Management of colorectal cancer: haematology

Critical Reviews in Oncology/Hematology 30 (1999) 207 – 214

Management of colo-rectal cancer: haematology Diana M. Tait * Royal Marsden NHS Trust, Institute of Cancer Research, Downs Road, Sutton SM2 5PT, Surry, UK Accepted 24 November 1998

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Local failure in rectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Adjuvant radiotherapy in rectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Pre, versus post-operative, radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . .

207 208 208

3. Radiotherapy influencing survival in rectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . .

209

4. Pre-operative chemo-radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

211

5. Reviewer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

213

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The role of radiotherapy in colorectal cancer is best defined for rectum which is associated with a significant local failure problem. In certain circumstances, local recurrence is also a problem in colon cancer, but much less frequently and the value of radiotherapy has not been addressed in randomised trials as it has been for rectal cancer. This section will therefore concentrate mainly on radiotherapy for rectal cancer. At any colorectal site, radiotherapy is employed as part of a multi-modality strategy which usually involves chemotherapy and surgery as well. Traditionally, surgery has been the primary treatment with chemotherapy and radiotherapy given in the adjuvant setting, but increasingly the sequencing is being modified, at least for certain clinical situations. The major challenge in this field is to find the optimum way * Tel.: +44-181-6426011. E-mail address: [email protected] (D.M. Tait)

to combine these three modalities in order to ensure maximum probability of tumour control, with consequent best long-term survival, whilst co-incidentally attaining good functional outcome.

2. Local failure in rectal cancer When surgery is used alone, local recurrence rates range from 23 to 35%, at least in the setting of randomised trials [1–3] However, since these trials were designed, and accrued patients, during the 1970s and early 1980s, they can be criticised for not reflecting current surgical practice. For example, the local recurrence rate with surgery alone, using total meso-rectal excision is reported as 5% [4]. However, these excellent results are from a single centre and have not been repeated. They may, therefore, not be representative of surgical practice in general and multicentre trial data may give a more realistic outcome. It should also be borne in mind that more aggressive surgical approaches

1040-8428/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 9 8 ) 0 0 0 5 0 - X

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will be accompanied by greater morbidity [5] and this should be considered when treatments are being given in combination.

2.1. Adju6ant radiotherapy in rectal cancer Randomised trials have demonstrated that both pre and post-operative radiotherapy can reduce local recurrence rates and that this occurs without chemotherapy, but is enhanced by combining the two adjuvant treatments. Whether radiotherapy should be given pre or post-operatively in rectal cancer remains a controversial issue and there are advantages, and disadvantages, to both approaches (Table 1).

2.1.1. Pre, 6ersus post-operati6e, radiotherapy The main advantage of the pre-operative approach is that radiotherapy is delivered prior to surgical alteration of both the tumour bed and normal bowel. The former provides better oxygenation within the tumour area, a condition associated with improved radiation cell kill. The latter allows normal bowel to remain mobile and thus to vary its position within the pelvis and prevent fixed sections of bowel receiving the high dose on every treatment occasion. The main disadvantage of scheduling radiotherapy pre-operatively, is that, as pre-operative staging does not yet allow reliable discrimination between surgical stages of disease, there will be over-treatment in some cases, that is those with early disease (Table 1). The points outlined in this table are largely theoretical and there is only one trial, from Sweden, which has directly compared the two approaches [6–8]. Table 1 Pre vs. post-operative radiotherapy for rectal cancer; advantages and disadvantages Pre-operative Advantages Better tissue oxygenation“improved cell kill Sterilisation cells subsequently disseminated. Decreased small bowel in pelvis

Post-operative

Patient selection by histopathological staging Marking of at risk sites by clips Surgical procedure to reduce pelvic small bowel

No fixed loops small bowel Possible avoidance of abdominoperineal resection No gap between RT&Surgery Disadvantages Overtreatment of early disease

Vascular compromise of tumour bed Fixed loops small bowel Required 4–6 week gap between surgery&RT

Fig. 1. Treatment protocol for pre vs. post-operative radiotherapy trial.

