This approach has been shown to be of value in rectal cancer.³ There have been six randomised trials of preoperative radiotherapy. Three trials were restricted to squamous carcinoma. One of these, by Gignoux et al., reported an improvement in local/regional recurrence (46% vs. 67%).⁴ Nygaard et al. report improved survival, but this series is complicated by the inclusion of some patients also receiving chemotherapy.⁵ One trial included both squamous and adenocarcinoma,⁶ and two do not specify the histology. Overall it is difficult to draw firm conclusions from these trials.

A meta-analysis of updated individual patient data from 1147 patients in randomised trials reported a hazard ratio of 0.89 (95% confidence interval (CI) 0.78–1.01) with an absolute survival benefit of 4% at 5 years.⁷ This result did not reach conventional statistical significance. The benefit therefore seems likely to be small, if present, and with little evidence of improved resectability.

Postoperative radiotherapy

Postoperative radiotherapy can be challenging in terms of tolerance for the refashioned gastric conduit, avoiding the critical normal tissues such as the spinal cord with a posteriorly placed anastomosis and where the anastomosis is situated some distance proximal to the surgical bed, if both require treatment.

There are four randomised trials in the literature. The numbers are small (totalling 843 adjuvant patients), and three out of the four include only squamous carcinoma. Teniere et al.⁸ showed no survival advantage in 221 patients. There was a small improvement in the failure rate but at the cost of significant side-effects. The benefit appears to be limited to node-negative patients. Fok et al.⁹ included both adenocarcinoma and squamous carcinoma. Whilst both curative and palliative resections were included, the patients were separately analysed and received different radiotherapy doses. The results show a significant morbidity (37%) and mortality related to bleeding from the transposed intrathoracic stomach. It should be noted that the dose per fraction of the radiotherapy was high (3.5 Gy), which may be significant. There was a lower intrathoracic recurrence rate, particularly relating to tracheobronchial disease.

A larger randomised study from China included 495 well-staged patients with squamous carcinoma randomised to receive either surgery alone (S) or surgery and postoperative radiotherapy (S + R).¹⁰ Whilst there are significant concerns about the ethics (the patients were not aware they were in a trial and so did not give appropriate consent), the study was still published because of its significant results. The surgery appears to be of a high standard and included a radical lymph node dissection. The radiotherapy was wide field and included the bilateral supraclavicular fossae (SCF), mediastinum and anastomosis to an initial dose of 40 Gy. A further 10 Gy was given to the SCF and 20 Gy to the mediastinum by a different technique, allowing a maximum dose to the transposed stomach of 50 Gy. There was a relatively high proportion of earlier stage IIA disease in the study compared with a UK population. The analysis showed a highly significant difference in 1-, 3- and 5-year survival in stage III disease between the S and S + R arms (67.5%, 23.3%, 13.1% vs. 75.5%, 43.2%, 35.1%, respectively). The pattern of relapse was different between the two arms, with significantly fewer recurrences in the neck, SCF and mediastinum. Unlike other studies, toxicity to the transposed stomach was minimal.

The role of postoperative radiotherapy-based treatment in the case of a histological R1 resection is even less clear. There have been no randomised trials addressing this group of patients; indeed, the quality of reporting of circumferential resection margin (CRM) involvement by microscopic disease, which is influenced by postoperative surgical dissection of the operative specimen, is variable. In the absence of randomised evidence, the knowledge that radiotherapy has a proven role in oesophageal cancer probably justifies considering patients with longitudinal resection margin involvement for postoperative radiotherapy on an individual patient basis. When undertaken, there is some evidence that one should attempt to encompass both the anastamosis and the tumour bed but in the case of a high anastomosis for a lower oesophageal cancer, which is difficult to see radiologically, this can be challenging and requires specialised multidisciplinary input. The role for radiotherapy treatment in the case of CRM involvement is unclear, but it would seem sensible to target those patients where the risk of systemic disease relapse is lower, i.e. those with a lower ratio of involved lymph nodes.¹¹

There is thus reasonable evidence that postoperative radiotherapy may be offered to pathological stage III squamous carcinoma of the oesophagus. To translate the results into UK practice, where many patients will have had preoperative chemotherapy, would require a step away from a pure evidence base, but is perhaps justifiable given the effect on relapse patterns. For adenocarcinoma the justification is less clear outside the context of a clinical trial. Use for patients with an R1, resection should be given within the context of specialised multidisciplinary team care with adequate expertise in radiology, pathology, surgery and oncology, taking into account risk of local failure, i.e. longitudinal or CRM involved margins, involved lymph node burden and postoperative patient fitness.

Preoperative chemotherapy

Preoperative chemotherapy in both squamous and adenocarcinoma appears to achieve consistently good clinical response rates, ranging from 47% to 61%.^12,¹³ Early studies, predominantly in squamous carcinoma, used combinations of cisplatin, vindesine and bleomycin. More recently, cisplatin and 5-fluorouracil (5-FU) combinations have been used in important randomised trials. New 5-hydroxytryptamine-3 (5-HT₃) antagonist antiemetic drugs have allowed cisplatin to be used with dramatically reduced toxicity. Protracted venous infusion (PVI) of 5-FU, and more recently capecitabine, an oral 5-FU prodrug, in combination with cisplatin and epirubicin (the ECF regimen) has produced increased response rates in non-randomised studies. These more modern cisplatin–5-FU combinations seem to be active in both squamous¹⁴ and adenocarcinoma,¹³ although the benefit of anthracycline therapy, i.e. epirubicin, in squamous cell carcinoma is less certain and is therefore often omitted.

Randomised trials of preoperative chemotherapy

The American Intergroup Trial (INT 0113) produced data on 440 randomised patients with a median follow-up of 46.5 months.¹⁵ Adenocarcinoma (54%) was the predominant histology. The chemotherapy given was three preoperative courses (cisplatin and 5 days of infusional 5-FU) and in stable or responding patients two postoperative courses. Overall, 83% of patients received the intended two preoperative cycles of chemotherapy. However, only 32% of patients received both postoperative chemotherapy cycles. There was no difference in treatment-related mortality between the two arms (6% surgery (S) vs. 7% chemotherapy (C) + surgery (S); P = 0.33). On an intent-to-treat basis there was no difference in median survival (16.1 months C + S vs. 14.9 months S), and 1-, 2- and 3-year (23% C + S vs. 26% S) survivals. Disappointingly, there was no difference in the pattern of metastatic disease between the two arms. However, there was a significantly higher rate of R1 resections in the surgery-alone arm.

The Medical Research Council (MRC) OEO2 study is the largest and arguably the most influential trial in this area.¹⁶ A total of 802 patients were randomised to receive two courses of cisplatin and a 4-day infusion of 5-FU followed by surgery (CS) after 3–5 weeks or immediate surgery alone (S) and showed a significant survival advantage for patients receiving preoperative chemotherapy.

The majority of patients (66%) had adenocarcinoma histology. The two arms appear balanced and criticisms of the staging, which was relatively poor by modern standards and could have been as little as a chest radiograph and an abdominal ultrasound, are largely mitigated by the size of the study. The majority of patients in the CS arm received both of the cycles of chemotherapy (90%), with another 6% having just one cycle. The overall operation rate was similar in both arms but there was a significant difference in the microscopic complete resection rate (60% CS vs. 53% S; P < 0.0001). There was good evidence for a downstaging effect in terms of size of primary and extent of nodal involvement. The postoperative mortality was equivalent in both arms at 10%.

