- Email: [email protected]
The management of non-seminomatous germ cell tumours (GCT)
Annals of Oncology 5: 457-462, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical case The management of non-seminomatous germ cell tumours (GCT)
Servicio de Oncologia Medica, Hospital Universitario 'Doce de Octubre', Madrid, Spain; 'CRC Department of Medical Oncology, University of Glasgow, Glasgow, UK; 2Laboratory of Molecular Immunopathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Key words: germ cell tumours, non-seminomatous tumours, cisplatin, chemotherapy, management
Case history
(106 IU/ml) and the appearance of two intraabdominal masses, one behind the left kidney hilum of 4 cm diameter and the other, in the left paraaortic area, of 2.5 cm (Fig. 2A). Chemotherapy was started, and the patient received 3 courses of BEP (bleomycin 30 U i.v. in continuous infusion, days 1-5, etoposide 100 mg/m2 i.v., days 1-5, and cisplatin 20 mg/m2 i.v., days 1-5, every 3 weeks) and one course of EP (the same regimen without bleomycin). Tolerance of chemotherapy was good, but grade II nausea/vomiting, universal alopecia and grade II tinnitus developed. AFP normalized after the second course of chemotherapy, but a CT scan after the third cycle showed persistent abnormalities in the sites of previous disease, although of reduced size. A further CT scan 5 weeks following the fourth course persisted unchanged (Fig. 2B), and the patient was sent back to the urologist for surgical removal of the residual masses. A unilateral retroperitoneal lymphadenectomy was carried out and histology showed mature teratoma in both macroscopically enlarged nodes (Fig. 3). Following the operation, the patient was followed closely for one year and then at decreasing intervals.
In April 1992, a 40-year-old TV assistant presented to his general practitioner with a two-day history of swelling of the left testicle. He had had no previous local injury or systemic symptoms apart from possible mild fever. Clinical examination revealed tenderness, swelling and increased temperature of the left gonad, but no separate mass. His family and past medical histories were unremarkable. He was on no medication. A suspected diagnosis of acute epididymo-orchitis was made and a 10-day course of antibiotics and analgesics was prescribed. As only a slight improvement was noted 14 days later, further investigations were performed, including alpha-fetoprotein (AFP), beta subunit of the chorionic gonadotropin (B-HCG), chest X-ray and testicular ultrasound. The ultrasound revealed a solid mass in the left testis and both tumour markers were elevated (AFP: 150 IU/ml; B-HCG: 25 IU/ml). A high inguinal orchidectomy was performed, and the patient was discharged 5 days following the procedure. The testis contained a 4.5-cm tumour which did not extend to the epididymis or involve the tunica vaginalis. The histology was reported as embryonal carcinoma with areas of mature teratoma. There were no other germ cell elements, and no vascular or lymphatic invasion (Fig. 1). On referral to the medical oncology department, the patient was asymptomatic and physical examination results were normal. A CT scan of chest, abdomen and pelvis showed no abnormal findings, and serum markers progressively normalized (B-HCG on day 7, and AFP on day 17 postoperatively). No further therapy was advised but close follow-up was arranged. The first four scheduled monthly examinations (physical exam, serum markers and chest X-rays) yielded normal results, as did a CT scan in the second month post-orchidectomy. This was reported as showing non-significant para-aortic lymph node enlargement <1.5 cm, without Fig. 1. Histological section of the primary tumour showing a prechanges since the previous study. Five months after dominance of undifferentiated germ cells (embryonal carcinoma). orchidectomy, relapse was detected by increased AFP No vascular or lymphatic invasion is apparent
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
L. Paz-Ares,1 P. Lianes2 & H. Cortes-Funes
458
Discussion
Although germ cell tumours (GCT) are not common (1%—1,5% of all cancers in males), they have a fundamental role in oncology for several reasons; (a), they usually arise in young individuals; (b), the availability of two serum markers (AFP, B-HCG) often allows more detailed assessment of the course of the disease; and (c), a high cure rate is achievable even in advanced stages. GCT have therefore been regarded as a model of a curable neoplasm [1]. The natural history of testicular tumours is of local growth involving the testicular layers, early spread to retroperitoneal lymph nodes, and thence to supradiaphragmatic regions, and vascular invasion with visceral metastases, particularly the lungs. Treatment varies for each patient, depending on the stage, histology and Fig. 2. Abdominal CT scans at the time of relapse (A) and 5 weeks other prognostic factors (AFP and B-HCG levels, following chemotherapy (B). Although the initial metastases de- burden of disease, visceral involvement, etc.) [2], as well creased in size, a persistent residual mass is easily detectable behind as patient characteristics. The case history presented the left kidney hilum (arrowed). here is not typical because most non-seminomatous GCT (NSGCT) patients are rendered continuously disease-free with first treatment. This case illustrates some important aspects of the current management of this There has been no evidence of recurrence in the last 5 disease. years. On the other hand, he complained of tinnitus, which improved initially during the first 6 months following chemotherapy but has persisted unchanged I. Diagnosis and staging since then. After lymphadenectomy, he lacked anterograde ejaculation for 2-3 months. Although he sub- The characteristic presentation of a testicular GCT is sequently recovered semen emission, the patient as a hard and painless mass. About 15%-20% of pacomplained of persistent decreased sexual appetite and tients complain of local pain with or without local potency. Endocrine investigations showed normal tes- inflammatory components. This may lead to the mistosterone levels with moderate increases in those of diagnosis of epididymo-orchitis and thus delay diagFSH (20-25 IU/ml) and LH (16-20 IU/ml) and sub- nosis. Therefore, in the presence of an asymptomatic fertility in semen analysis (4-6 x 106 sperms/ml). He testicular mass or with atypical evolution of an orchids, has been attending sessions of group psychotherapy as in our case history, testicular ultrasound is essential. without significant improvement. In addition, he devel- Determination of AFP and B-HCG in this context is oped hypercholesterolemia and hypertrigliceridemia in often helpful, but negative values do not negate the the second year post-treatment. With a low-fat diet and diagnosis. Delayed diagnosis is common, but is more treatment with clofibrate, his lipids levels have returned often due to patient delay in seeking medical evaluation to normal. than to physician misdiagnosis. Several studies have
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
Fig. 3. Histological section of one of the post-chemotherapy lymph nodes showing mature teratoma.
