Abdominal recurrences in Wilms' tumours: A report from the SIOP Wilms' tumour trials and studies

Abdominal recurrences in Wilms' tumours: A report from the SIOP Wilms' tumour trials and studies

Radiotherapy and Oncology, 5 (1986) 175-182 Elsevier 175 RTO 00198 Abdominal recurrences in Wilms' tumours: A report from the SlOP Wilms' tumour tr...

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Radiotherapy and Oncology, 5 (1986) 175-182 Elsevier

175

RTO 00198

Abdominal recurrences in Wilms' tumours: A report from the SlOP Wilms' tumour trials and studies F o r the T r i a l C o m m i t t e e : J. M a r i o n V. B u r g e r s * , M. F. T o u r n a d e , P. Bey, D. Biirger, M. Carli,

J. F. M . D e l e m a r r e , D. H a r m s , B. Jereb, J. de K r a k e r , J. L e m e r l e , C. G . M. M o o r m a n V o e s t e r m a n s , H. P e r r y , A. R e y , B. S a n d s t e d t , D. Sarrazin, P. A. Vofite a n d J. M. Z u c k e r From the International Society of Paediatric Oneology, Amsterdam, The Netherlands; Villejuif, France; Hannover, F.R.G.; Padova, Italy; Kiel, F.R.G.; Ljubljana, Yugoslavia; Stockholm, Sweden; Nancy, France; Paris, France

(Received 30 November 1984, revision received 14 October 1985, accepted 18 October 1985)

Key words: Wilms' tumours; Paediatric radiotherapy; Abdominal irradiation

Summary The Wilms' tumour trials and 'studies conducted from 1971 to 1980 registered 1042 patients, O f these, 82 patients developed an abdominal recurrence. Particulars of these were studied. Half of the recurrences occurred in stage III patients. Often several untoward prognostic factors could be identified, such as large tumour size, difficult operation, incomplete excision, peritoneal adhesions or metastases, tumour extending to renal vein or vena cava. A tumour rupture increases the chance for an abdominal recurrence, especially if appropriate radiotherapy is not given. In many of these cases, postoperative radiotherapy seems to have been insufficiently tailored to the operative findings. For stage III cases, a careful discussion between surgeon, radiotherapist, and pathologist should lead to the optimal radiotherapy field size and dose for each individual patient, so that the risk of abdominal recurrence can be reduced.

Introduction Wilms' tumours have been amongst the earliest of childhood malignancies that were amenable to cure. Already in the 1940's, 10-20% of these patients survived after adequate surgery [4]. When radiotherapy was introduced the ~survival rate for nonmetastatic patients rose to 40-50% [7,8]. Since the * Reprint requests: J. M. V. Burgers, Department of Radiology, Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

use of multiagent chemotherapy, survival has risen further and is now over 90% for stage I and II** patients after adequate management [1,2,5,11-13]. These improvements have been substantiated in prospective randomised clinical trials that have been conducted both in the United States and in Europe. Furthermore, it has become possible to cure a proportion of the patients that develop haematogenous metastases to the lungs. Liver and bone metastases, and the development of an ab** For the definitionof stages see Table V.

0167-8140/86/$03.50 9 1986 ElsevierSciencePublishers B.V. (BiomedicalDivision)

176 TABLE I Distribution over stages in SIOP trials no. 1, 2, and 5, in relation to preoperative treatment. n

Stage at surgery I

II

IIl

73 63

43% 22%

45% 45%

12% 33%

j'

85 53

51% 28%

22% 34%

27% 36%

}

89 77

44% 53%

36% 31%

20% 16%

}

S 1 0 P no. 1 (randomised):

Preoperative radiotherapy Immediate surgery

P < 0.004

S 1 0 P no. 2 (non-randomised) :

Preoperative radiotherapy plus actinomycin-D Immediate surgery for small tumours

P < 0.005

S 1 0 P no. 5 randomised:

