of the distal posterior mediastinum and upper abdominal ~ompartment.~~ Our own data analysis from transthoracic resection especially in the more advanced T3N+ stage shows a high incidence of lymph node involvement around the subcarinal and aortopulmonary region (27%) in both adenocarcinoma of the distal esophagus and GEJ.50,86 Moreover systematic resection of the thoracic duct, hard to perform through a transhiatal approach, showed in this subset of patients lymphatic involvement in up to 50% of the distal esophagea150tumors. Adding the so-called third field (i.e., a bilateral cervical lymhadenectomy) showed a 35% and 20% unforseen lymph node involvement for distal esophageal and GEJ T3N+ tumors, respe~tively.~~ Early Carcinoma

Especially in Barrett's carcinoma in many patients diagnosis will be made in an early stage because these patients are followed as part of ..* a survcii;afice prc;g-am. if detecCcn is oze obviousi-~.?rtn:t r -- ----- f z r tor for a favorable outcome complete removal is the second proven pillar contributing to the cure of the disease. Much debate has risen on the treatment modalities of carcinoma confined to the mucosa, i.e., high grade dysplasia-TI tumors. Endoscopic ablation by laser technology or by endoscopic mucosectomy has been advocated The rationale for this approach is based on the fact that in high grade dysplasia (carcinoma in situ) there is no lymphatic invasion, while lymph node metastasis in intramucosal (TI,) carcinoma is uncommon.32

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As a consequence reported 5-year survival for high grade dysplasia and intramucosal carcinoma is ranging between 90% and 100% both after endoluminal mucosectomy or after esophagectomy. Proponents of esophagectomy, however, argue that in patients with documented high grade dysplasia invasive adenocarcinoma is present in other areas of the metaplastic mucosa in approximately 50% of the cases when analyzing the resected ~pecimen.~, 69, 71 For this reason most surgical groups advocate esophagectomy in medically operable patients presenting with high grade dysplasia. A second critical issue is whether intramucosal (TI,) carcinoma can be correctly discriminated from submucosal tumor (Tlb)before surgery. Certainly 20 mHZ echoendoscopes can be helpful to solve this problem but these endoscopic ultrasonographic systems are not available in most centers6' Using conventional EUS a recent analysis of 11 EUS-diagnosed Tis-TI Barrett tumors at our institution revealed 6 Tlb tumors on final postresection pathology. The importance of the inability to discriminate TI, from Tlb tumors relates to the reported incidence of 25% to 50% lymph node involvement in Tlb tumors. Mostly the number of involved lymph nodes is rather limited in this subset of patients and most surgeons argue that this group of patients is benefiting most from surgery with curative intent. In an effort to minimize further the surgical trauma in early (TI)adenocarcinoma in Barrett's esophagus, Stein et a1 reported their results on limited resection and reconstruction by interposition of an isoperistaltic pedicled jejunal segment. At 15 months median follow-up there were no recurrences or death from cancer.85But this study was criticized for the inaccurate staging of TI, versus Tlb and therefore doing a too limited operation in Tlb patients and a too aggressive operation in TI, patients. MultimodalityTreatment In the advanced stages I11 and IV long-term survival is very much dependent on the possibility of achieving a R, resection and the number of involved lymph nodes. Difficulty in achieving this goal is the rationale for using induction regimens aiming at an increased I& resection rate and systemic effect of chemotherapy with prolongation of survival, eventually cure in the subset of responders. Other attempts to improve results of surgery have been made by using adjuvant (postoperative)regimens. Most attention has been focused on preoperative neoadjuvant therapies. The potential advantage of such an approach includes increasing the rate of curative resection by tumor downstaging, earlier treatment of micrometastasis,and decreased risk of tumor seeding at operation. The first attempts with multimodality regimens have made use of radiotherapy. Five randomized trials compare preoperative radiotherapy followed by surgery with surgery alone. None of these could demonstrate an improvement in resectability or overal s ~ r v i v a l .65,95 ~ ~A' meta~~~~~ analysis using updated patient series failed to show a survival benefit from preoperative radiotherapy7

