14 Applications in Esophageal and Gastric Cancer
Frank Zimmermann and Björn L. D. M. Brücher
F. Zimmermann, MD
Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany
B. L. D. M. Brücher, MD
Department of Surgery, Klinikum rechts der Isar der Tech- nischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany
14.1
Esophageal Cancer
14.1.1 Introduction
Esophageal cancer has been regarded traditionally as an aggressive malignancy with an increasing incidence of squamous cell cancer in developing countries due to increasing consumption of alcohol and tobacco during the last decades (odds ratio of 23.1 when both risk factors are present) (Lagergren
et al. 2000), and an even more pronounced rise of adenocarcinoma of the esophagogastric junction in the western world mainly caused by reflux disease.
For both entities, there is a poor outcome in all advanced stages. While surgical resection or defini- tive radio- or radiochemotherapy (RCT) may be cur- ative with better long-term outcome in early stage cancer, most patients with symptomatic esophageal cancer die within 3 years after diagnosis, in spite of complex treatment concepts. Therefore, continued clinical research is justified, including the evalua- tion of more aggressive neoadjuvant and adjuvant treatments as well as an improvement of combined RCT.
14.1.2
Epidemiology and Staging
Squamous cell cancer is the predominant histology in esophageal malignancies, with a heterogeneous worldwide pattern: regions with a very high inci- dence of up to 200 new cases per 100,000 inhabit- ants are in Iran, southern Russian republics, South Africa and central areas of China. In Europe and America, the incidence is approximately 6.6 per 100,000 residents, with male persons being affected five times more frequently than females, and a mor- tality of 6.1/100,000 (ESMO Guidelines 2005). Most patients are older than 30 years, with a median age of 65 years (Bareiss et al. 2002). Unfortunately, esophageal cancer is usually detected in advanced stages, with 70 % of all new cases being stage III or IV. Therefore, the 5-year survival rate of all patients is not higher than 5% (Bareiss et al. 2002).
Adenocarcinoma of the pericardial area (adeno- carcinoma of the esophagogastric junction, AEG) is the second most common cancer of the esopha- gus, and the most common one below the tracheal carina. It is subdivided into three groups, depend- ent on the relation to the cardia: AEG I from 5 cm to 1 cm cranial of the cardia, with a behavior similar to squamous cell cancer of the distal esophagus – and
CONTENTS
14.1 Esophageal Cancer 197 14.1.1 Introduction 197
14.1.2 Epidemiology and Staging 197 14.1.3 Anatomy and Tumor Spread 198 14.1.4 Therapy 198
14.1.4.1 Principles and Strategies 198 14.1.4.2 Radio- and Radiochemotherapy 199 14.1.4.3 Resection and Multimodal Concepts 201 14.1.4.4 Conclusion 207
14.2 Gastric Cancer and Adenocarcinoma of the Esophagogastric Junction (AEG II and III) 207
14.2.1 Introduction 207
14.2.2 Preoperative Treatment 207 14.2.2.1 Preoperative Radiotherapy 207 14.2.2.2 Preoperative Chemotherapy 207 14.2.2.3 Preoperative Radiochemotherapy 208 14.2.3 Intraoperative Radiotherapy 209 14.2.4 Postoperative Treatment 209 14.2.4.1 Postoperative Radiotherapy 209 14.2.4.2 Postoperative Chemotherapy 209 14.2.4.3 Postoperative Radiochemotherapy 210 References 211
therefore integrated into the sections on esophageal cancer – and AEG II and III, located in the cardia and from 2 cm to 5 cm distal of the cardia, respec- tively, mentioned in sections on gastric cancer.
14.1.3
Anatomy and Tumor Spread
The classification of esophageal cancer into sub- groups depends on the location of the cancer and the resulting therapeutic procedure: cancer of the cervical part, intrathoracic cancer with close rela- tion to the tracheobronchial tree, or infrabifurcal cancer, with the latter usually being resectable even in locally advanced stages. The former should be offered a multidisciplinary concept, in principle, with neoadjuvant chemo- or radiochemotherapy dependent on the histology and local growth, or definitive combined RCT.
The second, more historical classification into two subgroups – cervical and intrathoracic cancer – was based on the surgical approach and the dis- tribution of the lymph node involvement, but does not reflect the problems of R0 resection in all tumors close to the tracheobronchial tree, and the resulting multidisciplinary aspect.
The most important prognostic factor is the tumor stage (Daly et al. 1996), or local tumor spread – infiltration of the mediastinum, tracheo- bronchial tree, and pericardium – and the infiltra- tion of locoregional lymph nodes, with the latter being present in 5% of mucosal carcinoma, in 30%
of submucosal cancer, and in even more than 80%
of tumors extending beyond the esophagus (Hosch et al. 2001), causing about 40% of all local tumor recurrences.
Cancer of the upper third of the esophagus usu- ally infiltrates the cervical and mediastinal lymph nodes, whilst tumors of the middle third mainly spread to the mediastinal and upper perigastric lymph nodes, and carcinoma of the lower third to the lower mediastinal and abdominal lymph nodes. The distribution of lymph node infiltration has major implications on the target volume of both definitive and preoperative radiotherapy, and should be taken into account when customizing the radiation portals. Intraesophageal spread of tumor cells in submucosal lymphatics influences the target volume, too. Its likelihood increases from 4% in pT1 tumors to 30% in pT4 tumors. It should be noted that a metachronous or even syn- chronous secondary cancer of the upper aerodiges-
tive tract can occur in up to 10% of patients, which will have a major impact on treatment decision.
The classification of esophageal cancer follows guidelines by the UICC, recently actualised in 2002 (UICC 2002) (Table 14.1) and influences the treat- ment decision as well the prognosis: in an analy- sis of 4329 patients with esophageal cancer 5-year survival rates were 42% in stage I, 29% in stage II, 15% in stage III, and only 3% in stage IV (Daly et al. 1996). Besides tumor stage, the oral and aboral resection status (R classification) has a prognostic value, too, with a R0 resection being the primary goal of the surgeon (Hermaneck 1999). In recent years, a lot of different molecular markers have been evaluated regarding their prognostic impact, but none of them is established in clinical routine (gene aberration, transcription factors, apoptotic mechanisms, etc.).
An optimal and individual treatment decision is based on precise staging of the tumor: the depth of infiltration is evaluated by endoscopic ultrasound and the infiltration of adjacent organs by computed tomography (CT) and bronchoscopy. Further stag- ing procedures depend on clinical symptoms and are not recommended on a routine basis. Magnetic resonance imaging (MRI) of the mediastinum has failed to show a higher accuracy than CT to detect mediastinal infiltration, and is therefore not rec- ommended (Korst and Altorki 2004).
14.1.4 Therapy
14.1.4.1
Principles and Strategies
Esophageal cancer is a curable disease and the
treatment decision is based on tumor extension,
comorbidities and individual decision of the
informed patient. Whilst esophagectomy is usually
offered in early stages (uT1–2), both radical resec-
tion and combined RCT are standard procedures
in locally advanced cancer (uT3). For tumors with
close contact to the tracheobronchial tree preoper-
ative RCT is used by a number of centers. To define
the best individual concept, exact knowledge about
the functional operability, organ function (liver,
kidney, heart, lung) and expected tolerance to
radio- and/or chemotherapy is essential. Contin-
ued alcohol consumption, reduced general condi-
tion (Karnofsky performance status < 70), exces-
sive weight loss, and altered renal, hepatic, and/or
lung function are contraindications for aggres- sive treatment, regardless of whether resection or simultaneous RCT is considered (Law et al. 2004).