Preoperative chemotherapy with VCR and actinomycin-D Preoperative radiotherapy plus actinomycin-D

dominal recurrence are now the major hazards for survival. It is difficult to treat an abdominal recurrence as the previous treatments (surgery and often radiotherapy and chemotherapy) usually preclude a radical attack. It is of great importance to prevent local recurrence by adequate first treatment. The role o f preoperative radiotherapy in achieving local cure was one of the questions studied by the first Wilms' tumour trial of the SIOP. It became obvious that preoperative treatment reduced the number o f tumour ruptures [3,11], while in case of tumour rupture an extensive abdominal treatment is needed to prevent abdominal recurrence [4,9]. Preoperative radiotherapy furthermore increases the proportion of patients in stage I (Table I) in whom a lesser postoperative treatment seems sufficient. Since this first trial, in the philosophy of treatment of Wilms' tumours, a major concept amongst SIOP members has been the need for preoperative tumour shrinkage, as a means to reduce the total treatment load. In the SIOP no. 2 study, the preoperative treatment evolved to a combination of radiotherapy and chemotherapy, and in the SIOP no. 5 study, to chemotherapy alone. Nothwithstanding these developments, abdominal recurrences still occur. Such recurrences have a very unfavourable prognosis [4,9]. The present report studies the particulars of the patients who developed abdominal recurrences.

n.s.

Materials and methods

In the first Wilms' tumour trial and study, SIOP no. 1, conducted from September 1971 until October 1974 by 44 European centres, 390 patients were registered. Of these, 136 participated in the radiotherapy trial, comparing 20 Gy preoperative irradiation with direct surgery. Patients with a large tumour needing preoperative treatment were not eligible. Concurrently a chemotherapy trial on actinomycin-D was executed (160 patients). Postoperative radiotherapy was given depending on stage; dose and field size depended on preoperative treatment and rupture. The incidence o f ruptures was significantly decreased by preoperative irradiation. The results o f this trial have been reported by Lemerle et al. in 1976 and 1983 [9,10]. This trial was followed by Wilms' t u m o u r study SIOP no. 2, conducted from October 1974 to December 1976. Patients were treated by a c o m m o n protocol without randomisation, including preoperative chemotherapy and radiotherapy o f 20 G y to the tumour area, unless the tumour was very small. Guidelines were given for postoperative treatment. F o r the protocol patients (138) the 5-year survival is 98% for stage I, 90% for stage II and 66% for stage III [10]. The aim of the next study and trial, SIOP no. 5, executed from January 1977 to July 1980, was to maintain the benefit of preoperative treatment, but

177 to study whether radiotherapy with its well-known hazards could be omitted. Patients received either preoperative treatment as in SlOP no. 2, or more intensive chemotherapy only. Postoperative treatment depended on stage both for chemotherapy and radiotherapy. For the protocol patients (188) the 4 year actuarial survival was 93% for stage I, 88% for stage II, and 76~ for stage III. During SlOP no. 1,204 study patients were registered, who were not eligible for the trial because of age under one year, too large tumour, doubt in diagnosis, stage IV or V, or previous treatment outside the collaborating centre. During SlOP no. 2, 108 study patients were not treated according to the protocol. During SlOP no. 5, 242 study patients were registered. For SlOP no. 1 and no. 2, detailed information on all steps of treatment has been collected by questionnaire both for trial and study patients. For SlOP no. 5, the information available for study patients was more limited, but operative reports were collected for all patients. For SlOp no. 5, ruptures were coded either as massive (spillage) or minor. T u m o u r puncture, though not accepted as an appropriate diagnostic tool, was coded separately. Recurrences were separated according to site: lung, liver, abdomen, bone, others. A special secretariat in Amsterdam has the task of collecting all data. The computerisation and statistical analysis are done in the Institut Gustave-Roussy, Villejuif, France.

sites in 70 patients, and lung metastases, the major site of haematogenous spread, in 310 patients. Of the 82 patients with abdominal recurrence, 26 had no other metastases and 18 had only lung metastases. The 5-year survival for all patients in stage I was 88%, stage II 80%, stage III 66%, and the survival for patients with lung metastases was 44~ After abdominal recurrence, 5-year survival was 23% if all patients lost sight o f are just censored at the time of the last news and 15% if they were considered dead. Many of these patients returned home without treatment and no further information was available (Fig. 1). The influence of different factors for the development of an abdominal recurrence will be discussed. An abdominal recurrence is defined as a subdiaphragmal recurrence excluding liver metastases and bilateralisations.