459
Table 1. The WHO histological classification of testicular GCT [4]. Tumours of one histologic type Seminoma Spermatocytic seminoma Teratoma: mature, immature or with malignant transformation Embryonal carcinoma Polyembrioma Choriocarcinoma Yolk sac tumours Tumours of more than histologic type Embryonal carcinoma and teratoma Choriocarcinoma with or without embryonal carcinoma and/or teratoma (specify) Other combinations (specify)
Table 2. The Royal Marsden Hospital staging system [6]. Stage I
No metastases evident outside testis
Stage EM
No clinical evidence of metastases but persistent elevation of serum markers (AFP, B-HCG) after orchidectomy
Stage II A B C
Abdominal lymphadenopathy <2cm 2-5 cm >5 cm
Stage III O ABC
Supradiaphragmatic lymphadenopathy No abdominal disease Abdominal node disease as in stage II
Stage IV LI L2 L3 H+
Extranodal metastases < 3 lung metastases > 3 lung metastases all < 2 cm diameter > 3 lung metastases 1 or more > 2 cm Liver involvement
incorporates a grading of abdominal and visceral metastases [6]. II. Management of stage I NSGCT
A widely advocated policy for clinical stage I NSGCT consists of retroperitoneal lymphadenectomy (RPLDN), with the aim of pathological staging and treatment. Patients with no tumour at operation (70%75% of all cases) have a minimum risk of subsequent relapse (<10%) without further therapy. Those cases demonstrated to be truly stage II can be managed with 2 courses of adjuvant chemotherapy (relapse rate <2%) or observation (relapse rate 30%-40%). Both alternatives offer the same likelihood of survival (>95%) [7]. The refinements in surgical techniques have resulted in a substantial decrease in ejaculatory dysfunction, which is the most important complication of retroperitoneal lymph node dissection. Absence of anterograde ejaculation appeared in more than 90% of patients after bilateral radical procedures, while the current incidence is less than 5% in skilful hands using the nerve sparing technique and unilateral modified templates [8]. Some institutions, especially in Europe, have advocated a policy of observation without further therapy in patients without clinically apparent disease. The rationale for this approach is the high proportion of patients exposed to the morbidity of the lymphadenectomy without benefitting from it because they have already been cured with orchidectomy. Additionally, the 20%30% of patients who relapse have an excellent prognosis with cisplatin based programs, when the diagnosis is established early [9]. The disadvantages of this policy are the need for frequent follow-up visits and some emotional distress to the patient who may feel at constant risk of relapse. Consequently, before deciding on a 'wait-and-see' policy the oncologist should ensure that the patient understands the position and that facil-
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
found a direct relationship between the time from onset of symptoms to diagnosis, the stage at presentation and the survival [3]. It is to be hoped that public campaigns to increase public awareness of the disease (including self-examination) will result in earlier diagnosis. Diagnosis is confirmed by radical inguinal orchidectomy. Scrotal procedures, including trans-scrotal biopsy, are contra-indicated because of the risk of local recurrence or inguinal dissemination by altering the lymphatic drainage. The pathology report should include: (1) a description of all histological subtypes found (germ cell derivatives or not) (2) data concerning malignant involvement of the spermatic cord (free border) and testicular structures, and (3) assessment of the presence or absence of rumoral invasion in blood or lymphatic vessels. These are of special importance in planning treatment in early stages. In some instances, such as undifferentiated tumours with negative serum markers, immunohistochemistry and cytogenetics studies are valuable tools. The WHO histological classification of testicular GCT is given in Table 1 [4]. The essential investigations in staging the tumour are assays of AFP and B-HCG and radiological examinations. The latter should include a CT scan of chest, abdomen and pelvis. Other investigations depend on the previous findings and the planned therapy. A CT brain scan should be performed if there are very high levels of B-HCG or multiple lung metastasis. If chemotherapy is to be given, baseline measurement of creatinine clearance and lung function tests are necessary. Bipedal lymphography, which is unpleasant for the patient and sometimes technically difficult to perform, tends now to be abandoned in favour of CT scanning. Although in some circumstances lymphography can detect architectural abnormalities suggestive of metastases in normal size nodes, it does not appear to be more accurate than high-resolution CT imaging [5]. Several staging classification systems have been proposed for GCT but none is universally accepted. Most of them define three categories of disease: (1) confined to the testis, (2) retroperitoneal lymph node dissemination, and (3) supradiaphragmatic and/or visceral involvement. We employ the Royal Marsden Hospital staging criteria (Table 2) which affords simplicity and
460
At present, the chosen alternative for an individual stage I patient may vary, and it should be based on local urologist expertise with RPLDN, resources available for follow-up programs, tumour risk assignment and patient characteristics and preferences.
III. Chemotherapy for metastatic disease
There is no doubt that the availability of effective chemotherapeutic agents for metastatic NSGCT has dramatically changed the course of this disease. The most effective regimens are combinations of cisplatin the most active single drug - with other agents such as vinblastine, etoposide, bleomycin, ifosfamide and actinomycin-D. Their use, with appropriate postchemotherapy surgery, have yielded cure rates of over 85% in patients with advanced-stage disease during the last decade [11]. Was the chemotherapy program given to our patient optimal? The substitution of etoposide for vinblastine in the PVB regimen (cisplatin, vinblastine and bleomycin) has been shown in a randomized trial to decrease toxicity (mainly neuromuscular side effects) and to be associated with a possible survival gain in poor prognosis patients [12]. BEP is currently, therefore, a widely used regimen. We prefer to give the bleomycin as continuous infusion for 5 consecutive days (maximum cumulative dose: 450 U) instead of in weekly injections, in the hope of ameliorating the pulmonary toxicity. Recently, it has been possible to recognize two prog-
nostic subgroups of patients with metastatic testicular tumours in relation to the probability of complete remission and survival following cisplatin-containing chemotherapy (for review see 2). Sixty to 80% of the patients are included in the low-risk group. They usually present with low-burden metastatic disease and are highly curable (>90%). The remaining patients frequently have bulky disease and visceral involvement, and have a much worse prognosis (cure rate about 50%-60%). Current investigation is based on these findings. In low-risk patients, efforts are being made to decrease toxicity while maintaining the efficacy. Poorrisk patients are candidates for more intensive approaches in attempts to improve their outcome. In the good-risk setting, a randomized trial has shown that reduction of the number of cycles of BEP from 4 to 3 does not affect the outcome, although it reduces toxicity [13]. However, it is our policy, as well as that of other groups, to give two additional courses of chemotherapy after achievement of complete remission, instead of a predetermined number. Other approaches to reducing toxicity include omitting bleomycin and substituting cisplatin for carboplatin in the BEP regimen. With short follow-up, carboplatin has been associated with decreased disease-free survival in two randomized trials, and its use is discouraged [14]. Although four cycles of EP (cisplatin and etoposide) are as effective as four courses of VAB-6 using the MSKCC low-risk criteria, another three studies have not recommended the omission of bleomycin from the BEP combination [15]. In poor-risk patients, attempts to increase the efficacy of chemotherapy have been quite disappointing so far. An increase of the cisplatin dose to 200 m 2 /3 weeks, the use of alternating schedules, the introduction of ifosfamide in first-line schemes and the use of high-dose chemotherapy with bone marrow support have all been accompanied by greater toxicity but have not been shown to improve pronosis [16]. The results of further studies are awaited.