A risk score combining respiratory, hepatic, and cardiac function, as well as general condition of the patient, helps to create three classes of patients with regard to 30-day postoperative mortality: 3.6% in the low (11–15 points), 8.7% in the medium (16–21 points), and 28% in the high risk group (22–23 points), respectively (Bartels et al. 1998). It seems advisable not to offer multimodal concepts or even the procedure of esophagectomy to patients of the latter risk group. Optimal supportive care (per- cutaneous endoscopic gastrostomy, feeding tubes, etc. in patients with weight loss of more than 5%
within the last 3 months) is very important and should be started immediately after diagnosis.
14.1.4.2
Radio- and Radiochemotherapy
14.1.4.2.1 Radiotherapy
In principle, tumors of the esophagus are radio- sensitive, but usually high doses are necessary to produce remission rates of about 80% (54–60 Gy in conventional fractionation, or 39 Gy in hypofrac- tionated palliative regimens with doses of 3 Gy per fraction). Despite good palliative effects, long-term survival is dismal with 2-year survival between 4%–
27 % and 5-year survival rates below 15% (Badwe et al. 1999). To obtain long-lasting local tumor control, radiation doses might be increased by endoluminal brachytherapy or by shortening the overall treat-
Table 14.1. TNM stages [classification of the UICC (2002)]
TNM classification of esophageal cancer T stage
T1 Lamina propria, submucosa
T2 Muscularis propria
T3 Adventitia
T4 Adjacent structures and organs
N stage (regional lymph nodes)
N1 Regional
M stage (distant metastases) For tumors of the lower esophagus
M1a Coeliac lymph nodes
M1b Other distant metastases
For tumors of the upper esophagus
M1a Cervical lymph nodes
M1b Other distant metastases
For tumors of the middle thoracic esophagus
M1a Non-existent
M1b Distant lymph node or organ metastases
Stages in esophageal cancer
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T2, T3 N0 M0
Stage IIB T1, T2 N1 M0
Stage III T3 N1 M0
T4 All N M0
Stage IV All T All N M1
Stage IVA All T All N M1a
ment time, usually done with hyperfractionated accelerated schedules (i.e. 2 u 1.5 Gy per day from the 3rd week onwards to a total dose of 68.4 Gy).
The latter has shown advantages in two randomised trials (Shi et al. 1999; Wang et al. 2002). These stud- ies have found an improvement in mean survival to approximately 3 years, which is comparable to either resection or combined RCT. Such schedules should be used if resection and/or combined RCT is not feasible, but the patient is compliant and in good general condition.
14.1.4.2.2
Radiochemotherapy
For locally advanced tumors of the esophagus, combined RCT is the treatment modality chosen by approximately 30% of patients in the US (Daly et al. 1996). 5-Fluorouracil (5-FU) and cisplatin are the main compounds used with radiation therapy concurrently. There are close to 20 randomised trials on definitive RCT, comparing either primary RCT with primary radiotherapy alone (Rebecca and Richard 2003; Zhao et al. 2005), definitive RCT with preoperative RCT (Stahl et al. 2005;
Bedenne et al. 2002), or definitive RCT with pri- mary resection – the latter with very preliminary data from China (Chiu et al. 2005). There was tremendous heterogeneity across all the studies, with the sequence of chemotherapy (simultaneous better than sequential RCT) as a very important prognostic factor. Unfortunately, the results of the studies on sequential RCT were heterogeneous, so that they could not be pooled by the Cochrane Collaboration (Wong et al. 2003). So far, the out- come of all randomised trials does not support a recommendation for sequential RCT. It rather became evident that concomitant RCT provided significant improvement in overall survival (7%
after 1- and 2-year follow-up), disease-specific survival, and local tumor control (12%–45%).
Two sequential clinical trials attempted to define the optimal concept of RCT (Al-Sarraf et al. 1997; Minsky et al. 2002). Within the first trial, RCT was compared to radiotherapy alone. RCT consisted of conventionally fractionated radio- therapy to a total dose of 50 Gy and four cycles of cisplatin (75 mg/sqm day 1) and 5-FU (1000 mg/
sqm day 1–4), with the first two cycles given paral- lel to radiation therapy. Though the radiotherapy alone arm had a higher dose, the overall survival was significantly improved by simultaneous RCT (Al-Sarraf et al. 1997). In the second trial, con-
comitant RCT was given in both arms at two dif- ferent dose levels (50 Gy versus 64 Gy total dose) whilst chemotherapy was the same as in the former study. There was no advantage of the higher dose regimen due to a higher mortality rate. It is dif- ficult to explain the results, because the majority of the adverse events happened before reaching a dose of 50 Gy, but it confirms that a combined RCT can cause severe side effects and that an increase of the radiation dose should only be done with due caution. Using conventional fractionation schedules (five fractions of 1.8–2.0 Gy per week) and a concomitant chemotherapy, total doses between 50 and 60 Gy might be optimal for locally advanced, non-resectable esophageal carcinoma.
About four cycles of cisplatin- and 5-FU-based chemotherapy are also recommended. Based on the convincing data of radiotherapy alone given in accelerated and hyperfractionated manner (Shi et al. 1999), the idea to combine an altered fractionation schedule with concomitant chemo- therapy emerged and prompted an investigation by Zhao et al. (2005). A total dose of 68.4 Gy was applied in 41 fractions within 44 days – either alone or combined with cisplatin and 5-FU. There was no significant difference in survival (5-year survival 40% vs. 28% and median survival 30.8 vs. 23.9 months in favour of RCT; p=0.31), per- haps due to an increase in severe acute toxicity (Common Toxicity Score, CTC)°III/IV: 46% vs.
25%; death: 6% vs. 0%). Poor nutrition and inad- equate supportive care were suggested as major reasons for this. Therefore, altered fractionation schedules in RCT can not be recommended at the moment without further prospective data.
From other recent trials – but conducted to answer a different question – it can be concluded that a concomitant RCT analogous to the sched- ule in Table 14.2 is able to produce similar overall survival data as a radical esophagectomy with or without previous neoadjuvant RCT (Hironaka et al. 2003; Bedenne et al. 2002; Blazeby et al. 2003).
Therefore, in particular if the goal of R0 resection
is difficult to achieve, a definitive simultaneous
RCT will be the treatment of choice. In the pres-
ence of contradictions to chemotherapy (reduced
kidney and/or liver function, severe cardiac dis-
ease, etc.), radiotherapy alone should be chosen,
with the option of hyperfractionated-accelerated
schedules, which were superior to conventionally
fractionated treatment in a randomised trial (Shi
et al. 1999).
14.1.4.3
Resection and Multimodal Concepts
14.1.4.3.1 Surgical Resection
Radical en-bloc resection of the esophagus includ- ing systematic mediastinal lymph node dissection is the standard surgical approach and offers long- lasting local control. It is essential to achieve a complete resection of the tumor (R0 resection).
Otherwise, the resection has only palliative char- acter (Stein et al. 2000) and must be weighed against the high morbidity rate and long hospi- talisation. By optimal selection of patients carrying only minimal risk factors, standardized resection and operative reconstruction procedures – two- stage procedure with delay of reconstruction after resection for at least 8 days in patients with previ- ous preoperative radiochemotherapy or severely altered cardiopulmonary function – and improve- ments in postoperative intensive care, the rate of life-threatening morbidity and mortality could be decreased in specialized centers to no more than 5%. It has also been proven that hospital and sur- geon volume are major factors that determine post- operative mortality.
For tumors of the infra- or suprabifurcal esopha- gus, transthoracic en-bloc resection including the esophagus and locoregional mediastinal lymph nodes is recommended, which might be extended by coeliac lymph node dissection during abdomi- nal and left-cervical reconstruction (two-field lym- phadenectomy). Only for tumors of the lower medi- astinum without any contact to the tracheobronchial tree, and in patients with substantially impaired lung function, a transmediastinal approach is justi- fied, with a lymph node dissection of the lower pos- terior mediastinum and the upper abdomen only.
