Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery

Radiotherapy and Oncology 48 (1998) 15–21

Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery A.J. Sykes*, P.A. Burt, N.J. Slevin, R. Stout, J.E. Marrs Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK Received 4 July 1997; revised version received 10 March 1998; accepted 27 March 1998

Abstract Background and purpose: Despite advances in operative and postoperative care, long term survival rates following radical oesophagectomy are poor. Surgery remains the mainstay of radical treatment despite various series reporting similar results for treatment with radiotherapy, in particular in the upper third of the oesophagus. We have studied a cohort of patients treated with definitive radiotherapy to examine the influence on survival of changes in diagnostic scanning and radiotherapy computer planning as well as various patient and disease related prognostic factors. Patients and methods: From 1985 to 1994, 101 patients with clinically localised carcinoma of the oesophagus were treated at the Christie Hospital with definitive radiotherapy. This included 11 patients with oesophageal adenocarcinoma. Diagnostic and planning techniques changed over the period studied, with increasing use of both diagnostic and radiotherapy planning CT scanning. Radiotherapy doses ranged from 45 to 52.5 Gy in 15 or 16 fractions over 3 weeks. Results: The 3- and 5-year survival figures were 27% and 21%, respectively, corrected for intercurrent deaths. Survival was better for adenocarcinoma than squamous cell carcinoma, though not statistically significantly. The only significant prognostic factor (P = 0.01) was the use of diagnostic CT scanning (42% versus 13% 5-year survival with or without diagnostic CT scanning, respectively) which was associated with an increase in field size. Radiotherapy was well tolerated with no acute mortality or significant morbidity. Late stenosis requiring oesophageal was seen in five of 20 patients surviving 3 years or more. Conclusions: Survival following well planned radiotherapy is an effective alternative to surgery for both squamous cell and adenocarcinoma. Advances in staging and three-dimensional planning and the use of multimodality treatment may further improve survival.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Oesophagus; Carcinoma; Radiotherapy; Surgery; Chemotherapy

1. Introduction The incidence of carcinoma of the oesophagus in both Europe and North America has been gradually, but consistently increasing over a number of years. The number of cases registered in England and Wales has risen from 2239 in 1963, to 5181 in 1989 [6,7], accounting for 2% of cancer registrations. It accounts for 5% of all cancer deaths with an overall mortality of 95% at 5 years. In part this increase in incidence may reflect an increase in the incidence of adenocarcinoma of the oesophagus. It appears to be a true increase, rather than a shift towards the recognition of the diagnosis at sites other than the lower third [23,29]. Oeso* Corresponding author. Tel.: +44 161 4463000; fax: +44 161 4463084.

phageal adenocarcinoma has often been described as a radioresistant tumour, though this may be a perceived wisdom, rather than established fact. As a consequence many surgeons do not refer patients with oesophageal adenocarcinoma, either for radical or palliative radiotherapy. Surgery is traditionally the first choice of treatment for most squamous cell cancers. However not every patient will be fit for the major surgery that is entailed, and definitive radiotherapy offers an effective alternative. In particular, in the upper third of the oesophagus it may reasonably be considered the treatment of choice [31]. To date the only attempt at a prospective trial of surgery versus radiotherapy, the MRC trial of 1986 [13], failed owing to poor recruitment, and there remains a reluctance amongst surgeons to send fit patients with local disease for radiotherapy. Earlam

0167-8140/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0167-8140 (98 )0 0037-1

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and Cunha-Melo [15] have reviewed survival after radiotherapy and found 5-year survival values ranging from 6 to 20% [5,27]; more recent series have published values of 6 to 14% [17,18,20,26,31]. Allowing for the necessarily more rigorous selection of patients for radical surgery these values for 5-year survival are comparable to those for patients following radical oesophagectomy. We have studied a cohort of patients treated with definitive radiotherapy, with the following aims: (1) examination of the influence on outcome of advances in diagnostic CT scanning and computer based radiotherapy planning; (2) study of the various patient, disease and treatment related prognostic factors; (3) assessment of whether radiotherapy has a role in the radical treatment of oesophageal adenocarcinoma.

