The effect of antiemetics and reduced radiation fields on acute gastrointestinal morbidity of adjuvant radiotherapy in stage I seminoma of the testis: A randomized pilot study

Clinical Oncology(1997) 9:252-257 © 1997 The Royal College of Radiologists

Clinical Oncology

Original Article The Effect of Antiemetics and Reduced Radiation Fields on Acute Gastrointestinal Morbidity of Adjuvant Radiotherapy in Stage I Seminoma of the Testis: A Randomized Pilot Study V. S. Khoo, K. Rainford, A. Horwich and D. P. Dearnaley The Royal Marsden NHS Trust, Sutton, UK

Abstract. The purpose of this pilot study was to evaluate the acute gastrointestinal morbidity of adjuvant radiotherapy (RT) for Stage I seminoma of the testis. Ten Stage I patients receiving para-aortic and ipsilateral pelvic nodal (dog-leg) RT provided a toxicity baseline (group A). Twenty Stage I patients, randomized to dog-leg RT or para-aortic RT (10 per group) were further randomized to received prophylactic ondansetron or expectant therapy with metoclopramide (group B). Daily patient-completed questionnaires evaluated acute toxicity. In group A (n -- 10), nausea, vomiting, diarrhoea and abdominal discomfort were experienced in 90%, 80%, 70% and 90% respectively. Antiemetic and antidiarrhoeal agents were required in 70% and 10% respectively, with good response. For group B (n = 20), the overall incidences of nausea, vomiting, diarrhoea and abdominal discomfort were 80%, 45%, 60% and 80% respectively. The ondansetron group experienced less nausea (P = 0.02) and less vomiting (P = 0.06). Both reduced field size and ondansetron groups appeared to have less diarrhoea (P = 0.06). The use of antiemetics in the expectant therapy groups resulted in at least a two-level reduction of toxicity grade in 86% of patients. A high incidence of lethargy, anorexia and headaches was noted for all groups. The incidence of headaches was not increased with ondansetron. Dog-leg RT for Stage I seminomas is associated with readily demonstrable gastrointestinal tract (GIT) toxicity. The number of patients in this study is too small to produce definitive results, but there appears to be reduced GIT toxicity with prophylactic antiemetics. The effect of reduced RT fields has been assessed further in the MRC randomized trial of field sizes (TEl0). Keywords: Gastrointenstinal morbidity; Radiotherapy; Seminoma

Correspondence and offprint requests to; Dr D. P. Dearnaley, Bob Champion Senior Lecturer and Honorary Consultant, Department of Radiotherapy and Oncology, The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.

INTRODUCTION

The routine use of prophylactic para-aortic and ipsilateral pelvic radiotherapy (dog-leg RT) and the inherent radiosensitivity of testicular seminomas have produced cure rates exceeding 95% [1-4]. Recently, studies of surveillance following orchidectomy alone have shown equivalent overall survival figures and RT can be avoided in 85% of patients [5-7]. Although there are studies evaluating late RT toxicity [8,9], there are fewer reports quantitating acute toxicity for prophylactic radiotherapy. The aim of this pilot study was to establish the incidence of acute treatmentrelated morbidity based on detailed prospective data collection concurrent with modem RT techniques, and to assess the effects of a 5-HT3 antagonist, ondansetron, and radiation field sizes on acute gastrointestinal tract (GIT) side effects using a randomized 2 x 2 factorial design.

MATERIALS AND METHODS Thirty Stage I seminoma patients were evaluated. The mean age at presentation was 47 years (range 22-62). Details of staging investigations have been described elsewhere and the Royal Marsden Hospital staging classification was employed [5]. The details of the radiotherapy fields and techniques used have been published previously [8]. The prescribed dose was 30 Gy in 15 fractions (five fractions per week). The average treatment duration was 21 days (range 1925). Ten Stage I patients treated with dog-leg RT and standard antiemetic therapy provided a toxicity baseline (group A). The standard antiemetic policy was to provide metoclopramide 10-20 mg 8-hourly when requested by the patient. Twenty Stage I patients randomized in the Medical Research Council TEl0 trial of dog-leg RT (DL group) versus paraaortic RT (PA group) were further randomized to receive prophylactic oral ondansetron (8 mg 8-hourly) or expectant therapy with metoclopramide (group B; Fig. 1).