The overall survival rate was significantly improved with preoperative chemotherapy (P = 0.004; hazard ratio 0.79, CI 0.67–0.93), with an estimated reduction in risk of death of 21% and 2-year survival figures of 43% CS vs. 34% S. There was no evidence that the effect of chemotherapy varied with histology. Long-term follow-up with a median follow-up of 6 years has confirmed these results, with 5-year survivals of 23% CS vs. 17% S.¹⁷

The differing results between the two US and European trials are difficult to explain. Concerns about a low operation rate of 80% in the chemotherapy arm of the Intergroup Trial may reflect the more ambitious and prolonged chemotherapy regimen, leading to more toxicity. In the MRC trial there was no real difference in the rate of death from cancer and one could hypothesise that the important determinant of survival is the achievement of a potentially curative R0 resection, enhanced by the local downstaging effect of chemotherapy (it must remembered this trial was performed in the era prior to improved staging with endoscopic ultrasound (EUS) and computed tomography (CT)/positron emission tomography (PET) scans). Any factor that precludes such a resection, resulting from chemotherapy, such as excess toxicity or delay in surgery in non-responding patients, might counter any gains in the responding patients.

An updated Cochrane review of 11 randomised trials involving 2051 patients concludes that there was a 21% increase in survival at 3 years with preoperative chemotherapy, but that statistical significance was not reached until 5 years.¹⁸ Increased toxicity and mortality due to chemotherapy were evident and the pathological complete response (pCR) rate was a disappointing 3%. Preoperative chemotherapy has been adopted as a standard of care in the UK, although chemoradiation is more widely used in the USA.

The recently completed MRC/NCRI trial in the UK (OEO5) compared OEO2 chemotherapy with four cycles of ECX (epirubicin–cisplatin–capecitabine) in adenocarcinoma alone. The high completion rate and positive results of preoperative chemotherapy in the MRC MAGIC (ST02) study ¹⁹ for gastric and gastro-oesophageal cancer pointed to the strategy of using a modified ECF regimen, which is accepted in the UK as the best standard of care for advanced gastro-oesophageal cancer, and using it in a neoadjuvant setting to try and improve on the results of OEO2. The results of the REAL2 study,²⁰ a phase III trial of palliative chemotherapy, showed that the oral fluoropyrimidine (capecitabine) could be substituted for infusional 5-FU with safety and at least equivalent efficacy. The advantage of easier chemotherapy delivery without the use of Hickman lines and their associated morbidity is a step forward. This study is also important in that it places an emphasis on high-quality assurance of staging, surgery, chemotherapy and pathology. There is little doubt that at least one of the reasons for differing results in trials in the whole area of gastro-oesophageal cancer has been a wide variation in the quality of staging modalities and surgery, as well as the heterogeneity in the regimens tested and trial design. The MRC OEO5 trial attempted to set high standards that should translate into improved patient selection and outcomes, even within the control arm.

Postoperative chemotherapy

There are few useful trials that address the question of adjuvant postoperative chemotherapy. The trials reported by Roth et al.²¹ and Kelsen et al.¹⁵ both have an adjuvant component, coupled with preoperative treatment. The fact that only 32% completed the postoperative phase in the Intergroup study underlines a problem with this approach.¹⁵ Patients undergoing major resections for oesophageal carcinoma often have a prolonged postoperative phase. The start of chemotherapy may be delayed due to performance status. Patients may also choose not to continue. A strategy that relies solely on postoperative treatment may have significant problems. Improved patient selection and postoperative supportive care may allow this approach to be practical. The MAGIC gastric cancer trial latterly included tumours of the gastro-oesophageal junction and lower oesophagus and intended three postoperative courses of ECF as well as three given preoperatively in the protocol. Again, only 40% completed the postoperative chemotherapy. The trial has shown an improvement in overall survival, as described in the section on gastric cancer,¹⁹ which lends further support for the concept of neoadjuvant chemotherapy for cancers of the oesophagus or gastro-oesophageal junction.

Preoperative chemoradiotherapy

The rationale in using chemotherapy and radiotherapy together is that enhanced tumour cell kill might lead to improved outcomes. Chemotherapy can lead to a decreased ability of tumour cells to repair radiation-induced DNA damage. Many of the commonly used chemotherapy drugs with significant activity in oesophageal and gastric cancer appear to be radiation sensitisers (5-FU, cisplatin, mitomycin C and taxanes). There is good evidence that pCR rates are significantly higher with CRT than with radiotherapy or chemotherapy given alone. There is the significant attraction of achieving enhanced local therapy coupled with a systemic benefit as sought with preoperative chemotherapy alone. When added to surgery, it is not clear that pCR is necessarily the only useful end-point. Preoperative CRT has the added advantage in providing direct evidence to guide the process of developing and optimising combination chemotherapy and radiotherapy schedules for use as definitive treatments.

Both radiotherapy and chemotherapy rely on achieving an acceptable balance between increased response rates in the tumour on one hand and normal tissue morbidity coupled with patient tolerance on the other. Whilst many of the side-effects of chemotherapy are relatively early in presentation, for example hair loss, emesis and myelosuppression, radiotherapy side-effects can present late, from 6 months to years out from treatment. If radical surgery is added in combined modality therapy then the potential for high levels of morbidity becomes significant.

Non-randomised studies of CRT have appeared in the literature since the late 1980s. The review article by Geh et al.²² summarises 46 trials containing 20 patients or more. Overall, pooled data from these studies show that, of 2704 patients (squamous 68% and adenocarcinoma 32%), 79% were operated on with a pCR rate of 24% of those treated and 32% of those resected. As experience with this modality of treatment has grown, lessons have been learned. Attempts to escalate the dose of radiotherapy can lead to unacceptable rates of morbidity, especially if higher doses per fraction are used.^23,²⁴ Reported CRT-related deaths in the non-randomised series ranged from 0% to 15% (mean 3%). Postoperative deaths ranged from 0% to 29% (mean 9%). Adult respiratory distress syndrome, anastomotic leak and breakdown, pneumonia and sepsis were the commonest causes of death following oesophageal resection. Treatment-related deaths ranged from 3% to 25% (mean 9%) of all patients treated. It seems clear that the risk of chemotherapy-related toxicity, particularly myelosuppression, rises with the number of drugs used and the intensity of the CRT regimen.^25,²⁶ An increased risk of tracheobronchial fistula has been reported.²⁷ However, most of the reported series did not have the latest sophisticated radiotherapy techniques that allow greater precision and sparing of organs and tissues to within normal tissue tolerance.

Consistent reporting of pathology is important, and a grading of CRT response has been described by Mandard et al.²⁸ Five grades of response ranging from no identifiable tumour to complete absence of regression allow a more objective approach to be adopted. In this paper the significant predictor of disease-free survival after multivariate analysis was the tumour regression grade. There is evidence that pCR confers a survival advantage over those patients not achieving pCR.^29–34 In Fig. 9.1, different comparative outcomes, such as median survival in months, overall or disease-free survival in years, are plotted together in the series, quoting outcomes separately. The importance is in the consistent nature of the difference in outcomes in each series. It becomes clear that prediction of this response prior to treatment either through molecular markers or PET activity after induction chemotherapy alone might allow very different algorithms of treatment modalities (also see Chapter 3).