The reconstruction in locally advanced tumors and after preoperative RCT is usually placed in the ante- rior mediastinum behind the sternum. Either stom- ach, colon or small bowel can be used (von Rahden and Stein 2004).
In locally advanced stages (IIB and III) the 5- year survival rate is around 20 % –40 % even in experienced centers and decreases to less than 10%
in more advanced tumors (u/pT4 or pM1a), result- ing from a high local recurrence rate and early dis- tant spread. A complete resection can be achieved in only 54% of pT3 and 19% of pT4 tumours (Stein et al. 2000).
14.1.4.3.2
Multimodal Concepts
In several randomised clinical trials (> 35) and more than seven meta-analyses with more than 5000 patients in total, the value of multimodal concepts has been proven. Unfortunately, in con- trast to previous trials limited to squamous cell cancer, most very recent trials included patients with squamous cell and adenocarcinoma without any stratification. Furthermore, studies are het- erogeneous regarding other inclusion criteria such as tumor stage, staging procedures, and comor- bidities, as well as treatment concepts: selection and dose of chemotherapy, and total dose, frac- tionation, dose calculation, target volume as well as technique of radiotherapy. This makes meta- analyses very difficult and explains the inclusion or exclusion of the same studies into distinct meta- analyses (Malthaner et al. 2004; Patel et al.
2004; Tierney et al. 2005). However, some very relevant statements on pre- and postoperative, adjuvant as well as additive therapies in locally advanced esophageal cancer have been given by different authors and these will be presented here in summary.
Table 14.2. Recommended concept of combined radiochemotherapy (majority of studies being performed with conventional fractionated radiotherapy and chemotherapy with cisplatin and 5-fluorouracil) followed by two additional cycles of chemo- therapy thereafter (cisplatin, 5-FU)
Radiotherapy 1.8–2.0 Gy Days 1–39
Cisplatin 70 mg/m2 short infusion Days 1, 29, 58 and 85
alternative: 20 mg/m2 short infusion Days 1–5 and 29–33
5-Fluorouracil 1000 mg/m2 continuous infusion Days 1–4, 29–32, 58–61, and 85–88 Alternative: 225 mg/m2 continuous infusion Days 1–39
14.1.4.3.2.1
Preoperative Radio-, Chemo- and Radiochemotherapy
Preoperative Radiotherapy
Preoperative radiotherapy has been evaluated in eight randomised trials. Five trials compared this approach against surgery alone, one trial within a four-arm setting against surgery alone and against postoperative radiotherapy, one trial against post- operative radiotherapy, and one trial against preop- erative RCT (Malthaner et al. 2004). There was no significant increase in mortality compared to the other treatment arms. However, there was also no improvement in 1-year survival rate by preopera- tive radiotherapy – neither in any single study nor in pooled analysis. This can be explained at least in part by the modest number of patients in three trials with less than 70 patients per arm each, and non-standard radiation schedules in most trials [low total radiation doses in three trials (below 35 Gy), aggressive hypofractionated radiation therapy in the four-arm trial (up to 53 Gy in 20 fractions)].
Recently, a different analysis by the Cochrane Collaboration found an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 and of 4% at 5 years, respectively, with borderline significance (p=0.062) in pooled data of five properly designed randomised trials including 1147 patients with a median follow-up of 9 years. The studies used for the meta-analysis mostly included
patients with squamous cell cancer. It is therefore not possible to give any advise on the treatment of adenocarcinoma of the lower esophagus (AEG I) with preoperative radiotherapy. Due to the border- line significance, preoperative radiotherapy is not recommended as standard procedure even in squa- mous cell carcinoma of the esophagus (Tierney et al. 2005) (Table 14.3).
Preoperative Chemotherapy
Preoperative chemotherapy was investigated in eight, mostly very small randomised studies (seven comparisons against surgery alone and one in com- bination with postoperative chemotherapy again against surgery alone) (Malthaner et al. 2004;
Baba et al. 2004). Only in two trials a significant improvement in overall survival could be found (Medical Research Council 2002; Kok et al.
1997), with the latter being published as an abstract only. Thus, only one full publication in favour of preoperative chemotherapy is available, which has included adenocarcinoma in two-thirds of the cases.
Most other studies were poorly designed and too small to detect any significant difference in survival (Table 14.4).
Of several meta-analyses only one showed an advantage in overall survival – and only at 5 years – in favour of preoperative chemotherapy. This advantage was mainly caused by the large MRC trial.
Overall, there are rather weak arguments for chemo- therapy in adenocarcinoma of the lower esophagus
Table 14.3. Randomised trials of preoperative radiotherapy (RT) and surgery versus surgery (S) alone. [Modified from MALTHANER et al.( 2004) and PATEL et al. (2004)]
Author (year) Number of patients
RT schedule 2-Year survival (%)
5-Year survival (%)
30-Day mortal- ity (%)
S RT+S S RT+S S RT+S S RT+S
Launois et al.
(1981)
57 67 40 Gy/12 fr 35 20 12 10 23 23
Gignoux et al.
(1987)
114 115 33 Gy/10 fr 30 24 9 10 17 24
Wang et al.
(1989)
102 104 40 Gy/nr nr nr 30 35 6 5
Nygaard et al.
(1992)
50 58 35 Gy/20 fr 13 25 Nr nr 13 11
Arnott et al.
(1992)
86 90 20 Gy/10 fr 28 22 17 9 12 14
Fok et al. (1994) 39 40 24-53 Gy/10-20 fr 36 34 16 10 8 30
fr, Fractions, nr, not reported.
(AEG I) and none for the treatment of squamous cell carcinoma. Therefore, preoperative chemotherapy is not recommended in locally advanced esophageal cancer (Patel et al. 2004; Malthaner et al. 2004).
Preoperative Radiochemotherapy
Preoperative RCT has been investigated in 12 trials published so far: eight studies compared preopera- tive RCT with resection alone, one trial compared preoperative RCT with preoperative RT, one trial compared preoperative RCT alone with preopera- tive RCT and hyperthermia, and two trials com- pared preoperative RCT with definitive RCT for all responders to initial RCT (Malthaner et al. 2004;
Stahl et al. 2005; Bedenne et al. 2002). In most trials, cisplatin alone or in combination with 5-FU has been used, either in a simultaneous manner or as sequential RCT. A broad variation of radiation schedules has been applied, with different total doses (20 Gy–45.6 Gy), fractionations (1.8–2.0 Gy single dose to 1.2 Gy bid), and overall treatment time, resulting in a large difference in radiobiologi- cal effectiveness.
Just in one out of eight trials comparing surgery alone with preoperative RCT and esophagectomy, neoadjuvant RCT was able to improve overall sur-
vival, and in one further trial to increase disease-free survival (Table 14.5). However, the former of these trials has included adenocarcinoma only, and was criticised for premature closure with accrual of only 113 patients, unusually poor survival in the surgery- alone arm and the lack of staging CT before surgery (Walsh et al. 1996). One study described superior outcome for patients with tumor response to preop- erative treatment, with significantly improved over- all survival in this subgroup (Apinop et al. 1994).
The overall modest results can be explained at least in part by the small number of patients in six trials with less than 58 patients per arm each, and uncom- mon treatment concepts in two trials using sequen- tial RCT or very low doses of radiation (Nygaard et al. 1992; Le Prise et al. 1994).
In several meta-analyses, it became obvious that preoperative RCT improves overall survival after more than 3 years of follow-up for all histologies, though the number of patients with adenocarci- noma was very small [inclusion only in two trials (Urba et al. 2001; Walsh et al. 1996)]. At 3 years, the improvement was 11%, with a relative risk for multimodal treatment of 0.53 (p=0.03), even more pronounced for concurrent RCT (relative risk 0.45;
p=0.005) (Malthaner et al. 2004; Fiorica et al.