253

Acute GIT Morbidity of Adjuvant RT in Stage I Testis Seminoma

Group A ~ Dog-leg RT + expectant metoclopramide (10 pt) i~ expectant metoclopramide [DL_+M] (5pt) Group B /-' Dog-leg RT

L prophylactic ondansetron [DL+O] (5pt)

metoclopramide [PA_+M](5pt) L Para-aortic RT L expectant prophylactic ondansetron [PA+O] (5pt) Fig. 1. Stratification of Stage I seminoma patients according to their treatment groups.

Table 1. Grading system used to assess nausea, altered bowel

motions and abdominal discomfort Symptom

Grading

Nausea

0 = no nausea 1 = nausea present but not interfering with daily activities 2 = nausea interfering with daily activities and/or requiring treatment 3 bedridden due to nausea

Altered bowel motions (ABM) 0 = firm, well-formed stools 1 = soft but still formed stools 2 = semisolid and hardly formed stools 3 = watery motions Diarrhoea

ABM 2 and 3

Abdominal discomfort

0 = no abdominal discomfort 1 = abdominal discomfort present but not interfering with daily activities 2 = abdominal discomfort interfering with dally activities and/or requiring treatment 3 = bedridden due to abdominal discomfort

A baseline questionnaire, including previous medical history, was completed before treatment. Daily patient-completed questionnaires evaluated acute treatment-related morbidity. Weekly questionnaires evaluated headaches, lethargy and anorexia. Headache was included, as it is a recognized side-

effect of ondansetron [10]. The toxicity grades are shown in Table 1. Vomiting was scored as the number of emetic episodes counted per day. Headaches, lethargy and anorexia levels were scored using the following grades: none (0); a little (1); quite a bit (2); and very much (3). All daily and weekly questionnaires during RT were completed. Patients were scored according to the highest grade of toxicity achieved. A further follow-up questionnaire was sent to all patients 1 month post-treatment. Evaluations between the different treatment modalities were performed using Fisher's exact test. All P-values were two sided. Patients with or without any level of toxicity were compared between the treatment groups using the Mann-Whitney U-test. Full statistical analysis was not pereformed for a subset comparison of the randomized groups because of the small patient numbers. Descriptive analysis only was undertaken for evaluation of the overall incidence of patient-related toxicity during the radiotherapy treatment course.

RESULTS Nausea Although no group A patients experienced pretreatment nausea, 9/10 experienced nausea during their RT (Table 2). Antiemetic therapy was required by 7/9 patients, including 7/8 patients with grade 2 or 3 toxicity. Antiemetic therapy resulted in a lowering of reported nausea by at least two toxicity grade levels in 6/7 (86%) of these men. Vomiting occurred in 7/8 patients with grade 2/3 nausea and all responded to metoclopramide. No group B patients had pretreatment nausea. The incidence of nausea and vomiting was comparable between groups A and DI + M (Table 2). For each of the randomized groups, 21 nominal 'treatment' days were calculated for each patient, giving a total of 210 days in all (Fig. 2). For the DL groups, grade 0, 1, 2 and 3 nausea occurred in 47%, 31%, 17% and 5% of treatment days respectively, and in the PA groups,

Table 2. Number of patients with nausea and vomiting, and use of antiemetics

Symptom

Toxicity grade

Group A (10 pt)

Group B DL_+M (5 pt)

Group B PA±M (5 pt)

Group B DL+O (5 pt)

Group B PA+O (5 pt)

Nausea

0

1

0

1

1

1

2 3

4 4

Vomiting

No Yes

Use of antiemetics by nausea grade a

0

1

3

4

0

0

1

2

1 3

3 2

3 1

1 0

8 6

2 8

1 4

2 3

4 1

4 1

11 9

0

0

0

0

1

0

0

0

2 3

3 4

1 3

1 2

N/A N/A N/A N/A

N/A N/A N/A N/A

N/A N/A N/A N/A

DL, dog-leg RT; PA, para-aortic RT; M, metoclopromide; O, ondansetron; N/A, not applicable; pt, patient. ~The prophylactic antiemetic group is excluded.

