Pilot studies of 2 and 1 course carboplatin as adjuvant for stage I seminoma: Should it be tested in a randomized trial against radiotherapy?

Int. J. Radiatmn

Pergamon

Oncology

Bml. Phys., Vol. 2Y, No. 1. pp. 3-0, 1YY4 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. Al1 rights reserved 0360-30 I6/94 $6.00 + .OO

0360-3016(93)E0074-G

??Clinical Original Contribution

PILOT STUDIES OF 2 AND 1 COURSE CARBOPLATIN AS ADJUVANT FOR STAGE 1 SEMINOMA: SHOULD IT BE TESTED IN A RANDOMIZED TRIAL AGAINST RADIOTHERAPY? R. T. D. OLIVER, M.D., FRCP,’ P. M. EDMONDS, MRCP,’ J. Y. H. ONG, B.Sc., RGN,’ M. J. OSTROWSKI, FRCR,* A. W. JACKSON, FRCR,* H. BAILLE-JOHNSON,FRCR,2 M. V. WILLIAMS, FRCR,3 C. R. WILTSHIRE, FRCR,4 T. MOTT, FRCS,4 W. R. PRATT, FRCR,’ C. W. L. TRASK, FRCR6 AND H. F. HOPE-STONE, FRCR’ ‘Dept.of MedicalOncology,The Royal London; ‘Dept. of Radiotherapy and Oncology, Colchester; 3Dept. of Radiotherapy and Oncology,Addenbrooke’s; 4Dept. of Radiotherapy and Oncology, Ipswich; ‘Dept. of Radiotherapy and Oncology, Norfolk and Norwich; 6Dept. of Radiotherapy and Oncology, Southend Genera1 Hospita1 Purpose: Underpinned by increasedconfidencein cure of metastatic seminoma by chemotherapy during the past 12 years, three management strategies for Stage 1 seminoma have been evaluated by six collaborating centers within the Anglian Germ Cel1 Tumor Group. This paper evahtates the efficacy of surveillance, prophylactic radiotherapy and adjuvant chemotherapy, and discusses these differing management approaches. Methods and Materials: Patients were recruited into the study between 1982 and 1992. There was no randomization between treatment groups. Seventy-nine patlents received prophylactic radiotherapy (median follow-up = 51 months), 67 patients had surveillance alone (median follow-up = 61 months) and 78 patients were treated with adjuvant single agent platinum (median follow-up = 44 months). Fifty-three of these patlents received two courses of phttinum (median follow-up = 51 months) and 25 patients received one course (median follow-up = 29 months, range 2272 months). Results: There were 18 (27%) recurrences on surveillance, five (6%) after radiotherapy, one (1%) after two courses ofant single agent platinum and none after one course of carboplatin. There was one death from testis cancer after radiotherapy and none after adjuvant chemotherapy treatments. Two patients died with drug resistant disease after relapse on surveillance. There was one death from a myocardial infarction after prophylactic radiotherapy and one death from suicide in the surveillance group. A retrospective quality of life questionnaire reviewing the incidence of early and late toxicity revealed no major differences though they suggest that those treated with one course adjuvant carboplatin had somewhat less sickness and an earlier return to work. Conclusion: Single agent carboplatin appears wel1 tolerated and is an effective adjuvant treatment for Stage 1 seminoma. A multicenter randomized trial of the different treatment modalities is required to further evaluate its use. Adjuvant, Seminoma, Carboplatin. INTRODUCI’ION

Nearly 30 years have elapsed since radiotherapy first achieved close to 90% cure of Stage 1 seminoma. With more than 94% event-free survival, 98% cure of 2376 patients reported in the literature between 198 l- 1989 (27) and the most recent report in this journal showing no deaths in patients treated since 1984 (4), there seems at first sight little justification to consider alternative options. However, because of considerable improvements in

clinical and pathologie staging since that time, Stage 1 seminoma today bears little relation to those patients whose 60% relapse rate led to use of prophylactic radiotherapy ( 18). The demonstration that radiological and tumor marker surveillance was a safe strategy for Stage 1 nonseminoma (for review see Ref. 16) led to its use for Stage 1 seminoma (18). Although there was a 25% relapse rate in patients staged with computed tomography (CT) alone (13) and a 15% relapse rate in those staged with CT and lymphog-

