Etoposide and etoposide-ifosfamide therapy for refractory testicular tumors

¢'~',,,' 7,.~a-~u..~ R~,..~-J :1982' 9 , , ~

A:, 79 84

E t o p o s i d e t a d e t o p o s i d e - l f o s f a m i d e therapy for refractory testlcular tumors K . B r e m e r , N. N i e d e r l e , W. K r i s c h k e , M. H i g i , M. E. S c h e u l e n , C. G. S c h m i d t s a d S. S e e b e r *

l ~ t t t A'lisitund Poliklimk ~ "l-um~forJclmslI),IS:rst G . m a n Tumor C'¢mI#, l_:niv,'rsily of F~en, 4.~00 Esjen. I" R.G.

Introduction The introduction of vinblastine, blcomycin, ,~-platinum and adriamycin for testicular tumors h&~ prt~luced a considerable improvement in the results oF treatment over the past 10 years; so much so in fact that today tcsticular tumors may | ~ ranked among those. malignant dLseascs which are potentially curable (5, 7~9, 1I, I2). Nonetheless, complete and stable remissions have so far been achieved in only a proportion of patients (5, 7-9, 1 I, 12). For rrcurrent or resistant forms, ifos/'amide (I, 10) and etoposide (2, 3, 6, 13) are increasingly being used. T o evaluate the therapeutic effectiveness ofctoposide administered as a single agent and in combination with ifos/'amide, patients attending the West G e r m a n T u m o r Center in Essen with testicu "lar tumors refractory to chemotherapy were analysed retrospectively after this treatment and the response rates determined.

]Materials ~

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In the period from I January 1976 to 31 April 1981, 165 patientssufferingf~om malignant testicular tumor received ~ e n t with ~ alone or with ifosfandde. N o measurable tumor p a r a m e t m were availableat the time ofetopaside administration in 92 patients and the e f f e c t i ~ of etoposide I ~ a t m e n t oould therefore be analyaed retrospectively in only 73 patients. O f these patients, ;-~7received treatment withetoposide alone and 36 received the combination o f ~ a ~ ifcsfamide after failure to a c h i c ~ a complete remission, or when the tumor h a d r e c . ~ : ~ . •s . ~

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Prior cytostatic tTealment All 37 patients who had been treated with etoposide alone had previously received chemotherapy over a period of several months with the combination vinhlastine and bleomycin alternating in sequence with adriamycin and c/s-platinum (9, 12). Sixteen of these patients were further treated with ifosfamide, 14 were treated with other cytostatics (cyclophosphamide, actinomycin D, chlorambucil, DTIC, methotrexate, vincristine etc.) and 5 patients had received supplementary radiotherapy treatment. O f the 36 patients who had received a combination ofetoposide and ifosfamide, 33 were similarly pretreated with vinblastine, bleomycin, adriamycin and cis-platinum. Finally, 4 patients received chemotherapy with various other drugs, and 3 patients received radiotherapy.

Etoposide dosage Twenty-nine of the 37 patients (78.3%) who received etoposide alone received it in a dosage of 120 mg/m 2 orally on 5 consecutive days at an inte~'al of 4 weeks. Eight o f t h e 37 patients (2/.7%) received inu'avenous administration of etoposide 120-150 mg/m 2 on 3 consecutive days every 3--4 weeks. The combined chemotherapy with etoposide and ifoslhmide was carried out in all 36 patients with the following dosages: etoposide 120 mg/m z i.v. days !, 3, 5 and ifosfamide 40 mg/kg i.v. days 1-5, repeated on days 21-28. The schedule provided for the alternation of the cytostatics after two cycles of chemotherapy for all patients in order to prevent any resistance from developing (9, I l, 12).

Criteria of remission A complete remission (CR) was taken to be when all radiographic, ultrasound or CT scan evidence of tumor had completely disappeared. This included the normalization of serological tumor parameters such as ~-I-lipoprotein, ~-HCG and-LDH. A greater than 50% regression of the tumor and/or other tumor parameters was considered a partial remission (PR) and a reduction of more than 25% was deemed to be a response (R). A tumor response of less than 25% was regarded as a failure (F).

Histology The histological classification of Dixon & Moore was used (4).

Tumor status The classification ofthe stages ofprogremion o f t h e tumor followed the guidelines observed in the West German T u m o r Center at Ea.~n (9, 12).