2004). There have been no significant advantages
Table 14.4. Randomised trials of preoperative chemotherapy (CT) and surgery versus surgery (S) alone. [Modified from Malthaner et al. (2004) and Patel et al. (2004)]
Author (year) Number of patients
CT substances 2-Year survival (%) 5-Year sur- vival (%)
30-Day mortality (%)
S CT+S S CT+S S CT+S S CT+S
Nygaard et al.
(1992)
50 56 Cisplatin, bleomycin 13 6 nr nr 10 11
Schlag et al. (1992) 24 22 Cisplatin, 5-FU 32 (1 year)
20 (1 year)
nr nr nr nr
Maipang et al.
(1994)
22 24 Cisplatin, vinblastine, bleomycin
40 31 nr nr 0 7
Law et al. (1997) 73 74 Cisplatin, 5-FU 31 44 0 28 9 8
Kok et al. (1997)a,b 74 74 Cisplatin, etoposide 11 months
18.5 months
nr nr 0 1
Baba et al. (2000) 21 21 Cisplatin, 5-FU;
leucovorin
41 months
34 months
44 38 0 2
Ancona et al.
(2001)
47 47 Cisplatin, 5-FU 55 55 22 34 nr nr
MRC OE02 (2002)a 402 400 Cisplatin, 5-FU 34 43 15 26 10 10
a Significant advantage for preoperative CT.
b Only median survival data reported.
either in overall or disease-free survival at 1- or 2- years of follow-up. However, the most recent ran- domised trial has not been included in any of these meta-analyses, and this trial was negative for neoad- juvant treatment, due to a high local recurrence rate, probably based on the extraordinarily high sur- gery drop-out rate in the combined treatment arm, mainly caused by patient refusal (Lee et al. 2004).
This study demonstrates the potential difficulties of neoadjuvant protocols. Toxicity can be severe, with up to more than 50% CTC II–IV haematologi- cal and gastrointestinal sequelae, each. Therefore, and based on studies comparing combined neoad- juvant RCT with definitive RCT (Stahl et al. 2005;
Bedenne et al. 2002), neoadjuvant RCT can not be recommended as standard care outside of clinical trials. When offered, an optimal supportive care is essential, including a dedicated intensive care unit for perioperative monitoring of the patient (Stein et al. 2000).
Radiochemotherapy vs. Esophagectomy
So far, no study has been able to demonstrate any significant improvement in overall survival com-
paring preoperative RCT and resection with high dose RCT alone, or resection alone with RCT. Stahl et al. (2005) and Bedenne et al. (2002) both started with cisplatin- and 5-FU-based RCT and ran- domised patients to esophagectomy or continued RCT if the tumor was not progressing (Table 14.6).
Bedenne et al.(2002) started with 455 patients, with 259 of them responding to RCT (30–46 Gy).
They were randomised to resection or further RCT (up to 45–64 Gy total dose). Although they had a break for response evaluation, median survival (19.3 months vs. 17.7 months) and 2-year survival (40% vs. 34%) were not significantly different, and quality of life was similar in both arms. Dysphagia was worse in the RCT-alone arm, and social life, nausea, and vomiting were significantly worse after resection (Blazeby et al. 2003; Bonnetain et al.
2003). Stahl et al. (2005) conducted a randomised trial with a sequential chemo- and radiochemother- apy, and could not detect a significant difference in overall survival. However, they described a signifi- cant advantage in local tumor control for the resec- tion arm, resulting in a significant improvement in recurrence-free survival at 2 years. This has been confirmed by Liao et al. (2004) in a retrospective
Table 14.5. Randomised trials of preoperative radiochemotherapy (RCT) and surgery versus surgery (S) alone. [Modified from Malthaner et al. (2004) and Patel et al. (2004)]
Author (year) Number of patients
RCT concept 2-Year survival (%)
5-Year survival (%)
30-Day mortality (%)
S RCT+S S RCT+S S RCT+S S RCT+S
Nygaard et al.
(1992)
50 53 Cisplatin, bleomycin sequential RT 35 Gy
13 23 nr nr 10 10
Le Prise et al.
(1994)
45 41 Cisplatin, 5-FU con- current RT 20 Gy
33 27 nr nr 7 9
Apinop et al.
(1994)
35 34 Cisplatin, 5-FU con- current RT 40 Gy
23 30 10 24 0 6
Bosset et al.
(1997)
139 143 Cisplatin, con current RT 37 Gy
43 48 32 33 4 13
Walsh et al.
(1996)a
55 58 Cisplatin, 5-FU con- current RT 40 Gy
26 37 nr nr 3 8
Urba et al. (2001) 50 50 Cisplatin, 5-FU, vin- blastine concurrent RT 45 Gy
38 42 10 20 4 2
Burmeister et al.
(2005)
128 128 Cisplatin, 5-FU con- current RT 35 Gy
nr nr 24 26 6 4
Lee et al. (2004) 50 51 Cisplatin, 5-FU con- current RT 45.6 Gy
57 55 nr nr 2 2
nr, not reported; a significant advantage for preoperative RCT
study with stage II and III esophageal cancer, where local tumor control was significantly improved by esophagectomy after previous RCT, but radiation dose was low in this trial.
As known from both experimental and clini- cal studies, sequential RCT as used by Stahl et al.
(2005) is not the optimal concept of RCT, because initial chemotherapy might alter the patients tol- erance for consecutive RCT, produce radioresist- ant tumor cells, or induce repopulation of cancer cells. Furthermore, the chemotherapy protocol with etoposide and leucovorin was far from opti- mal, because of the toxicity of these drugs and the fact that they have no proven value in esophageal cancer.
Very preliminary data were published from a Chinese group (Chiu et al. 2005), where stand- ard esophagectomy was randomised against RCT in esophageal squamous cell cancer. This very small trial did not report a significant difference in overall or recurrence-free survival. Therefore, it confirms previous studies that could not find a significant difference in survival even after neoadjuvant treatment in the resection arm. In summary, preoperative radio- and chemotherapy are not standard procedures in locally advanced esophageal cancer, independent of histologi- cal subgroup. For locally advanced tumors and those with close contact to the tracheobronchial tree, definitive RCT or preoperative RCT should
be considered. Optimal supportive care and close follow-up of the patients is an essential prerequi- site in any case.
14.1.4.3.2.2
Postoperative Radio-, Chemo- and Radiochemotherapy
Postoperative Radiotherapy
Nine randomised trials have been conducted with esophagectomy and postoperative radiotherapy as one treatment arm: five trials versus resection alone, and one trial versus pre- and postoperative radio- therapy (the latter with a significantly higher mor- tality rate in 207 eligible patients), one trial versus preoperative radiotherapy (82 patients included during 13 years, no difference in survival), one trial versus postoperative chemotherapy (253 patients, cisplatin and vindesine, no significant difference in survival), and one four-arm trial with immu- notherapy versus postoperative RCT (174 patients, no significant advantage for any treatment arm) (Malthaner et al. 2004).
The five trials comparing postoperative radio- therapy and resection with resection alone failed to show any improvement in overall survival (Table 14.7), confirmed by a negative meta-analy- sis (Malthaner et al. 2004), with one single trial
Table 14.6. Randomised trials comparing resection +/– neoadjuvant radiochemotherapy (RCT) with definitive RCT
Number of patients
CT RT Resection Median
survival (months)
Mortality Other
Bedenne et al. (2002)
259 (of 455)
Cisplatin, 5-FU 30–46 Gy Esophagectomy 17.7 9 % 2-Year survival 34%
Cisplatin, 5-FU 45–64 Gy 19.3 (ns) 1 % (s.) 2-Year survival
40% (ns) Stahl et al.