2. Methods and materials Between January 1985 and December 1994, a total of 699 patients were treated with radiotherapy at the Christie hospital, Manchester, UK, for a diagnosis of carcinoma of the oesophagus. One hundred and one (14.5%) were treated with definitive radiotherapy. The remainder were treated with palliative radiotherapy for locally advanced or metastatic disease. Patients were referred for radical treatment with radiotherapy either due to patient preference, or because it was considered that they were medically unfit for surgery. They were considered suitable for radical treatment if their primary tumour was judged to be no longer than 5 cm in length and there was no evidence of metastatic spread. This apparently arbitrary choice of 5 cm is based on the finding that tumours that exceed this length will have metastasised to the mediastinal lymph nodes in approximately 90% of cases [16]. A few exceptions were made to the maximum tumour length for young patients with good performance status. Because this is a non-surgical series and transoesophageal ultrasound investigation is not available in the North-West of the UK, it was not possible to classify tumours according to the TNM staging system. A retrospective study of survival was made, with information obtained from case notes and cancer registries. Fiftysix patients were female and 45 were male, their median age was 68 years (range 39–86 years). As expected, most patients were initially investigated for symptoms of painless dysphasia, but a small number (17 patients), had complained of pain at some time prior to treatment. Most patient were managing either a soft, or liquid diet, but five required feeding through a percutaneous gastrostomy tube. Thirty eight patients had weight loss exceeding 10% of their initial body mass. Staging investigations included upper GI endoscopy, barium swallow and liver ultrasound, which confirmed that 96 tumours were 5 cm or less. Four were described as 6 cm and one was 8 cm in a patient in otherwise excellent general health. Increasingly during the study period diagnostic CT

Table 1 Distribution of cases of carcinoma throughout the oesophagus

SCC Adeno Carcinoma NOS

Upper third

Middle third

Lower third

Total

35 1 5 41

36 3 3 42

10 7 1 18

81 11 9 101

SCC, squamous cell carcinoma; Adeno, adenocarcinoma.

scanning was utilised, and was available in 30 cases. Transoesophageal ultrasound is not available for staging throughout the North-West region. As expected the most common histology was squamous cell carcinoma, but eleven cases of adenocarcinoma, were also seen at sites throughout the oesophagus (Table 1). Radiotherapy techniques changed throughout the period of study. For the first half of the study period, tumours of the lower two thirds were treated with a rotation technique, localised using a barium swallow and simulator. Over the later part of the period studied however, more patients were planned on a radiotherapy planning CT scan, as is now our standard technique. In some cases this still used a fixed field rotation, but more frequently a three field arrangement, with a single anterior and two posterior oblique fields, was used. This allows for a greater flexibility of individual field sizes and arrangements. A more recent refinement has been the introduction of three-dimensional radiotherapy planning which will be discussed later. Upper third tumours were treated with an immobilisation shell and beam directed radiotherapy. No attempt was made to routinely include mediastinal nodes in the treatment field, because it is our opinion that the presence of node metastases makes treatment palliative, and these patients are either treated with intraluminal radiotherapy or an anteroposterior parallel opposed pair arrangement of fields. A total of 93 out of 101 cases were prescribed our standard radical regime of 50 Gy in 15 or 16 fractions in 3 weeks [12], but three patients with tumours of the upper third of the oesophagus were prescribed 52.5 Gy. Two patients had both external beam and intraluminal radiotherapy. Intraluminal doses of 10 Gy at 1 cm in two fractions and 7.5 Gy at 1 cm as a single fraction, gave combined doses of 57.5 and 47.5 Gy, respectively. Three other patients received less than 50 Gy in total, two were prescribed 47.5 and one 45 Gy. The median field length was 12 cm, with the majority being from 10 to 15 cm. The shorter field lengths were seen in patients with tumours of the upper third of the oesophagus. The median field width was 6 cm (range 4–9 cm). Various factors were examined for prognostic significance, including patient age and sex, symptoms on presentation and radiotherapy field size. Survival curves were produced using the Kaplan–Meier method and compared using the logrank test [28].