Figure 9.1 Relative survival outcomes – pathological complete response (pCR) to CRT.

Table 9.1 summarises nine reported randomised trials of preoperative CRT compared with surgery alone. In four of these the chemotherapy was given sequentially to the radiotherapy and in four synchronously. Two trials using sequential treatment in squamous carcinoma received relatively low doses of radiotherapy and showed no convincing evidence of improved survival with the combined treatment.^6,³⁵ In a larger European Organisation for Research and Treatment of Cancer (EORTC) trial involving 282 patients, the cisplatin chemotherapy was given in close sequence with the radiotherapy.²⁴ The radiotherapy was given in a split course and at a relatively high dose per fraction (two courses of 18.5 Gy in five daily fractions split 2 weeks apart). The CRT patients were more likely to have a curative resection. The disease-free survival was significantly longer (3-year CRT + S 40% vs. S 28%). There was no difference in the overall survival, largely due to a significantly higher postoperative mortality in the CRT arm (12% vs. 4%). Apinop et al.³⁶ reported a synchronous CRT series of 69 squamous histology patients with no improvement in survival.

Table 9.1

Randomised trials of preoperative chemoradiation

^*Bleo, bleomycin; Carbo, carboplatin; Cis, cisplatin; 5-FU, 5-fluorouracil; Tax, paclitaxel; Vbl, vinblastine.

^†DFS, disease-free survival; OS, overall survival.

There are four larger trials of preoperative synchronous CRT.

The Walsh et al. study has been influential in changing practice, particularly in the USA.³⁷ In 113 patients with adenocarcinoma, cisplatin and 5-FU were given with 40 Gy in 3 weeks of radiotherapy. There was an overall survival benefit in favour of the CRT arm (median 16 months vs. 11 months; 3-year survival 32% vs. 6%). Morbidity in this series was not inconsiderable. The radiotherapy technique and fractionation may explain this. Most open to question, however, is the noticeably poor survival in the surgery alone control arm. The basic standards of staging could potentially have led to an imbalance of true staging in the treatment arms.

The University of Michigan trial ³⁸ randomised 100 patients including both squamous and adenocarcinoma. The surgery was a transhiatal resection. Patients in the CRT arm received 45 Gy in 30 fractions with cisplatin, 5-FU and vinblastine. At first analysis there was no significant difference between the arms but at 3 years a statistically significant benefit to the combined treatment emerged, with overall survival of 32% vs. 15%. A final analysis has shown no survival advantage and demonstrates the danger of early publication of a trial that was essentially underpowered.

The results of the Australasian Gastro-Intestinal Trials Group (AGITG)³⁹ have been criticised for having a low radiotherapy dose and only one cycle of cisplatin and 5-FU chemotherapy. Although the trial was negative overall there are some clues for the direction of future approaches. There was a significant survival difference in patients with squamous histology (36% of the total) with the addition of CRT and a much higher pathological complete response rate.

The US trial NCCTG-C9781 (CALGB 9781) closed prematurely as a result of poor recruitment due to a reluctance to recruit patients to a trial with a no treatment arm. However, mature results from CALGB 9781 are available and despite small numbers show a significant improvement in overall survival in preoperative CRT compared to surgery alone (5-year survival of 39% vs. 16%).⁴⁰ Resection rates were high in the preoperative CRT arm (87%) and there was no increase in operative mortality. The trial included higher quality staging and surgery.

Interpretation of such heterogeneous trials, in the regimen being tested, design and outcomes, is difficult. Nevertheless, a meta-analysis of randomised trials has shown that this approach increases R0 resection rates, reduces locoregional recurrence and improves survival compared with surgery alone.⁴¹ More recently, and not included in the meta-analysis above, a randomised phase III study comparing surgery alone to preoperative CRT has shown a near doubling of overall survival (OS) in favour of the preoperative arm (OS 49 vs. 26 months, hazard ratio (HR) 0.67), a pCR rate of 32% and no increase in surgical mortality (3.8% (S) vs. 3.4% (CRT-S)).⁴² In the ‘CROSS’ trial, 363 patients with operable oesophageal or gastro-oesophageal junction tumours were randomised to surgery alone or to a preoperative CRT regimen of weekly carboplatin (AUC2) and paclitaxel (50 mg/m²) concurrent with radiotherapy (41.4 Gy in 23 fractions). Of the 175 patients assigned to the CRT arm, 163 completed protocol treatment and the study reported a low incidence of grade 3/4 CRT toxicity (haematological, 6.8%; non-haematological, 16%). The R0 resection rates in the surgery and CRT + surgery arms were 67% and 92.3%, respectively (P = 0.002). The results of this study, performed in patients with a similar stage and morphological distribution to those in the UK, would suggest that where preoperative CRT is delivered safely, this may lead to a significant improvement in outcome.

Neoadjuvant chemoradiotherapy or chemotherapy?

There are still major questions to be answered, but a surgery-alone arm is not likely to be considered acceptable in the UK or in the USA for stage III disease. The good outcomes from surgery alone in stage I and II disease make neoadjuvant therapy difficult to justify.

Early experience with neoadjuvant CRT in the UK was very variable in terms of its impact on operative risk and toxicity. The results of OEO2 have meant that the UK has continued with a chemotherapy approach in the current OEO5 study.

A recent meta-analysis of both chemotherapy and CRT raises some interesting questions.⁴³ It included 10 randomised neoadjuvant CRT versus surgery-alone trials and eight neoadjuvant chemotherapy versus surgery-alone trials. It concluded that the hazard ratio for CRT was 0.81 (corresponding to a 13% absolute difference in survival at 2 years), with similar results for adenocarcinoma and squamous carcinoma. The hazard ratio for chemotherapy was 0.90 (corresponding to a 7% absolute difference in survival at 2 years), with a marked difference between a benefit demonstrated for adenocarcinoma and no benefit for squamous carcinoma. The results of the most recent Gaast study, not included in the above meta-analysis, performed in patients with a similar stage and morphological distribution to those in the UK would suggest that where preoperative CRT is delivered safely, this may lead to a significant improvement in outcome.

There is rightly a clear separation in future trials for adenocarcinoma and squamous carcinoma. As the trend moves towards squamous cancers being treated with primary CRT, the role of preoperative CRT may be revisited as a means of improving the outcome for patients with adenocarcinoma. The majority of such patients will present with stage III disease (at least T3 with lymph node metastases). Such tumours frequently threaten the circumferential margin of surgical resection (CRM), although a clear plane for surgical excision does not exist as it does for other anatomical sites such as the rectum. Disease present at or within 1 mm of the circumferential margin (R1) occurs in more than 50% of stage III cases ^11,⁴⁴ and is a poor prognostic factor. In the OEO2 study, the 3-year and median survival for patients with R0 and R1 resection were reported as 42.4% vs. 18% and 2.1 years vs. 1.1 years, respectively.¹⁶ Preoperative chemoradiotherapy (CRT) has become a standard management strategy in rectal cancer for patients who have a threatened CRM on preoperative staging.