This Multicentre Swedish Trial, randomised 471 patients with resectable rectal, or rectosigmoid cancer, to either pre-operative radiotherapy, using 25.5 Gy in 5c (236 patients) or post-operative radiotherapy with 60 Gy in 30c (235 patients) (Fig. 1). However, post-operative radiotherapy was actually only offered to those patients with high risk pathological features (B2, C1 or C2) of which there were 137. Of these, 115 actually received radiotherapy; the reasons for not proceeding were post-operative death (9), prolonged post-operative recovery (8), distant metastases (4), and patient refusal (1). The major end-point of this trial was local recurrence, but acute and late toxicity were also recorded. Local recurrence was 12% in the pre-operative group compared with 21% (PB 0.02) in the post-operative group. The trial identified the problem of delivering high dose radiotherapy within 6 weeks of anterior, or abdomino-perineal, resection, with only 50% of patients achieving this, and for 24% the delay was greater than 2 months. For the most part, problems with post-operative recovery were the reasons for this delay. There was no difference in post-operative mortality rate (3 and 4%) between the two arms of the trial and post-operative complications were equivalent, apart from perineal wound sepsis following abdomino perineal resection. This particular complication was seen

D.M. Tait / Critical Re6iews in Oncology/Hematology 30 (1999) 207–214

significantly more frequently (P B0.01) in the pre-operative group than in the post-operative (33 vs. 18%). In this, and other Swedish trials, sepsis resulted in the hospital stay being lengthened by approximately 2–3 days. It is of interest that although pre-operative radiotherapy was not associated with an increased post-operative mortality in this trial it was in two previous trials [9,10] both of which used a two, directly opposed anterior and posterior, field technique whereas the pre versus post-operative Swedish Trial employed a three field technique for all patients. Late follow-up data is also available for this pre versus post-operative Swedish Trial and allows comparison not only of the two radiotherapy schedules, but also of surgery alone by analysis of those patients in the post-operative arm who did not receive radiotherapy because of good prognostic features (Dukes’ stage A and B1). The cumulative risk of small bowel obstruction, with follow-up of 10 years, is just less than 10% for surgery alone and for pre-operative radiotherapy, whereas it is nearly 20% for patients in the post-operative group [8]. Other trials have demonstrated that this figure for small bowel obstruction may be as high as 30 – 40%, depending on the superior extent of the treatment volume [11,12]. This trial is important, being unique in the published literature in providing a randomised comparison between pre and post-operative radiotherapy and in having collected normal tissue toxicity data, with follow up out to 10 years. A current Dutch trial (CKVO-95-04) is asking a similar question, also in the setting of no concomitant chemotherapy, and there is a proposed UK trial (CRO-7), which will incorporate chemotherapy. Of two North American trials comparing pre with post-operative radiotherapy, one, the RTOG 94-01 Trial has recently been closed because of poor accrual, and the other, NSABP R-03, is precarious for the same reason.

3. Radiotherapy influencing survival in rectal cancer The role of radiotherapy in colorectal cancer is generally considered one of local control and this assumption is supported by data from large clinical trials. It seems likely that local control is radiotherapy’s main contribution, but it is also conceivable that it might have an impact on survival via this function, and there is some evidence that this may in fact be the case. This would not be entirely surprising as loco-regional control seems to have an effect upon subsequent development of metastatic disease for other cancer sites, such as head and neck [13,14], Prostate [15,16], and breast. As this sort of data increasingly emerges, it seems likely that other tumour types, where local control is a significant issue, will also reveal some impact of radiotherapy on survival.