Reprint requests to: Prof. R. T. D. Oliver, Dept. of Medical Oncology, Royal London Hospital, Whitechapel Rd., London El 1BB England. Acknowledgements-We gratefully acknowledge the help of junior hospital, nursing, and secretarial staff in the management

of these patients and Gwen Walsh for considerable help in preparation of the manuscript. This work was funded by The Imperia1 Cancer Research Fund supported by donations from The Grand Metropolitan, Barclay and Mercury Trusts. Accepted for publication 18 November 1993.

4

1. J. Radiation Oncology 0 Biology0 Physics

raphy (8, 25), al1 were cured with subsequent treatment (8, 13, 25). However, the psychological stress of surveillance, with cases lost to follow-up and the slow pattern of recurrence beyond 2 years often proving difficult to confìrm, led to the conclusion that some form of adjuvant treatment was the preferred management approach (8, 13, 25). With peptic ulcer (6) and second malignancy (7) wel1 recognized late events after radiotherapy, there has been interest in alternatives. The higher cure rate of metastatic seminoma compared to nonseminoma with single agent cisplatin has led to the conclusion that seminoma is even more curable by chemotherapy than nonseminoma ( 19). Furthermore retrospective review suggests that chemotherapy, even single agent cisplatin, is more effective than radiotherapy against an equivalent volume of metastatic seminoma (12). The less toxic analogue of cisplatin, carboplatin, has now been in clinical use for more than 8 years (23) and so far there have been no obvious late toxic effects, and the acute toxicity profile is little worse than radiotherapy. This paper attempts to evaluate its use as adjuvant therapy for patients with Stage 1 seminoma. METHODS

AND MATERIALS

Patients included in this review were diagnosed between 1982 and 1992 and al1 have a minimum of 9 months follow-up. Routine staging consisted of chest X ray, CT scan of para-aortics (and, if indicated, pelvis) and serial markers afp and PhCG if positive preorchiectomy. Lymphangiography was not used after 1985. Follow-up on surveillance was every 6 weeks for the first year, every 3 months for the second, every 6 months for the third year and annually thereafter. Patients receiving adjuvant treatment had follow-ups after 2 months in the first year, every 4 months in the second year, every 6 months in the third year and annually thereafter. CT stans were to be performed at 2, 12, and 24 months,

Volume 29, Number 1, 1994

though not al1of the earlier cases treated with radiotherapy had al1 of the follow-up stans. At each visit &P and PhCG were measured as were HBD and PLAP in some centers. Histology was reviewed locally. Informed consent was obtained from al1 patients entering the study. The first three patients receiving adjuvant chemotherapy received cisplatin 50 mg/m2 days 1 and 2 q21 X 2. Al1 subsequent patients received carboplatin. Carboplatin dosage was calculated according to the area under the curve formula of Calvert et al. (3), that is 7 X (GFR + 25) mg. In those patients receiving two courses, treatment was repeated after 2 1 days. The surveillance patients were treated mainly during 1983- 1985. The two-course adjuvant chemotherapy patients were treated from 1985-1990 and the one-course adjuvant chemotherapy patients were mainly treated from 199 1 to the present. The radiotherapy patients were treated during the whole period under review and received an average of 30 Gy in 15 fractions to the paraaortics and ipsilateral pelvis (i.e., dog leg field). There was not universa1 agreement about the safety of surveillance or adjuvant protocols between centers, or between al1 individuals within the same centers, so it was not possible to conduct a randomized trial. As a consequente it was agreed to undertake a prospective audit of practice evaluating the three treatment options. In an attempt to assess the recall of toxicity, patients were asked to complete a toxicity questionnaire. RESULTS

Table 1 reviews the characteristics of the patients in the two groups and compares age, time from first symptom and year of first diagnosis. Figure 1 shows the overall relapse-free survival with 68% surveillance, 97%.radiotherapy, and 99% adjuvant carboplatin patients relapse free at 5 years. Table 2 documents the number of events after treatment.