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Several trials using preoperative chemotherapy mainly based on cisplatinum and 5-fluorouracil (5-FU) demonstrated a response rate in 45% to 70%.5, n.25'37, 43,56,77 Randomized trials comparing chemotherapy plus surgery with surgery alone, however, showed no improvement in survival except for complete responses seen in 5% to 10%of the patients. A meta-analysis of published randomized trials again showed no survival benefit from cisplatinum-basedchemotherapy in esophageal carcinoma.14 In addition, the large intergroup 0113 Trial randomizing 467 patients with resectable squamous cell and adenocarcinoma of the esophagus could not indicate any benefit in resectability and median and 3-year survival. The UK MRC OE 02 of 801 patients with resectable squamous cell carcinoma has recently been completed comparing cisplatinum-5-FU (2 cycles) plus surgery versus surgery alone. The early results indicate a significantly higher curative resection (Ro)rate of 84%versus 71% in favor of the multimodality arm with a consequent survival benefit at 2 years of 45% versus 35%. From this trial little is known about the difference in diagnostic approach and surgical techniques used in the different participating centers, which may result in an important bias. Because of the relatively modest response rate and the lack of evidence of any overall survival benefit much attention is now focused on the use of preoperative cisplatinum-5-FU based chemotherapy combined with radiotherapy (CTx/RTx). Early studies have demonstrated the much higher complete pathologic response rate (pCR)27,49,84 in patients treated with CTx/RTx plus surgery, higher than would be the case after preoperative chemotherapy or radiotherapy on its own.25,37 As a result many studies on the use of preoperative RTx/CTx have been published. Most of these studies are using a combination of 5-FUcisplatinum and 30 to 40 Gy radiation. Complete pathologic response rates are seen in as many as 40%of the patients but not seldom at a price of increased morbidity and mortality exceeding 20% in some of these studies. Patients with pCR consistently live longer than those who do not achieve pCR with survival rates at 3 years ranging from 29%to 92%. On top of these results there are presently six trials comparing preoperative chemotherapy and radiotherapy followed by surgery with surgery alone in resectable esophageal cancer (Table 3).6,17,47, 65, 89, 94 These trials confirm with one exception that there is no benefit in resectability nor in overall survival, but patients showing pCR seem to do better. The so-called Irish did show a significant survival benefit for the combined arm of 32% versus only 6% in the surgery-alone arm. This . .. irLai iias beei-, severely ci.iti&ed, hewever, becauseof poorselection criteria and a surprisingly low survival rate for the surgery-alone arm, much lower than the historical survival figures for surgery from that same group. The Bosset trial17had a significantly longer disease-free survival rate in the multimodality arm (40%versus 28%)at 3 years but there was no difference in overall survival rate (36% versus 34%)at 3 years. This discrepancy was explained by a 12%mortality rate in the multimodality arm versus 4%in the surgery-alone arm.

Table 3. RANDOMIZED TRIALS OF INDUCTION CHEMORADIOTHERAPY IN OPERABLE CANCER OF THE ESOPHAGUS AND GASTROESOPHPAGEAL JUNCTION Histology Reference

Year

No. of Patients

SCC

Adeno

Resection (%)

pCR (%)

Operative Mortality (%)

3-Year Survival (%)

Nygaard et a16' CRT+surgery Surgery alone Le Prise et a147 CRT+surgery Surgery alone Apinop et a16 CRT+surgery Surgery alone Walsh et a194 CRT+surgery Surgery alone Bosset et all7 CRT+surgery Surgery alone Urba et aIa9 CRT+surgery Surgery alone SSC = squamous cell carcinoma; Adeno = adenocarcinoma; pCR = pathologic complete response; CRT = chemoradiotherap; NS = not stated