(2005)
177 Cisplatin, 5-FU, leucovorin, etoposide
40 Gy Esophagectomy 16 12.8 % 19% Local
recurrence
Cisplatin, 5-FU, leucovorin, etoposide
> 60 Gy 15 (ns) 3.5 % (s.) 36% Local
recurrence (ns)
Chiu et al.
(2005)
76 Esophagectomy nr 6.8 % 2-Year survival
54.5%
Cisplatin, 5-FU 50–60 Gy nr 0 % 2-Year survival
58.3% (ns) nr, not reported; ns, not significant.
even demonstrating an adverse effect of additional radiotherapy (Fok et al. 1993). However, three trials were able to demonstrate a significant decrease in local recurrence rate, but in two trials morbid- ity was increased. One trial included patients with close margins or even incomplete tumor resection (R1 resection), and even this study with an extraor- dinary risk of postoperative local tumor progression was not positive for additive radiotherapy (Fok et al.
1993). Therefore, there is neither a standard indica- tion for postoperative radiation after complete nor after incomplete resection. Such treatment might be offered if the risk of distant metastases is low and the patient has recovered rapidly and completely from resection. The individual recommendation should be based on multidisciplinary discussion as well as the decision with an informed patient.
Postoperative Chemotherapy
Postoperative chemotherapy with cisplatin-based regimens has been compared with postoperative radiotherapy in one (mentioned above) and with surgery alone in three randomised trials. The latter failed to demonstrate any improvement in overall survival, both in early stage carcinoma (Ando et al.
1997) and in locally advanced tumors (Pouliquen et al. 1996), as did a pooled analysis by the Gastroin- testinal Cancer DSG (Malthanher et al. 2004).
A subgroup analysis in nodal-positive squamous cell carcinoma from a randomised Japanese trial described a significant advantage in 5-year survival in favour of postoperative chemotherapy (52% vs.
38% with resection alone, p=0.041) (Ando et al.
2003). However, stratification was based only on resection margin and not on nodal status. There-
fore this single study does not sufficiently justify postoperative chemotherapy in clinical routine.
Postoperative Radiochemotherapy
In the postoperative situation, the value of combined RCT has only been evaluated in one, very small ran- domised trial so far (Tachibana et al. 2003). A total of 45 patients have been included, and chemotherapy was based on cisplatin and 5-FU plus 50 Gy in the RCT arm. There was no significant difference in over- all survival at 1, 3, and 5 years of follow-up. There- fore, there is no evidence or indication for adjuvant RCT in esophageal cancer even in locally advanced carcinoma (Malthaner et al. 2004). It might be rea- sonable to offer additive RCT in case of incomplete tumor resection (R1–2 resection) because of a high risk of local tumor progression as the first localisa- tion of clinically apparent relapse. However, there is no data supporting this hypothesis and therefore, in individual cases the decision should be made together with the informed patient.
Summarizing the conflicting data, there is no evi- dence supporting the idea of postoperative radio-, chemo- or radiochemotherapy – independent of the result of esophagectomy: R0 or R1–2 resection. How- ever, in individual cases and with informed consent of the patient, it might be justified to offer an addi- tional treatment to patients after incomplete tumor resection to avoid an early local tumor progression.
The high toxicity after previous esophagectomy (hematotoxicity CTC III–IV > 20%, gastrointestinal toxicity CTC°III–IV > 30%) should be taken into account, and the patient should be offered a com- prehensive supportive care program.
Table 14.7. Randomised trials of postoperative radiotherapy (RT) and surgery versus surgery (S) alone. [Modified from Malthaner et al. (2004) and Patel et al. (2004)]
Author (year) Number of patients
RT concept 2-Year survival
(%)
5-Year survival (%)
S RT+S S RT+S S RT+S
Teniere et al. (1991) 119 102 45–55.8 Gy/25–31 fr 51 50 19 21
Fok et al. (1993)a 65 65 49–52.5 Gy/14–15 fr 25 18 nr nr
Fok (1994) 39 42 45–53 Gy 36 17 16 10
Zieren et al. (1995) 35 33 45–55 Gy/25 fr 31 29 nr nr
Xiao et al. (2003) 275 220 50–60 Gy/25–30 fr nr nr 32 41
fr, Fractions; nr, not reported.
aSignificant disadvantage for postoperative RT.
14.1.4.4 Conclusion
Treatment decision and administration is a multi- disciplinary task – radiologist, endoscopist, sur- geon, medical and radiation oncologist should be involved, as well as the informed patient. There is evidence supporting concomitant RCT or resection for locally advanced disease with no superiority of one of these strategies, and less evidence for com- binations of both – preoperative RCT and resec- tion – for unresectable carcinoma in patients with good clinical condition. Even patients with locally advanced carcinoma (stage III) can be cured, with 5-year recurrence-free survival of about 20% (Wong et al. 2003; Kosho et al. 2004; Malthaner et al.
2004; Patel et al. 2004). However, combined treat- ment can cause severe side effects and, therefore, demands an extraordinary experience of the physi- cian and a comprehensive supportive care program, starting immediately after diagnosis.
14.2
Gastric Cancer and Adenocarcinoma of the Esophagogastric Junction (AEG II and III)
14.2.1 Introduction
Survival of gastrointestinal junction (AEG II and III) and gastric cancer patients is poor given that they frequently present with locally advanced or even regional or distant metastatic disease. The mainstay of care still is surgical resection. No additive treat- ment can compensate for a poor resection. It was recently confirmed that extended lymphadenectomy – gastrectomy with resection of the complete locore- gional lymph nodes, so-called D2-resection – is the standard procedure, being superior to limited (D1) lymphadenectomy, presumed that splenectomy and distal pancreatectomy are avoided in order to limit the risk of toxicity. In adenocarcinoma of the esoph- agogastric junction (AEG II and III) total gastrectomy with transhiatal resection of the lower esophagus and a D2-lymphadenectomy are usually recommended.
Nevertheless, the prognosis of patients with locally advanced tumors remains unsatisfactory in spite of radical resection. Locoregional tumor recurrence is common, with 30%–80% in stage II–IIIB, and dis- tant metastases are also frequent, up to at least 40%
(Gunderson 2002, Hundahl 2002). About 80% of
these recurrences emerge in the original tumor bed, at the anastomotic sites, or in non-resected regional lymph nodes. Approximately 25% are pure local recurrences, making it obvious that additional local treatment is essential (Smalley 2002). Noteworthy is that a more aggressive resection could not dem- onstrate improved results in two randomised trials.
Therefore, it was reasonable to integrate pre- and postoperative chemo- and radiochemotherapy.
14.2.2
Preoperative Treatment
14.2.2.1
Preoperative Radiotherapy
Preoperative radiotherapy might sterilize tumor cells and induce a tumor remission, to increase the chance of R0 resection and to avoid tumor cell spread during resection. In one randomised trial from China 360 patients with tumors of the cardia received preoperative radiotherapy with 40 Gy, which significantly reduced the local recurrence rate from 52% after resection alone to 39% (p<0.025).
The recurrence rate in the regional lymph nodes declined from 54% to 39% (p<0.005). Therefore, though the number of distant metastases was not influenced, the overall and recurrence free-survival was significantly improved (5-year overall survival:
30% vs. 20%, p=0.009). There was no increase in severe perioperative side effects, encouraging fur- ther studies of preoperative radiotherapy (Zhang et al. 1998). As long as such data are not available preoperative radiotherapy is not yet a standard pro- cedure.
14.2.2.2
Preoperative Chemotherapy
Phase II trials have shown that preoperative chemo- therapy is feasible, with acceptable toxicity and peri- operative morbidity (Lordick and Siewert 2005).