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A meta-analysis, published in 1988, including all randomised trials of pre-operative radiotherapy suggested a marginally positive effect for radiotherapy on survival [17]. This effect would now seem to be substantiated, with a recent meta-analysis demonstrating a reduction in rectal cancer mortality with pre-operative radiotherapy. This meta-analysis, performed by the Colo-rectal Cancer Collaborative Group, has not yet been published. What has recently been published is a further Swedish Rectal Study, comparing surgery alone with pre-operative radiotherapy, which was designed to address the question of a survival benefit [18]. The aim of this randomised trial was to be able to detect a 10% increase in survival (50–60%) at 5 years, with an 80% probability and at a 5% significance level, and to do this 750 curatively resected patients had to be recruited. However, it was anticipated that approximately 20% of patients undergoing this type of surgery would have metastatic disease detected at primary surgery, and allowing for a further 10% drop-out rate, 1100 patients were required. In the event, 1168 patients were entered and randomised, 583 and 585 to each arm, and although the percentage with metastases was much lower than anticipated, the overall drop-out rate, for a variety of reasons, was in the region of the 30% initially anticipate (Table 2). This table, as published in the paper, is not comprehensive and the accompanying text further confuses the issue of patient selection. For example, ‘no resection’ was performed in 19 and 17 patients in the radiotherapy and surgery arms respectively, and after careful scrutiny, it appears that these are the 3% of patients referred to in the first part of the results section as having unresectable primary tumour or having metastatic disease. Whether this extent of their disease was established by pre-operative investigation or at Table 2 Selection of the study cohort Swedish rectal cancer trial Patient category

Radiotherapy-plussurgery group

Surgery-alone group

Randomised Ineligible Eligible Refused surgery No resection performed Local resection performed Distant Metastases found Locally noncurative surgery Local cure uncertain Curatively treated

583 10 573 1 19

585 11 574 0 17

553

557

42

41

14

19

43

43

454

454

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laparotomy, is not clear. Additionally, a further 42 and 41 patients, respectively for each arm of the trial, and another 14 and 19 patients, were described as having distant metastases or locally non curative primary disease, but proceeded to local resection. Presumably these findings were made at laparotomy. From the point of view of determining local recurrence rate, all patients who underwent local resection, whether or not they had distant metastases or local non curative surgery, were included in the analysis, 553 patients in the radiotherapy arm and 557 in the surgery alone arm. For survival, overall survival was based on all eligible patients, 573 and 574 patients respectively whereas cancer specific survival was established from the 454 patients categorised as having had curative resections, in each arm of the trial. In each arm of the trial, 43 patients were assigned to the ‘local cure uncertain’ category when either the pathologist or surgeon reported questionable margins. Despite the difficulty in teasing out the information from this section, the two arms seems to be remarkably well balanced with regards to the number of patients in each of the major, and sub, categories. Post-operative mortality was the same in both arms of the trial, 4 and 3% respectively. However, in the 48 patients in the radiotherapy arm, whose radiotherapy violated the protocol on account of their treatment being given by a two, rather than a three, field technique, a mortality rate of 15% (7/48) was recorded. Although the authors conclude that the two field technique was responsible for this increased mortality, no details were given as to the characteristics of this group of patients, the cause of death, or why two fields were used. If these patients came from a number of the 70 contributing hospitals, why were they selected for the simpler technique and the possibility that they were older or more frail has not been addressed in the analysis presented. Local recurrence rate was convincingly lower in the radiotherapy group, 11% compared to 27% in the surgery alone arm (P B 0.001), and it would have been interesting to see the local recurrence rate for those patients in whom local cure was uncertain, on the basis of either the surgery or histopathological findings. These results are very much in keeping with local recurrence rates reported in some of the previous Swedish Trials of pre-operative radiotherapy. What was more celebrated in the trial, was the question of a survival benefit. Previous trials of pre-operative radiotherapy have detected a significant increase in survival in sub-group analyses, but not for the total group of patients. This trial, unlike the others, was set up with the prospect of detecting a survival advantage in the order of 10% and did in fact demonstrate an overall 5 year survival rate of 48% for surgery alone and 58% for pre-operative radiotherapy, a highly significant result (P=0.004). Unfortunately, in one of the key figures the graphs for the sub-group analysis for

Table 3 Swedish rectal cancer trial (1997) Dukes’ staging Stage

Pre-Op RT

Surgery

A B C

181 (33%) 195 (35%) 177 (32%)

