Neoadjuvant Treatment for Oesophago-Gastric Cancer

In the United Kingdom, oesophageal cancer ranks as the ninth most common cancer with a rising incidence of 13 per 100,000 head of population. Some two-thirds of all oesophageal lesions are adenocarcinomas, the rest are squamous cell carcinomas. The incidence of stomach cancer is similar but a decline has been registered over the past two decades. For both conditions the age at presentation is 60 years or more in over two-thirds of patients. Tumours of the oesophago-gastric junction have received detailed attention over the past years. This is in part because surgical excision through a single operative field may not be possible. Moreover, for this subset of lesions, a rising incidence and worse survival have been registered. Oesophago-gastric malignancies carry a poor prognosis especially when diagnosed at an advanced stage outside screening programmes. In Western countries, this is reflected as overall five year-survival rates ranging from 5 to below 20%. Over the years, treatment has evolved into a multi-modality strategy which is best formulated and overseen in a multidisciplinary setting. The treatment of an individual patient will depend on accurate and reliable tumour staging, assessment of the patient’s fitness for radical surgical and/or oncological treatment, the level of expertise available locally and, of course, the patient’s informed decisions. In a typical surgical unit in the United Kingdom, resection rates will not usually surpass 20%. After radical surgery with curative intent the median disease free survival is of the order of two years with 50% of cases developing metastases and/or recurrence in the first year. These disheartening figures offer the rationale for the addition of further oncological treatment to radical surgery. Neoadjuvant chemotherapy and/or radiotherapy is administered before surgery with the aim of shrinking the primary tumour and theoretically ablating micrometastases and reducing the risk of haematogenous and lymphatic dissemination. This treatment, however, has the potential for toxicity and complications and must be used carefully in patients with co-morbidity. There are concerns that pre-operative treatment may influence the patient’s ability to withstand the surgical insult and the percentage of patients who are fit enough to complete post-surgical treatment regimens is also diminished. This chapter will review the main influential randomised trials employing neoadjuvant treatment for these cancers. It will also comment on the other randomised and nonrandomised series published in the literature focusing on the effect of treatment on resectability, peri-operative morbidity and mortality, resection specimen pathological


Introduction
In the United Kingdom, oesophageal cancer ranks as the ninth most common cancer with a rising incidence of 13 per 100,000 head of population. Some two-thirds of all oesophageal lesions are adenocarcinomas, the rest are squamous cell carcinomas. The incidence of stomach cancer is similar but a decline has been registered over the past two decades. For both conditions the age at presentation is 60 years or more in over two-thirds of patients. Tumours of the oesophago-gastric junction have received detailed attention over the past years. This is in part because surgical excision through a single operative field may not be possible. Moreover, for this subset of lesions, a rising incidence and worse survival have been registered. Oesophago-gastric malignancies carry a poor prognosis especially when diagnosed at an advanced stage outside screening programmes. In Western countries, this is reflected as overall five year-survival rates ranging from 5 to below 20%. Over the years, treatment has evolved into a multi-modality strategy which is best formulated and overseen in a multidisciplinary setting. The treatment of an individual patient will depend on accurate and reliable tumour staging, assessment of the patient's fitness for radical surgical and/or oncological treatment, the level of expertise available locally and, of course, the patient's informed decisions. In a typical surgical unit in the United Kingdom, resection rates will not usually surpass 20%. After radical surgery with curative intent the median disease free survival is of the order of two years with 50% of cases developing metastases and/or recurrence in the first year. These disheartening figures offer the rationale for the addition of further oncological treatment to radical surgery. Neoadjuvant chemotherapy and/or radiotherapy is administered before surgery with the aim of shrinking the primary tumour and theoretically ablating micrometastases and reducing the risk of haematogenous and lymphatic dissemination. This treatment, however, has the potential for toxicity and complications and must be used carefully in patients with co-morbidity. There are concerns that pre-operative treatment may influence the patient's ability to withstand the surgical insult and the percentage of patients who are fit enough to complete post-surgical treatment regimens is also diminished. This chapter will review the main influential randomised trials employing neoadjuvant treatment for these cancers. It will also comment on the other randomised and nonrandomised series published in the literature focusing on the effect of treatment on resectability, peri-operative morbidity and mortality, resection specimen pathological stage and completeness of excision and longer-term outcomes. Finally, future prospects will be explored.