There has been only one randomised phase III trial comparing preoperative chemotherapy with preoperative CRT. This study by Stahl et al. aimed to recruit 354 patients to detect a 10% improvement in OS in favour of CRT (from 25% to 35%) but closed early as only 126 patients could be recruited in 5 years. Nonetheless, it showed a non-significant trend towards improved 3-year survival in favour of CRT (47.4% vs. 27.7%, P = 0.07).⁴⁵

The undoubted extra toxicity may be justified for this selected group and is infinitely preferable to postoperative treatment. New radiotherapy technology allows more accurate treatment delivery and lower morbidity, and when coupled with higher quality surgery and perioperative care should allow the sort of overall results from the Dutch trial ⁴² to be reproduced. Whatever improvements in locoregional treatments are proposed, the highest risk to be faced and addressed with new trials for stage III adenocarcinoma is ultimate systemic relapse. Trials with new biological agents added to standard chemotherapy or selective CRT are likely to be the next step, with advance knowledge from their use in the advanced and metastatic disease setting.

At present preoperative CRT in the UK should be considered within the context of a clinical trial, or at least within the context of a specialist upper gastrointestinal multidisciplinary team (MDT) that can demonstrate the safe delivery of preoperative CRT. A trial should be designed to directly compare neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy approaches, possibly targeting those patients likely to have an R1 resection.

Definitive radiotherapy and chemoradiotherapy

Surgery as a local treatment modality with neoadjuvant chemotherapy or CRT for stage III disease still remains a gold standard against which new approaches to potentially curative treatment must be compared. However, it is clear that there are long-term survivors in series of definitive non-surgical treatment. With an ageing population it must be remembered that ‘inoperable’ due to the nature of local disease or comorbidity and performance status does not mean treatment is therefore palliative.

Definitive radiotherapy

With an increasingly elderly population it is not uncommon to be faced with patients who have localised disease on staging, particularly squamous cancers, but who clearly are not candidates for an operation and who, because of comorbidity, may not tolerate the chemotherapy component of a CRT treatment. There still is a role for radical radiotherapy alone.

Classical figures quoted for survival from radical radiotherapy come from the paper from Earlam and Cunha-Melo.⁴⁶ Mean survival figures of 8489 patients at 1, 2 and 5 years were 18%, 8% and 6%, respectively. Approximately 50% of patients were treated with curative intent. Older series tend to be of squamous carcinoma treated with radiotherapy alone. Modern radiotherapy in more selected patients can produce impressive survival results. In a series of 101 patients treated at the Christie Hospital in Manchester between 1985 and 1994, 3- and 5-year survival figures of 27% and 21%, respectively, were recorded.⁴⁷ There was a slightly better survival for adenocarcinoma, but not reaching statistical significance. The majority of tumours (96/101) were of 5 cm or less in length. Importantly, the only significant prognostic factor was the use of diagnostic CT, introduced during the latter part of the study. This was used to plan the radiotherapy and led to an increase in field sizes. The conclusion of the paper was that radiotherapy provided an effective alternative to surgery and that modern radiotherapy planning techniques may improve results.

There is no reason to compromise on staging or treatment planning standards and with modern technology high doses can be given with low morbidity. A selected series of 51 patients 80 years and over with squamous carcinoma treated with 66 Gy of radiotherapy in Japan produced median survival of 30 months and a 3-year survival rate of 39%.⁴⁸

Definitive chemoradiotherapy

The adoption of CRT stems from high response rates and in particular high pCR rates seen in patients going on to resection. There are four randomised trials comparing radiotherapy alone with CRT. Three of these use low doses or low intensity of chemotherapy. A small series of 59 patients from Brazil did not demonstrate a significant survival advantage.⁴⁹ The response rates and 5-year survival rates (6% vs. 16%) were better in the CRT arm but at a cost of increased acute toxicity. An important non-randomised series is reported by Coia et al.⁵⁰ Treatment was with infusional 5-FU and mitomycin C with 60 Gy of radiotherapy. Patients with early-stage disease are reported separately. The respective 5-year survival and local failure rates, in clinical stages I and II combined, were 30% and 25%. There was no treatment-related mortality, although there was increased acute toxicity (22% grade III and 6% grade IV).

The biggest series with a major impact on treatment patterns has been the RTOG 85-01, Herskovic study.⁵¹ A total of 123 patients were randomised to receive either radiotherapy alone to a dose of 64 Gy or two courses of cisplatin and infusional 5-FU concurrent with 50 Gy of radiotherapy. Two more courses of chemotherapy were scheduled after the completion of the radiotherapy. A summary of the results of the randomised patients is shown in Table 9.2 and demonstrates the significant advantage of combined therapy.

Table 9.2

Summary of results of the RTOG 85-01 study of Al-Sarraf et al. (1997)⁵¹

CT, chemotherapy; RT, radiotherapy.

In a confirmatory study, 69 non-randomised patients were treated with the CRT protocol and achieved similar results in terms of median survival and a 3-year survival of 26%. The acute toxicity in the combined treatment arm was significantly higher, with notably haematological and renal pathology and mucositis as the major problems. There was no significant difference in the late complication rates. In all, 80% of patients in the combined modality arm received the protocol treatment. The poor overall survival in the radiotherapy-alone control arm remains a question mark against the study.

The high local failure rate of 45% in the Herskovic trial led to the Intergroup study 00123 (Minsky) that compared a regimen similar to the Herskovic regimen (modified with narrower radiotherapy fields, radiotherapy using 1.8 Gy/fraction and an alteration in the chemotherapy schedule to reduce anticipated toxicity), to the same schedule but with a higher dose of radiotherapy (64.8 Gy in 36 fractions).⁵² In total, 236 patients, once again predominantly with squamous cell cancer, were randomised within this study. The trial had to be closed prematurely due to an excess of treatment-related deaths in the experimental arm (11 vs. 2), although the majority of these occurred before the higher dose section of the treatment protocol had been received. Although this trial did not show better disease control with higher doses of radiotherapy (56% failure at 2 years compared to 52% in the standard arm) it did demonstrate remarkably consistent outcomes of, approximately 30% survival at 3 years with definitive chemoradiotherapy.

Another approach to improve local control was to use brachytherapy to intensify the radiotherapy dose to the tumour. Study RTOG 92-07 used the 50-Gy external beam and chemotherapy protocol from the Herskovic protocol and added an intraluminal brachytherapy boost with one of two methods of delivery, high dose rate or low dose rate.⁵³ Six of the 35 patients developed an oesophageal fistula and this toxicity was deemed unacceptable.

Following successful CRT or radiotherapy alone there is a significant rate of benign stricture formation. This ranges from 12%⁵⁴ to 25%⁵⁰ in more modern studies. However, good swallowing function can be maintained in the majority of patients. Even in those with a benign stricture, a full or soft diet can be maintained by dilations in 71% of cases.⁵⁵ The treatment of post-CRT benign stricture with stents has not been successful in the authors’ experience and gives rise to mediastinal pain.

The higher pCR rates seen with CRT, the improved local control rates and altered patterns of failure in the literature have all contributed to CRT being largely adopted as a standard of care. The management of patients with CRT is complex and requires good support from specialist nurses and dieticians, and high standards of technical radiotherapy. The risk of morbidity is real but can be overcome. It should be seen as a single integrated modality of therapy rather than two different treatments that happen to be delivered at the same time.

