the management of metastatic seminoma testis

The Management of Metastatic Seminoma Testis

DAVID BALL, MB, MRACR,' ANN BARRETT, MB, FRCR, MICHAEL J. PECKHAM, MD, MRCP, FRCP(G), FRCR

Clinical details of 85 men presenting with previously untreated metastatic seminoma are presented. In Stage I1 disease relapse rate was related to the size of metastases. In IIA (32 patients) the relapse rate was 9.4%; IIB (11 patients), 18.2%; and IIC (23 patients), 39.1%. The continuous disease-free survival rate was significantly worse for IIC than IIA and IIB patients (P = 0.023). No instance of first relapse in supradiaphragmatic nodes was observed in 13 men with Stage I1 disease treated with irradiation limited to infradiaphragmatic nodes. In relapsing Stage IIC patients, extralymphatic metastasis was as frequent as abdominal relapse. On the basis of these observations, together with preliminary data in nine men receiving Cis-platinum-containing chemotherapy, all of whom are in complete remission, it is proposed that patients with Stage IIA and IIB disease should receive infradiaphragmatic irradiation with chemotherapy deferred until relapse. Stage IIC patients should receive chemotherapy initially, followed by irradiation. In Stage 111 and IV disease chemotherapy should be initial therapy with radiotherapy for bulky disease on an individualised basis. Moderate elevation of blood B-HCG levels is not inconsistent with a diagnosis of pure seminoma and does not appear to influence adversely the outcome of radiotherapy.

Cancer 50:2289-2294, 1982.

HE MAJORITY of patients with testicular seminoma T have no clinical evidence of metastases at presentation. In a recent analysis by Schultz' of Danish Na- tional Data of 487 consecutive cases, 376 (77.2%) had Stage I disease. Of the remainder only six (1.2%) had extralymphatic metastases detected at the time of initial diagnosis. The early stage presentation and remarkable radiosensitivity of seminoma results in excellent survival figures. Caldwell et al.' in a recent literature review found that 83% of 1476 patients with Stage I-IV disease were alive and disease-free. Of this group, 1032 had Stage I disease and 983 (95%) were disease-free. In spite of these gratifying results a proportion of patients die of uncontrolled malignancy; in Caldwell's review the fail- ure rate in Stage I1 was 22% and in Stages 111 and IV 72%. It is the purpose of this report to identify patients at high risk of relapse following radiotherapy and to present preliminary results of combination chemotherapy in advanced disease.

Patients and Methods

Clinical details of 85 previously untreated patients with Stage 11,111 and IV seminoma referred to the Royal

From the Institute of Cancer Research and The Royal Marsden

* Present address: Cancer Institute, Peter MacCallum Clinic, 48 1,

Address for reprints: Professor M. J . Peckham, The Royal Marsden

Accepted for publication October 12, 198 I .

Hospital, London and Surrey, England.

Lt. Lonsdale Street, Melbourne, Victoria, Australia. 3000.

Hospital, Downs Road, Sutton, Surrey, SM2 SPT, England.

Marsden Hospital between 1963 and 1979 have been analysed. It is convenient to consider them in two groups. The first (75 patients) were treated by radiotherapy alone (66 patients) or radiotherapy and alkylating agent chemotherapy (nine patients) (Table 1). The second group of ten recently treated patients received chemotherapeutic combinations in current use for nonseminomatous germ cell tumors (Table 2).

Staging

Staging included lymphography, intravenous urog- raphy, chest radiograph, liver function tests and, in more recent years, routine monitoring of serum alpha-fetoprotein (AFP) and beta human chorionic gonadotrophin (B-HCG). Liver and bone scans were carried out if in- dicated and 67Gallium scanning was carried out in se- lected patients. Lymph node masses were localized by ultrasonic scans and more recently by computerized axial tomographic (CT) x-ray scanning. A total of I 1 Stage IIC patients underwent laparotomy prior to radiotherapy in most cases for diagnostic rather than staging purposes. Three patients had laparotomy for staging and tumor localization purposes in the period before CT scanning was available.