Table 1. Characteristics of patients Surveillance Median age Histology delay < 2 months > 3 months Year of orchidectomy 1983-1985 1986-1988 1989-1992 Preorchidectomy markers AFP +ve HCG -ve AFP -ve HCG +ve AFP +ve HCG +ve AFP -ve HCG -ve Not tested * 1 course treatment.

Radiotherapy

Chemotherapy

(n = 67)

(n = 79)

(n = 78)

37

34

36

33 29

44 32

37 38

37 19 11

22 29 28

3 26 (l)* 49 (24)*

2 5 0 32 28

1 2 0 47 29

0 2 1 35 40

Adjuvant carboplatin 0 R. T. D. OLIVER I II 111 l i_flJzii ;t j

II I

II I

(! I

adj chemo (n=78) //, 1’i_Aj DXT (rk79)

IIII ui; /jj !I / j 1 //ia

II I

! II I II

I

5

et al.

!I MI

MI

I

I

Surveillance

(n=W

T 1 U ~60

--

m 1 N40

CHI P

--

=

21.37

<

.aa1w

R E n

1 S20 S

--

1 0 N

1

2

3 TINE

Fig. 1. Cumulative

Overall

4

5

7

6

a

I 9


relapse-free survival of Stage 1 seminoma patients in Anglian germ cel1 tumor group studies.

2 19 of 224 patients treated (98%) are currently

alive and disease free. There is no evidente of any difference between the three regimens in terms of survival, though the relapse rate on surveillance (27%) was significantly higher (x217.7, p < 0.001) than the other two groups. The differente in relapse rate is almost entirely due to relapse in the retroperitoneum, though there was an excess of relapses in the iliac nodes and second tumors in the surveillance patients. Second testis tumors occurred in 3% of surveillance patients, 1% of radiotherapy patients, and none to date in those who received adjuvant chemotherapy (Table 3). Though not randomized there is no evidente for any differente between adjuvant carboplatin or radiotherapy in terms of relapse rate. The only relapse after adjuvant carboplatin was in a 67 year-old man who received two courses, then relapsed at 19 months, but who on review of diagnostic CT stans had smal1 volume lymph nodes between the aorta and vena cava. He has now survived 2

after a fourth relapse. Prognostic factor analysis (Table 4) shows no significant risk factors for relapse, though there was a nonsignificant trend for higher relapse in older patients, those with more prolonged delay in diagnosis, and those who had positive markers prior to orchidectomy. Treatment of relapse is summarized in Table 5. Given the selection of combination treatment for more advanced cases at relapse and the smal1 numbers, the differences observed are not significant. Retrospective review of toxicity symptoms recalled by the patients revealed little differente between the two adjuvant options (Table 6). There was a trend for more diarrhea in the patients who received radiotherapy and more acute nausea and vomiting in the patients receiving two courses of adjuvant chemotherapy. Most of these were treated before the availability of 5-HTs antagonist antiemetics. Relative to surveillance patients, there was some delay in return to work in patients receiving either radiomore

years and is in remission

Table 2. Outcome according to treatment protocol Adjuvant carboplatin

Median fellow-up (range) % > 24 months follow-up % disease recurrence % deaths testis cancer % deaths other causes % disease-free

Surveillance n = 67

Radiotherapy n = 79

2 courses n = 53

1 course Tl = 25

61 (24-118) 88 27 3 95.’