It has been shown that patients who responded to neoadjuvant treatment had improved survival compared with non-responders (Ott et al. 2003).
A small randomised trial of preoperative chemo- therapy compared with surgery alone in 56 patients could not demonstrate a benefit of chemotherapy, but was statistically underpowered (Songun et al.
1999).
Recently, the first results of the only large ran-
domised trial of perioperative chemotherapy (three
cycles of epirubicine, cisplatin, 5-FU pre- and post- operatively each) were presented (Allum et al. 2003).
A total of 503 patients with resectable stage II and III gastric cancer (89%) or lower esophageal cancer (11%) were enrolled in this multi-institutional study (Table 14.8). There was a significant downstaging in the chemotherapy arm (T3=49% vs. 64% in the sur- gery-only arm), but it failed to increase the R0 resec- tion rate. Preoperative chemotherapy resulted in a statistically significant improvement in recurrence- free survival at 2 years (45% vs. 30%, p=0.002), but in just a borderline improvement of 2-year overall survival (48% vs. 40%, p=0.063). Long-term sur- vival data is still lacking. There was no excess in surgical complication rates for neoadjuvant cases, and toxicities were acceptable with 91% of all preop- erative chemotherapy applied as planned. However, there are some objections: only 53% of the patients started the planned postoperative chemotherapy due to toxicity. The surgical quality control was not optimal, with the type of resection being left to the discretion of the local surgeon. And the staging procedures did not in general include endoscopic ultrasound or diagnostic laparoscopy (Lordick and Siewert 2005; Macdonald 2005).
In summary, there is a proven value of preop- erative chemotherapy, but it is not yet the standard procedure for all locally advanced gastric cancers, because long-term follow-up and confirmatory data from other randomised trials are missing. It might be offered to patients with good performance status, optimal supportive care, high risk of incomplete resection (R1), locally advanced cancer (T3–4) and
proven positive regional lymph nodes. If preopera- tive chemotherapy is offered, it should be done in a dedicated and experienced center, and it should be discussed interdisciplinary whether postoperative chemo- or radiochemotherapy should be offered on the basis of the relative risk for locoregional versus distant tumor recurrence.
14.2.2.3
Preoperative Radiochemotherapy
A simultaneous RCT should theoretically increase the remission rate and, therefore, allow for higher rates of R0 resection. It combines the improved local efficacy of radiation therapy with simultane- ous reduction of the high risk of distant microme- tastases. Several phase-I/II studies of combined simultaneous RCT (40–50 Gy total dose, 5-FU, cis- platinum, leucovorin or paclitaxel) reported tumor remission in about 40%–70%, with complete remis- sion in roughly 10%, but up to 30% in some very recent trials (Ajani et al. 2004). Recurrence-free survival (50% after 3 years) and overall survival (4-year survival of 60% in resected patients) were promising (Allal et al. 2005; Ajani et al. 2004).
The perioperative morbidity and mortality seem not to be significantly increased, making preoperative RCT an interesting treatment modality for further studies in gastric cancer.
In summary, data of preoperative treatment is scarce and, therefore, neither preoperative radio- nor radiochemotherapy can be recommended as a routine strategy, although the integration of new
Table 14.8. Preoperative chemotherapy in gastric cancer: results of selected phase II and III trials. [Modified from Lordick and Siewert (2005) and Allum et al. (2003)]
Author (year) Regimen Number of
patients
Median survival 2-Year survival
Wilke et al.(1989) EAP 34 18 months 26%
Ajani et al. (1991) EFP 25 15 months 44%
Kelsen et al. (1996) Preop FAMTX
Postop. ip. CDDP/FU,iv.FU
56 15 months 40%
Siewert et al. (1997) CDDP,FU,FA 41 ns 56%
Ott et al. (2003) PLF 42 25 months ns
Hartgrink et al. (2004) FAMTX 27 18 months 44%
Allum et al. (2003) ECF 281 ns 48%
EAP, etoposide-adriamycin-cisplatin; EFP, etoposide-fluorouracil-cisplatin; FAMTX, fluorouracil-doxorubicin-methotrexate;
FU, fluorouracil; FA, folinic acid; ip, intraperitoneal; iv, intravenous; PLF, cisplatin-leucovorin-fluorouracil; ECF, etoposide-cis- platin-fluorouracil; ns, not specified.
substances (gemcitabine, irinotecan) showed prom- ising results, which warrant larger clinical trials.
Preoperative chemotherapy is proven effective in one large randomised trial, but the results were worse than in the Intergroup trial on postoperative RCT. Therefore, the search for the optimal periop- erative treatment continues.
14.2.3
Intraoperative Radiotherapy
The value of intraoperative radiotherapy (IORT) has been tested in three randomised trials with small patient numbers (<100 in each study) and in one large Japanese trial (211 patients), either alone or in combi- nation with external beam radiotherapy. All studies confirmed an improved local tumor control. In those trials with high total doses and a complete coverage of the gastric area including locoregional lymph nodes, overall survival was also significantly improved: 5- year survival rate of 83.5% vs. 61.8% in stage II, of 62.3% vs. 36.8 % in stage III, and 14.7% vs. 0% in stage IV, respectively, and 8-year survival rates of 55% vs.
35% in stage III with pure IORT. The median survival was increased from 9.1 to 21.4 months in another trial (Kramling et al. 1997; Ogata et al. 1995; Skoropad et al. 2000). The study by Skoropad et al. (2000) included only patients with no less than a D1 resec- tion, sometimes extended to a D2 resection if suspi- cious lymph nodes were present, making this study comparable to trials with European surgical stand- ard. In all trials radiosensitive structures and organs (small and large bowel, liver, kidneys) were spared and, therefore, all studies found no increase of peri- operative morbidity. Therefore, IORT seems feasible and warrants further investigation in clinical trials, with D2 resection being performed in all patients. It is not yet proven whether the positive influence of IORT on local and regional tumor control will persist under these conditions.
14.2.4
Postoperative Treatment
14.2.4.1
Postoperative Radiotherapy
In most clinical trials, postoperative radiotherapy was applied after incomplete tumor resection or in tumors with an extraordinary high risk of local tumor recurrence such as T3 and N+. There is only one randomised study comparing postoperative radiotherapy with gastrectomy alone, with postop- erative chemotherapy (mitomycin C, 5-FU, doxoru- bicin) being tested in a third arm. 436 patients have been included. Local tumor control was improved significantly by postoperative radiotherapy (90%
vs. 81 % with resection vs. 73% with postoperative chemotherapy). This did not result in an improved 5-year survival (12% vs. 20% with resection vs. 19
% with postoperative chemotherapy) (Hallissey et al. 1994). However, one third of the patients did not receive the prescribed adjuvant treatment, with 24
% of the patients in the radiotherapy arm not being irradiated at all, and only 68 % being treated with at least 40.5 Gy. It can be concluded that there is no proven value of postoperative radiotherapy alone.