154 (28%) 173 (31%) 230 (41%)

overall survival in Dukes’ B & C patients have been transposed so that Dukes’ B patients appear to do much worse that those with Dukes’ C tumours; a minor indiscretion. What is of more concern with regard to tumour stage in this trial is the imbalance between the treatment arms with statistically significant more patients having Dukes’ A or B tumours in the radiotherapy plus surgery arm than in the surgery alone group (P= 0.008) (Table 3). The authors interpretation of this difference is a ‘down-staging’ effect of pre-operative irradiation. Such an effect has certainly been observed in trials using longer radiation schedules and with an interval of several weeks between radiation and surgery [17]. However, intuitively, it seems unlikely that the scheduling involved in this trial would allow such a significant shift in stage and, certainly, such an effect was not seen in the pre versus post-operative radiotherapy trial. In that trial, there was very close equivalence between the two arms (Table 4). This raises the possibility that, for some reason, the two arms of the trial were not balanced with regard to stage. Such a discrepancy might account for the difference in survival. The Swedish Trial did include a Cox regression analysis to see whether the survival difference persisted after adjustment for this imbalance in Dukes’ staging. It was reported that the relative hazard of death from all causes changed only marginally, to 0.81. A short schedule of this sort is certainly attractive to patients and to radiotherapy departments. However, despite not knowing why patients in this and other Swedish Trials received less sophisticated planning and treatment delivery, it appears that technique may be important. The adoption of pre-operative radiotherapy must, therefore, be in the setting of high precision treatment. What will be an important legacy of this trial, and one that should not be dependent on a stage imbalance, will be the late effects on normal tissues and Table 4 Pre vs. post-operative RT Trial 1990 Dukes’ staging Stage

Pre-op RT

Post-op RT

A B1 B2 C1 C2

15 52 71 6 65

13 54 66 13 58

(7%) (25%) (34%) (3%) (31%)

(6.5%) (26.5%) (32%) (6.5%) (28.5)

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quality of life. The authors report on a preliminary analysis based on a questionnaire addressing the question of anal function which was sent to all recurrencefree patients who had undergone a sphincter saving procedure, at least 5 years previously. This indicated that patients in the pre-operative radiotherapy arm had more problems with the number of bowel movements, incontinence, urgency and soiling than those assigned to surgery alone. This needs to be more formally assessed, as no doubt the Swedish Group intend.

4. Pre-operative chemo-radiation

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Table 5 Influence of radiotherapy alone and chemo-radiation on curative resection rate in adherent or fixed rectal cancer Curative res. rate Pre-op RTa

Reference Pre-op CRTb

44% 64% 34% 48% 64% 0–6% 40–86%

MRC (1984) [19] Chan (1993) [23] Minsky (1991) [22] Frykholm (1989) [24] Mendenhall (1987) [20] Dosoretz (1983) [21]

89% 90% 71%

CRc rates Nodes

20% 15–30%+ve

a

Pre-operative strategies offer several possibilities. Radiotherapy and chemotherapy may both bring about downstaging of the primary which, at its most effective, may convert an inoperable to an operable tumour and, or, permit preservation of the sphincter. Pre-operative chemotherapy also allows the earliest possible influence on micrometastatic disease. Pre-operative chemo-radiation is, therefore, being increasingly adopted for ‘locally advanced colorectal cancer’ a frequently used, but rarely defined, term. Studies in this area undoubtedly represent heterogeneous patient and tumour groups, but the factors most often considered in allocating tumours to this group include: 1. Limited mobility or tethering. 2. Fixation to, and invasion into, adjacent structures. 3. Frozen pelvis. 4. Large tumours, 5 cm or more with more than 50% circumferential involvement. The term ‘locally advanced’ is therefore applied both to operable and inoperable tumours and, in any case, ‘operable’ is a flexible term which is highly surgeon dependent. However, what these tumour characteristics have in common is a high likelihood of local recurrence and poor long term survival rate. The prognostic significance of fixation in rectal cancer has been clearly demonstrated in the first UK MRC trial where curative resection rates were 80% for mobile, 50% for partially fixed and 30% for fixed tumours [19]. Moreover, this translated into a survival influence with 5 year figures of 48% for mobile and 29% for fixed, or partially fixed, cancers. The incorporation of pre-operative treatment into the management of these unfavorable rectal tumours can increase resection rates, decrease the extent of surgery, achieve clear margins, at best, and leave minimal residual disease, at worst. For the reasons cited above, combining chemotherapy with radiation pre-operatively might increase the success of these local aims, whilst, at the same time, treating micro-metastatic disease and influencing subsequent development of clinical metastases.