IV. Residual mass management
After completion of chemotherapy for GCT it is common to find persistent radiological abnormalities despite complete remission as judged by tumour markers. The almost universally accepted strategy in these circumstances is a surgical attempt to remove all residual masses with both therapeutical and prognostic aims. Pathological study of resected specimens shows fibrosis and/or necrosis in 30%-40% of the cases, mature teratoma in 30%-40% and viable tumour in the remaining 20%-30%. Their prognostic implications are clear [6]. Patients with fibrotic or teratoma containing masses rarely relapse provided that resection was complete. Thus, no additional therapy is needed for these patients. On the other hand, when viable malignant disease persists, two adjuvant courses of chemotherapy
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
ities are available for a rigorous follow-up schedule. Several factors have been reported in surgical and observation series to predispose to the presence of undetectable retroperitoneal disease. A recent study of the MRC found four predictors of likelihood of relapse in this setting:(a) the presence of embryonal carcinoma, (b) the absence of yolk sac elements, (c) the presence of vascular invasion or (d) lymphatic invasion in the primary tumour [9]. In a subsequent study 101 patients with 3 or 4 risk factors (expected relapse rate on observation: 53%) were given two cycles of BEP, and after a median follow-up of 2 years only one has relapsed [10]. Therefore, short-course adjuvant chemotherapy in patients with high-risk pathological features is a safe and logical third possibility for management. Furthermore, the associated toxicity appears to be minimal [10]. The likelihood of post-orchidectomy relapse of a patient with two risk criteria, as in our case, is 20%, following the MRC model. With this basis no elective therapy is a reasonable alternative. The real significance of mature teratoma present in the primary remain uncertain in this context. Some authors would recommend staging RPLDN for these patients, as they predict a higher incidence of differentiated GCT also in the retroperitoneum. Other studies have, by contrast suggested that these patients have a lower risk of retroperitoneal disease.
461
V. Late post-treatment events Are our patient's tinnitus, sexual dysfunction and hypercholesterolemia therapy related? The success of cisplatin combinations has resulted in an increasing number of long-term survivors among patients with advanced GCT. Concomitantly, several sequelae have been described and others presumably will be in the future. Both cisplatin and vinblastine are known to produce peripheral neuropathy, predominantly sensory. Paresthesia is a common complaint during therapy but in most cases resolves in the succeeding months. Although only 10%-30% of patients remain symptomatic over the long term, the incidence of subclinical abnormalities is much higher, with 75% having abnormalities in conduction velocities and sensory action potentials [20]. A specific problem of cisplatin is ototoxicity, probably due to hair cell damage in the organ of Corti. Clinically, tinnitus is the predominant symptom (10%30% of patients). High frequency hearing loss is easily demonstrable by audiometry although it seldom represents a problem for the patient. The degree of reduction in auditory function, as is the case for nephrotoxicity, seems to be related to the dose of cisplatin given and the mode of administration. The main renal consequence is a deterioration in glomerular function,
measured as an average fall in GFR of 10%-30%. Among tubular disturbances hypomagnesemia is the most commonly reported [21]. It has recently been recognized that there may be an increased incidence of raised blood cholesterol levels in survivors treated with chemotherapy [22]. Raynaud's phenomenon and, less frequently, arterial hypertension and major vascular events, may also occur. Chronic pulmonary fibrosis is associated with bleomycin, especially when the cumulative dose exceeds 450 U. Three factors may contribute to the decreased fertility which can affect GCT patients [23]. The first is ejaculatory dysfunction following retroperitoneal surgery. In specialized centres using current nerve sparing techniques, the incidence of permanent failure of ejaculation is less than 10%. Not uncommonly, a transient disturbance may occur, and some patients benefit from medical treatment (ephedrine, tricyclic antidepressants, etc.) or selective neural stimulation. Second, azo-oligospermia may occur and is frequently present at diagnosis. However, sperm count recovery is less frequent in patients treated with chemotherapy than in those with stage I disease who are followed without additional treatment. Third, some degree of Leydig cell dysfunction is present, as shown by normal serum testosterone levels with increased LH and FSH, as in our case. Our recommendation is to offer sperm banking to suitable patients before commencing cytotoxic treatment. Psychological morbidity, apart from anxiety and depression in 10% of the patients, also affects sexual activity. These disturbances, reported in 10%-40% of the cases, include impotence, premature ejaculation and loss of libido and sexual satisfaction [22]. Finally, an increased number of second malignancies arises in individuals treated for GCT (relative risk: 1.3-2). These include contralateral testicular tumours, solid tumours and haematological malignancies. Contralateral GCT appear in 3%-5% of survivors, usually within the 10 years following the first diagnosis. However, the risk, if any, is minimal in patients treated with chemotherapy, probably due to a protective effect against the pre-invasive lesion, in situ carcinoma [24]. Also a higher incidence of solid neoplasms has been reported (skin cancers, gastrointestinal tumours, lung tumours, urothelial carcinomas, etc.), particularly if radiotherapy is used. The actual incidence of leukaemia is unknown, but most cases involve patients treated with radiotherapy or etoposide [25]. A peculiar syndrome of non-therapy-induced haematological malignancies has been described in patients with primary mediastinal tumours. Both haematological and germ cell diseases seem to arise from a common progenitor [26]. Conclusion The present case emphasizes the advantages of early diagnosis at presentation and relapse which correlates
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
are usually given. With this approach, 60% of patients will remain disease-free, a figure which compares favourably with 9% without post-surgery chemotherapy [17]. Why is residual mass surgery indicated? First, viable chemo-refractory tumour can be removed and the patient benefit from further cytotoxic treatment. The latter, in our opinion, should be different from the regimen employed during the induction. Removal of differentiated teratoma which is unresponsive to chemotherapy is a second reason for surgery, since, when left in situ, the teratoma may grow, invade and compress surrounding tissues. Also, it may dedifferentiate to malignancy (of germ cell or non-germ cell histology) or result in a late recurrence [18]. Conversely, there is no clear advantage for resection of necrotic or fibron'c tissues. For this reason several investigators have tried to identify prognostic predictors of postsurgery histology. Most of the series have found an association between teratoma in the testicle and its presence in the residual mass. The finding of no benign or malignant tumour is more frequent when residual masses are of small size (e.g., <2 cm), those with high shrinkage of the original metastases (e.g., >90%), presurgery negative markers and, as mentioned, an absence of teratoma in the primary. Unfortunately, even when all these variables coincide in a patient, the chance of viable tumour or teratoma is 15%-20% [19]. Therefore, surgery to removal residual masses should be offered of any patient after chemotherapy, once markers are normalized.
