Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura

Articles

Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune

thrombocytopenic purpura

(oral prednisone

Summary The most serious

complication of childhood

acute immune intracranial thrombocytopenic purpura (ITP), haemorrhage, occurs in about 1% of children with platelet counts below 20 × 109/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (>6 months and <18 years old) with typical acute ITP and platelet counts of 20 x 109/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIG) 1 g/kg on 2 consecutive days (n=34), 0·8 g/kg once (n=35), intravenous anti-D 25 µg/kg on 2 consecutive days (n=38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n=39). The rate of response as reflected by the number of days with platelet counts at 20 x 109/L or lower and the time taken to achieve a platelet count 50 × 109/L or more was significantly faster for both IVIgG groups than for the anti-D group (p<0·05); the difference between prednisone and IVIG was significant (p<0·05) only for the IVIgG 0·8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 × 109/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0·8 g/kg × 1), 6% (IVIgG 1 g/kg × 2), 18% (anti-D), and 21%

Department of Pediatrics (V Blanchette FRCP, M Adams) and Clinical Epidemiology Unit (E Wang FRCPC, J McMillan MSc), Hospital for Sick Children, Toronto, Ontario, Canada; Children’s Hospital, University of Basel, Switzerland (Prof P Imbach MD); Department of Pediatrics, Children’s Hospital at Chedoke, McMaster University Medical Centre, Hamilton, Ontario (Prof M Andrew FRCPC); Research Consulting Unit, BC Children’s Hospital, Vancouver, British Columbia (R Milner MS); Division of Pediatric Oncology, Saskatoon Cancer Centre, Saskatoon, Saskatchewan (K Ali FRCPC); Division of Hematology, Izaak Walton Killam Hospital for Children, Hailfax, Nova Scotia (D Barnard FRCPC); Hematology Service, Montreal Children’s Hospital, Montreal, Quebec (M Bernstein FRCPC, D Esseltine FRCPC); Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas, USA (K W Chan FRCPC); Children’s Hospital of Western Ontario, London, Ontario (Prof B deVeber FRCPC); Manitoba Cancer and Treatment Research Foundation, Winnipeg, Manitoba (S Israels FRCPC); Department of Pediatric Oncology, Roger Marls Cancer Center, Fargo, North Dakota (N Kobrinsky FRCPC); Division of Hematology/Oncology, Children’s Hospital of Eastern Ontario, Ottawa, Ontario (B Luke FRCPC) Correspondence to: Dr Victor Blanchette, Division of Haematology/ Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with

IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 × 109/L or lower. A single dose of 0·8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 109/Lor less at 48-72 hours after the start of treatment.

Introduction Childhood acute immune thrombocytopenic purpura (ITP) is generally a benign self-limiting disorder in young, previously healthy children.1 Characteristic features include bruising, petechial rash, isolated and often severe thrombocytopenia, and megakaryocytic hyperplasia. Most affected children have a history of an infectious illness in the weeks before onset of purpura. Children with these clinical and laboratory features have an excellent prognosis. In over 80% of cases, permanent and complete recovery occurs, irrespective of treatment. The major concern in children with acute ITP is the risk of intracranial haemorrhage (ICH). This complication occurs in approximately 1 % of children with ITP 1,2 and platelet counts below 20 x 109jL.3 Fear of this complication prompts many physicians to recommend treatment for children with such counts. Unfortunately the debate over treatment versus no treatment for children with acute ITP cannot be resolved by a randomised clinical trial with ICH as an end-point because of the large number of subjects required. We therefore studied the rate of platelet response to available treatments. In a previous randomised study, an expectant (no treatment) approach was compared with high-dose (1 g/kg x 2 days) intravenous immunoglobulin G (IVIgG) and oral prednisone (starting dose 4 mg/kg per day) in children with acute ITP and platelet counts less than 20 x 109/L.’ The rate of platelet response was significantly faster in children who received treatment, and IVIgG was associated with a more rapid and predictable platelet response than oral prednisone.’’ The purpose of this second study was to further define treatment options in a

comparison of platelet responses prednisone, and intravenous anti-D.