Overall group B (20 pt)

254

V.S.

D o g - l e g group

Khoo

et al.

Non-ondansetron group

10

1°8 +T

62 4

0

1 1 1 1 I 1

3

5

: 1 I ; 7

9

1 [ ; ;

~ ; 1

11

15

13

17

19

21

1

3

5

7

Day of radiotherapy treatment

9

11

13

15

17

19

21

Day of radiotherapy treatment

Para-Aortic group

Ondansetron group

1° T =

"6

10 T 8

l • Grade 3

~ Grade 2

~ Grade 1 ]

4+

~= 2 0

0 , 1

3

5

7

9

11

13

15

17

19

21

1 I 1

I 3

I

I 5

Day of radiotherapy treatment

F i g . 2. T h e i n c i d e n c e

of daily nausea

I

i 7

i

I 9

I 11

I

I

I

13

I

I

I

15

17

;

I 19

1u

I 21

Day of radiotherapy treatment

grades

55%, 35%, 8% and 1% respectively. Field size did not appear to affect the incidence of nausea in this small group of patients. A similar comparison between the groups treated with metoclopramide 'on request' and prophylactic ondansetron gave 34%, 42%, 18% and 6% compared with 67%, 26%, 7% and 0.5% respectively. When grade 0 nausea was compared with grade 1-3 toxicity, the ondansetron groups demonstrated a significant reduction compared with the metoclopramide 'on request' groups (P = 0.02). Although there appeared to be a trend for less emetic episodes with the ondansetron groups (P = 0.06), there were no differences when comparing field sizes. There was no correlation between the severity of nausea and the incidence of vomiting. All patients in the metoclopramide 'on request' groups (DL __ M and PA _+ M) suffered nausea at some time (Table 2). Antiemetics were required in 7/10 of these men and metoclopramide reduced nausea by at least two toxicity grades in 6/7 (86%) patients. For the ondansetron groups, 3/10 patients did not use their antiemetics regularly and, of these, two experienced vomiting, which resolved with regular usage. No additional antiemetic treatment was required for the ondansetron groups.

Altered Bowel Motions and Abdominal Discomfort Although no group A patients experienced pretreatment diarrhoea, 7/10 reported diarrhoea during RT. antidiarrhoeal agents were required in 1/7 patients (grade 3, with complete response). No group B patients reported pretreatment diarrhoea. When each of the randomized groups were analysed on the total number of treatment days (n =

1-3 for group B patients

during radiotherapy.

210), for the DL group, grades 0 + 1, 2 and 3 altered bowel motions (ABM) occurred in 76%, 21% and 3% respectively, and in the PA group, 83%, 16% and 1% respectively. A similar comparison between the groups treated with metoclopramide 'on request' and prophylactic ondansetron gave figures of 69%, 28%, and 3% compared with 90%, 8%, and 2% respectively (Fig. 3). There appeared to be a trend for less diarrhoea with para-aortic RT and ondansetron (P = 0.06). No patients with grade 2 ABM (n = 8) required antidiarrhoeal agents, compared with 2/4 men with grade 3 ABM. Abdominal discomfort was experienced in 9/10 group A patients. There was no grade 3 abdominal discomfort. Only paracetamol was required in 4/10 and 5/10 group A patients with grades 1 and 2 respectively. Abdominal discomfort was reported by 16/20 men in the B subgroups. Grades 1, 2 and 3 abdominal discomfort occurred at some time during treatment in 6/20 (30%), 7/20 (35%) and 3/20 (15%) respectively. Paracetamol alone was required in 1/6 (17%), 3/7 (43%) and 2/3 (67%) of patients with grades 1, 2 and 3 abdominal discomfort respectively. The group PA+O had the lowest incidence of abdominal discomfort (12% versus 25-31%) compared with all of the other groups. There was no correlation between the level of abdominal discomfort and the incidence of diarrhoea.