Neoadjuvant radiotherapy for oesophageal cancer
Preoperative radiotherapy in oesophageal cancer patients aims to reduce tumour size, decrease the extent of localised microscopic residual disease and lower the risk of tumour dissemination at the time of surgery. The first published study suggesting that such treatment may improve survival for this group of patients was by Kakyama et al in 1967. The study reported a 5 year survival rate of 37.5% for the group receiving preoperative radiotherapy compared with 19.1% 5 year survival rate in the surgery alone arm. The criticisms of the study are that it was retrospective with no statistical analysis of the data. During the 1980's and early 1990's five randomised controlled trials were published comparing neoadjuvant radiotherapy and surgery alone (Launois et al 1981, Gignoux et al 1987, Wang et al 1989, Arnott et al 1992and Nygaard et al 1992. All these studies except for Arnott et al were restricted to treating squamous cell carcinoma. Radiation doses ranged from 20Gy to 40Gy and were given over a period of eight to twenty eight days. A summary of the five trials is shown in Table 1. None of the trials proved any significant improvement in 5 year survival. However, Nygaard et al 1992 did report 3-year survival rates of 20% in those patients receiving preoperative radiotherapy compared to 5% in the surgery alone arm. This improved survival was only achieved after pooling data from the radiotherapy group with patients receiving preoperative chemo-radiotherapy and did not prove to be statistically significant.

Study
Each of the five trials mentioned contained relatively small numbers of patients. Therefore in order to investigate any small benefit afforded by preoperative radiotherapy, data from all 1147 patients were used in a meta-analysis published by Arnott et al 1998

Neoadjuvant chemotherapy for oesophageal and gastric cancer
Chemotherapy aims to downstage tumours and remove distant micro metastasises. There have been many randomised controlled trials comparing overall survival of oesophageal cancer patients receiving neoadjuvant chemotherapy followed by surgery with surgery alone (Roth et al 1988, Nygaard et al 1992, Schlag et al 1992, Maipang 1994, Law 1997, Kelsen 1998 The surgery alone group numbered 227 patients who had primary surgery. The chemotherapy arm of the trial consisted of 213 patients. Both underwent the same surgical procedure. Surgical mortality was similar in each group, 10% in the chemotherapy arm and 13% in surgery alone group. The patients in the chemotherapy arm received three cycles of cisplatin and fluorouracil before surgery. 71% of patients completed all three cycles. 7% of patients showed a complete clinical regression while 12% achieved a partial regression. Complete responses (T0N0M0) were found in 2.5% of patients. Following chemotherapy 133 patients went on to have a R0 resection. This sub group was due to receive two post-operative cycles of chemotherapy, however, only 32% completed both courses due to patient or physician choice. Overall median survival in the surgery alone group was 16.1 months compared to 14.9 months in the chemotherapy group (p=0.53). Two year survival was 37% and 35% respectively (p=0.74). There was no difference in outcome between patients with adenocarcinoma and squamous cell carcinoma. Among patients whose resection was curative, there was no significant difference in survival between those who did and those who did not undergo chemotherapy (median survival, 27.4 and 25 months, respectively). Kelsen et al concluded that neoadjuvant chemotherapy did not improve survival in oesophageal cancer. It must be noted that the operative mortality in this study is higher than would be deemed acceptable at present (less than 5%).
Kelsen et al 2007 published an update on their 1998 paper in which they looked at the longer term survival of the same group of patients. This again showed no difference in overall survival between patients receiving preoperative chemotherapy compared to those receiving surgery alone although patients with objective tumour regression after preoperative chemotherapy did have an improved survival. The paper also evaluated failure patterns on the basis of completeness of resection, concluding that only R0 resection results in substantial long term survival irrespective of whether neoadjuvant chemotherapy is given. Like Kelsen et al the MRC study was a multi-centre trial recruiting patients suffering from either adenocarcinoma or squamous cell carcinoma of the oesophagus. 802 patients took part and were randomised into two groups, surgery alone n=402 and preoperative chemotherapy plus surgery n=400. Two cycles of chemotherapy were given using cisplatin and fluorouracil. Unlike Kelsen's study, the MRC trial allowed clinicians to give patients preoperative radiotherapy (25-32.5Gy). Nine percent of patients in both groups received radiotherapy.
Of the 400 patients assigned to the chemotherapy arm, 372 received chemotherapy, 350 completed two cycles while 22 patients only completed one. Pathological data from the resected specimens showed that patients who received preoperative chemotherapy had smaller tumours (p=0.0001) that extended less frequently into surrounding tissue and showed less lymph node involvement than tumours in the surgery alone group. Nodes at any site were involved in 195 (58%) of the chemotherapy group and 216 (68%) of the surgery alone patients (p=0.009). Median survival in the chemotherapy group was 16.8 months compared with 13.3 months in the surgery alone group. Two year survival rates were 43% compared with 34%, respectively. There was no evidence to suggest that the effect of chemotherapy varied in accordance with histology. The MRC trial concluded that overall survival was better in the neoadjuvant chemotherapy group than the surgery alone group (HR 0.79; 95% CI 0.67-0.93; p=0.004) with an estimated reduction in risk of death of 21%. Critics of the MRC study suggest that the inclusion of patients receiving preoperative radiotherapy as well as neoadjuvant chemotherapy may be the cause for the improved survival in the chemotherapy group. However, the estimate of treatment effect on overall survival was not altered by removal of those patients from the analysis who received preoperative radiotherapy; hazard ratio for the 728 patients (364 CS, 364 S) who did not receive radiotherapy was 0.78 (95% CI 0.66-0.93; p=0.005). In the chemotherapy group compared with the surgery alone group, more patients were alive without residual or recurrent disease (