Results After treatment with Ctoposide alone, a reb'porJse was observed in only 9 o£the 37 patients (24.3%) (I patient C~, 3 patients PR, and 5 p a t i e n t s R ; ~T a b l e 1). The combination of etoposide and ifos£amide on the other hand resulted in tumor regression in 21 of the 36

p~tients or 58.3?/0 (4 patients GR, 11 patients PR. and 6 patients R; Table 2)~.Depending

ETOPOSIDE THERAPY FOR REFRACTORY TESTICULAR TUMORS

81

Table 1. E t o p o ~ d e tdnllle-tlLeat t x z t t m e a t : . # e t of rernlss/on as s function o f the phase o f tile disease

Phase of disease

a

CR

PR

R

Residual Progressive Total

14 23 37

1

2

1

0 1

1 3

4 5

Total response rate (%) 28,4 21.7 24.3

on the stage o f the t u m o r at the start o f etoposide treatment, a t e n d e n c y toward higher remission a n d response rates was observed w h e r e only residual t u m o r was present t h a n w h e n there was evidence of progression (Tables l a n d 2). T h e d u r a t i o n o f complete remissions could not be d e t e r m i n e d since the cytostatics were c h a n g e d after 2 cycles o f chemotherapy. T h e etoposide-ffosfamide c o m b i n a t i o n resulted in remissions in all patients in stages I I b and I I c a n d in stage II I, while t h e r a p e u t i c failure was observed only in the m o r e a d v a n c e d stage IV ( T a b | e 3). O n the o t h e r h a n d , in the patients treated with etoposide alone, n o n e o f the various t u r n o u t stages responded ( T a b l e 4). In neither case, i.e. etoposide administered alone or c o m b i n e d administration o f etoposide a n d ifosfamide, was a d e p e n d e n c e of the results o f c h e m o t h e r a p y on t u m o r histology or on the d u r a t i o n o f the prior c y t o s t a d c t r e a t m e n t observed.

Discussion

In published findings, the t h e r a p e u t i c activity o f etoposide was studied on a total of 58 patients with a d v a n c e d m a l i g n a n t testicular tumors refractory to c h e m o t h e r a p y . T h e remission rates claimed b y various a u t h o r s v a r y between 33 a n d 100%, b u t the total response rate is 50% (Table 5). T h e total response rate for the 37 padents in our series treated with etoposide alone was 24.3%, w h i c h is c o m p a r a t i v e l y low. Since previous results ofetoposide t h e r a p y d o not reveal a d e p e n d e n c e o n either the r o u t e o f a d m i n i s t r a t i o n (oral or intravenous), t u m o r histology, or the d u r a t i o n o f the previous cytostatic t r e a t m e n t , this relatively low remission rate is most likely a t t r i b u t a b l e to differences in the previous cytostatic t r e a t m e n t , despite similar etoposide dosages. O n e especially crucial difference is

TeJble 2. Etoposlde-ff~uL4~dde c o m b i ~ t i o n Ums~ ~C 8rrsd~ of remission as a Function of p h ~ e ~t the d l s e u e Total Phase ofdiaease

n

CR

PR

R

response rate (%)

Residual Progrcmve Toted

21 15 $6

3 I 4

6 5 II

4 2 6

61,9 5S.3 58.3

82

K. B R E M E R T a b l e 3.

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Etoposide-ifosfan~ide treatment: Response tumor stage

Stage

n

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combination as a function of

Responses 2 3

2 3

Fai|ur~s -....

111

I

I

IV (pulmonary) IV (pulmonary and abdominal) Total

7

4

3

23 36

11

12 !5

21

that a d r i a m y c i n was used r e g u l a r l y in t h e i n d u c t i o n t h e r a p y o f all the patients it, the present s t u d y , and, a d r i a m y c i n is at least partially cross-resistant with etoposide. T h e c o m b i n a t i o n o f e t o p o s i d e a n d ifosfamide raised t h e overall response rate to n e a r l y 6 0 % ('Fable 2). Since ifosfamide a d m i n i s t e r e d alone c a n b r i n g a b o u t t u m o r remissions in 4 0 % o f p a t i e n t s w i t h refractory testicular t u m o r s (10), this positive overall response rate is p r o b a b l y to be a t t r i b u t e d to the ifosfamide c o m p o n e n t . In the light o f these d a t a , the effectiveness of e t o p o s i d e on refractory or r e c u r r e n t testicular t u m o r s s h o u l d n o t be o v e r e s t i m a t e d . H o w e v e r , because o f its relatively low toxicity a n d g o o d subjective t o l e r a n c e we use etoposide, first, f o r e m o s t a n d r e g u l a r l y in c o m b i n a t i o n with ifosfamide (10). I n a d d i t i o n we h a v e been using the c o m b i n a t i o n e t o p o s i d e - i f o s f a m i d e increasingly in p r i m a r y i n d u c t i o n t h e r a p y , especially w h e n there are c o n t r a i n d i c a t i o n s to s o m e o f the d r u g s in t h e established c o m b i n a t i o n s v i n b l a s t i n e / b l e o m y c i n a n d / o r adriamycin/cis-pladnum.,.