to

IVIgG,

oral

703

Patients and methods Children with acute ITP and platelet counts 20x 109/L admitted to any of the ten participating centres during July, 1988, to May, 1991, were considered eligible. Eligibility criteria were: months and < 18 age >6 years; platelet count 20 x 109/L; haemoglobin concentration, total white blood cell count, and differential cell count consistent with a diagnosis of ITP; and megakaryocytes normal or increased in a bone marrow aspirate. Exclusion criteria were: time from diagnosis of ITP at participating institution to entry into the trial 72 hours; previous treatment for ITP; history of chronic ITP, defined as a platelet count of < 150 x 109 /L for > 6 months; splenectomy; presence of an alternative cause for thrombocytopenia; and history of varicella contact in the 35 days before entry into the trial in a child susceptible to varicella. Informed consent was obtained for all children enrolled in this study. Eligible children who were rhesus positive were randomised to receive IVIgG (Sandoglobulin, Swiss Red Cross, Basel, Switzerland) 1 g/kg daily for 2 days; or 0-8 g/kg once; oral prednisone 4 mg/kg per day in three divided doses; or intravenous anti-D (WinRho, Winnipeg Rh Institute, Winnipeg, Canada) 25 J.1g/kg daily for 2 days. Children who were rhesus negative were randomised to IVIgG (1 g/kg daily for 2 days or 08 g/kg once) or oral prednisone. IVIgG was administered intravenously as a 6% solution in normal saline over 6 hours; anti-D was administered intravenously in 50 mL normal saline over 30 minutes. Children randomised to receive oral prednisone were initially prescribed 4 mg/kg per day (to a maximum daily dose of 180 mg) for a total of 7 days. The dose of prednisone was then decreased to 2 mg/kg per day; 1 week later the dose was decreased to 1 mg/kg per day with tapering over 7

days. Eligible patients

stratified by age: < 10 years and 10 coordinated centrally (Toronto), and a separate randomisation schedule was used for each participating were

years. Randomisation

was

center.

Outcomes

were

analysed by intention-to-treat:

events

and

responses for patients retreated were counted towards the group to

which they were randomised. The Cox proportional hazards models was used to analyse the number of days with platelet counts < 20 x 109/L, number of days to reach a platelet count of 50 x 109/L, and time to initial retreatment; p-values for the proportional hazards model were calculated with Wald’s X2. In the presence of an overall group effect, pairwise comparisons were made. Significance was adjusted by the Bonferroni correction for multiple comparisons. The frequency of adverse effects was analysed by Fisher’s exact test. Changes in haemoglobin were analysed with repeated-measures analysis of co-variance. The percent increase in weight over time was analysed by the Kruskal-Wallis test.

Results 210 children (114 male, 96 female) were eligible for entry. 146 (table 1) were recruited. Reasons for refusal to participate in the trial included fear of blood producttransmitted viral illness, parent or referring physician preferences for a specific treatment, and religious affiliation that precluded acceptance of IVIgG or anti-D. The characteristics of eligible children enrolled and not enrolled were similar. Of the 146 children randomised, 34 received IVIgG 1 g/kg 2 doses, 35 IVIgG 08 g/kg once, 38 intravenous anti-D, and 39 prednisone (table 1).

IgG IgG concentrations (g/L) were: 9-7 (3-6) (pre-therapy), 17-6 (3-5) g/L (day 3), and 12.8 (3-6) (day 21) for children randomised to IVIgGO 8 g/kg once; and9 2 (29), 29 1 (76), and 17 (42), respectively, for children randomised to 704

Table 1: Clinical and

laboratory characteristics of study groups

were not

1 g/kg twice. Significant changes in IgG observed in children randomised to intravenous

anti-D

prednisone.

receive

IVIgG or

Number of days with platelet counts < 20 x 109/L The period of maximum risk for ICH, defined as the number of days with a platelet count 20 x 109/L following the start of treatment is shown in table 2 and individual values in figure 1. At 72 hours after the start of treatment, the percentages of children with platelet counts 20 x 109/L were: 6% or 2 of 34 cases (IVIgG 1 g/kg); 3% or 1 of 35 cases (IVIgG 08 g/kg); 18% or 7 of 38 cases (anti-D) and 21 % or 8 of 39 cases (prednisone). For the outcome of time with platelet counts 20 x 109/L, both IgG protocols proved superior to intravenous anti-D (p 0 002 for IVIgG 08 g/kg vs anti-D, and p=001 for IVIgG 1 g/kg x 2 vs anti-D). The differences between IVIgG 08 g/kg and intravenous anti-D remained significant after adjustment for multiple =