The staging classification used was as follows: Stage I: No clinical evidence of metastases. Tumor

confined to the testis. Stage ZZ: Clinical evidence of involvement of para-

aortic lymph nodes: (IIA) metastases < 2 cm in maximum diameter; (IIB) metastases 2-5 cm in maximum

0008-543X/82/1201/2289 $ I . 10 0 American Cancer Society

2289

2290 CANCER December 1 1982 Vol. 50

TABLE 1. Previously Untreated Patients with Seminoma Testis Receiving Radiotherapy ? Alkylating Agent Chemotherapy

(Royal Marsden Hospital 1963- 1979) ~~~~ ~~ ~~ ~~ ~ ~~~~

Time since orchiectomy No. receiving

(months) chemotherapy as Total part of planned

Stage patients Range Median initial therapy

IIA 32 13-216 I44 0 IIB 1 I* 24- 180 106 0 IIC 23 36-204 90 2 I11 5 67-2 I3 151 4 IV 4 15-89 53 3

* One lost to follow-up at 24 months.

diameter; (IIC) metastases > 5 cm in maximum diameter.

Stage ZZZ: Involvement of supradiaphragmatic lymph nodes.

Stage ZV Extralymphatic metastases (lung, liver, bone, etc.)

Histologic Characteristics

The histologic characteristics of the primary tumor or metastases, if these had been sampled, was reviewed in all cases. All patients had pure seminoma with the exception of one Stage 111 patient who had a component of fully differentiated teratoma in his primary tumor but whose metastases were pure seminoma.

Radiotherapy

Details of radiotherapy have been published elsewhere by Peckham3. Stage I1 patients received radiotherapy to para-aortic and ipsilateral pelvic nodes. Both pelvic node

areas were irradiated if low para-aortic disease was present. The minimum tumor dose was 30 Gray in three weeks with daily fractionation using anterior and pos- terior fields. In patients with bulky disease boost doses up to 10 Gray were given. Of the Stage I1 group, 53/66 patients proceeded, one month after infradiaphragmatic irradiation, to irradiation of mediastinal and supracla- vicular lymph node areas. Stage 111 patients received infra- and supradiaphragmatic irradiation.

Chemotherapy

Of the nine patients given alkylating agent chemotherapy as part of their planned initial management, three received melphalan, two cyclophosphamide, one melphalan and cyclophosphamide, and one cyclophosphamide and chlorambucil. One patient, initially thought to have a nonseminoma, was given vinblastine, dactinomycin and methotrexate (to which there was little response) before radiotherapy, and a second received dactinomycin and provera electively although he was in complete remission after radiotherapy.

Ten patients were treated with drug combinations used in the current management of nonseminomatous germ cell tumors (Table 2). Of these, one patient received vinblastine and bleomycin (VB) and the remainder Cis-platinum, in eight patients in combination with vinblastine and bleomycin (PVB), and in one with VPI 6 and bleomycin (BEP).

The schedules used for VB and PVB were those de- scribed by Samuels et aL4 and Einhorn and D o n o h ~ e , ~ respectively. Their use in this Unit in the management of nonseminomas has been reported elsewhere.6 In the BEP combination vinblastine was omitted from PVB and VP16 (120 mgm/m2) was given intravenously days 1-5.

TABLE 2. Combination Chemotherapy for Advanced Seminoma (Royal Marsden Hospital 1976- 1980)

Chemotherapy* Outcome of treatment (months)

vp16 Elective post- Cis-DDP Cis-DDP Result of chemotherapy Dead of

Patient Stage VB PVB Bleo Bleo VP,6 chemotherapy radiotherapy Disease-free seminoma

1 +le 6 CR 14 2 IIC 4 PR + 14 3 IIC 2 PR + 12 4 IIC 4 PR + 8 5 111 4 PR + 24

PR + 17 CR 18

6 1VCHt.g 6$ 7 IVH t bone + 2 2 2 8 IVCL, 3 2 CR 21 9 IV Bone 2 3 CR 34

10 IVAL, 6 CR + 14

* Number of courses. + Primary mediastinal seminoma involving lung. $ Histologically positive after chemotherapy.