Influence of stage The division by stage in patients who developed an abdominal recurrence is shown in Table II. Those in stage V will not be further discussed as these are 100

80

60

Results

Amongst the 1042 patients registered between September 1971 and July 1980, 82 (7.8%) were reported to have an abdominal recurrence, with or without other metastases. The division by site and sex was not different from that of the total group, but patients with abdominal recurrences tended to be older, with a mean age of 54 months, against 43 months for the patients without an abdominal recurrence (p = 0.03). In the same period, liver metastases were reported in 77 patients, bone metastases in 37 patients, metastases in miscellaneous

40

20

0 0

I 1

I 2

I 3

I 4

I 5

I 6

I 7 years

Fig. 1. Wilms tumour trials and study 1971-1980. Survival after abdominal recurrences. O - - Q , Patients lost sight of censored; O - - O , patients lost sight of considered dead (see text).

178 TABLE II Incidence of abdominal recurrences in relation to stage and to study period.

All Stage I Stage II Stage III Stage IV Stage V Unknown

SIOP 2

SlOP 5

SLOP1 + 2 + 5

SlOP 1

n

%

n

%

n

%

n

%

82/1042 11/329 5/270 36/232 15/129 7/43 8/39

7.8 3.3 1.8 15.5 13.1 16.3 20.5

34/390 4/104 3/108 15/94 5/57 2/12 5/15

8.7 3.8 2.8 16.0 8.8 16.7 33.0

22/246 5/83 0/56 7/57 6/26 3/I 1 1/13

8.9 6.0 12.3 23.0 27.0 8.0

26/406 2/142 2/106 14/81 4/46 2/20 2/11

6.4 1.4 1.9 17.3 8.7 I0.0 18.0

TABLE III Incidence of tumour rupture and abdominal recurrence. No rupture All patients Abdominal recurrence

Rupture

839 126 47 (5.6%) 25 (20%) p < 0.001

b i l a t e r a l i s a t i o n s . O f the 15 cases in stage IV, the a b d o m i n a l t u m o u r was in stage II for five p a t i e n t s a n d in stage I I I for 10 patients. T h e stage o f the a b d o m i n a l t u m o u r was u n k n o w n in eight cases. T h e h i g h e s t incidence o f a b d o m i n a l r e c u r r e n c e was in stage III, 15%, a n d this c o r r e l a t i o n was highly significant (p < 0.0001).

Influence of tumour rupture A t u m o u r r u p t u r e o c c u r r e d in 126 p a t i e n t s a m o n g s t 965 p a t i e n t s for w h o m this i n f o r m a t i o n was k n o w n (13%). Twenty-five o f these p a t i e n t s d e v e l o p e d a n a b d o m i n a l recurrence ( 2 0 % ) ( T a b l e III), while in stage I I I as a whole, this o c c u r r e d o n l y in 15%. F o r S I O P no. 5 trial a n d study, the d a t a o n r u p t u r e were c o d e d s e p a r a t e l y for spillage ( m a j o r r u p t u r e ) , f o r simple fissure, a n d for d o u b t f u l r u p t u r e . A n a b d o m i n a l recurrence d e v e l o p e d in 5/19, in 4/19, a n d in 2/12 cases respectively, f o r a t o t a l o f 11/50 (22%). I n the r e m a i n i n g cases o f S I O P no. 5 witho u t r u p t u r e , o n l y 15 a b d o m i n a l recurrences develo p e d (4%). A f t e r r u p t u r e , the p r o t o c o l p r e s c r i b e s p o s t o p e r ative i r r a d i a t i o n to the w h o l e a b d o m e n . This a d v i c e

TABLE IV Type of rupture and type of radiotherapy, and abdominal recurrence in SlOP no. 1 (trial and study) and SIOP no. 5 trial.

Total abdominal radiotherapy Tumourbed radiotherapy

SIOP no. 1 trial and study

SIOP no. 5 trial

Massive spillage

Minor rupture

Massive spillage

Minor rupture

22 (2) 9 (4)

5 21 (3)

2 2 (1)

1 (1) 7 (0)

Numbers in parentheses = number of abdominal recurrences.

179 TABLE V

T A B L E VII

Staging used in the trials.

Relation between tumour size and weight and abdominal recurrence.