comparisons. Time to platelet count 50 x 109/L The time taken to reach a platelet count of 50 x 109/L or more in the four treatment groups is shown in table 2 and figure 2. At 72 hours after the start of treatment, the percentages of children with platelet counts > 50 x 109/L were: 88 %, or 30 of 34 cases (IVIgG 1 g/kg x 2); 83 %, or 29 of 35 cases (IVIgG 0-8 g/kg x 1); 68%, or 26 of 38 cases (IV anti-D 25 ug/kg x 2); and 72 %, or 28 of 39 cases (prednisone 4 mg/kg per day). Both IgG protocols and prednisone proved superior to intravenous anti-D (p 0 007 for IVIgG 08 g/kg vs anti-D, p 0 03 for IVIgG 1 g/kg x 2 vs anti-D, =

=

Table 2:

Response to treatment

Acute ITP= platelets 150 x 10’/L for 3 months with patient off all therapy and minimum follow-up of 6 months. Chronic ITP platelet150 x 10°/L for 6 months. *p=0 80 (X’). Early retreatment= retreatment within 28 days of onset of ITP.

Table 3: Retreatment and long-term

Each circle

=

one

patient

Figure 1: Time with platelet counts 20 x 108fL 0-03 for prednisone vs anti-D). After correction for multiple comparisons, the difference between IVIgG 0-8 g/kg and intravenous anti-D remained significant.

and p

=

Adverse effects The incidence of fever, nausea, vomiting, and headache was significantly higher (p<0-05) in children randomised to IVIgG than to intravenous anti-D or oral prednisone: on the second treatment day, 16% (IVIgG 1 g/kg x 2 days), 18% (IVIgG 0-8 g/kg), 3% (anti-D), and 0% (prednisone). Except for headache in children randomised to IVIgG 1 g/kg for 2 days, symptoms had disappeared by day 3. The fall in was greatest in children receiving intravenous anti-D: in 24% (9 of 38) haemoglobin concentrations fell to < 100 g/L in the 7-14 days after the start of treatment. The corresponding figures for children who received IVIgG 1 g/kg twice was 12%(4/34 cases); for the IVIgG 0-8 g/kg group, 6% (2/35 cases); and for children on prednisone, 0% (0/39 cases). Lowest recorded haemoglobin concentrations (g/L) were: 66, 71, 82, 85, 87, 92,95,95, and 97 in the anti-D group; 83, 86, 94, and 99 in the IVIgG 1 g/kg twice group; and 88 and 93 in the IVIgG 0-8 g/kg group. Weight gain was observed in children randomised to prednisone. At day 21 the median weight gain in this treatment group was 6 % above entry weight compared with 2% for the IVIgG 1 g/kg x 2 days group, 1 % for the IVIgG 0-8 g/kg x 1 day group, and 1 % for children randomised to IV anti-D (p=0001).

haemoglobin

Each circle

=

one

patient

Figure 2: Time to achieve a platelet count of 50 x 10°/L

follow-up

Follow-up 26% (38 of 146 children) received additional treatment in the 28 days after randomisation. When continuation of treatment beyond day 21 in children randomised to prednisone was taken into consideration, rates of retreatment in the four therapeutic groups were not significantly different (table 3). For the children who received additional treatment, the median interval to first 10 days (range 5-24 days) and the median platelet count before retreatment 15 x 109/L (2-35). The overall frequency of resolved acute ITP defined as a platelet count 150 x 10/Lfor 3 months with the patient off all treatment and a minimum follow-up of 6 months was 79% (102 of 129 evaluable patients) (table 3). The median follow-up at the time of analysis was 12 months (6-32). The remaining 27 cases developed chronic ITP. Splenectomy was done in 7 children because of failure to respond to or dependence on medical treatment. retreatment was