51 (6-116) 79 5 1 1 98

5 1 (30-106) 100 2 0 0 99

29 (22-72) 88 0 0 0 100

6

1. J. Radiation Oncology 0 Biology0 Physics Table 3. Site of recurrence according to treatment protocol Surveillance % n = 67

Sites of recurrence 2nd primary Iliac nodes Paraaortic nodes Outside abdomen

Adjuvant chemotherapy % n = 78

Radiotherapy % n = 79

3 3

1 0

0 0

22

1

1

0

4

0

therapy or two courses of chemotherapy (Table 7), though preliminary results suggest one course was better tolerated and there was an earlier return to work. DISCUSSION

Risking less treatment for patients with a high cure rate is always more difficult than intensifying treatment for patients with a poor chance of survival ( 15). This is particularly so when the simplification of the treatment means that there would be reduced referral of testis cancer to specialist centers that have sufficient experience to discriminate between high and low risk patients (14). Success in treating high risk patients is stil1 important in achieving the current leve1 of overall survival in testis cancer when more than 95% of al1 patients presenting with germ cel1 tumors can be expected to be cured ( 17). However, despite the long experience and limited but only recently wel1 documented (1) acute toxicity of prophylactic radiotherapy, there are wel1 recognized late events after this treatment such as peptic ulcer (6) and late malignancy, particularly in the field of treatment (7), as wel1 as higher overall death rate in mediastinally irradiated patients over the age of 40 (4). It is possible that one course of carboplatin might improve on these results.

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Table 5. Treatment

of relapse patients No. of cases

Continuous diseasefree survival %

3 7 12

100 86 75

Radiotherapy Single agent carboplatin Combination chemotherapy

It has long been known that seminoma is more radiosensitive than nonseminoma (5). This has provided the principal justification for radiotherapy remaining the primary treatment modality of Stage 1 seminoma throughout the world today. Increasingly, it is accepted from retrospective comparisons of metastatic series that when matched volume for volume those treated by chemotherapy do better than those treated by radiation (12). The observed higher cure rate of relapsed surveillance patients with primary chemotherapy than radiotherapy [ 14% of relapsed patients treated by radiation have had a second relapse compared to 5% of chemotherapy treated patients (8, 13, 25)] would also support this view. The observation that metastatic seminoma has a higher cure rate than metastatic nonseminoma when treated with single agent chemotherapy, whether melphalan (2) or platinum (9, 19), would support the view that there is a differential chemotherapeutic sensitivity, as wel1 as radiotherapeutic sensitivity between seminoma and nonseminoma. In view of these observations, it would seem to be more rational to use the more effective agent as adjuvant therapy, provided toxicity and tost is equivalent. As the results presented in Table 5 show, this is the case for carboplatin. The results reported in this paper suggest that carboplatin alone offers a realistic alternative to radiation at the dosage used (i.e., 30 Gy in 15), at a similar tost, particularly if additional prolonged follow-up of the patients having a single course confirms the safety and low toxicity of this approach. However, it wil1 be vita1 that follow-up

Table 4. Prognostic factors for relapse Table 6. Quality of life survey 1993: summary of results

Age 18-31 32-78 Delay in diagnosis < 2 months > 2 months Preorchidectomy markers Negative Positive Unknown Pathology staging plrp 1r+/rQp3 PX

No. cases

Recurrence rate %

Death rate %

77 146

12

1.3 1.4

114 99

8 10

2 1

114 13 97

8 15 11

3

109 50 65

9 10 11

2 2

5

Immediate side effects Sickness % Surveillance n = 27 Radiotherapy n = 50 Chemotherapy Two courses n = 34 One course n = 20

Late side effects

Diarrhea %

Indigestion %

Fertility problems %

6

4

11

6

36

60

30

14

50

12

24

6

25

0

nla

nla

Adjuvant carboplatin 0 R. T. D. OLIVER et al.