Stage 1." Stage II: Stage II1:

Stage IV. Stage V:

Tumour limited to the kidney and completely excised Tumour extending outside the kidney, but completely excised Incomplete excision, including tumour biopsy or rupture before or during surgery, but without haematogenous metastases Distant metastases Bilateral renal tumours

Abdominal

recurrence No

Yes

T u m o u r size on I V U (810)

116 cm 2 147 cm z

p = < 0.03

Weight of specimen (788)

440 g

p = < 0.04

635 g

N u m b e r s in parentheses = n u m b e r of cases for w h o m information available.

is not always followed. In SIOP no. 1 (trial and study) details for further treatment are known for 57 of the ruptured patients. When tumourbed irradiation only was given, the chance to develop an abdominal recurrence was much higher (Table IV). The two recurrences after full abdominal irradiation were in the shielded liver area and after partial surgery. For SlOP no. 5, the field size o f radiotherapy was only known for trial patients.

Influence of preoperative treatment In the first trial, it was shown that preoperative irradiation reduced significantly the risk of rupture, from 32 to 4%. Furthermore, the division over the stages at operation changed in favour of stage I (Table I). In such "posttreatment stage I" cases, postoperative radiotherapy is not necessary. This was shown in SIOP trial no. 5, where the 3-year

T A B L E VI Chance of abdominal recurrence in relation to preoperative

treatment. Preoperative treatment Given SIOP no. 1 SIOP no. 2 SIOP no. 5 All

10/145 10/112 15/271 35/538

6.5% 8.9% 5.5% 6.5%

N o t given

Unknown

20/221 9/119 10/125 39/465

4/14 3/12 I/9 8/38 (21%)

9.0% 7.6% 8.0% 8.4%

survival for stage I is 93%. Furthermore, this trial showed that preoperative chemotherapy without radiotherapy is equally efficient. In the study cases registered concurrently with each trial, preoperative treatment was sometimes not given, either because the tumour was small or the diagnosis doubtful, or because the patient was referred for further treatment to a centre after surgery or after development of metastases. The incidence of abdominal recurrence was slightly larger in this group nothwithstanding the greater proportion of small tumours (Table VI). However, the incidence was much higher for patients for whom information about primary treatment could not be retrieved.

Influence of tumour size and weight T u m o u r size was measured on the intravenous pyelogram made before treatment. The size was not corrected for age or length of the patient. F o r the whole series, the average tumour length is 12 cm, width 9 cm, and surface 116 cm 2. In SIOP no. 1, the size o f the primary was known in 23/34 cases with an abdominal recurrence with a mean value of 179 cm2; 154 and 205 cm 2 without or with rupture respectively. In SIOP no. 2 and no. 5, the size when known, differed to a lesser degree. T u m o u r size remained significantly greater in case o f abdominal recurrence (Table VII). For a number of cases, the weight o f the specimen is known. In SIOP no. 1, the average weight

180 for the trial patients was 555 g.(126 patients), for study patients the average weight was 624 g (105 patients). For patients with an abdominal recurrence in SlOP no. 1 and 2, the average weight in 21 cases without preoperative treatment was 829 g.

Influence of pathology Several pathological features appeared to increase the chance of a tumour rupture, such as infiltration of renal capsule or fat, infiltration in renal veins or emboli in tumour vessels. These features are not directly correlated with the risk of abdominal recurrence. The presence of regional lymph nodes does not seem to increase the risk of abdominal recurrence, but the pathology of those was not examined systematically. The incidence of unfavourable histology (sarcomatous differentiation or anaplasia) was rare in SIOP material (6%). An abdominal recurrence occurred in 13 %, not significant because o f small number of subjects.

Influence of the operativefindings In the case of an abdominal recurrence, the operative report often mentions major problems encountered, such as adhesions or infiltration into surrounding tissues, peritoneal metastases, tumour embolus in the renal vein or the vena cava. To judge whether the operation has been radical becomes extremely difficult. Postoperative irradiation was often given to the tumourbed only, although the operative report seems to indicate a much wider area at risk. Sometimes the recurrence can be regarded as a true "geographical miss", when an important organ, e.g. liver was shielded, after dissection of the tumour from the liver. In SIOP no. 1, resection in 5 out of 32 abdominal recurrences was coded as incomplete and for 4 this information was lacking. Peritoneal infiltrations were found in seven cases and for another six this was unknown.