0 IVC: = Abdominal mass > 5 cm; Bone + = bone metastases: H t = Liver positive; L, = <3 lung metastases.

229 1 No. I I METASTATIC SEMINOMA TESTIS Bull et al.

TABLE 3. Results of Radiotherapy for Stage I1 Seminoma Testis (Royal Marsden Hospital 1963-1979)

Deaths Alive disease-free

Number of Partial Intercurrent Stage patients Relapses % Seminoma disease Number 7%

9.4 2 5 25 78. I - 9* 81.8

IIA 32 3 1IB I 1 2 18.2 1 1IC 23 9 39. I 6 4 13 56.5

Total 66 14 21.2 9 9 47 71.2

* One patient lost to follow-up at 24 months.

Results

Patients Receiving Radiotherapy Plus or Minus Single Agent Chemotherapy (total 75)

Siage I I : There were 66 patients, of whom 14 (2 1.12%) relapsed and nine ( 13.6%) died of seminoma. There were nine deaths from intercurrent disease: four cardiac, one accidental, one non-Hodgkin’s lymphoma, one carcinoma of lung, one carcinoma of colon and one of intestinal obstruction presumed to represent late radiation damage. Two patients (both IIC) received chemotherapy prior to radiotherapy for massive disease. One had cyclophosphamide and one melphalan, in both cases producing some tumor shrinkage. This was followed by radical radiotherapy and both patients are alive and well at three and five years respectively.

Influence of tumor volume on radiotherapy results: As shown in Table 3. and Figure 1 the percentage relapse rate increases with tumor size. During the period under consideration 153 Stage I patients received radiotherapy and only four relapses were observed. Actuarial survival and disease-free survival curves are shown in Figures 2A and 2B, respectively. The difference between IIA and IIB and IIC patients is significant ( P = 0.023). Further subdivision of IIC patients into those with masses <10 cm (nine patients) and > 10 cm in diameter (I 4 patients) was not associated with significant differences in survival or disease-free survival rate (Fig. 3).

Pattern of relapse: Table 4 summarizes the relapse pattern in Stage I1 patients. Both patients relapsing in the scrotum had had scrotal interference but not received scrotal irradiation. Although it is likely that the number of abdominal relapses was underestimated, it seems clear that with bulky disease extralymphatic dis- semination constitutes a significant part of the pattern of spread. Two men developed marrow involvement.

Outcome of treatment in relation to radiotherapeutic approach: As shown in Table 5, none of 13 patients who had infradiaphragmatic irradiation relapsed in supradiaphragmatic lymph nodes. The overall relapse rate in

these patients and those receiving infra and supradiaphragmatic irradiation was closely similar. The inci- dence of cardiac deaths, which might possibly have been increased in men receiving mediastinal irradiation was higher in patients receiving infradiaphragmatic irradiation only.

Stage IIZ: All five patients are alive and disease-free at 67, 86, 15 1, and 213 months, respectively. Only one had radiotherapy alone. A second patient received dactinomycin after radiotherapy. He was in complete remission before starting chemotherapy and it is likely that the latter treatment was irrelevant. Two patients received alkylating agents in addition to radiotherapy.

Stage IV: There were four patients. Two died ( 15 and 19 months) of uncontrolled seminoma after treatment with radiotherapy and melphalan, and cyclophosphamide and dactinomycin, respectively. One patient has been cured (disease-free 89 months) by radiotherapy followed by surgery for pulmonary metastases. The fourth patient received vinblastine, dactinomycin and methotrexate on the assumption he had a nonseminomatous tumor. There was little tumor response, he was shown

+ Based on re l apse r a t e in s tage I Proport ion of patients with me tas t a ses unknown

L I I I I

Microscopic < 2 c m 2-5cm ? 5 c m Size of Abdominal Node Metastases

FIG. I . Relapse rate and size of infradiaphragmatic metastases in patients receiving radiotherapy for Stage I and I1 disease.