462
12. 13.
14.
15. 16. 17.
Acknowledgement
18.
Dr. Luis Paz-Ares is supported by a fellowship from the European Society of Medical Oncology (ESMO). 19.
References 20. 1. Einhorn LH. Treatment of testicular cancer: A new and improved model. J Clin Oncol 1990; 8:1877-81. 2. Droz JP, Kramar A, Rey A. Prognostic factors in metastatic disease. Sem Oncol 1992; 19:181-9. 3. Medical Research Council Working Party on testicular tumours. Prognostic factors in advanced non-seminomatous germ-cell testicular tumours: Results of a multicenter study. Lancet 1985; I: 8-11. 4. Mostofi FK, Sibin LH. Histological typing of testis tumors. International classification of tumors, No. 16. Geneva, World Health Organization, 1977. 5. Husband J. Advances in tumour imaging. In Horwich A (ed): Testicular cancer: Investigation and management Chapman and Hall Medical: New York 1991; 2:15-31. 6. Tait D, Peckham MJ, Hendry WF et al. Postchemotherapy surgery in advanced non-seminomatous germ cell tumours: The significance of histology with particular reference to differentiated (mature) teratoma. Br J Cancer 1984; 50: 601-9. 7. Williams SD, Stablein DM, Einhorn LH et al. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 1987; 317:1433-8. 8. Donahue JP, Thornhill JA, Foster RS et al. Retioperitoneal lymphadenectomy for clinical stage A testis cancer (19651989): Modifications of technique and impact on ejaculation. J Urol 1993; 149:137-43. 9. Read G, Stenning SP, Cullen MH et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. J Clin Oncol 1992; 10:1762-8. 10. Cullen MH on behalf of the Medical Research Council (MRC) Testicular Tumour Working Party. Short course adjuvant chemotherapy in high risk stage I non seminomatous germ cell tumours of the testis (NSGCTT): An MRC study report. Proc QT Germ Cell Tumour Conference 1993; 3:47 (Abstract). 11. Mead GM, Stenning SP, Parkinson MC et al. The Second Medical Research council study of prognostic factors in non-
21.
22. 23. 24.
25.
26. 27.
seminomatous germ cell tumors. J Clin Oncol 1992; 10: 8594. Williams SD, Birch B, Einhorn LH et al. Treatment of disseminated germ cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med 1987; 316:1435-40. Einhorn LH, Williams SD, Loehrer PJ et al. Evaluation of optimal duration of chemotherapy in favourable-prognosis disseminated germ cell tumors: A Southeastern Cancer Study Group protocol. J Clin Oncol 1989; 7: 387-91. Bejorin DF, Sarosdy MF, Pfister DG et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multiinstitutional study. J Clin Oncol 1993; 11: 598-606. Levi JA, Raghavan D, Harvey V et al. The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. J Clin Oncol 1993; 11:1300-5. Paz-Ares L, Kaye SB. Intensive treatment schedules. Proc HJ Germ Cell Conference 1993; 3: 56. Einhom LH, Williams SD, Mandelbaum I et al. Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer 1981; 48: 904-10. Paz-Ares L, Lianes P, Diaz-Puente M et al. Late relapses (LR) in malignant germ cell tumors (MCGT) treated with cisplatinbased chemotherapy. Proc Am Ass Cancer Res 1992; 34: 222 (Abstract). Toner CG, Panicek DM, Heelan RT et al. Adjuntive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 1990; 8: 1683-94. Hansen SW, Helweg-Larsen S, Trojaborg W. Long-term neurotojricity in patients treated with cisplatin, vinblastine and bleomycin for metastatic germ cell cancer. J Clin Oncol 1989; 7: 1457-61. Hansen SW, Groth S, Daugaard G et al. Long term side-effects on renal function and blood pressure of treatment with cisplatin, vinblastine and bleomycin in patients with germ cell cancer. J Clin Oncol 1988; 6:1728-31. Boyer M, Raghavan D. Toxicity of treatment of germ cell tumors. Sem Oncol 1992; 19:128-42. Fossa SD, Kreuser ED, Roth GJ et al. Long-term side effects after treatment of testicular cancer. Prog Clin Biol Res 1988; 357:321-30. von der Maase H, Rorth M, Walbom-Jorgesen S et al. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer. A study 27 cases in 500 patients. Br Med J 1986; 293:1398-401. Pedersen-Bjergaard J, Daugaard G, Hansen ST et al. Increased risk of myelodisplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ cell tumours. Lancet 1991: 338: 35963. Rodriguez E, Mathew S, Reuter VE et al. Cytogenetic analysis of 124 prospectively ascertained male germ cell tumors. Cancer Res 1992; 52: 2285-91. Harding MJ, Paul J, Gillis CR et al. Management of malignant teratoma: Does referral to a specialist unit matter? Lancet 1993; 341:999-1002.
Received 28 October 1993; accepted 19 January 1994. Correspondence to: Dr. H. Cortes-Funes Servicio de Oncologja Medica Hospital Universitario TJoce de Octubre' Carretera de Andalucia Km. 5.400. 28041 Madrid Spain
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
with lower-burden disease in both circumstances. Careful follow-up is needed if RPLDN and chemotherapy are omitted in stage I. Once metastatic disease is present, the outcome is excellent if appropriate cisplatin chemotherapy is instituted and resection of residual masses undertaken when appropriate. Continuous follow-up should be offered to long-term survivors in order to detect and institute early management of late sequelae of treatment and other delayed complications. The appropriate management of this highly curable disease requires the collaboration of several welltrained and experienced specialists. Given the rarity of GCT, both physicians and health service organizations should try to ensure that these rumours are treated in specialized centres [27].