7

Table 7. Impact of treatment policy on return to work Adjuvant chemotherapy % Radiotherapy % n = 42

2 courses n = 30

1 course

(weeks)

Surveillance % n = 27

<4 4-12 > 12

30 67 3

29 50 21

33 43 23

50 50 0

Time off work after orchidectomy

of these patients is prolonged, as we cannot exclude the possibility of a late toxicity such as leukemia which has recently emerged from studies of etoposide in nonseminoma (2 1, 24). Given the two-fold increased incidence of late second tumors after radiotherapy (7), it wil1 also be interesting to know if carboplatin enables patients to avoid this risk. It is wel1 recognized that seminoma is an immunogenic tumor as assessed by its degree of lymphocyte infiltration and the high incidence of spontaneous regression of primary and metastatic disease (20). Part of the curative effect of chemotherapy may be due to unblocking of the immune response. This is suggested by the massive lysis of bulk metastatic seminoma seen after a single dose of carboplatin chemotherapy, similar to what is wel1 known to occur in Burkitt lymphoma. The results from surveillance studies are equally encouraging from the point of view of patient survival. It is not however a treatment policy to give encouragement in the service setting because of the prolonged period of anxiety due to late relapse which can occur as late as 3-4 years. Furthermore two of our three deaths from testis cancer occurred in those treated by surveillance. The issue of late relapse is also critical because of the wel1 recognized occurrence in the old literature, albeit rarely, of patients presenting with paraplegia as a first manifestation of relapse ( 11).

n = 20

An additional possible benefit of adjuvant treatment is the suggestion that there may be a lower incidence of second germ cel1 tumors in the contralateral testis after adjuvant treatment when compared to that seen after surgery alone. Given a similar observation in a recently published Scandinavian study (22), there is a need for further investigation of this point in a multicenter randomized trial. A final justification for such a study on the different treatment options of Stage 1 seminoma is the stil1 unresolved issue as to whether late second nontesticular malignancy is increased after radiotherapy (7, 10, 26).

CONCLUSION

This study has established the short-term safety of using carboplatin in the adjuvant setting for Stage 1 seminoma. This justifies more extensive evaluation with quality of life assessment given that the toxicity profile is certainly no worse and possibly better than seen with radiotherapy. Subsequent to completion of studies reported in this paper, an additional 20 patients have received 1 course of Carboplatin and been followed for 12-24 months. NO relapses have been observed.

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2. 3. 4. 5.

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14. Oliver, R. T. D. Rare cancers and specialist centres. Br. Med. J. 292:64l-642; 1986. 15. Oliver, R. T. D. Risking less treatment in cancer patients: Lessons from germ-cel1 tumours. Lancet ii:430-43 1; 1988. 16. Oliver, R. T. D.; Freedman, L.; Parkinson, C.; Peckham, M. J. Medical options in the management of Stages 1 and 2 (No-N3 Mo) testicular germ cel1 tumours. Urol. Clin. N. Am. 14:721-728; 1987. 17. Oliver, R. T. D.; Hope-Stone, H. F.; Blandy, J. P. Modern management of germ cel1 tumours. In: Oliver, R. T. D., Hope-Stone, H. F., Blandy, J. P., eds. Urological and genital cancer. Oxford: Blackwells; 1989:359-38 1. 18. Oliver, R. T. D.; Hope-Stone, H. F.; Blandy, J. P. Possible new approaches to the management of seminoma of the testis. Br. J. Urol. 56:729-733; 1984. 19. Oliver, R. T. D.; Love, S.; Ong, J. Alternatives to radiotherapy in management of seminoma. Br. J. Urol. 65:6167; 1990. 20. Oliver, R. T. D.; Nouri, A. M. E. T cel1 immune response to cancer in humans and its relevante for immunodiagnosis and therapy. Cancer Surv. 13: 173-204; 1992. 2 1. Oliver, R. T. D.; Ong, J. Y. H.; Raja, M. A.; Sperandio, P.

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