Neoadjuvant chemo-radiotherapy for oesophageal cancer
Neoadjuvant chemo-radiotherapy aims to downstage tumours preoperatively and reduce the risk of both local and distant metastatic recurrence. There has been great interest in this area with nine randomised control trials comparing overall survival between patients receiving neoadjuvant chemo-radiotherapy plus surgery (CRTS) and surgery alone (S) in oesophageal cancer patients. Table 6 summarises the treatment regimens while Table 7 shows the overall mortality estimates for each trial. As shown in Tables 4 the numbers of patients taking part in each chemo-radiotherapy trial is relatively small. Treatment regimens also differ with radiation doses ranging from 20 to 50.4 Gy given either concurrently with the chemotherapy or sequentially which would reduce radiosensatisation of the tumour. The type of chemotherapeutic agents administered also varies. However, in the majority of trials, this is in the form of cisplatin (20-100mg/m 2 ) and 5-fluorouracil (300-1000mg/m 2 ). This point was also noted in the meta-analysis by Fiorica et al (2004).

Conclusion
To date, no randomised control trial has shown any survival benefit from neoadjuvant radiotherapy in the treatment of resectable oesophageal cancer. A number of trials have suggested preoperative chemotherapy could improve survival (Roth et al 1988, Law et al 1997, Ancona et al 2001& MRC 2002 However, only the MRC 2002 and MRC MAGIC trial 2006 (only 26% of which had lower oesophageal/gastro-oesophageal junction tumours) showed a small improvement that was statistically significant. For chemo-radiotherapy, the studies by Walsh et al (1996) and Tepper et al (2008) are the only two trials to show a significant survival benefit. All the trials investigating neoadjuvant chemotherapy or chemo-radiotherapy were small in size, often lacking the power necessary to detect small differences between groups. In order to detect a small yet worthwhile benefit from these different treatment modalities, data have been pooled for meta-analysis. The most comprehensive of these by Gebski et al (2007) showed an overall survival benefit from neoadjuvant chemo-radiotherapy of 13% at two years and a benefit of 7% at two years from preoperative chemotherapy. When looking at histological subtypes; chemo-radiotherapy improved survival for both adenocarcinoma and squamous cell carcinoma patients; chemotherapy also improved survival in those with adenocarcinoma however, no benefit was shown for patients with squamous cell carcinoma. Although chemo-radiotherapy has been shown to provide the greatest survival benefit, it has been associated with a higher post-operative mortality (Fiorica et al 2004& Jin et al 2008. As a consequence, clinicians are still divided as to which treatment would be best for their patients.
In this chapter, the majority of trials discussed have employed cisplatin and 5-FU. However, the doses and radiation given to those patients receiving chemoradiotherapy have varied, which makes comparisons between trials more difficult. All the randomised control trials were designed over a decade ago. Since then, new chemotherapeutic agents have become www.intechopen.com available and the delivery of radiotherapy has also advanced. In recent years the use of taxanes, when given concurrently with radiotherapy in the treatment of non-small cell lung cancer, have shown potential (Choy et al 1998, 2000& Lau 2001 Chemo-radiotherapy appears more effective, however, is associated with a higher postoperative mortality than preoperative chemotherapy. Further large scale randomised control trials using new chemotherapeutic agents are on the horizon and new treatments such as immunotherapy which have the ability to specifically target only malignant tissue may provide further improvement in survival in these patients. The most significant advances in cancer therapy in recent years have involved the development of systemic therapeutics. With improvements in response rates in solid tumors, opportunities have arisen to enhance the effectiveness of surgery. Administration of systemic therapy prior to surgery -neoadjuvant chemotherapyrepresents one approach by which clinicians have successfully reduced the extent of surgery and, in some instances, positively impacted on clinical outcomes. This collection of works by expert clinicians from a variety of disciplines represents an exploration of the current knowledge of the role of neoadjuvant chemotherapy in diverse tumor types.

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