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the couch, while the oblique fields will often have a collimator twist resulting in a non-coplanar treatment. Although the computer planning facility offers the ability to generate parameters for a coplanar treatment, there are disadvantages. The anterior field requires an additional couch twist and the marked obliquity of incidence causes a greater integral dose within normal tissue and may result in a hot spot at the thin end of the steep vertical wedge used as a compensator. In extreme cases the gantry angle is unachievable as the gantry would touch the patient. In practice the resulting isodose from the coplanar technique offer very little improvement and the combination of a direct anterior field and two oblique fields with a collimator twist is preferred.

Fig. 1. Survival following radical radiotherapy for carcinoma of the oesophagus Corrected for intercurrent deaths.

3. Radiotherapy technique Radiotherapy is currently delivered using megavoltage photons of 4–8 MeV. Treatment is planned isocentrically on a radiotherapy planning CT scan using 1 cm slices through the thorax. For tumours of the upper third of the oesophagus the patient is supine with arms down. No special form of immobilisation is used, the fields being set up on skin tattoos. In the past an immobilisation shell was used with wax compensators which theoretically offered advantages. However, in practice the dose distribution was not significantly better; constructing the immobilisation shell was time consuming and labour intensive, and in some cases the weight of wax required to compensate caused distortion of the shell which could alter the dose distribution. For tumours of the middle and lower third of the oesophagus the patient lies supine with arms above the head supported on a purpose built rest designed for treating patients with thoracic malignancies. This ensures both immobilisation and reproducibility. Upper third tumours are treated with an anterior three field arrangement of an anterior and two lateral oblique fields. The oblique fields are steeply wedged in the horizontal plane and the anterior field is wedged vertically. A collimator twist is required on the lateral oblique fields to follow the vertical axis of the oesophagus and avoid the spinal cord. Middle and lower third tumours are treated with an anterior and two posterior oblique fields. A vertical wedge may be required on the anterior field as a compensator, but wedges are rarely required on the oblique fields. Lung compensation is made where required. Treatment of lower third tumours especially, may require a collimator twist, though in the middle third the oesophagus tends to run parallel to the couch. In the lower third the oesophagus also runs from right to left and to avoid an additional couch twist the anterior beam is set slightly wider. With both techniques the anterior field is perpendicular to

4. Results The 3- and 5-year survival values and median survival were 27%, 21% and 15 months, respectively (Fig. 1), corrected for intercurrent deaths. Five deaths were accepted as due to causes other than carcinoma of the oesophagus (Table 2). Only three patients died of recurrent disease after 36 months, the last death occurred at 45 months. Absolute survival at 3 and 5 years was 25% and 17%, respectively, with median survival of 15 months. The characteristics of those patients surviving 3 years or more are shown in Table 3. Retrospectively it was not possible to analyse patterns of failure. Survival following recurrence is so poor, that extensive investigations to determine the extent of loco-regional recurrence, or presence of distant metastases are rarely indicated. A number of prognostic factors for survival were examined (Table 4). It is of interest, though with small numbers, that survival was better for adenocarcinoma than squamous cell carcinoma (27% versus 21%). This is contrary to the often held belief that surgery is the only curative treatment for oesophageal adenocarcinoma. The only prognostic factor that achieved significance (P = 0.01), was the use of diagnostic CT scanning as a staging investigation. This is associated with a statistically significant increase in mean treatment field width (P = 0.002) from 5.7 to 6.3 cm. Five year survival values were 42 and 13% for patients with and without diagnostic CT scanning, respectively (Fig. 2). Table 2 Patients dying of causes other than carcinoma of the oesophagus Patient Age Site at death

Histology Cause of death

Time from treatment (months)

DS AM IS EB FB

SCC SCC SCC SCC SCC

66 24 57 25 44

63 74 59 74 87

Middle Middle Middle Middle Middle

SCC, squamous cell carcinoma.