Discussion Children with

ITP and platelet counts of less than risk of life-threatening haemorrhage.2.3 109/L Although controversial, treatment of all such patients is supported by the randomised studies of Sartorius et a16 and Blanchette et a14 showing that the platelet response is faster in treated than in untreated patients. The goal of treatment should be rapidly to increase the platelet count to a haemostatically safe value. This study compared three approaches: oral corticosteroids, high-dose IVIgG, and intravenous anti-D; and the results support the use of IVIgG (0 - 8 g/kg xl) or oral prednisone (4 mg/kg per day) as initial therapy for children with acute ITP and platelet counts of less than 20 x 109/L. Oral corticosteroids are the gold standard of treatment for childhood ITP. The traditional dose of prednisone 1-2 mg/kg per day does not result in a rapid increase in platelet count in most children with acute ITP. In a randomised study of children with acute ITP, Buchanan and colleagues’7 reported no benefit for oral prednisone (2 mg/kg per day) over no treatment. By contrast, the platelet response to higher doses of corticosteroids, orally or parenterally, is often striking.4,8-11 In the study of Ozsoylu et al," 69% (11/16) of children treated with 30 mg/kg methylprednisolone intravenously for 3 days achieved platelet counts above 150 x 109/L within 72 hours. Similar results have been reported by others.8-10 In our first ITP study,4 79% of children who received 4 mg/kg per day of oral prednisone achieved platelet counts above 20 x 109jL within 72 hours. Although adverse effects after very-highdose intravenous methylprednisolone were not reported by some investigators,9,11 others have observed glycosuria and behavioural changes for doses greater than 3-4 mg/kg per day.1,10 If corticosteroid therapy is selected as initial treatment for children with acute ITP and very low platelet 20

x

acute

are at

705

counts, the

and potential toxicity of very-high-dose administered corticosteroids over 4 mg/kg per parenterally of oral day prednisone does not appear warranted. The benefit of high-dose intravenous IVIgG in children with ITP was first reported by Imbach et al in 198112 and has since been confirmed.13,14 In our first trial, high-dose IgG (1 g/kg x 2 days) was compared to 4 mg/kg oral prednisone per day and no treatment.4 For the outcome of number of days with a platelet count of 20 x 109/L or less, either treatment was superior to none. IVIgG was superior to oral prednisone for the end-point of number of days taken to achieve a platelet count of 50 x 109/L or higher. In the current trial, two IgG protocols (1 g/kg daily and 0-8 g/kg once) were selected to allow comparison with data reported by Imbach et al,12 as well as with our first ITP trial. cost

platelet responses observed in children randomised IVIgG, either 1 g/kg x 2 days or 0-8 g/kg once, were striking (figures 1, 2). By 72 hours, 88% of children randomised to IVIgG 1 g/kg x 2 days and 83 % of those randomised to IVIgG 0-8 g/kg once had achieved platelet counts 50 x 109/L; comparable values for 4 mg/kg per day of oral prednisone and intravenous anti-D were 72% and 68%, respectively. Most important, the number of children at risk for life-threatening haemorrhage, based on a platelet count of less than 20 x 109/L, was 6% of children randomised to IVIgG 1 g/kg x 2 and 3% of those randomised to IVIgG 08 g/kg once, compared with 20% for oral prednisone and 18% for intravenous anti-D. Adverse effects of IVIgG—fever, nausea, vomiting, and headache-were as anticipated. Symptoms were more frequent for the higher dose (1 g/kg x 2 days) and were maximal on the second treatment day. In general, symptoms disappeared within 24 hours and were easily controlled with oral paracetamol. The benefit of anti-D in patients with ITP was first reported by Salama et al.16 Most reports relate to patients with chronic ITP, and no large study of intravenous anti-D has been reported in children with acute ITP. The dose of anti-D selected (25 Jlgjkg daily for 2 days) is the same as the starting dose of anti-D used in a multicentre study of the treatment of children with chronic ITP.1’ Although intravenous anti-D is easy to administer, the rate of platelet response was significantly slower than that observed in children randomised to receive IVIgG. The major toxicity associated with anti-D was a predictable fall in haemoglobin. The nadir of haemoglobin concentration was seen in the 7 to 14 day period after starting anti-D; in 24% (9/30) of children, haemoglobin values of less than 100 g/L were recorded. Although no children required red blood cell transfusion, haemoglobin levels of 66 and 71 g/L were recorded in 2 children. In both cases, thrombocytopeniarelated blood loss (epistaxis in 1 case and menorrhagia in the other) may have contributed to the fall in haemoglobin. We caution against use of intravenous anti-D in children with acute ITP, severe thrombocytopenia, and haemorrhagic symptoms, since such cases may experience significant falls in haemoglobin. The

to

On the basis of this trial, intravenous anti-D cannot be recommended as initial treatment of choice for children with acute ITP. The rate of platelet response was significantly slower than that achieved with IVIgG, and the

therapy-related fall in haemoglobin concentration is a potential problem in children who are severely thrombocytopenic and who may be actively bleeding. 706