Influence of deficient information The last factor which seems to play a role is deficient information. This occurs often in patients with

abdominal recurrences. O f the 75 patients with an abdominal recurrence excluding stage V, no data were available on stage in 8, on rupture in 7, on tumour size in 23, on tumour weight in 23. In eight cases, it was unknown whether preoperative treatment had been given (Tabel VI). When data on tumour size, stage, operative report, radiotherapy etc. cannot be sent to the SlOP registry, it might indicate that these data were also not available to plan the treatment exactly. Often these patients were referred to a collaborating centre after first treatment elsewhere.

Discussion Although an abdominal recurrence after treatment of a Wilm's tumour in fortunately rare, it carries a high risk of killing the patient (Fig. 1). This problem is not frequent in stage I and II, and when it occurs, a very large tumour is often found retrospectively. In stage IV, the chance of abdominal recurrence is related to the local stage in the abdomen. Half the abdominal recurrences occurred in patients who had stage III tumours. This staging is based on (a) tumour rupture; (b) peritoneal metastases; (c) incomplete excision; and (d) invasion of lymph nodes beyond the regional nodes. In stage III, the percentage of abdominal recurrences, 15%, has not diminished over the years, but the proportion of patients who are stage III at the time of operation has diminished notably, due to the more routine use of preoperative treatment (chemotherapy with or without radiotherapy). At the same time, the chance of developing an abdominal recurrence in stage I and II has not increased. This preoperative treatment is therefore an important tool in preventing abdominal recurrence by reducing the postoperative stage. When preoperative treatment has been given with chemotherapy, postoperative radiotherapy for stage III patients can be given without tolerance problems by previous irradiation, The whole area at risk can receive a homogenous dose. This is a decided advantage over the situation where the area

181 of preoperative irradiation would need to be shielded although spill of viable tumour cells could be situated in that area. The area at risk should be the whole peritoneal cavity after peritoneal spillage or when t u m o u r was cut through. When t u m o u r infiltrated in organs which were excised or when peritoneal adhesions or infiltrations were present, it is much more difficult to decide on the limits of the radiotherapy field. It is clear that for optimal treatment of the stage III patient, full information on details of the surgical intervention and its pathological interpretation has to be discussed between radiotherapist and paediatrician. F r o m the material of the SIOP no. 1 study, it was obvious that insufficient information to the registry office, mostly for patients who had their diagnosis and treatment outside one of the collaborating centres, could be a reflection of insufficient exchange of information between the treating physicians resulting in suboptimal treatment. In case of an abdominal recurrence, usually several unfavourable prognostic factors can be found in the history, such as large tumour size, difficult operation, incomplete excision, adhesions or peritoneal metastases, and tumour extending into renal vein or vena cava. The influence of pathological type and of lymph node involvement on prognosis in the SIOP material has been described by Delemarre [6] and Jereb [10]. Patterns of intra-abdominal relapse were reported for the National Wilms' T u m o u r Trial and Study by Tefft (1980) [15]. In that study, the guidelines for radiotherapY differ little from those of SIOP. There were 27/336 (8%) abdominal recurrences, ranging from 6% for favourable histology, to 18% for unfavourable histology and 21% when histology was unknown. A division over stages was not given. In 5/27 cases the volume treated by radiotherapy was retrospectively considered insufficient. In the British Medical Research Council study, 142 operable patients in stage I, II and I I I were registered. The definition of stage I I I is somewhat different from the SIOP. N o abdominal recurrences were found, and only 13 patients developed metastases. In this study, whole abdominal irradiation from Th 9 to the pelvic brim (S1) is given with

shielding of the remaining kidney, for all the 71 patients in stage II and I I I [14].

Conclusion The incidence o f abdominal recurrences, which are a great hazard to survival, are gradually diminishing in frequency in the SIOP studies and trials. This could be due to more systematic preoperative treatment nowadays with chemotherapy alone, and the resultant reduction in incidence o f stage I I I cases. In the cases where an abdominal recurrence developed, several unfavourable prognostic factors as recognized during operation were usually present. In these cases, the execution of the postoperative treatment, notably regarding radiotherapy field size and dose, was apparently insufficiently adapted to these findings.

Acknowledgements This work was supported by a grant from the K o n ingin Wilhelmina Fonds, the Netherlands Organization Against Cancer, and a grant f r o m the Caisse Nationale de l'Assurance Maladie, France.

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