14.2.4.2
Postoperative Chemotherapy
Adjuvant systemic therapy has been widely tested in clinical trials, either alone or as part of com- bined RCT with curative intent. Only very few single trials have shown an advantage in disease-specific or overall survival, and only two trials outside of Asia with a small number of included patients have revealed a significant improvement in survival by adjuvant chemotherapy. Several meta-analyses could demonstrate only minimal effects of border- line significance in favour of adjuvant chemotherapy (Lordick and Siewert 2005). This can be explained in part by the high number of poorly designed trials and the limitations of literature-based meta-analy-
Table 14.9. Meta-analyses based on publications of randomised trials on postoperative chemotherapy in gastric cancer
Author (year) Number of studies Number of patients Odds ratio (confidence interval)
Hermans et al. (1993) 11 2096 0.88 (0.78–1.08)
Earle and Maroun (1999) 13 1990 0.80 (0.66–0.97)
Mari et al. (2000) 21 3658 0.82 (0.75–0.89)
Janunger et al. (2002) 21 3962 0.84 (0.74–0.96)
Table 14.10. Randomised trials on postoperative radiochemotherapy in gastric cancer
Gunderson (2002) 5-Year survival Median survival
(months)
Locoregional recur- rence rate
Op 23 patients 4% 15 54%
Op + postop RCT (5-FU) 39 patients 23% 24 39%
Macdonald et al. (2001, 2005) 3-Year survival Median survival (months)
Local recurrence rate
Op 275 patients 41% 26 29%
Op + postop CTx/RCT (5-FU, leucovorin)
281 patients 50% 35 19%
sis without original patient data. All authors con- cluded that there is no sufficient evidence to recom- mend adjuvant chemotherapy as a routine treatment (Table 14.9). Nevertheless, it might be important that subgroups apparently showed some benefit, such as the patients from the Asian studies and the patients with node-positive disease (Janunger et al. 2002).
This can guide the design of new trials.
14.2.4.3
Postoperative Radiochemotherapy
Several phase I/II and two randomised phase III trials have shown a significant improvement in locoregional tumor control and overall survival in favour of postoperative RCT. They usually used 5- FU (425 mg/sqm) and leucovorin (20 mg/sqm), and a conventionally fractionated radiotherapy (five fractions of 1.8 Gy per week, up to 45 Gy). In the largest trial, SWOG9008/INT0116, 603 patients were enrolled, with 556 of them being eligible. In both arms 85% of the patients had node-positive cancer (stage IIIA–IV). Gastrectomy without relevant lymph node dissection (<D1 dissection) was the most common type of resection (54%), and only 10% were treated with the European standard D2 dissection. The local recurrence rate (19% vs. 29%), the recurrence-free survival (48% vs. 31%) and the overall survival (50%
vs. 41%) were improved significantly at 3 years by the adjuvant treatment. Median time to relapse was 30 months in the RCT arm and 19 months in the control arm (p<0.0001), and median overall sur- vival was 35 months vs. 26 months in favour of RCT (Table 14.10). These results made combined RCT a standard procedure in patients with resected gastric cancer (Smalley et al. 2002). However, side effects were considerable, with only 1% treatment-related
mortality but 73% grade III and IV toxicity, with 54% being hematological and 33% intestinal tox- icity. This resulted in a limited tolerability, with only 181 out of 281 patients (64%) completing treat- ment as planned. It became obvious that radiation treatment planning had to be reviewed carefully to deliver this combined modality therapy safely and effectively. In all, 34% of radiation treatment plans had to be modified after review, and two-thirds of these deviations would have resulted in under-treat- ment whilst one-third might have caused severe or even life-threatening toxicity. There is some impor- tant criticism on this study, mainly related to the surgical procedure: the large number of inadequate lymph node resections makes it difficult to com- pare the results to European standards. There was no stratification for type of resection, and due to the small number of patients with D2 resection it remains unclear whether the improvement of sur- vival would be maintained under adequate surgical conditions.
More recently published data indicates that even
after a more radical resection, postoperative RCT
is feasible and results in extraordinary high local
control rates (>90%) with 5-year survival of more
than 40% (Kollmannsberger et al. 2003). In sum-
mary, there is a proven value of postoperative RCT
in locally advanced gastric cancer, especially after
limited resection with less than D1 lymph node dis-
section. It should be offered to patients with good
performance status after resection and optimal sup-
portive care when there was an incomplete resection
(R1–2), T2–3 tumor without any locoregional lymph
node dissection or T3 tumor with incomplete lymph
node dissection (D1 dissection). It might be reason-
able to offer adjuvant RCT to patients with positive
lymph nodes after D2 dissection, but this has not
been proven by prospective trials. If RCT is offered, it should be done in a dedicated and experienced center and according to the consensus report of the Intergroup to avoid undertreatment as well as severe and life-threatening toxicity (Macdonald 2005). It might be reasonable to avoid leucovorin concurrent with radiotherapy, based on data in rectal cancer where it increased toxicity without any improve- ment in tumor control.
References
Ajani JA, Ota DM, Jessup JM, et al. (1991) Resectable gastric carcinoma. An evaluation of preoperative and postopera- tive chemotherapy. Cancer 68:1501–1506
Ajani JA, Mansfield PF, Janjan N, et al. (2004) Multi-institu- tional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric adenocarcinoma. J Clin Oncol 22:2774–2780
Allal AS, Zwahlen D, Bründler MA, et al. (2005) Neoadjuvant radiochemotherapy for locally advanced gastric cancer:
long-term results of a phase I trial. Int J Radiat Oncol Biol Phys 63:1286–1289
Allum W, Cunningham D, Weeden S on behalf of the NCRI Upper GI Clinical Study Group (2003) Perioperative chem- otherapy in operable gastric and lower esophageal cancer.
A randomized controlled trial (the MAGIC trial ISRCTN 93793971). Proc Am Soc Clin Oncol 998a
Al Sarraf M, Martz K, Herskovic A, et al. (1997) Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 15:277–284
Ancona E, Ruol A, Santi S, et al. (2001) Only pathologic com- plete response to neoadjuvant chemotherapy improves sig- nificantly the long term survival of patients with resect- able esophageal squamous cell carcinoma: final report of a randomized, controlled trial or preoperative chemotherapy versus surgery alone. Cancer 91:2165–2174
Ando N, Iizuka T, Kakegawa T, et al. (1997) A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg 114:205–209
Ando N, Iizuka T, Ide H, et al. (2003) Surgery plus chemo- therapy compared with surgery alone for localized squa- mous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study JCOG 9204. J Clin Oncol 21:4592–4596
Apinop C, Puttisak P, Preecha N (1994) A prospective study of combined therapy in esophageal cancer. Hepatology Gas- troenterol 41:391–393
Arnott SJ, Duncan W, Kerr GR, et al. (1992) Low dose pre- operative radiotherapy for carcinoma of the oesophagus:
results of a randomized clinical trial. Radiother Oncol 24:108–113
Baba M, Natsugoe S, Shimada M, et al. (2000) Prospective evaluation of preoperative chemotherapy in respectable squamous cell carcinoma of the thoracic esophagus. Dis Esophagus 13:136–141
Badwe RA, Sharma V, Bhansali MS, et al. (1999) The quality of swallowing for patients with operable esophageal carci- noma. Cancer 85:763–768
Bareiss D, Stabenow R, Müller R, et al. (2002) Aktuelle Epide- miologie des Ösophaguskarzinoms und des Kardiakarzi- noms in Deutschland (German). Dtsch Med Wochenschr 127:1367–1374
Bartels H, Stein HJ, Siewert JR (1998) Preoperative risk analy- sis and postoperative mortality of oesophagectomy for resectable oesophageal cancer. Brit J Surg 85:840–844 Bedenne L, Michel P, Bouche O, et al. (2002) Randomized phase
III trial in locally advanced esophageal cancer: radioche- motherapy followed by surgery versus radiochemotherapy alone (FFCD 9102). Proc Am Soc Clin Oncol No. 519 Blazeby LM, Conroy T, Hammerlid E, et al. (2003) Clinical and
psychometric validation of an EORTC questionaire module, the EORTC QLQ-OES 18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer 39:1384–1394 Bosset JF, Gignoux M, Triboulet JP, et al. (1997) Chemoradio-
therapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337:161-167
Burmeister BH, Smithers BM, Gebski V, et al., Trans Tasman Radiation Oncology Group, Australasian Gastrointestinal Trials Group and Clinical Trials Centre (2005) Surgery alone versus chemoradiotherapy followed by surgery for respectable cancer of the esophagus: a randomised control- led phase III trial. Lancet Oncol 6:659–668
Chiu PW, Chan AC, Leung SF, et al. (2005) Multicenter pro- spective randomized trial comparing standard esophagec- tomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the Chinese Univer- sity Research Group for Esophageal Cancer (CURE). J Gas- trointest Surg 9:794–802
Daly JM, Karnell LH, Menck HR (1996) National cancer data base report on esophageal carcinoma. Cancer 78:1820–
1828
ESMO European Society of Medical Oncology Guidelines (2005). www.esmo.org
Earle CC, Maroun JA (1999) Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients:
revisiting a meta-analysis of randomized trials. Eur J Cancer 35:1059–1064
Fiorica F, Di Bona D, Schepis F, et al. (2004) Preoperative chem- oradiotherapy for oesophageal cancer: a systemic review and meta-analysis. Gut 53:925–930
Fok M, Sham JST, Choy D, et al. (1993) Postoperative radio- therapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 113:138–147 Fok M, McShane J, Law SYK, Wong J (1994) Prospective ran-
domised study in the treatment of oesophageal carcinoma.