Clinical case The management of non-seminomatous germ cell tumours (GCT)
Servicio de Oncologia Medica, Hospital Universitario 'Doce de Octubre', Madrid, Spain; 'CRC Department of Medical Oncology, University of Glasgow, Glasgow, UK; 2Laboratory of Molecular Immunopathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Key words: germ cell tumours, non-seminomatous tumours, cisplatin, chemotherapy, management
Case history
(106 IU/ml) and the appearance of two intraabdominal masses, one behind the left kidney hilum of 4 cm diameter and the other, in the left paraaortic area, of 2.5 cm (Fig. 2A). Chemotherapy was started, and the patient received 3 courses of BEP (bleomycin 30 U i.v. in continuous infusion, days 1-5, etoposide 100 mg/m2 i.v., days 1-5, and cisplatin 20 mg/m2 i.v., days 1-5, every 3 weeks) and one course of EP (the same regimen without bleomycin). Tolerance of chemotherapy was good, but grade II nausea/vomiting, universal alopecia and grade II tinnitus developed. AFP normalized after the second course of chemotherapy, but a CT scan after the third cycle showed persistent abnormalities in the sites of previous disease, although of reduced size. A further CT scan 5 weeks following the fourth course persisted unchanged (Fig. 2B), and the patient was sent back to the urologist for surgical removal of the residual masses. A unilateral retroperitoneal lymphadenectomy was carried out and histology showed mature teratoma in both macroscopically enlarged nodes (Fig. 3). Following the operation, the patient was followed closely for one year and then at decreasing intervals.
In April 1992, a 40-year-old TV assistant presented to his general practitioner with a two-day history of swelling of the left testicle. He had had no previous local injury or systemic symptoms apart from possible mild fever. Clinical examination revealed tenderness, swelling and increased temperature of the left gonad, but no separate mass. His family and past medical histories were unremarkable. He was on no medication. A suspected diagnosis of acute epididymo-orchitis was made and a 10-day course of antibiotics and analgesics was prescribed. As only a slight improvement was noted 14 days later, further investigations were performed, including alpha-fetoprotein (AFP), beta subunit of the chorionic gonadotropin (B-HCG), chest X-ray and testicular ultrasound. The ultrasound revealed a solid mass in the left testis and both tumour markers were elevated (AFP: 150 IU/ml; B-HCG: 25 IU/ml). A high inguinal orchidectomy was performed, and the patient was discharged 5 days following the procedure. The testis contained a 4.5-cm tumour which did not extend to the epididymis or involve the tunica vaginalis. The histology was reported as embryonal carcinoma with areas of mature teratoma. There were no other germ cell elements, and no vascular or lymphatic invasion (Fig. 1). On referral to the medical oncology department, the patient was asymptomatic and physical examination results were normal. A CT scan of chest, abdomen and pelvis showed no abnormal findings, and serum markers progressively normalized (B-HCG on day 7, and AFP on day 17 postoperatively). No further therapy was advised but close follow-up was arranged. The first four scheduled monthly examinations (physical exam, serum markers and chest X-rays) yielded normal results, as did a CT scan in the second month post-orchidectomy. This was reported as showing non-significant para-aortic lymph node enlargement <1.5 cm, without Fig. 1. Histological section of the primary tumour showing a prechanges since the previous study. Five months after dominance of undifferentiated germ cells (embryonal carcinoma). orchidectomy, relapse was detected by increased AFP No vascular or lymphatic invasion is apparent
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
L. Paz-Ares,1 P. Lianes2 & H. Cortes-Funes
458
Discussion
Although germ cell tumours (GCT) are not common (1%—1,5% of all cancers in males), they have a fundamental role in oncology for several reasons; (a), they usually arise in young individuals; (b), the availability of two serum markers (AFP, B-HCG) often allows more detailed assessment of the course of the disease; and (c), a high cure rate is achievable even in advanced stages. GCT have therefore been regarded as a model of a curable neoplasm [1]. The natural history of testicular tumours is of local growth involving the testicular layers, early spread to retroperitoneal lymph nodes, and thence to supradiaphragmatic regions, and vascular invasion with visceral metastases, particularly the lungs. Treatment varies for each patient, depending on the stage, histology and Fig. 2. Abdominal CT scans at the time of relapse (A) and 5 weeks other prognostic factors (AFP and B-HCG levels, following chemotherapy (B). Although the initial metastases de- burden of disease, visceral involvement, etc.) [2], as well creased in size, a persistent residual mass is easily detectable behind as patient characteristics. The case history presented the left kidney hilum (arrowed). here is not typical because most non-seminomatous GCT (NSGCT) patients are rendered continuously disease-free with first treatment. This case illustrates some important aspects of the current management of this There has been no evidence of recurrence in the last 5 disease. years. On the other hand, he complained of tinnitus, which improved initially during the first 6 months following chemotherapy but has persisted unchanged I. Diagnosis and staging since then. After lymphadenectomy, he lacked anterograde ejaculation for 2-3 months. Although he sub- The characteristic presentation of a testicular GCT is sequently recovered semen emission, the patient as a hard and painless mass. About 15%-20% of pacomplained of persistent decreased sexual appetite and tients complain of local pain with or without local potency. Endocrine investigations showed normal tes- inflammatory components. This may lead to the mistosterone levels with moderate increases in those of diagnosis of epididymo-orchitis and thus delay diagFSH (20-25 IU/ml) and LH (16-20 IU/ml) and sub- nosis. Therefore, in the presence of an asymptomatic fertility in semen analysis (4-6 x 106 sperms/ml). He testicular mass or with atypical evolution of an orchids, has been attending sessions of group psychotherapy as in our case history, testicular ultrasound is essential. without significant improvement. In addition, he devel- Determination of AFP and B-HCG in this context is oped hypercholesterolemia and hypertrigliceridemia in often helpful, but negative values do not negate the the second year post-treatment. With a low-fat diet and diagnosis. Delayed diagnosis is common, but is more treatment with clofibrate, his lipids levels have returned often due to patient delay in seeking medical evaluation to normal. than to physician misdiagnosis. Several studies have
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
Fig. 3. Histological section of one of the post-chemotherapy lymph nodes showing mature teratoma.