Summary

A total o f 165 p a t i e n t s f r o m t h e W e s t G e r m a n T u m o r C e n t e r in Essen suffering from a m a l i g n a n t testicular t u m o r received t r e a t m e n t with e t o p o s i d e a l o n e or in c o m b i n a t i o n . Since this was a d j u v a n t t h e r a p y a n d n o m e a s u r a b l e t u m o r p a r a m e t e r s were a v a i l a b l e at the time o f e t o p o s i d e a d m i n i s t r a t i o n in 92 patients, t h e efficacy o f e t o p o s i d e t r e a t m e n t could be a n a l y s e d retrospectively in o n l y 73 patients. T h i r t y - s e v e n o f these p a t i e n t s received t r e a t m e n t w i t h e t o p o s i d e alone (dosage usually 120 m g / m a p.0. d a y s l - 5 e v e r y 4 weeks) a n d 36 received t r e a t m e n t w i t h a c o m b i n a t i o n o f e t o p o s i d e a n d ifosfamide (dosage: Ta3ble4.

i~0,oside s~le-~ent sponse as s tuoctlon

treatmcnt: reof tumor s t a ~

Stage

.

Responses

lib llc

---

~ --

Ul

FaU.res

1

~

-!

13

3

10

IV (pulmonary) IV (pu/monary ~nd abdom/n~l)

2S

6

17

Tota/

37

9

28

ETOPOS1DE T H E R A P Y FOR R E F R A C T O R Y T E S T 1 C U L A R T U M O R S

83

T a b l e 5. E t o p o s i d e a c t i v i t y on m a l i g n a n t tmalesdmr t u n a o r s r e f a ' a c t o r y to c h e n a o t h e r ~ p y

Authors

Re£

n

CR

Cavalli a a/. ( E O R T C ) Fitzharrls tt M. Williams et aL Monfardini el el. Total Bremer et aL

2 6 13 3

28 24 3 3 58 37

~ 3 --

-3 1

R

F

5

7

8

2 -~ 9 5

3 t 17 3

Total r~ponse rate (%) 42.9 54 100 33.3 50 24.3

etoposide 120 m g f m z i.v. days 1, 3, 5 and ifosfamide 40 m g / k g i.v. days 1, 5 every 3 - 4 weeks) when prior treatment with cytostatics had not been able to achieve complete remi~ion, or the tumors had recurred. In patients treated with etoposide alone a total response rate of 24..3% was observed. In contrast, remission o f the tumor was achieved in 58.3% of the patients receiving the etoposide-ifosfamide combination. Despite prior comprehensive cytostatic treatment, etoposide was still effective in some patients with refractory malignant testicular tumors. This was especially true o f the etoposide-ifosfamide combination, as ifosfamide showed little cross-resistance with the previously administered cytostatics.

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(Stadium IV). Et/.. Wx&,tg&,. 5 ~ 81t-821. 10. Schculen, M. E., lqiederle,]q. & seeber, S. (1980) E r g e ~ bei t h e r a p i e ~ a ' a k t ~ ' n ~ ~n..Vetgleich

,,at

Diu, ,e ,rod

d.

ether " ~ ~ der uro~tlven

Phase-II-Studie yon Ifmfamid Wirkung yon Ummlt~an~l~

X.X.,,.

11. S c h , ~ t , C+ O, & Sector, S.O979) Chemotherapie t e ~ . l a r e r T ~ 1488-149s.

DWJ. M + . W e ~ m = ~ r . t e e

84

K. BREMER E T AL.

12. Sceber, S., Scheulen, M. E., Schilcher, R. B., Higi, M., Nieder]e, N., Mouratidou, D., Bierbaum, W. C. & Schmidt, C G. (1980) Sequential combination chemotherapy with vinblastine-bleomycin and adriamycinJ cisplatinum in early and late testlcular cancer. In (Prestayko, A. W., Grooke, S. T. & C.larter, S. K., ed.,~Uisp~alinura. Currtn: S:atus cad.New Developmtnts. New York: Academic Press, pp. 329-344. ! 3. Williams, S. D., Einhorn, L. H., Greco, F. A., Oldham, R. & Fletcher, R. (1980) VP 16-213 salvage therapy fi~r refractory germinal ncoptasms. Cancer46: 21562158.