RT, radiotherapy. CRT, chemo-radiation. c CR, pathological CR. b

There is no randomised comparison of pre-operative radiotherapy with pre-operative chemo-radiation in this setting, but data from phase I/II studies on response, toxicity and resectability suggest a higher curative resection rate, approximately 90%, with the combined approach, compared to 50–60% with radiotherapy alone (Table 5) [19–24]. One recent publication reported on two phase I dose escalation trials of combined pre-operative 5-Flurouracil (5FU), low dose Leucovorin (LV) and pelvic radiotherapy, followed by post-operative 5FU/LV, in patients with locally advanced or inoperable rectal cancer [25]. The study group consisted of 36 patients, 30 having primary tumour and six local recurrence. Publications in this area are often vague as to the criteria used to Table 6 Response to pre-operative therapy (n =35)a Trial

No of patients Resection margins Negative Microscopic positive Pelvic nodes positive Complete response Pathologicalb Clinicalc Totald a

Sequential

Concurrent

Total group

10

25

35

9 (90%) 1 (10%)

25 (100%) 0

34 (97%) 1 (3%)

2 (2%)

8 (32%)

10 (29%)

1 (10%) 1 (10%) 2 (20%)

3 (12%) 4 (16%) 7 (28%)

4 (11%) 5 (14%) 9 (25%)

This analysis is limited to patients who underwent surgery. T0N0M0. c One or two microscopic foci of tumour in the bowel wall and negative lymph nodes. d Pathological plus clinical complete repsonse. b

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No

Local failure

Abdominal failure

Distant failure

Crude

No. at risk

4 Year actuarial

Crude

No. at risk

4 Year actuarial

Crude

No. at risk

4 Year actuarial

Unresectable Locally advanced

9 26

3 (33%) 2 (8%)

2 4

34% 11%

1 (11%) 3 (12%)

2 4

17% 13%

3 (33%) 2 (8%)

2 4

40% 8%

Total

35

5 (14%)

5

30%

4 (11%)

5

13%

5 (14%)

5

16%

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Table 7 Patterns of failure (n=35)

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describe tumours as tethered, fixed, frozen pelvis, locally advanced disease etc., but the authors, here, clearly state the basis for inclusion into each tumour category. Locally advanced (tethered) disease is assigned to tumour which by clinical examination is tethered to adjacent structures and primary surgery is likely to leave microscopic tumour. Unresectable disease is defined as tumour which by clinical examination and, or, CT is contiguous with, adherent to, or fixed to adjacent pelvic structures and primary surgery is likely to leave gross tumour. The problem is that these definitions are based on subjective criteria, but, at present, there are no firm objective measures on which to base accurately predict local extent of disease and operability. This is an area which requires attention in order that uniform groups of patients can be treated in defined protocols and their outcome compared. The dose escalation in these two trials concerned 5FU in the pre-operative combined therapy segment, with this initially being given at 325 mg/m2 for 5 days, in conjunction with Leucovorin at a dose of 20 mg/m2. Two courses were given, 4 weeks apart, in combination with pelvic radiotherapy. The dose of 5-FU was escalated by 50 mg/m2 until the MTD was reached. The radiotherapy aimed to deliver 46.8 Gy to the pelvis with a further 3.6 Gy boost to bring the dose to the tumour to 50.40 Gy. The difference between the two trials reported in this paper, lay in the timing of the start of radiotherapy with the initial course of chemotherapy. The radiotherapy began on day 1 in 25 patients (concurrent) and on day 8 in 11 (sequential). Four courses of post-operative chemotherapy with fixed doses, 5-FU at 435 mg/m2, Leucovorin at 20 mg/m2, were planned. This paper sets good standards in terms of its clarity in defining tumour site, with all tumours being below, or at, the peritoneal reflection, and also in terms of specifying patterns of failure. The latter were categorised as local, abdominal or distant. Response data, clinical and pathological, is comprehensively displayed in tabular form (Table 6). What is impressive with this and other combined pre-operative regimes is that for some patients (11%) there is no pathologically detected tumour in the resected specimen, or only one or two microscopic foci within the bowel wall and negative lymph nodes (14%). However, only a pathological CR seems to confer a local control benefit with none of the four patient in this category developing local recurrence, whilst 16% of the remainder, regardless of the extent of their clinical or pathological response, failing locally. Patterns of failure, according to the defined categories of local, abdominal and distant, and according to the tumour categories of unresectable and locally advanced, are shown in Table 7. The number of patients in any of these sub-groups is very small but, as might be anticipated, unresectable disease carried a