459
Table 1. The WHO histological classification of testicular GCT [4]. Tumours of one histologic type Seminoma Spermatocytic seminoma Teratoma: mature, immature or with malignant transformation Embryonal carcinoma Polyembrioma Choriocarcinoma Yolk sac tumours Tumours of more than histologic type Embryonal carcinoma and teratoma Choriocarcinoma with or without embryonal carcinoma and/or teratoma (specify) Other combinations (specify)
Table 2. The Royal Marsden Hospital staging system [6]. Stage I
No metastases evident outside testis
Stage EM
No clinical evidence of metastases but persistent elevation of serum markers (AFP, B-HCG) after orchidectomy
Stage II A B C
Abdominal lymphadenopathy <2cm 2-5 cm >5 cm
Stage III O ABC
Supradiaphragmatic lymphadenopathy No abdominal disease Abdominal node disease as in stage II
Stage IV LI L2 L3 H+
Extranodal metastases < 3 lung metastases > 3 lung metastases all < 2 cm diameter > 3 lung metastases 1 or more > 2 cm Liver involvement
incorporates a grading of abdominal and visceral metastases [6]. II. Management of stage I NSGCT
A widely advocated policy for clinical stage I NSGCT consists of retroperitoneal lymphadenectomy (RPLDN), with the aim of pathological staging and treatment. Patients with no tumour at operation (70%75% of all cases) have a minimum risk of subsequent relapse (<10%) without further therapy. Those cases demonstrated to be truly stage II can be managed with 2 courses of adjuvant chemotherapy (relapse rate <2%) or observation (relapse rate 30%-40%). Both alternatives offer the same likelihood of survival (>95%) [7]. The refinements in surgical techniques have resulted in a substantial decrease in ejaculatory dysfunction, which is the most important complication of retroperitoneal lymph node dissection. Absence of anterograde ejaculation appeared in more than 90% of patients after bilateral radical procedures, while the current incidence is less than 5% in skilful hands using the nerve sparing technique and unilateral modified templates [8]. Some institutions, especially in Europe, have advocated a policy of observation without further therapy in patients without clinically apparent disease. The rationale for this approach is the high proportion of patients exposed to the morbidity of the lymphadenectomy without benefitting from it because they have already been cured with orchidectomy. Additionally, the 20%30% of patients who relapse have an excellent prognosis with cisplatin based programs, when the diagnosis is established early [9]. The disadvantages of this policy are the need for frequent follow-up visits and some emotional distress to the patient who may feel at constant risk of relapse. Consequently, before deciding on a 'wait-and-see' policy the oncologist should ensure that the patient understands the position and that facil-
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
found a direct relationship between the time from onset of symptoms to diagnosis, the stage at presentation and the survival [3]. It is to be hoped that public campaigns to increase public awareness of the disease (including self-examination) will result in earlier diagnosis. Diagnosis is confirmed by radical inguinal orchidectomy. Scrotal procedures, including trans-scrotal biopsy, are contra-indicated because of the risk of local recurrence or inguinal dissemination by altering the lymphatic drainage. The pathology report should include: (1) a description of all histological subtypes found (germ cell derivatives or not) (2) data concerning malignant involvement of the spermatic cord (free border) and testicular structures, and (3) assessment of the presence or absence of rumoral invasion in blood or lymphatic vessels. These are of special importance in planning treatment in early stages. In some instances, such as undifferentiated tumours with negative serum markers, immunohistochemistry and cytogenetics studies are valuable tools. The WHO histological classification of testicular GCT is given in Table 1 [4]. The essential investigations in staging the tumour are assays of AFP and B-HCG and radiological examinations. The latter should include a CT scan of chest, abdomen and pelvis. Other investigations depend on the previous findings and the planned therapy. A CT brain scan should be performed if there are very high levels of B-HCG or multiple lung metastasis. If chemotherapy is to be given, baseline measurement of creatinine clearance and lung function tests are necessary. Bipedal lymphography, which is unpleasant for the patient and sometimes technically difficult to perform, tends now to be abandoned in favour of CT scanning. Although in some circumstances lymphography can detect architectural abnormalities suggestive of metastases in normal size nodes, it does not appear to be more accurate than high-resolution CT imaging [5]. Several staging classification systems have been proposed for GCT but none is universally accepted. Most of them define three categories of disease: (1) confined to the testis, (2) retroperitoneal lymph node dissemination, and (3) supradiaphragmatic and/or visceral involvement. We employ the Royal Marsden Hospital staging criteria (Table 2) which affords simplicity and
460
At present, the chosen alternative for an individual stage I patient may vary, and it should be based on local urologist expertise with RPLDN, resources available for follow-up programs, tumour risk assignment and patient characteristics and preferences.
III. Chemotherapy for metastatic disease
There is no doubt that the availability of effective chemotherapeutic agents for metastatic NSGCT has dramatically changed the course of this disease. The most effective regimens are combinations of cisplatin the most active single drug - with other agents such as vinblastine, etoposide, bleomycin, ifosfamide and actinomycin-D. Their use, with appropriate postchemotherapy surgery, have yielded cure rates of over 85% in patients with advanced-stage disease during the last decade [11]. Was the chemotherapy program given to our patient optimal? The substitution of etoposide for vinblastine in the PVB regimen (cisplatin, vinblastine and bleomycin) has been shown in a randomized trial to decrease toxicity (mainly neuromuscular side effects) and to be associated with a possible survival gain in poor prognosis patients [12]. BEP is currently, therefore, a widely used regimen. We prefer to give the bleomycin as continuous infusion for 5 consecutive days (maximum cumulative dose: 450 U) instead of in weekly injections, in the hope of ameliorating the pulmonary toxicity. Recently, it has been possible to recognize two prog-
nostic subgroups of patients with metastatic testicular tumours in relation to the probability of complete remission and survival following cisplatin-containing chemotherapy (for review see 2). Sixty to 80% of the patients are included in the low-risk group. They usually present with low-burden metastatic disease and are highly curable (>90%). The remaining patients frequently have bulky disease and visceral involvement, and have a much worse prognosis (cure rate about 50%-60%). Current investigation is based on these findings. In low-risk patients, efforts are being made to decrease toxicity while maintaining the efficacy. Poorrisk patients are candidates for more intensive approaches in attempts to improve their outcome. In the good-risk setting, a randomized trial has shown that reduction of the number of cycles of BEP from 4 to 3 does not affect the outcome, although it reduces toxicity [13]. However, it is our policy, as well as that of other groups, to give two additional courses of chemotherapy after achievement of complete remission, instead of a predetermined number. Other approaches to reducing toxicity include omitting bleomycin and substituting cisplatin for carboplatin in the BEP regimen. With short follow-up, carboplatin has been associated with decreased disease-free survival in two randomized trials, and its use is discouraged [14]. Although four cycles of EP (cisplatin and etoposide) are as effective as four courses of VAB-6 using the MSKCC low-risk criteria, another three studies have not recommended the omission of bleomycin from the BEP combination [15]. In poor-risk patients, attempts to increase the efficacy of chemotherapy have been quite disappointing so far. An increase of the cisplatin dose to 200 m 2 /3 weeks, the use of alternating schedules, the introduction of ifosfamide in first-line schemes and the use of high-dose chemotherapy with bone marrow support have all been accompanied by greater toxicity but have not been shown to improve pronosis [16]. The results of further studies are awaited.