Pneumonia Gastric adenocarcinoma Myocardial infarction SCC tongue Pneumonia

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Table 3 Characteristics of 20 patients surviving 3 years or more following radiotherapy for carcinoma of the oesophagus Patient

Age

Diagnostic CT scan

Histology

Site

Sex

Dose (Gy)

FU (months)

Stricture

ML LM KG DS AL HK EJ DH JR TG MM JS EL GH FB SR JC CF DHe EB AM

62 61 65 58 61 80 68 76 66 66 71 54 71 76 83 70 81 54 69 72 74

No No Yes No Yes No No Yes No Yes Yes Yes No Yes No Yes Yes No Yes Yes Yes

SCC SCC SCC SCC Adeno SCC SCC Adeno SCC Adeno SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC

L L L Mi L U Mi Mi Mi L Mi Mi U Mi Mi Mi Mi L U Mi Mi

F F M M M F F F F M M M F F F F M M F F F

50 50 50 50 50 50 50 47.5 50 50 50 50 50 50 50 50 50 50 40 50 50

100 84 75 66* 66 61 61 60 60 60 60 57* 56 47 44* 43 41 40 40 36 36

No No No No Yes No No No No No No No Yes No No Yes Yes No No No Yes

SCC, squamous cell carcinoma; Adeno, adenocarcinoma; U, upper third; Mi, middle third; L, lower third. FU, Follow up from treatment. *Intercurrent death.

The acute reaction to radiotherapy was well tolerated. There were no unscheduled treatment interruptions and every patient received the prescribed dose of radiotherapy. No patient died within 30 days of treatment. The only clinically significant late morbidity was oesophageal stenosis. As with acute morbidity it is very difficult to determine whether subsequent symptoms represent late morbidity, or are the result of tumour recurrence. Twenty patients however were identified as having survived at least 3 years, with no evidence of recurrence, of whom five (25%) had experienced oesophageal stenosis requiring regular oesophageal dilatation.

critical review of the results of surgical treatment for carcinoma of the oesophagus in 1980. Their value for 5-year survival for operated patients was 9%, which must be offset against a postoperative mortality of 29%. The introduction of prophylactic antibiotics, perioperative parenteral nutrition and improvements in anaesthesia, surgical techniques and intensive care have lead to a significant reduction in postoperative mortality. Several series now demonstrate mortality values of 10% or less in specialist units with modern post operative care [10,11,30]. More recently Muller et al. [25] have looked at survival and mortality following

5. Discussion The mainstay of treatment for carcinoma of the lower two thirds of the oesophagus is surgery. Earlam and Cuna-Melo [14] set the historical standard for surgical treatment, with a Table 4 Prognostic factors for cancer specific survival following radiotherapy for carcinoma of the oesophagus and their P values Prognostic factors

P value

Age Sex Site Histology Weight loss Pain at presentation Diagnostic CT scan

0.32 0.65 0.48 0 96 0.29 0.13 0.01

Fig. 2. Survival following radical radiotherapy for carcinoma of the oesophagus for patients with and without diagnostic CT scanning. The difference in survival is statistically significant (P = 0.007). (- - - -) Patients treated after diagnostic CT scanning; (——) Patients treated without diagnostic CT scanning.

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oesophageal resection. Reviewing 130 papers published during the period 1980 to 1988, with a total of 76 911 patients, mortality was 13% and 5-year survival of patients suitable for a radical resection was 20%. The only study to examine survival following radical oesophagectomy by degree of surgical speciality found no difference between units [24]. Despite these advances in postoperative care, oesophageal surgery remains a major undertaking, with disappointing 5-year survival rates. Radiotherapy provides an alternative, which in the past has been reserved for those either medically unfit for surgery, or who refuse surgery. Historical survival figures following radical radiotherapy have been distorted by a combination of poor patient selection and poor planning. With modern diagnostic CT scanning and computerised planning both these issues are addressed, and the results published here are comparable with the best surgical series. There were more female than male patients in our sample, which is contrary to the incidence of the disease in the general population. We have no explanation for this finding, but it is consistent with other radiotherapy series [26,31]. Five-year survival was better for women than men, 25% versus 17%, though this did not achieve statistical significance (P = 0.65). Although the numbers were small (11 patients), the 5year survival of patients with adenocarcinoma was better than that of squamous cell carcinomas (27% versus 21%). This is an important finding, which is contrary to the belief of many surgeons who feel that surgery is the only effective radical treatment for adenocarcinoma. We feel that this is not the case, and that adenocarcinoma and squamous cell carcinoma can be treated with equal success. That survival is better in those patients staged with CT scanning would seem to be the obvious result. It is difficult determine retrospectively though whether this is due to stage migration, or a true effect of better treatment with more accurate information. The number of patients treated with radical radiotherapy at the Christie Hospital has not fallen since the advent of routine diagnostic CT scanning, either as a crude total, or as a percentage of all patients referred with oesophageal carcinoma (Fig. 3). What has changed has been the field size. Field length is relatively fixed, by the requirement to give a generous margin of 3–5 cm beyond tumour that can be seen on screening with barium, to a maximum of 15 cm. Field width, however, is limited by the proximity of the spinal cord, particularly at the upper and lower boundaries where the cord curves into the lateral fields. Before the advent of diagnostic CT scanning the choice of width has been inexact, based on clinical experience and plain X-ray findings. This may not always be sufficient for bulky tumours, or where the tumour is eccentric. With the use of CT scanning there has been a significant increase in field width, matched by a significant improvement in survival. This supports the argument that survival has improved with better planning. Our experience