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greater risk of both local (34 vs. 11%) and distant (40 vs. 8%) failure. Furthermore, as has been found in other series [26,27], local failure was higher in recurrent compared with primary disease (50 vs. 7%). This study was designed as a phase I dose-escalation trial and therefore end points such as local control and survival need to be viewed with caution. However, it is difficult not to be optimistic, or at least enthusiastic, for pursuing this combined pre-operative approach, with 4 year survival of 90% for locally advanced disease and 50% for unresectable disease. Many centres are now adopting this type of approach and it may be difficult, or impossible, to conduct a randomised trial comparing pre with post-operative chemo-radiation for locally advanced disease. What is more likely is that comparisons will be made between schedules of different intensity and sequencing. It would be vital to evaluate functional outcome in any such comparison. What this present trial should herald is precise definition of tumour categories and failure pattern, and the systematic assimilation of Phase III trials of restructuring of the conventional sequencing of treatment modalities.

Reviewer This paper was reviewed by Dr Bengt Glimelius, Department of Oncology, University Hospital, S-751 85 Uppsala, Sweden; Dr Harry Bleiberg, Institut Jules Bordet, Centre des Tumeurs, Universite´ Libre de Bruxelles, Rue He´ger-Bordet, B-100 Brussels, Belgium and Dr Roberto Labianca, Medical Oncology Department, Ospedale S. Carlo Borromeo, Via Pio II, 3, 20153 Milan, Italy.

References [1] Stockholm Rectal Cancer Study Group. Pre-operative shortterm radiation therapy in operable rectal cancer A prospective randomised trial. Cancer 1990;66:49 – 55. [2] Gerrard A, Buse M, Nordlinger B, et al. Pre-operative radiotherapy adjuvant treatment in rectal cancer. Final results of randomised study of the EORTC, Ann. Surg. 1988;4:601 –614. [3] Fisher B, Wolmark N, Rockette H, et al. Post-operative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Nat Cancer Inst 1988;80(1):21–9. [4] MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993;341:457 – 60. [5] Karanjia N D, Corder A P, Bearn P, et al. Leakage from stapled low anastomosis after total meso-rectal excision for carcinoma of rectum. Br J Surg 1995;81:1224 – 6. [6] Glimelius B, Graffman S, Pa˚lman L, et al. Pre-operative irradiation with high-dose fractionation in adenocarcinoma of the rectum and rectosigmoid. Acta Radiol (Oncol) 1982;31:373–9. [7] Pa˚lman L, Glimelius B. Pre and post-operative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomised multicentre trial. Ann Surg 1990;211:187 – 95.