IV. Residual mass management
After completion of chemotherapy for GCT it is common to find persistent radiological abnormalities despite complete remission as judged by tumour markers. The almost universally accepted strategy in these circumstances is a surgical attempt to remove all residual masses with both therapeutical and prognostic aims. Pathological study of resected specimens shows fibrosis and/or necrosis in 30%-40% of the cases, mature teratoma in 30%-40% and viable tumour in the remaining 20%-30%. Their prognostic implications are clear [6]. Patients with fibrotic or teratoma containing masses rarely relapse provided that resection was complete. Thus, no additional therapy is needed for these patients. On the other hand, when viable malignant disease persists, two adjuvant courses of chemotherapy
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
ities are available for a rigorous follow-up schedule. Several factors have been reported in surgical and observation series to predispose to the presence of undetectable retroperitoneal disease. A recent study of the MRC found four predictors of likelihood of relapse in this setting:(a) the presence of embryonal carcinoma, (b) the absence of yolk sac elements, (c) the presence of vascular invasion or (d) lymphatic invasion in the primary tumour [9]. In a subsequent study 101 patients with 3 or 4 risk factors (expected relapse rate on observation: 53%) were given two cycles of BEP, and after a median follow-up of 2 years only one has relapsed [10]. Therefore, short-course adjuvant chemotherapy in patients with high-risk pathological features is a safe and logical third possibility for management. Furthermore, the associated toxicity appears to be minimal [10]. The likelihood of post-orchidectomy relapse of a patient with two risk criteria, as in our case, is 20%, following the MRC model. With this basis no elective therapy is a reasonable alternative. The real significance of mature teratoma present in the primary remain uncertain in this context. Some authors would recommend staging RPLDN for these patients, as they predict a higher incidence of differentiated GCT also in the retroperitoneum. Other studies have, by contrast suggested that these patients have a lower risk of retroperitoneal disease.
461
V. Late post-treatment events Are our patient's tinnitus, sexual dysfunction and hypercholesterolemia therapy related? The success of cisplatin combinations has resulted in an increasing number of long-term survivors among patients with advanced GCT. Concomitantly, several sequelae have been described and others presumably will be in the future. Both cisplatin and vinblastine are known to produce peripheral neuropathy, predominantly sensory. Paresthesia is a common complaint during therapy but in most cases resolves in the succeeding months. Although only 10%-30% of patients remain symptomatic over the long term, the incidence of subclinical abnormalities is much higher, with 75% having abnormalities in conduction velocities and sensory action potentials [20]. A specific problem of cisplatin is ototoxicity, probably due to hair cell damage in the organ of Corti. Clinically, tinnitus is the predominant symptom (10%30% of patients). High frequency hearing loss is easily demonstrable by audiometry although it seldom represents a problem for the patient. The degree of reduction in auditory function, as is the case for nephrotoxicity, seems to be related to the dose of cisplatin given and the mode of administration. The main renal consequence is a deterioration in glomerular function,
measured as an average fall in GFR of 10%-30%. Among tubular disturbances hypomagnesemia is the most commonly reported [21]. It has recently been recognized that there may be an increased incidence of raised blood cholesterol levels in survivors treated with chemotherapy [22]. Raynaud's phenomenon and, less frequently, arterial hypertension and major vascular events, may also occur. Chronic pulmonary fibrosis is associated with bleomycin, especially when the cumulative dose exceeds 450 U. Three factors may contribute to the decreased fertility which can affect GCT patients [23]. The first is ejaculatory dysfunction following retroperitoneal surgery. In specialized centres using current nerve sparing techniques, the incidence of permanent failure of ejaculation is less than 10%. Not uncommonly, a transient disturbance may occur, and some patients benefit from medical treatment (ephedrine, tricyclic antidepressants, etc.) or selective neural stimulation. Second, azo-oligospermia may occur and is frequently present at diagnosis. However, sperm count recovery is less frequent in patients treated with chemotherapy than in those with stage I disease who are followed without additional treatment. Third, some degree of Leydig cell dysfunction is present, as shown by normal serum testosterone levels with increased LH and FSH, as in our case. Our recommendation is to offer sperm banking to suitable patients before commencing cytotoxic treatment. Psychological morbidity, apart from anxiety and depression in 10% of the patients, also affects sexual activity. These disturbances, reported in 10%-40% of the cases, include impotence, premature ejaculation and loss of libido and sexual satisfaction [22]. Finally, an increased number of second malignancies arises in individuals treated for GCT (relative risk: 1.3-2). These include contralateral testicular tumours, solid tumours and haematological malignancies. Contralateral GCT appear in 3%-5% of survivors, usually within the 10 years following the first diagnosis. However, the risk, if any, is minimal in patients treated with chemotherapy, probably due to a protective effect against the pre-invasive lesion, in situ carcinoma [24]. Also a higher incidence of solid neoplasms has been reported (skin cancers, gastrointestinal tumours, lung tumours, urothelial carcinomas, etc.), particularly if radiotherapy is used. The actual incidence of leukaemia is unknown, but most cases involve patients treated with radiotherapy or etoposide [25]. A peculiar syndrome of non-therapy-induced haematological malignancies has been described in patients with primary mediastinal tumours. Both haematological and germ cell diseases seem to arise from a common progenitor [26]. Conclusion The present case emphasizes the advantages of early diagnosis at presentation and relapse which correlates
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
are usually given. With this approach, 60% of patients will remain disease-free, a figure which compares favourably with 9% without post-surgery chemotherapy [17]. Why is residual mass surgery indicated? First, viable chemo-refractory tumour can be removed and the patient benefit from further cytotoxic treatment. The latter, in our opinion, should be different from the regimen employed during the induction. Removal of differentiated teratoma which is unresponsive to chemotherapy is a second reason for surgery, since, when left in situ, the teratoma may grow, invade and compress surrounding tissues. Also, it may dedifferentiate to malignancy (of germ cell or non-germ cell histology) or result in a late recurrence [18]. Conversely, there is no clear advantage for resection of necrotic or fibron'c tissues. For this reason several investigators have tried to identify prognostic predictors of postsurgery histology. Most of the series have found an association between teratoma in the testicle and its presence in the residual mass. The finding of no benign or malignant tumour is more frequent when residual masses are of small size (e.g., <2 cm), those with high shrinkage of the original metastases (e.g., >90%), presurgery negative markers and, as mentioned, an absence of teratoma in the primary. Unfortunately, even when all these variables coincide in a patient, the chance of viable tumour or teratoma is 15%-20% [19]. Therefore, surgery to removal residual masses should be offered of any patient after chemotherapy, once markers are normalized.