Headaches, Lethargy and Anorexia There were no headaches or anorexia before treatment in group A. Anorexia developed in 8/10 patients during treatment. Headaches were reported by 3/10 patients and paracetamol provided effective relief.

Acute GIT Morbidity of Adjuvant RT in Stage I Testis Seminoma

255

Dogleg Group

Non-ondansetron Group lo

g 6

z 2

Z

. . . . . . . . . . . . . . . . 1

3

5

7

9

11

13

i~; 15

17

....

0

19

21

3

5

7

9

11

13

15

17

19

21

Day of radiotherapy treatment

Day of radiotherapy treatment

Para-aortlc Group

Ondansetron Group

lO-

10"I

f

[EGd3 =Gd2

8 -

64

4,

z 2

Z

0 3

5

7

9

11

13

15

17

19

21

3

5

7

9

11

13

15

17

19

21

Day of radiotherapy treatment

Day of radiotherapy treatment

Fig. 3. The incidence of daily diarrhoeal grades 2-3 for group B patients during radiotherapy.

Lethargy was maximal by the second week of RT. All patients reported lethargy at the end of treatment compared with 30% before the start of RT. For group B, the overall frequency of headaches, lethargy and anorexia was 70%, 90% and 80% respectively (Table 3). Although headaches are a recognized side effect of ondansetron, the ondansetron groups reported slightly fewer and less severe headaches. The incidence of anorexia was similar between groups A and B. Grade 1 lethargy was present in 40% of group B patients before treatment. This incidence increased and was maximal by the end of treatment.

There was no correlation between the incidences of lethargy and headaches with RT field size or antiemetic group.

Follow-up Questionnaires Only 47% of the follow-up questionnaires were completed and returned. There were no apparent differences between the groups but detailed analysis was not undertaken in view of the small number of responding patients.

Table 3. Number of patients with headaches, lethargy and anorexia Symptom

Toxicity grade

Group A (10 pt)

Group B DL + M (5 pt)

Group B PA _+M (5 pt)

Headaches

0 1 2 3

7 3 0 0

1 3 1 0

0 1 2 3

0 7 3 0

0 1 3 1

1

0

2

0

1

3

2

2 3

5 0

3 0

Lethargy

Anorexia

Group B DL+O (5 pt)

Group B PA+O (5 pt)

1

0

4

6

3 0

4 0

1 0

1l 1

1

1

0

2

0 2 2

0 3 2

2 3 0

2 9 7

0

0

2

0

1

3

4

1

2

1

6

4 0

1 1

1 0

9 1

DL, dog-leg RT; PA, para-aortic RT; M, metoclopromide; O, ondansetron; pt, patients. Toxicity grades: 0 = none; 1 = a little; 2 = quite a bit; 3 = very much.

Overall group B (20 pt)