The choice between IVIgG and oral prednisone (at a starting dose of 4 mg/kg per day) is not clear-cut; both cause prompt and impressive platelet responses. Although a significant difference was not achieved in this trial between these two regimes for the clinically important outcome of platelet count less than 20 x 109jL, the trend favoured IVIgG: at 72 hours, 4% (3 of 69) randomised to IVIgG (at either dose) had platelet counts below 20 x 109/L compared with 18% (7 of 38 children) treated with oral prednisone. The most important result of this study is the observation that the lower dose of IVIgG achieved an equivalent short-term platelet response when compared with the higher dose of 2 g/kg, administered in this trial as 1 g/kg on 2 consecutive days. An argument can therefore be made that, for children with acute ITP and platelet counts of less than 20 x 109/L, IVIgG treatment should be started with a single dose of 0 8 g/kg; the minimum effective treatment for at least two-thirds of children. For selected children, treatment could be given on an outpatient basis with additional IVIgG or oral prednisone reserved for those whose platelet counts at 48-72 hours remained below 20 x 109/L. Pretreatment bone marrow aspirates would be optional, and only recommended for non-responders in whom oral corticosteroid treatment was planned. In their randomised study of children with acute ITP, Imbach et ap5 reported that a higher percentage of cases randomised to IVIgG maintained a platelet count of over 150 x 109/L than did those randomised to oral corticosteroids. Although significant differences in longterm outcome were not observed in this study, the number of children studied was too small to allow definitive conclusions to be drawn. We thank physicians from participating centres who referred children for entry into this trial. Children were recruited from one often Canadian paediatric haematology units: Hospital for Sick Children, Toronto; Children’s Hospital at Chedoke, McMaster University Medical Centre, Hamilton; Children’s Hospital of Eastern Ontario, Ottawa; Children’s Hospital of Western Ontario, London; Montreal Children’s Hospital, Montreal; Janeway Medical Centre, Newfoundland; Izaak Walton Killam Memorial Children’s Hospital, Halifax; Health Sciences Center, Winnipeg; Children’s Hospital of Saskatoon, Saskatoon; and British Columbia’s Children’s Hospital, Vancouver. At the start of the trial, a local nurse coordinator was appointed in each participating centre. The trial was coordinated centrally from the Hospital for Sick Children, Toronto. This trial was supported by grants from the Canadian Red Cross Society Research and Development Program and the Swiss Red Cross. We thank the Swiss Red Cross and the Winnipeg Rh Institute for provision of the IgG and anti-D. This paper was prepared with the assistance of Editorial Services, The Hospital for Sick Children.

References

Beardsley DS. Platelet abnormalities in infancy and childhood. In: Hematology of infancy and childhood. Vol 2, 4th ed. Nathan DG, Oski FA, eds. Saunders: Philadelphia, 1993: 1561-604. 2 Blanchette VS, Turner C. Treatment of acute idiopathic thrombocytopenic purpura. J Pediatr 1985; 108: 326-27. 3 Woerner SJ, Abildgaard CF, French BN. Intracranial hemorrhage in children with idiopathic thrombocytopenic purpura. Pediatrics 1981; 1

4

5

67: 453-60. Blanchette VS, Luke B, Andrew M, et al. A prospective randomised trial of high-dose intravenous immunoglobulin G (IVIgG), oral prednisone and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr 1993; 123: 989-95. Cox DR. Regression models and life tables. J R Stat Soc 1985; 34: 187-220.

6

7

Sartorius JA. Steroid treatment of idiopathic thrombocytopenic purpura in children: pulmonary results of a randomized cooperative study. Am J Pediatr Hematol/Oncol 1984; 6: 165-68. Buchanan GR, Holtkamp CA. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura: a randomized clinical trial. Am J Pediatr Hematol/Oncol 1984; 6: 355-61.

8

Saurez ER, Rodemaker D, Hasson A, Mangogna L. High-dose steroids in childhood acute idiopathic thrombocytopenia purpura.

13 Blanchette

Am J Pediatr Hematol/Oncol 1986; 8: 111-15. 9

Jayabose S, Patel P, Inamder S, et al. Use of intravenous methylprednisolone in acute idiopathic thrombocytopenic purpura.