p

878

LERUT et a1

These mixed and often conflicting results are the consequence of differences in patient selection and patient characteristics, and differences in treatment modalities (dose, dose fractionation, timing, and so forth). Nevertheless many centers have adopted a policy of administring CTx/RTx mostly in locally advanced carcinomas (i.e., clinical T4 carcinoma). Van Raemdonck et a1 studied 42 patients presenting with clinical TQ lesions who had been treated with CTx/RTx preoperatively. Twenty percent showed complete remission at time of resection. The 4-year survival of this subset of patients is 63%and for the remaining patients who underwent resection 20% (Fig. 9).92The price to pay, however, was a substantial increase in morbidity although this did not affect mortality. A number of studies have shown that CTx/RTx in higher dose without surgery may result in similar survival rates as those obtained with surgery alone,2.'9,31,42,72,82 questioning the need for surgery at all as primary treatment for cancer of the esopahgus. It seems, however, that the local recurrence rate is much higher at 40% to 60%.This is because of the impossibility of assessing whether patients presenting with a potential pCR truly have no more remaining viable cancer cells in the mucosal esophageal wall. Detecting complete response is major challenge. The correlation between pathologic staging and accuracy or response assessment by barium swallow, CT scan, and EUS is very low. In this respect PET may offer promising perspectives through its interaction with the cell metabolism. Experiments have shown that the intensity of FDG accumulation after chemo- or radiotherapy is strongly related to the number of residual viable tumor cells.76 100 I

80

89%

Complete Response (pTONOM0)

89%

P < .05

(n=9)

67%

40

49% 31%

21%

Months after Treatment Figure 9. Survival curves according to response after induction chemoradiotherapy followed by surgery in clinical T4tumors.

CARCINOMA OF THE ESOPHAGUS AND GASTROESOPHAGEAL TUNCTION

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In our institution the value of PET scans in assessing induction therapy response was evaluated in a series of 37 patients with clinical T, treated with preoperative CTx/RTx. Postinduction PET scan was compared with findings at pathologic examination. Overall accuracy of PET for the assessment of CTx/RTx response was 78% (28 of a patient base of 36). A pCR was found in 6 patients (17%).The sensitivity and positive predictive value of a completely normal PET for the diagnosis of pCR was 67% and 50%. The study, however, demonstrated a strong correlation between the CTx/RTx response as assessed by PET and survival, the median survival of PET responders being 16.3versus 6.3 months for the nonresponders. Twenty-five patients showed on the pre CTx/RTx PET scan positive regional or distant lymph node involvement. Six patients of this subgroup had a PET response with a median survival of 16.7 months versus only 5.9 months in patients with no PET response. This finding raises the question of the value of post CTx/RTx esophagectomy with curative intent in this subset of patients. Therefore these findings may provide a good basis for further research on using PET as a tool for prediction of response more early during preoperative CTx/RTx. This could allow one to avoid unnecessary morbidity and further tumor progression, perhaps offering better chances by proceeding directly to surgery in some selected cases. Finally as to the value of postoperative adjuvant therapy, few data are available. The randomized studies could not reveal any difference between patients receiving cisplatinum-based chemotherapy and those who did not after primary surgery.

SUMMARY

Overall prognosis of patients with carcinoma of the esophagus and GEJ remains poor in a majority of patients despite marked advances in diagnosis, staging, and surgical therapy during the last decades. Surgery remains the mainstay of primary treatment with cure rate now exceeding 30%. A majority of patients, however, will die from locoregional and distant metastasis. Therefore much attention has been paid to multimodality regimens. Data from the literature, however, are conflicting and it seems for potentially resectable tumors little or no survival benefit is to be expected. In the locally advanced tumors the combination of induction chemotherapy and radiotherapy is resulting in a complete response in a substantial number of patients. It is this subset of patients that seem to benefit in terms of survival and cure. Unfortunately there is a lack of predictive factors allowing one to identify a response of induction therapy. Perhaps PET scans, through their interference with cell metabolism, will offer better perspectives not only in more precise staging but also as a predictor of response in the early phase of induction therapy.

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Further research also needs to focus on identification of responders using molecular biology. In early carcinoma the value of endoscopic mucosal ablation and photodynamic therapy needs to be further elucidated. Prospective randomized trials should focus on role, extent, and timing of different therapeutic regimens using better standardized protocols including more standardized surgical techniques and pathologic examination. Finally, other therapeutic alternatives (e.g., hyperthermia, immunotherapy, postoperative adjuvant therapy) require further attention. ACKNOWLEDGMENT The authors wish t o thank Ulas Bitter for his help in reviewing the patient material.

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