Future directions in definitive chemoradiation

The ability to predict which patients will respond to chemotherapy or CRT would allow greater certainty in a primary non-surgical approach. Molecular markers predicting response to chemotherapy hold some promise.56–58 Conventional reassessment following treatment, with a negative endoscopic biopsy³⁵ and CT,⁵⁹ appears unreliable. However, the use of a positive surveillance endoscopic biopsy to direct salvage surgery in squamous carcinoma treated with definitive CRT has been reported.⁶⁰ Reports of the value of endoscopic ultrasound (EUS) are more variable, with some showing a good correlation with final pathological stage⁶¹ and others suggesting it is not reliable.⁶² There are reports advocating that this failure to reliably predict pCR necessitates resection.³⁴

There is increasing evidence to show that PET scanning may be extremely useful in predicting which patients are responding to chemotherapy and CRT.⁶³ Changes in metabolic activity on PET, 14 days after the start of treatment, appear to be significantly correlated with tumour response and patient survival. The ability to predict response in this way might be an attractive tool to determine if definitive CRT should be continued or a change made to a policy of resection. This would avoid surgical delay and increased morbidity in patients who are unlikely to benefit from chemotherapy or CRT. Such a policy would clearly need validation in a trial setting.

Improvements in CRT outcomes are likely to come from refinements in chemotherapy and radiotherapy technique. Results from preoperative phase II studies suggest a steady improvement in pCR rates, with more acceptable toxicity. The rates of pCR range from 24%³¹ in 1993 to reports of 56%⁶⁴ in 1998. Care must be taken in interpreting the literature as pCR rates can vary depending upon whether rates are quoted as intent to treat or of completed resections, and in the protocols and quality assurance procedures associated with the histological examination. Careful staging can ensure that patients with established metastatic disease are appropriately managed. There has been a trend to accept lower standards of staging in non-surgical series. It is important that all patients who are deemed to have a potentially curative therapy have access to comparable staging, including EUS and PET. In the preoperative setting new protocols can be assessed for toxicity and response rates before use in a phase III randomised setting.⁶⁵

Central to improving treatment strategies is an understanding of patterns of treatment failure. An important series of a detailed analysis of CRT has been published from Australia using combined data from Trans-Tasman Radiation Oncology Group studies.⁶⁶ This looks at results from 274 patients treated with definitive CRT and 92 patients treated with preoperative CRT. A summary of survival and recurrence patterns is given in Table 9.3. The overall local control rate for definitive CRT is almost 55%, rising to 70% in upper squamous cancers. The striking difference in outcome for these upper cancers includes an apparently lower distant failure rate and improved overall survival. It may be that these tumours are inherently different and respond more like squamous carcinomas of the head and neck. The persisting high distant failure rate in adenocarcinoma treated with CRT and surgery underlines a need for either earlier diagnosis and treatment or improved systemic therapy. There is no doubt that the success of CRT as definitive treatment is determined by similar factors to the outcomes of surgery, namely stage, performance status and the length of the tumour.

Table 9.3

Five-year survival and cumulative incidence of relapse in the study of Denham et al. (2003)⁶⁶

^*Def CRT, definitive chemoradiation; CRT + surgery, preoperative chemoradiation + surgery.

There are huge changes in the technology available for radiotherapy treatment. The development of three-dimensional and conformal radiotherapy treatment planning systems directly linked to spiral CT data allows the shape of radiotherapy fields to be individually tailored to an irregular-shaped target volume. In order for this to be successful, however, reliable imaging techniques are essential, including using EUS ⁶⁷ and PET⁶⁸ to help delineate the gross tumour volume, and also localise the tumour on the axial planning CT scans. A reduction in normal tissue damage and so potentially the toxicity of combining therapy will be possible. The ability to define varying dose intensity within a radiotherapy field (intensity-modulated radiotherapy treatment, IMRT) may be helpful in being able to safely increase the dose, especially to tumours in the upper third of the oesophagus. One of the major concerns for tumours in the lower third is the movement of these tumours during treatment as a result of peristalsis, cardiac ejection cycles and especially respiratory motion. This can be up to 2 cm in the superior–inferior direction. There is no doubt that even better distributions of dose can be achieved with proton therapy but availability and cost may preclude this being feasible for some years. Improvements in CRT will also come from a better understanding of the effects on normal tissue near the clinical target volume, such as heart and lung.

The use of new radiosensitising chemotherapy drugs in combination with radiotherapy may allow some small incremental gains in response rates (oxaliplatin/taxanes/capecitabine) and hence local control. Lastly, more attention to the treatment of elective nodal irradiation, perhaps wider fields to a lower dose, may reduce locoregional failure.

The current NCRI study of definitive CRT (SCOPE 1) aims to compare cisplatin and capecitabine with 50 Gy of radiotherapy in the control arm and add the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab to the investigational arm. There is evidence that one mechanism of radiotherapy resistance is through activation of the EGFR pathways and clinical evidence from a randomised trial in squamous cancer of the head and neck of improved local control and overall survival.⁶⁹ This study is important in also defining very high radiotherapy technical standards for the UK, ensuring the accuracy of target volume definition and minimising normal tissue morbidity. It is open to both adenocarcinoma and squamous carcinoma selected by multidisciplinary teams, the entry criteria broadly being patients with disease treatable by chemoradiotherapy who have been deemed unsuitable for surgery due to the extent of local disease, patient comorbidities or patient choice.

Definitive CRT versus surgery

Definitive CRT treatments now report good survival figures ^51,⁵⁹ rivalling those of surgery, stage for stage.^70,⁷¹

In squamous carcinoma there seems to be increasing evidence that a policy of primary CRT with surgery as salvage may be the direction for the future.⁷²

Many squamous cancers are in the mid and upper oesophagus and their pattern of lymph node spread is less predictable. These areas can be safely treated with CRT with increasing sophistication. The evidence base for equipoise in efficacy in the treatment of patients with oesophageal adenocarcinoma is less robust. Tumours primarily of the lower oesophagus or limited to the gastro-oesophageal junction might be candidates for CRT but target volumes are more difficult and perhaps CRT should be reserved where a surgical approach is ruled out by age, performance status or comorbidity.

There have been few trials that allow a direct comparison between a primary CRT policy and surgery, and indeed CRT studies may have had a selection bias against them. The results of CRT alone tend to have 5-year survival figures generally comparable to those seen in Tables 9.2 and 9.3, of the order of 30% overall, which are similar to surgical series. Squamous cancers, in particular of the mid and upper thirds, have better outcomes. It does allow CRT to be considered as a viable option to chemotherapy and surgery for adenocarcinoma and as primary treatment for squamous carcinoma.

There are two trials that address the additional value of surgery after CRT and would give some support to a selective approach to its use, particularly in squamous carcinoma. The conflicting results of these trials suggest surgery is not routinely necessary following definitive CRT.

In a French study, patients were assessed after induction CRT using 5-FU and cisplatin.⁷³ If they had achieved an objective response they were randomised (295 of 455 patients) to carry on with CRT or go to surgery. There was no significant difference between the 2-year survival rates for patients who had surgery (33.6%) and those who had CRT alone (39.8%). There were more early deaths in the surgery arm but CRT required more dilatations and stents.