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IIA (32 patients)

IIB (11 patients) 7 0 4 LI

IIC (23 patients)

* 40

20 304 *oLll-n 40 80 120 160 200 0

Months FIG. 2A. Disease-free survival of patients with Stage I1 treated with

radiotherapy (Royal Marsden Hospital 1963- 1979).

subsequently to have a pure seminoma and received irradiation to the abdomen (including liver) and lungs. He was explored for abdominal recurrence and was reir- radiated. Subsequently he developed evidence of chronic inferior vena caval obstruction and died 87 months after initial treatment. Unfortunately no autopsy was per- formed.

Signijiicance of elevated serum B-HCG levels: Of 29 Stage 11, 111, and IV patients in whom HCG levels were

IIA (32 patients)

IIB (11 patients)

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December 1 1982 Vol. 50

5 601 IIC (23 patients) a,

8 40 501 20 30 1

U I I I I I 40 80 120 160 200

FIG. 2B. Survival of patients with Stage 11 treated with radiotherapy

Months

(Royal Marsden Hospital 1963-1979).

9 o i

Stage I IC 5-10cm dia. metast. 70

30-1 2ol 10

Stage I IC >10crn dia. metast. (14 patients)

0- 40 80 120 160

Months

roperitoneal mass (Royal Marsden Hospital 1963- 1979). FIG. 3. Survival of patients with Stage IIC according to size of ret-

measured, 14 (48.3%) showed raised titers (Table 6). The range was 10-501 1 iu/l. As shown in Table 7, of 17 men with metastatic disease treated by radiotherapy alone elevation of HCG titre was not an adverse prognostic factor.

Patients with Metastatic Seminoma Treated with ‘Nonseminoma ’ Combination Chemotherapy

Details of ten men treated with vinblastine and bleomycin (VB) or Cis-platinum-containing regimes are summarized in Table 2. This includes one patient with a bulky primary mediastinal seminoma involving lung. Of the ten, five achieved complete clinical emission. The one patient receiving VB had positive histology after six cycles of chemotherapy. The remaining four patients who did not achieve complete remission showed good responses to PVB but residual masses were detectable at CT scanning. Six patients had elective irradiation to sites of initial disease after chemotherapy. All nine patients treated with cis-platinum-containing combinations are alive and disease-free.

Discussion

As previously reported from this center the overall results for seminoma are e~cellent.~ Death from tumor should be an exceptional event in Stage I disease and infradiaphragmatic lymph node irradiation is the treatment of choice. In our experience of treating 153 Stage I patients between 1963 and 1979 there were only two relapses in supradiaphragmatic lymph nodes and both were successfully treated with further irradiation. [Over- all there were four relapses in this group but only one

No. 1 1 METASTATIC SEMINOMA TESTIS - Ball et af . 2293

TABLE 4. Stage I1 Seminoma Testis: Pattern of Relapse After Radiotherapy

Sites of initial relapse

Infra- Abdomen Supra- Extra- Total diaphragmatic Scrota1 + other diaphragmatic Lung k lymphatic

Stage relapses nodes only Sac sites nodes mediastinum sites only

- IIA 3 1 1 1 IIB 2

IIC 9 2 - - 2 -

1

2 -

- I 2

Total 14 3 2 2 I 3 3

TABLE 5. Radiotherapy for Stage 11 Seminoma: Outcome of Treatment in Relation to Extent of Lymph Node Irradiation

Supradiaphragmatic Total Number nodes as initial Cardiac

Radiotherapeutic approach patients relapsing site of relapse deaths

Infradiaphragmatic irradiation only 13 3 (23.1%) 0 2 ( 1 5.4%) 2 (3.8%) Infra + supradiaphragmatic irradiation 53 I I (20.8%) I (1.9%)