Asian J Surg 17:223–229
Gignoux M, Roussel A, Paillot B, et al. (1987) The value of preoperative radiotherapy in esophageal cancer: results of a study of the E.O.R.T.C. World J Surg 11:426–432 Gunderson LL (2002) Gastric cancer – patterns of relapse after
surgical resection. Semin Radiat Oncol 12:150–161 Hallissey MT, Dunn JA, Ward LC, Allum WH (1994) The second
British Stomach Cancer Group trial of adjuvant radiother- apy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 343:1309–1312
Hartgrink HH, van de Velde CJ, Putter H, et al. (2004) Neo- adjuvant chemotherapy for operable gastric cancer: long
term results of the Dutch randomised FAMTX trial. Eur J Surg Oncol 30:643–649
Hermanek P (1999) Tumor of the gastrointestinal tract and the pancreas: histopathology, staging, and prognosis. Antican- cer Res 19:2393–2396
Hermans J, Bonenkamp JJ, Boon MC, et al. (1993) Adjuvant therapy after curative resection for gastric cancer: meta- analysis of randomized trials. J Clin Oncol 11:1441–1447 Hironaka S, Ohtsu A, Boku N, et al. (2003) Nonrandomized
comparison between definitive chemoradiotherapy and radical surgery in patients with T (2–3) N (any) M (0) Squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 57:425–433
Hosch SB, Stoecklein NH, Pichlmeier U, et al. (2001) Esopha- geal cancer: the mode of lymphatic tumor cell spread and its prognostic significance. J Clin Oncol 19:1970–1975 Hundahl SA (2002) Staging, stage migration, and patterns of
spread in gastric Cancer. Semin Radiat Oncol 12:141–149 Janunger KG, Hafstrom L, Glimelius B (2002) Chemotherapy
in gastric cancer: a review and updated meta-analysis. Eur J Surg 168:597–608
Kelsen D, Karpeh M, Schwartz G et al. (1996) Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil. J Clin Oncol 14:1818–1828
Kok TC, van Lanschot J, Siersema PD, van Overhagen H, Tila- nus HW, for the Rotterdam Esophageal Tumor Study Group (1997) Neoadjuvant chemotherapy in operable esophageal squamous cell cancer: final report of a phase III multicen- ter randomized controlled trial (abstract). Proc Am Soc Clin Oncol 16:277a, abstract 984
Kollmannsberger C, Budach W, Stahl M, et al. (2003) Adju- vant radiochemotherapy using 5-FU/Folinacid/cisplatin +/– paclitaxel and radiation in patients with completely (R0) resected high-risk gastric cancer (UICC stages II-IV (M0): A phase II study of the AIO/ARO/ACO. Onkologie 26 Sonderheft 5:32–34
Korst RJ, Altorki NK (2004) Imaging for esophageal tumors.
Thorac Surg Clin 14:61–69
Kosho M, Esiashvillie N, Landry JC, et al. (2004) Multiple management modalities in esophageal cancer: combined modality management approaches. Oncologist 9:147–159 Kramling HJ, Willich N, Cramer C, et al. (1997) Early results of
IORT in the treatment of gastric cancer. Front Radiat Ther Oncol 31:157–160
Lagergren J, Bergstrom R, Lindgren A, Nyren O (2000) The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int J Cancer 85:340–346
Launois B, Delarue D, Campoin JP, Kerbaol M (1981) Preop- erative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet 153:690–692
Law S, Wong J (1997) The roles of multimodality treatment and lymphadenectomy in the management of esophageal cancer. Chin Med J (Engl). 110(11):819–825
Law S, Wong KH, Kwok KF, et al. (2004) Predictive fac- tors for postoperative pulmonary complications and mortality after esophagectomy for cancer. Ann Surg 240:791–800
Lee JL, Park SI, Kim SB, et al. (2004) A single institutional phase III trial of preoperative chemotherapy with hyperfrac- tionation radiotherapy plus surgery versus surgery alone
for resectable esophageal squamous cell carcinoma. Ann Oncol 15:947–954
Le Prise E, Etienne PL, Meunier B, et al. (1994) A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 73:1779–1784
Liao Z, Zhang Z, Jin J, et al. (2004) Esophagectomy after con- current chemoradiotherapy improves locoregional control in clinical stage II or III esophageal cancer patients. Int J Radiat Oncol Biol Phys 60:1484–1493
Lordick F, Siewert JR (2005) Recent advances in multimo- dal treatment for gastric cancer: a review. Gastric Cancer 8:78–85
Macdonald JS, Smalley SR, Benedetti J, et al. (2001) Chemo- radiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725–730
Macdonald JS (2005) Role of post-operative chemoradiation in resected gastric cancer. J Surg Oncol 90:166–170
Maipang T, Vasinanukorn P, Petpichetchian C, et al. (1994) Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol 56:191–197 Malthaner RA, Wong RKS, Rumble B, Zuraw L, Gastrointesti-
nal Cancer Disease Site Group of Cancer Care Ontario´s Program in Evidence-based Care (2004) Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a sys- tematic review and meta-analysis. BMC Medicine 2:35–52 Mari E, Floriani I, Tinazzi A, et al. (2000) Efficacy of adjuvant
chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. Ann Oncol 11:837–843
Medical Research Council Oesophageal Cancer Working Party (2002) Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized con- trolled trial. Lancet 359:1727–1733
Minsky BD, Pajak TF, Ginsberg RJ, et al. (2002) INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial combined-modality therapy for esophageal cancer: high- dose versus standard-dose radiation therapy. J Clin Oncol 20:1167–1174
Nygaard K, Hagen S, Hansen HS, et al. (1992) Pre-operative radiotherapy prolongs survival in operable esophageal car- cinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 16:1104-1109 Ogata T, Araki K, Matsuura K, et al (1995) A 10-year experience
of intraoperative radiotherapy for gastric carcinoma and a new surgical method of creating a wider irradiation field for cases of total gastrectomy patients. Int J Radiat Oncol Biol Phys 32:341–347
Ott K, Sendler A, Becker K, et al. (2003) Neoadjuvant chemo- therapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: a prospective phase II study. Gas- tric Cancer 6:159–167
Patel M, Ferry K, Franceschi D, et al. (2004) Esophageal carci- noma: current controversial topics. Cancer Invest 22:897–912 Pouliquen X, Levard H, Hay JM, et al. (1996) 5-Fluorouracil
and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. French Association for Surgical Research.
Ann Surg 223:127–133
Rebecca WO, Richard MA (2003) Combined chemotherapy and radiotherapy (without surgery) compared with radi-