In a German trial, 177 patients with T3 or T4 squamous carcinoma were randomised to receive CRT + surgery or CRT alone.⁷⁴ The rate of response to initial CRT was the same for both arms. There was a strong trend towards improved local tumour control in the arm with surgery. In responding patients the 3-year survival (45% and 44%, respectively) was equivalent in both arms, whereas in non-responding patients the rates were 18% and 11%, respectively. The 3-year survival rate improved to 35% in non-responding patients undergoing complete tumour resection, implying that a subgroup of non-responding patients may benefit from surgery as an elective salvage procedure. Longer-term results confirm no clear survival difference between a surgical versus CRT approach. This trial did show that a clinical response to induction chemotherapy may be a valuable surrogate for predicting prognosis.

There is evidence collected from the literature that selected salvage surgery is possible after CRT failure, with acceptable operative mortality of 11.4% and 5-year survival rates of 25–35%.⁷⁵ Clearly such a high-risk policy should be after CT-PET restaging and only within the context of a tertiary MDT with audited results for the safe delivery of both chemoradiation and surgery.

Small-cell oesophageal cancer

Small-cell oesophageal cancer (SCOC) is a rare entity, accounting for up to 2.5% of primary oesophageal cancers and associated with a poor prognosis due to a high rate of metastatic disease. It thus requires a distinct approach to management with similarities to primary small-cell lung cancer (SCLC), which has similar histological features.

The literature is made up of small retrospective series from major institutions. It tends to have male preponderance and occurs in the mid and lower oesophagus. Series vary but most, even with staging that would be considered less than optimum today, have a majority of patients with metastases at presentation. The median survival of untreated metastatic patients is less than 3 months.

The treatment of SCOC is dependent on a separation between limited disease and extensive disease. Table 9.4 shows the outcomes in two of the larger and most recent series in the literature.^76,⁷⁷ Both have good references and discussion.

Table 9.4

Outcomes of small-cell oesophageal cancer series

ED, extensive disease; LD, limited disease.

The treatment of patients with extensive disease is palliative chemotherapy based on etoposide- and platinum-containing regimens if the performance status allows. Response rates to treatment are high and there is definite improvement in overall survival, but outcomes are universally poor, with median survivals of 8–11 months.

Due to the very high rate of systemic relapse, limited stage disease requires primary treatment with chemotherapy, again based on etoposide- and platinum-containing regimes. There is a role for consolidation treatment to enhance local control and to prevent local symptomatic progression. There are surgical series with good local control rates, but the majority of series concentrate on radiotherapy (doses up to 50 Gy) or chemoradiotherapy as would be considered for SCLC, thus avoiding the mortality risk and morbidity of surgery.

Local control rates with surgery are high but overall prognosis poor, with survival dictated by metastatic disease and median survivals in the range of 15–24 months. There is no literature on prophylactic cranial irradiation, which has been shown to be an advantage in SCLC after successful systemic and local therapy.

Gastric cancer

Potentially curative treatment

Perioperative adjuvant chemotherapy

The goal of systemic therapy for gastric cancer is to reduce the late patterns of failure following successful surgical resection. The pattern of spread includes nodal, transcoelomic and haematogenous. A significant proportion of patients with intra-abdominal, hepatic, peritoneal or omental disease will fail. Extended lymphadenectomy has been advocated to improve the local/regional control rates. Chemotherapy, either systemic or intraperitoneal, has been used to try to reduce the incidence of widespread recurrence. Despite encouraging results for chemotherapy in advanced disease, proof of a benefit for adjuvant postoperative chemotherapy has been elusive. Standard approaches have been with postoperative chemotherapy but more recent studies have looked at a combination of preoperative and postoperative treatment.

There have been a wide range of randomised adjuvant chemotherapy trials. Regimens with significant activity in the advanced disease setting have been tested since the 1980s. There are variations in the surgery used, the timing of the start of chemotherapy and the toxicity, which all make interpretation and comparisons difficult.

Three meta-analyses exist.78–80 In summary, these demonstrate a small survival benefit of borderline significance that was more marked in trials, with greater than two-thirds of patients having node-positive disease.

However, many of the regimens in the older studies have low response rates (10–30%) in advanced disease, compared with the higher expected response of more modern regimens such as ECF.

The MRC STO2 (MAGIC) trial was opened in 1994 and aimed to recruit 500 patients testing the role of three courses of ECF before and after resection in operable gastric cancer. The results suggest a significant downstaging effect of the chemotherapy.¹⁹ As the MRC OEO2 neoadjuvant oesophageal trial was completed, the eligibility criteria were widened in 1999 to include adenocarcinoma of the lower oesophagus. The type of resection was left to the discretion of the participating surgeon and the staging was relatively permissive by modern standards. The arms of the study were well balanced and included 74% stomach, 14% oesophageal and 12% junctional cancers. Toxicity of the chemotherapy was acceptable but only 40% of patients received both cycles of postoperative treatment. In fact, the majority of resections were at least D1, with 40% having a D2. The proportion deemed to have had a potentially curative resection was 10% higher with chemotherapy (79% vs. 69%). There was a significant effect on tumour size, T stage and nodal status. Recent results with a median follow-up of > 3 years have demonstrated an improvement in overall survival (hazard ratio of 0.75, P = 0.009), with 5-year survival rates of 36% for chemotherapy and surgery vs. 23% for surgery alone. Progression-free survival was also significantly prolonged.

In a similar French multicentre trial, of perioperative fluorouracil plus cisplatin in resectable gastro-oesophageal adenocarcinoma, 224 patients with resectable adenocarcinoma of the lower oesophagus, gastro-oesophageal junction (GEJ) or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111).⁸¹ Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m²) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m²/day) for 5 consecutive days (days 1–5) every 28 days and three or four postoperative cycles of the same regimen. The CS group had a better overall survival (5-year rate 38% vs. 24%; HR for death: 0.69; 95% CI 0.50–0.95; P = 0.02). The postoperative morbidity was similar in the two groups.

It is thus reasonable to adopt a standard approach using perioperative chemotherapy for tumours other than early-stage gastric cancer.

The current NCRI study ST03 or ‘MAGIC 2’ compares three cycles of pre- and postoperative ECX with the addition of bevacizumab and three cycles of maintenance bevacizumab, a humanised monoclonal antibody against vascular endothelial growth factor (VEGF).

Intraperitoneal chemotherapy

The pattern of peritoneal and hepatic recurrence in gastric cancer makes the early use of intraperitoneal chemotherapy attractive. The most positive trial is from Japan,⁸² using mitomycin C adsorbed on to activated charcoal, acting as a delayed-release preparation. Fifty patients with serosal involvement were randomised to immediate treatment or observation. A highly significant difference in survival at 2 years was seen (68.6% vs. 26.9%), with the treatment group maintaining its advantage at 3 years. The treatment was reported to be well tolerated. However, when an attempt was made to repeat these results, in an Austrian multicentre study,⁸³ serious toxicity caused the trial to be suspended. A significantly higher postoperative complication rate (35% vs. 16%) and 60-day mortality rate (11% vs. 2%) were seen in the treatment arm of the study. No benefits were found in overall or recurrence-free survival.

Postoperative chemoradiotherapy

Radiotherapy has not been routinely used in the management of stomach cancer. However, local recurrence can be a significant problem. The stomach and nodal areas are close to many crucial normal tissues with dose-limiting susceptibility to toxicity, such as kidney, spinal cord and small bowel.