Total 66 14 (21.2%) 1 (1.5%) 4 (6.1%)

death from seminoma and this occurred in a patient who developed a contralateral tumour that metastasised into the previously irradiated retroperitoneum. Tradi- tionally, abdominal lymph node irradiation has been employed in Stage I seminoma on the assumption that a proportion of patients may harbor micrometastatic disease. Since there is no information on the natural history of patients with negative lymphograms managed by orchiectomy alone and since radical lymph node dissection has not been employed in seminoma the in- cidence of metastases in clinical Stage I disease is unknown.] The results of radiotherapy in patients with Stages IIA and IIB are good with relapse rates of 9.4% and 18.2% respectively. On the other hand, almost 40% of patients with more bulky tumor deposits (IIC) relapsed after irradiation. Although the number of patients receiving infradiaphragmatic irradiation only for Stage I1 disease is small the results suggest that supradiaphragmatic relapse may be infrequent if mediastinal and su- praclavicular irradiation is omitted. It is recommended that Stage IIA and IIB patients are managed by infradiaphragmatic node irradiation only since, should relapse occur, experience from the management of patients with nonseminoma has shown that subsequent chemotherapy is practicable and effective.* On the other hand, if relapse occurs after infra- and supradiaphragmatic irradiation chemotherapy is hazardous.

Because advanced presentations of seminomas are uncommon, experience using chemotherapeutic regimes commonly employed for nonseminomas is limited. Preliminary experience in ten patients in the present series is encouraging and all nine men receiving cis- platinum are alive and disease-free. It is of interest that

one patient treated with six cycles of VB had positive histology after chemotherapy. The role of radiotherapy after chemotherapy cannot be assessed. Residual masses were identified in 4/9 patients receiving cis-platinum- containing chemotherapy and these patients have re- mained disease-free after irradiation. On the other hand, it is clear that some patients successfully treated with radiotherapy alone for bulky seminoma have residual

TABLE 6. Elevated B-HCG* Levels in Patients with Metastatic, Histologically Pure Seminoma Testis

Serum B-HCG levels (iu/l)t

Total Number with Stage patients raised HCG titres Range Median

10-501 1 37

IIA 10 6 IIB 2 I IIC 9 3 111 2 2 IV 6 2

Total 29 14 (48.3%)

* One patient only had urinary HCG levels measured. t Normal levels < I iu/l.

TABLE 7. Result of Radiotherapy in Relation to Serum B-HCG Levels in Seminoma

Total patients receiving HCG HCG not radiotherapy alone elevated elevated

17 8*/8 8 t l l o

* Number disease-free/total treated. t One patient died of intercurrent disease

2294 CANCER December 1 1982 Vol. 50

masses which persist and which, if explored, prove to be densely adherent fibrous tissue.

On the basis of these observations it is recommended that Stage IIC patients receive up to four cycles of chemotherapy followed by individually planned radiation therapy directed to initially involved nodes. The optimal chemotherapy remains to be defined. Preliminary reports suggest Cis-platinum may be effective as a single agent.' Although the PVB regime appears to be active as shown by the present experience and reports by Ein- horn and Williams" it is associated with considerable toxicity which appears to be age related. Since seminoma presents approximately one decade later than nonseminoma, a less toxic regimen would be advantageous. Preliminary experience suggests that the combination of bleomycin, VP 16 and Cis-platinum (BEP) may prove equally efficacious and less toxic.

Experience with Stage 111 and IV disease is limited by the rarity of these presentations. It is encouraging that two patients with bone involvement (one with liver metastases) are alive and disease-free at 18 and 34 months, respectively.

the presence of slight or moderate elevations of serum B-HCG levels does not adversely influence the outcome of radiotherapy. However, the presence of elevated HCG levels should make rigorous histologic examination of the primary tumor mandatory to exclude the presence of a nonseminomatous component.

As reported by Mauch et a1.I' and Javadpour et

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the management of metastatic seminoma testis

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