10

van

Semin Hematol 1992; 29: 77-82. 14 Bussel JB, Pham LC. Intravenous treatment with gammaglobulins in adults with immune thrombocytopenic purpura: review of the literature. Vox Sang 1997; 52: 206-11. 15 Imbach P, Wagner HP, Berchtold W, et al. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet 1985; ii: 464-68. 16 Salama A, Kiefel V, Amberg R, Mueller-Eckhardt C. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies (antiRho [D]). Blut 1984; 49: 29-35. 17 Andrew M, Blanchette VS, Adams M, et al. A multicentrer study of the treatment of childhood chronic idiopathic thrombocytopenic purpura with anti-D. J Pediatr 1991; 120: 522-27.

Am J Pediatr Hematol/Oncol 1987; 9:

133-35.

Hoff J, Riutchey AK. Pulse methylprednisolone therapy for acute childhood idiopathic thrombocytopenic purpura. J Pediatr 1988; 113: 563-66.

11

12

Özsoylu S, Irken G, Karabent A. High-dose intravenous methylprednisolone for acute childhood idiopathic thrombocytopenic purpura. Eur J Haematol 1989; 42: 431-35. Imbach P, Barandum S, d’Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; i: 1228-30.

VS, Kirby MA, Turner C. Role of intravenous immunoglobulin G (IVIgG) in autoimmune hematologic disorders.

Role of circumferential margin involvement in the local recurrence of rectal cancer

Summary

Introduction

Local recurrence after resection for rectal cancer remains common despite growing acceptance that inadequate local excision may be implicated. In a prospective study of 190 patients with rectal cancer, we examined the circumferential margin of excision of resected specimens fortumour presence, to examine its frequency and its relation to subsequent local

Local recurrence of rectal cancer after surgery is common and probably influences survival. The frequency of local recurrence varies according to the treating surgeon. 1,2 Several mechanisms have been postulated as the cause of local recurrence, including the implantation of exfoliated tumour cells at the anastomosis during resection and the promotional effects of the anastomosis on tumour growth.4 However, these factors do not explain that in many cases tumour recurrence is not mucosal but intramural or extramuralthe difference in frequency of local recurrence in rectal and colonic cancer, or the variation of frequency between surgeons. In a series of 52 patients we found that tumour involvement of the circumferential resection margin was a powerful predictor of subsequent local recurrence.6 We concluded that most local recurrences occurred as a direct result of inadequate tumour resection and that this factor may explain variation in local recurrence rates between

recurrence.

Tumour involvement of the circumferential margin was seen in 25% (35/141) of specimens for which the surgeon thought the resection was potentially curative, and in 36% (69/190) of all cases. After a median 5 years’ follow-up (range 3·0-7· 7 years), the frequency of local recurrence after potentially curative resection was 25% (95% Cl 18-33%). The frequency of local recurrence was significantly higher for patients who had had tumour involvement of the circumferential margin than for those without such involvement (78 [95% Cl 62-94] vs 10 [4-16]%). By Cox’s regression analysis tumour involvement of the circumferential margin independently influenced both local recurrence (hazard ratio=12·2 [4·4-34·6]) and survival (3·2 [1·6-6·53]). These results show the importance of wide local excision during resection for rectal cancer, and the need for routine assessment of the circumferential margin to assess

prognosis.

surgeons.l,2 Since that study6 support for wide local surgical clearance of rectal cancer has grown. However, two other studies have yielded conflicting results: one study7 did not confirm the association with local recurrence, although it found a significant influence on survival, whereas the other confirmed the results in 80 patients by meticulous wholemount sections, but could only present data based on 2 years’ follow-up. In our study, 190 patients were followed up for a median of 5 years with the aim of clarifying the importance of complete local excision at the circumferential

margin. Patients and methods October, 1985, and June, 1990, specimens from all rectal patients who had had resection at the Leeds General Infirmary were examined by pathologists who routinely recorded the Dukes’9 and JasslO stages and various pathological variables. Examination for tumour at the circumferential resection margin has been reported in detail." It involved slicing the resected specimen transversely to provide multiple coronal sections through Between cancer

Academic Units of Surgery (I J Adam FRCS, I G Martin FRCS, PJ Finan MD Prof D Johnston MD) and Pathological Sciences (M O Mohamdee MRCPath, N Scott MRCPath, M F Dixon MD, P Quirke PhD), Centre for Digestive Diseases, The General Infirmary at Leeds, Leeds LS1 3EX, UK

Correspondence to: Dr P Quirke

the tumour and the associated mesorectum. The mesorectum above the tumour was also coronally sliced from the posterior aspect and examined for deposits of tumour at the circumferential margin. 3 or 4 tissue blocks were taken where tumour approached

707