In the British Stomach Cancer Group trial,⁸⁴ postoperative radiotherapy was one of the arms of the study. The other arms were FAM chemotherapy and a control surgery-only group. There was no difference in survival but the local recurrence rate was significantly better (54% surgery vs. 32% with radiotherapy; P < 0.01).

The American Intergroup INT 0116 (SWOG 9008) study (commonly referred to as the Macdonald study) has produced important results. Postoperative CRT has been reported to show a significant benefit to survival following gastric resection.⁸⁵

The regimen consisted of 5-FU–leucovorin (folinic acid) given in the first and last weeks of radiotherapy (45 Gy) and two 5-day courses of 5-FU–leucovorin given monthly. With a median follow-up of 3.3 years both the disease-free survival (49% vs. 32%) and overall survival (52% vs. 41%) were improved in the CRT arm. There was some significant haematological and gastrointestinal morbidity. However, the treatment-related mortality was only 1%. The need for great care in the technical quality and placement of the radiotherapy was apparent. However, a significant proportion of the patients (54%) had only a D0 resection and the survival in the surgery-alone arm was relatively poor (41% 3-year survival). It is possible that the CRT is making up for less than adequate surgery, and may not translate into routine practice where more extensive surgery is undertaken. It is the most obvious source of criticism of the trial. However, in a subsequent paper,⁸⁶ using a different surgical quality assurance measure for the likelihood of undissected disease (the Maruyama Index), the group concluded that surgical under-treatment clearly undermines survival. Major concerns about the toxicity and chemotherapy used and the poor radiotherapy technique are being addressed, which should significantly reduce the potential for long-term morbidity and make the most of sophisticated IMRT and radiotherapy planning techniques. Despite criticisms, postoperative CRT has been patchily adopted throughout the world.

Thus there are now two major trials demonstrating improved survival with the addition of perioperative therapy in gastric cancer. One study (MAGIC)¹⁹ involves pre- and postoperative chemotherapy, and the other (INT 0116)⁸⁵ the use of postoperative CRT. Whilst one can argue the relative merits of each approach, one certain conclusion is that for all but early-stage tumours surgery alone is no longer a standard of care.

Palliative chemotherapy

Squamous carcinoma of the oesophagus

Cisplatin-containing combination chemotherapy is the standard for the treatment of advanced and recurrent squamous carcinoma. The indications for use are limited by the relative infrequency of the disease, and in particular the age and performance status of patients requiring palliation. Very often the indication is to improve symptoms and quality of life caused by the primary leasion and local therapy with a stent or radiotherapy will be adequate. However, good response rates of the order of 35% can be achieved with cisplatin and 4- or 5-day 5-FU infusion.⁸⁷ Response duration is variable and can range from 3 to 6 months. Consideration should be given to consolidation palliative radiotherapy after successful chemotherapy to improve local control where recurrent growth may produce symptoms for patients with a better performance status and expectation of life. There is some evidence that the improved response rates seen with PVI of 5-FU in adenocarcinoma can be achieved in squamous carcinoma.¹⁴ New agents such as paclitaxel are clearly active as single agents but have yet to demonstrate their clear superiority in combination regimens. Some results are promising, with response rates nearer 50%.⁸⁸

Adenocarcinoma of the oesophagus and stomach

Whilst earlier literature tends to report activity in pure gastric cancer, the changing pattern of disease has meant that more recent reports deal with oesophagogastric cancer. The single agents most commonly used in the treatment of advanced oesophagogastric cancer include 5-FU, methotrexate, mitomycin C, the anthracyclines doxorubicin and epirubicin, cisplatin and etoposide. More recently the oral 5-FU prodrugs such as UFT and capecitabine, the taxane drugs, irinotecan and gemcitabine all feature in new phase II studies. Biological agents such as EGFR monoclonal antibodies represent a new potential means of improving outcomes.

There are early randomised clinical trials of palliative chemotherapy versus best supportive care that clearly show improved survival (8–12 months chemotherapy vs. 3–5 months best supportive care).89–91

The FAM regimen (5-FU, doxorubicin and mitomycin) initially seemed to have a high response rate of 40%.⁹² However, in the setting of a randomised trial by the North Central Cancer Treatment Group, it seemed to be no better than 5-FU alone.⁹³ In an attempt to modulate the activity of 5-FU within the FAM regimen, high-dose methotrexate was given 1 hour before the 5-FU in the FAMTX regimen (fluorouracil, doxorubicin and methotrexate). Klein produced impressive results in a study of 100 patients.⁹⁴ The response rate was 58%, with a complete remission rate of 12%. There were only 3% treatment-related deaths and a long-term survival rate of 6%. The response rate seen in subsequent studies was slightly lower but still confirmed acceptable toxicity. This regimen has now been tested against other combinations. A randomised EORTC trial with 208 evaluable patients demonstrated its superiority against FAM.⁹⁵ Median survival was better (42 weeks vs. 29 weeks; P = 0.004), with 41% and 9% of the FAMTX patients alive at 1 and 2 years, respectively, compared with 22% and 0% for FAM patients. The EAP regimen (etoposide, doxorubicin and cisplatin) was found to have similar survivals, similar overall response rates but lower complete remission rates and was significantly more toxic.⁹⁶ The recent EORTC trial has compared three regimens, FAMTX, ELF (etoposide, leucovorin and bolus 5-FU) and FUP (infusional 5-FU and cisplatin), in 399 randomised patients.⁹⁷ There was no significant difference in median survivals between the regimens. The response rates were lower than in some previous trials (ELF 9%, FUP 20%, FAMTX 12%) but this trial had tight objective response criteria and required measurable disease. The conclusion is that they all produce modest response with comparable survival and toxicity.

The ECF regimen developed at The Royal Marsden Hospital was shown to have high activity against advanced oesophagogastric cancer.¹³ It has become widely used in the UK and is well tolerated. Its status as the current gold standard was confirmed in a multicentre randomised trial of ECF against FAMTX.⁹⁸ A total of 274 patients with adenocarcinoma or undifferentiated carcinoma of the oesophagus, oesophagogastric junction or stomach were treated.

Patients were predominantly of good performance status with a median age of 60 years. The overall objective response rate was 45% in the ECF arm and 21% in the FAMTX arm (P = 0.0002). The response of locally advanced disease to ECF has previously been shown to be higher than in metastatic disease.¹³ This was confirmed in both arms of the trial (56% ECF vs. 23% FAMTX). Of the 121 patients receiving ECF, 10 were able to undergo a resection due to improved status, six of whom remain disease free. There were three cases of histological pCR. Only 5% of patients had progression whilst on either chemotherapy regimen.

The 2-year survival figures and median survival were 14% and 8.7 months for ECF and 5% and 6.1 months for FAMTX, respectively (P = 0.03).

The ECF results have opened up a grey area in locally advanced gastric and junctional cancer management. Whilst a patient may not be operable, or it may be deemed inadvisable to operate due to the extent of disease at presentation, it may be possible to consider a potentially curative resection in some cases after chemotherapy. The intent of treatment may therefore need to be revisited by close reassessment after chemotherapy. This emphasises the need for teamwork between the surgeon and oncologist within a multidisciplinary setting.

In a study from Leeds of advanced upper gastrointestinal cancer patients, oral UFT and leucovorin were substituted for PVI of 5-FU in ECF in an attempt to create a more practical, acceptable and cheaper alternative (the ECU regimen) without the need for central lines and pumps.⁹⁹ In this dose-escalation pilot study 30 patients were treated. Toxicity was acceptable and of 20 assessable patients, nine of the 15 with gastro-oesophageal cancer had an objective response and two of these were complete radiological responses.