214

D.M. Tait / Critical Re6iews in Oncology/Hematology 30 (1999) 207–214

[8] Frykholm GJ, Glimelius, Pa˚lman L. Pre-operative or post-operative irradiation in adenocarcinoma of the rectum: Final treatment results of a radnomsied trial and an evaluation of late secondary effects. Dis. Colon Rectum, June 1993: 564–572. [9] Goldberg PA, Nicholls RJ, Porter NH, Love S, Grimsey JE. Long term results of a randomised trial of short course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer 1994;30A:1602–6. [10] Stockholm Rectal Cancer Study Group. Pre-operative short term radiation therapy in operable rectal cancer, a prospective randomised trial. Cancer 1990;66:49–65. [11] Balslev IB, Pedersen M, Teglbjacrg PS, et al. Post-operative radiotherapy in Dukes’ B & C carcinoma of the rectum and recto-sigmoid, a randomised multi-centre study. Cancer 1986;58:22 – 8. [12] Letschert JG, deBoer RW, Hart A. High dose-volume correlation in radiation related late small bowel complications: a clinical study. Radiother Oncol 1990;18:307–20. [13] Merino OR, Fletcher GH, Lynberg RD. An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1977;40:145–51. [14] Leibel S A, Scott Mohiuddin M, Marcial V, Coia CB, et al. The effects of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: results of an analysis from the RTOG head and neck database. Int J Radiat Oncol Biol Phys 1991;21:549–56. [15] Fuks Z, Leibel SA, Wallner KE, et al. The effects of local control on metastatic dissemination in carcinoma of the prostate: long terms results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991;21:537–47. [16] Zagars GK, von Eschenbach AC, Ayala AG, et al. The influence of local control on metastatic dissemination of prostate cancer treated by external beam megavoltage radiation therapy. Cancer 1991;68:2370 – 7. [17] Buyse M, Zeleniuch-Jacquotte, Charlmers C, et al. Adjuvant therapy of colorectal cancer; why we still don’t know. J Am Med Assoc 1988;259:3571–8. [18] Swedish Rectal Cancer Trial. New Eng J Med 1997;336(14):980– 7. [19] Second Report of MRC Working Party. The evaluation of low dose pre-operative X-ray therapy in the management of operable rectal cancer: results of a randomly controlled trial. Br J Surg 1984;71:21 – 5. [20] Mendenhall WM, Bland KI, Pfaff WW, Million. Endocarcinoma

.

[21]

[22]

[23]

[24]

[25]

[26]

[27]

treated with pre-operative irradiation and surgery. Ann Surg 1986;205:41 – 4. Dosoretz DE, Gunderson LL, Hednerg S, Hoskins B, Blitzer PH, Shipley W, Cohen A. Pre-operative irradiation for unresectable rectal and rectosigmoid carcinomas. Cancer 1993;52:814 – 8. Minsky BD, Cohen AM, Enker WE, Harrison LB, Sigurdson E. Radiation therapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1991;21:1283 – 9. Chan A, Wong A, Langevin J, et al. Pre operative concurrent 5-flurouracil infusion, mitomycin C and pelvic radiation therapy in tethered and fixed rectal carcinoma. Int J Radiat Biol Phys 1993;25:791 – 9. Frykholm G, Glimelius B, Pahlman L. Pre-operative irradiation with and without chemotherapy (MFL) in the treatment of primarily nonresectable adenocarcinoma of the rectum. Results from two consecutive studies. Eur J Cancer Clin Oncol 1989;25– :1535 – 41. Minsky B D, Cohen A M, Enker W, et al. Preoperative combined 5 – FU, low dose leucovorin and radiation therapy for locally advanced and unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1997;37:289 – 95. Willett, et al. Intraoperative electron beam radiation therapy for recurrent locally advanced rectal or rectosigmoid carcinoma. Cancer 1991;37:1504 – 8. Gunderson, et al. The role of intraoperative irradiation in locally advanced primary and recurrent rectal adenocarcinoma. World J Surg 1992;16:495-501.

Biography Diana Tait was appointed as a consultant in clinical Oncology, at The Royal Marsden NHS Trust in January 1987. She became an Honorary Senior Lecturer at the University of London in the following year. She has a special interest in breast, gastro-intestinal tumours, and TBI and systemic isotope therapy. Her main research interests involve the evaluation of new technologies in radiation which are aimed at giving better protection to the normal tissues whilst allowing escalation of the tumour dose.