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Fig. 3. Number of patients treated annually with radiotherapy with either palliative or radical intent at the Christie Hospital.

is matched by that of Girinsky et al. [19], who have reported a 40% 3-year survival following definitive radiotherapy for a cohort of patients with stage T1 carcinoma of the oesophagus. Although their radiotherapy schedule was different, it confirms our observation that well planned and delivered radiotherapy is an effective treatment for carcinoma of the oesophagus. Radiotherapy as practised at the Christie hospital is well tolerated, with no treatment related mortality and little in the way of acute morbidity. Our figures for symptomatic late radiation stenosis of 25% compare with those of Newaishy (31%) [26] and must be set in the context of an aggressive tumour with a high mortality and morbidity even when carefully selected for radical treatment. Values for late surgical morbidity are hard to find, but Svanes et al. [32] report 22% of patients required dilatation for anastomosis of the stoma, a value very similar to ours. Further improvements in staging such as the use of transoesophageal ultrasonography may lead to improvements in 5-year survival, but the gains are likely to be small and at the expense of those patients excluded from radical radiotherapy. Likewise, advances in planning techniques such as intensity modulated radiotherapy are unlikely to lead to a dramatic improvement in survival. A major question remains over the use of multimodal treatment. Experience with combined surgery and radiotherapy [3,18,33,36] has not proved a success. Similarly, the initial results of combined surgery and chemoradiation have not been a success [34], though a more recent series comparing preoperative chemoradiotherapy followed by oesophagectomy with oesophagectomy alone for the treatment of adenocarcinoma [35] has found a statistically significant survival advantage for the combined modality group. To avoid the acute mortality of surgery a number of groups have looked at chemoradiotherapy versus radiotherapy alone. The feasibility of applying this to oesophageal

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carcinoma has been shown in several phase II studies [8,9,22], and more recently has been repeated in randomised trials. A small study from Brazil [2], and a larger study from the United States [1,21] have reported a survival advantage for patients treated with chemoradiotherapy, though only the American study reached statistical significance. The number of patients treated with chemoradiotherapy in a prospective trial remains small and it should be noted that the 5-year survivals for the radiotherapy alone arms of the two trials were only 6% and 0%, well below the survival that we have demonstrated. Bhansali et al. [4] have performed a meta-analysis to examine the effect of chemotherapy on the survival from oesophageal cancer. This included four randomised trials comparing chemoradiotherapy with radiotherapy alone, but revealed no significant benefit from cisplatinum based adjuvant/neoadjuvant chemotherapy. At this time we can only speculate whether the addition of chemotherapy to our radiotherapy technique would improve survival without introducing unacceptable morbidity. In conclusion definitive radiotherapy as practised at the Christie hospital is an effective treatment for localised carcinoma of the oesophagus, which stands comparison with the best surgical results. It is well tolerated by patients with an acceptable level of late effects.

Acknowledgements The authors would like to acknowledge the contribution of D. Ryder in compiling the statistics in this paper.

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