The NCRI REAL2 trial was designed to address some practical problems that surrounded delivery of the gold standard ECF regime.²⁰ Infusional 5-FU has problems associated with Hickman lines, particularly thrombosis and infection. Cisplatin causes renal toxicity and requires prehydration and inpatient admission for higher doses. It tested the toxicity and response rates of oxaliplatin as a substitute for cisplatin, and of capecitabine (an oral fluoropyrimidine) as a substitute for infusional 5-FU in a randomised 2 × 2 study based on statistics of non-inferiority against ECF.

The REAL2 results demonstrated that oxaliplatin can be substituted for cisplatin with less renal toxicity and neutropenia and that capecitabine is a valid substitution for 5-FU.²⁰ Although a secondary end-point, there was a significant improvement in median survival for the EOX (epirubicin–oxaliplatin–capecitabine) regimen compared to the ECF regimen (11.2 months vs. 9.9 months). There was no significant difference in response rates between regimens and a response rate of 40.7% in the ECF arm.

The EOX regimen has been taken forward as the control arm in the next REAL3 study, with the addition of panitumumab (an EGFR antibody) in the investigational arm. Other attempts to improve treatment outcomes using the addition of docetaxel to cisplatin and 5-FU have uncovered high potential toxicities with neutropenia, treatment withdrawal rates of nearly 50% due to grade 3 and 4 toxicity, and no improvement in response rates or survival, raising a question as to whether a plateau has been nearly reached with conventional approaches to chemotherapy.¹⁰⁰ New biological agents possibly bring new distinctions between different agents even within antibodies to the same receptor and very different response rates of gastric and gastro-oesophageal/oesophageal cancers.¹⁰¹ This emphasises the need for good tissue collection and analysis in parallel with clinical studies. The recent closure of REAL3 as a result of insufficient benefits seen in the trial arm of EOX plus panitumumab suggests that we have not yet found the right targets or the optimum agents with which to counter these targets.

Trastuzumab (herceptin), a monoclonal antibody against human epidermal growth factor receptor 2 (HER-2; also known as ERBB-2), was investigated in combination with chemotherapy for first-line treatment of HER-2-positive advanced gastric or gastro-oesophageal junction cancer. The ToGA trial was an international phase 3 study undertaken in 594 patients, randomised to capecitabine or fluorouracil plus cisplatin plus or minus trastuzumab.¹⁰² Median overall survival was 13.8 months (95% CI 12–16; 16.0 months in those who would be considered HER-2 positive by today’s definition (HER-2 3 + or HER-2 2 + + FISH +)) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (95% CI 10–13) in those assigned to chemotherapy alone (HR 0.74; P = 0 · 0046). There were no significant differences in toxicities, including cardiac, between the two groups. The proportion of HER-2-positive tumours ranges from approximately 10% to 30% of all gastric cancers, being higher in gastro-oesophageal junctional cancers, Caucasians and intestinal type pathology.

Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer.¹⁰²

The selection of patients who are likely to benefit from palliative chemotherapy may be helped by the development of prognostic scoring methods. One study has demonstrated that performance status, liver metastases, peritoneal metastases and alkaline phosphatase can be used to separate different risk groups.¹⁰³ Problems in the literature with myelosuppression, and in particular toxic deaths, may be avoided by the use of growth factors to reduce the incidence of neutropenic sepsis. Many of the problems of severe emesis have already been improved by the use of 5-HT₃ antiemetic drugs.

Second-line chemotherapy using taxanes and irinotecan has been reported, with some evidence of worthwhile activity. In practice, however, great care will need to be taken in the selection of suitable patients, and such treatment should really only be undertaken within the context of a trial.

The success in palliative chemotherapy has brought about problems and patterns of recurrence that have not been common before. Brain metastases and bone metastases are increasingly seen. Palliative radiotherapy can be helpful in controlling symptoms.

Palliative radiotherapy

External beam radiotherapy

The whole literature surrounding radiotherapy in a palliative setting is poor. Nonetheless, the role of radiotherapy is important. There are many instances where patients have local symptoms from metastatic disease. With a high proportion of patients presenting with T3N1 disease it is not surprising that many will fail despite more complex and aggressive therapy. The pattern of metastases seems already to be changing in that patients are living to get metastases in brain, bone and skin, as well as recurrent nodal masses. These clinical problems are amenable to short fractionated radiotherapy, which provides good symptomatic relief.

The role of external beam radiotherapy to treat dysphagia has changed with the ready availability of oesophageal stents. Radiotherapy can be very effective in relieving dysphagia but it can take weeks to accomplish this, and it can even temporarily worsen symptoms with radiation oesophagitis. The role of radiotherapy following successful stent placement is unproven. A UK trial has been proposed, largely to explore the possibility of improvements in survival and symptom-free survival. The attraction is in achieving a measure of local disease control and in treating the mediastinum. There is also an intermediate group of patients with good performance status and relatively localised disease who are clearly not appropriate for potentially curative treatment. Some short CRT regimes or primary chemotherapy with consolidation radiotherapy have been used, with some suggestion of improved results. This group of patients deserves greater study to optimise palliation.

There is a major difference between the fractionation regimens used in the USA and in the UK. ‘Palliative’ doses of 40–60 Gy in 4–6 weeks are quoted in the US literature. These are in the radical dose range and are felt to be inappropriate for UK practice, where doses of 20–30 Gy in 1 or 2 weeks are more likely to be used. These can be combined with brachytherapy. Good resolution of tumour and symptom relief in a majority of patients have been reported.¹⁰⁴ Often, however, whichever palliative technique is used first, other modalities have a role for patients with longer survival, to maintain swallowing.

Brachytherapy

Brachytherapy involves the placement of a high-dose-rate radioactive source, usually iridium-192, down the oesophagus in proximity to the tumour. The aim is to get direct tumour cell kill, thereby relieving dysphagia, or in the case of its use as a boost to external beam radiotherapy, to achieve an increased dose to the tumour with minimal dose to surrounding normal tissues. It does not require a general anaesthetic and can be done as a day-case procedure. Occasionally, placement of a nasogastric guide tube is required under endoscopic vision. Pagliero and Rowlands ¹⁰⁵ describe a single dose of 15 Gy with a response rate of about 60% measured at 6 weeks from treatment. It can be repeated in cases of symptomatic relapse.

The optimum dose of brachytherapy has been addressed in a randomised trial using three schedules.¹⁰⁶ Three doses and schedules were tested in 172 patients with advanced oesophageal cancer These were 12 Gy/two fractions (A), 16 Gy/two fractions (B) and 18 Gy/three fractions (C).

Patients were assessed for relief of dysphagia and survival. Dose and tumour length were found to be significant for survival on multivariate analysis. Brachytherapy dose had a significant effect on tumour control. Overall survival for the whole group was 19.4% at 1 year.

The survival by group, although not statistically significant, suggests a trend towards better outcomes with the higher dose schedules of brachytherapy (at 12 months: A = 9.8%, B = 22.5%, C = 35.3%).¹⁰⁶

There are good published guidelines ¹⁰⁷ for the use of brachytherapy, taking into account the potential wide range of applications for this technique.