256

DISCUSSION Nausea, vomiting and diarrhoea are recognized side effects of abdominal RT. In this study, the acute side effects of prophylactic RT for seminoma were prospectively evaluated by patients using a daily diary card. This method of assessment has been previously validated as a reliable measure of collecting information [11]. A high incidence of acute GIT toxicity was demonstrated, which is contrary to some earlier qualitative reports suggesting little acute toxicity for prophylactic RT for seminoma [1-3, 8]. Previous retrospective studies of dog-leg RT reported an incidence of nausea between 1% and 91% [12-15]. Some of these reports may underestimate toxicities, as only severe side effects were documented. A recent prospective Norwegian series, which included 39 patients, reported a 100% incidence of nausea during RT [16]. Antiemetic treatment was required in 92% of three patients, with 5% requiring intravenous management; 5% had their last one or two fractions of RT omitted. These toxicities are a little higher than those observed with comparable groups in the current report, where 14 of 15 patients treated with dog-leg RT plus or minus metoclopramide had nausea, and 11 of 15 required antiemetics, but radiation treatments were always given as prescribed. The higher median dose (36 Gy) and RT treating only one field per day may be the reasons for the higher morbidity in the Norwegian study. The results of randomized studies in the prevention of RT-induced emesis using ondansetron appear to show that this drug is active with 58%-92% complete or major control efficacy (0-2 emetic episodes) in trials of fractionated [17] and single-dose [18] RT. However, although ondansetron significantly reduced vomiting during fractionated RT when compared with prochlorperazine, there was no significant effect on the incidence or severity of nausea [17]. In our study, the use of prophylactic ondansetron was associated with a lower incidence of nausea and vomiting, but reducing the field size from dog-leg to a para-aortic strip alone apparently made no difference. These observations should be regarded as preliminary in view of the small total number of patients studied. The antiemetics were compared using different schedules, ('on demand' versus 'regular'), introducing bias in favour of prophylactic ondansetron. Metoclopramide was effective in controlling established nausea in 80% of patients and our policy is now to use this agent prophylactically, reserving ondansetron for refractory nausea. The incidence of diarrhoea in our study falls within the reported range of 20%-87% [13,15]. One study reported that one-third of patients required antidiarrhoeal therapy [16], however, only 3/30 patients in our study required such therapy. All diarrhoea was successfully controlled. Similarly, abdominal discomfort was adequately controlled with paracetamol only. The present study confirms that a substantial proportion of patients suffer from headaches, lethargy and anorexia. An increased consumption of both tranquillizers and hypnotics have been reported

V.S. Khoo et al.

during RT, emphasizing the patient stress involved [14]. The aetiology is multifactorial. Early medical and psychological intervention may reduce these side effects. The Medical Research Council has undertaken studies to optimize both field size and radiation dose for prophylactic RT of Stage I seminoma. Dog-leg and para-aortic RT have been compared in study TEl0. Doses of 20 Gy and 30 Gy are being compared in study TEl8. Preliminary results suggest that reducing field size to a para-aortic strip alone was associated with a small increase in pelvic relapse (3%), but overall 2-year relapse-free survival was similar for both para-aortic and dog-leg fields. The use of para-aortic fields was associated with significantly reduced haematological and gonadal toxicity [19]. Our pilot study, using a patient questionnaire to assess side effects, has confirmed that abdominopelvic RT for seminoma causes significant acute GIT morbidity. Prophylactic antiemetics are warranted, given the prevalence of nausea. The impact of reduced RT field sizes, the choice of the optimum prophylactic antiemetic agent and drug scheduling will remain unclear until larger randomized and costeffectiveness studies have been completed.

Acknowledgements. We are grateful to A. R. Norman (Computing Department) for his assistance with statistics and to Christine Evans for help in preparing the manuscript. D. P. Dearnaley is supported by the Bob Champion Cancer Trust. The study was supported by Glaxo Laboratories Ltd, who supplied ondansetron as part of the open clinical trial GLZOF003.

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257 prospective study. Int J Radiat Oncol Biol Phys 1992;22:1057-64. 17. Priestman TJ, Roberts JT, Upadhyaya BK. Randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol 1993; 5:358-63. 18. Collis CH, Priestman TJ, Priestman S, et al. The final assessment of a randomized double-blind comparative study on ondansetron vs metoclopramide in the prevention of nausea and vomiting following high-dose upper abdominal irradiation [letter]. Clin Oncol 1991;3:241-2. 19. Foss~ SD, Horwich A, Russell JM, et al. Optimal field size in adjuvant radiotherapy (XRT) of Stage I seminoma - a randomised trial [abstract 595]. Proc ASCO 1996;15:239.

Received for publication February 1996 Accepted following revision May 1997