462
12. 13.
14.
15. 16. 17.
Acknowledgement
18.
Dr. Luis Paz-Ares is supported by a fellowship from the European Society of Medical Oncology (ESMO). 19.
References 20. 1. Einhorn LH. Treatment of testicular cancer: A new and improved model. J Clin Oncol 1990; 8:1877-81. 2. Droz JP, Kramar A, Rey A. Prognostic factors in metastatic disease. Sem Oncol 1992; 19:181-9. 3. Medical Research Council Working Party on testicular tumours. Prognostic factors in advanced non-seminomatous germ-cell testicular tumours: Results of a multicenter study. Lancet 1985; I: 8-11. 4. Mostofi FK, Sibin LH. Histological typing of testis tumors. International classification of tumors, No. 16. Geneva, World Health Organization, 1977. 5. Husband J. Advances in tumour imaging. In Horwich A (ed): Testicular cancer: Investigation and management Chapman and Hall Medical: New York 1991; 2:15-31. 6. Tait D, Peckham MJ, Hendry WF et al. Postchemotherapy surgery in advanced non-seminomatous germ cell tumours: The significance of histology with particular reference to differentiated (mature) teratoma. Br J Cancer 1984; 50: 601-9. 7. Williams SD, Stablein DM, Einhorn LH et al. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 1987; 317:1433-8. 8. Donahue JP, Thornhill JA, Foster RS et al. Retioperitoneal lymphadenectomy for clinical stage A testis cancer (19651989): Modifications of technique and impact on ejaculation. J Urol 1993; 149:137-43. 9. Read G, Stenning SP, Cullen MH et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. J Clin Oncol 1992; 10:1762-8. 10. Cullen MH on behalf of the Medical Research Council (MRC) Testicular Tumour Working Party. Short course adjuvant chemotherapy in high risk stage I non seminomatous germ cell tumours of the testis (NSGCTT): An MRC study report. Proc QT Germ Cell Tumour Conference 1993; 3:47 (Abstract). 11. Mead GM, Stenning SP, Parkinson MC et al. The Second Medical Research council study of prognostic factors in non-
21.
22. 23. 24.
25.
26. 27.
seminomatous germ cell tumors. J Clin Oncol 1992; 10: 8594. Williams SD, Birch B, Einhorn LH et al. Treatment of disseminated germ cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med 1987; 316:1435-40. Einhorn LH, Williams SD, Loehrer PJ et al. Evaluation of optimal duration of chemotherapy in favourable-prognosis disseminated germ cell tumors: A Southeastern Cancer Study Group protocol. J Clin Oncol 1989; 7: 387-91. Bejorin DF, Sarosdy MF, Pfister DG et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multiinstitutional study. J Clin Oncol 1993; 11: 598-606. Levi JA, Raghavan D, Harvey V et al. The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. J Clin Oncol 1993; 11:1300-5. Paz-Ares L, Kaye SB. Intensive treatment schedules. Proc HJ Germ Cell Conference 1993; 3: 56. Einhom LH, Williams SD, Mandelbaum I et al. Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer 1981; 48: 904-10. Paz-Ares L, Lianes P, Diaz-Puente M et al. Late relapses (LR) in malignant germ cell tumors (MCGT) treated with cisplatinbased chemotherapy. Proc Am Ass Cancer Res 1992; 34: 222 (Abstract). Toner CG, Panicek DM, Heelan RT et al. Adjuntive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 1990; 8: 1683-94. Hansen SW, Helweg-Larsen S, Trojaborg W. Long-term neurotojricity in patients treated with cisplatin, vinblastine and bleomycin for metastatic germ cell cancer. J Clin Oncol 1989; 7: 1457-61. Hansen SW, Groth S, Daugaard G et al. Long term side-effects on renal function and blood pressure of treatment with cisplatin, vinblastine and bleomycin in patients with germ cell cancer. J Clin Oncol 1988; 6:1728-31. Boyer M, Raghavan D. Toxicity of treatment of germ cell tumors. Sem Oncol 1992; 19:128-42. Fossa SD, Kreuser ED, Roth GJ et al. Long-term side effects after treatment of testicular cancer. Prog Clin Biol Res 1988; 357:321-30. von der Maase H, Rorth M, Walbom-Jorgesen S et al. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer. A study 27 cases in 500 patients. Br Med J 1986; 293:1398-401. Pedersen-Bjergaard J, Daugaard G, Hansen ST et al. Increased risk of myelodisplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ cell tumours. Lancet 1991: 338: 35963. Rodriguez E, Mathew S, Reuter VE et al. Cytogenetic analysis of 124 prospectively ascertained male germ cell tumors. Cancer Res 1992; 52: 2285-91. Harding MJ, Paul J, Gillis CR et al. Management of malignant teratoma: Does referral to a specialist unit matter? Lancet 1993; 341:999-1002.
Received 28 October 1993; accepted 19 January 1994. Correspondence to: Dr. H. Cortes-Funes Servicio de Oncologja Medica Hospital Universitario TJoce de Octubre' Carretera de Andalucia Km. 5.400. 28041 Madrid Spain
Downloaded from https://academic.oup.com/annonc/article-abstract/5/5/457/211611 by University of Otago Science Library user on 19 January 2019
with lower-burden disease in both circumstances. Careful follow-up is needed if RPLDN and chemotherapy are omitted in stage I. Once metastatic disease is present, the outcome is excellent if appropriate cisplatin chemotherapy is instituted and resection of residual masses undertaken when appropriate. Continuous follow-up should be offered to long-term survivors in order to detect and institute early management of late sequelae of treatment and other delayed complications. The appropriate management of this highly curable disease requires the collaboration of several welltrained and experienced specialists. Given the rarity of GCT, both physicians and health service organizations should try to ensure that these rumours are treated in specialized centres [27].