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1 Acta Oncologica ISSN: X (Print) X (Online) Journal homepage: Testicular Cancer Michael Peckham To cite this article: Michael Peckham (1988) Testicular Cancer, Acta Oncologica, 27:4, , DOI: / To link to this article: Published online: 08 Jul Submit your article to this journal Article views: 118 View related articles Citing articles: 27 View citing articles Full Terms & Conditions of access and use can be found at Download by: [ ] Date: 14 December 2017, At: 11:29

2 Reviews in Oncology I (1988) No. I (in Acta Oncologica Vol. 27, Fax. 4) FROM THE BRITISH POSTGRADUATE MEDICAL FEDERATION, LONDON, ENGLAND. TESTICULAR CANCER MICHAEL PECKHAM Abstract Testicular cancer, which predominantly occurs in young men, has become increasingly common; it is presently the most common malignancy in men aged Despite a lack of knowledge of aetiology, empirical advances, particularly in the management of patients with advanced disease, have been dramatic. Prior to the development of effective chemotherapy in the 1970s, less than 10% of men with metastatic non-seminomatous germ cell tumours were cured; nowadays approximately 90% of patients are potentially curable. The introduction of effective chemotherapy has led to a reappraisal of surgery and radiotherapy in the management of early stage disease and the introduction of a policy of surveillance in patients without evidence of metastases at the time of removal of the primary tumour. Following chemotherapy, surgery is required in approximately 25% of patients with advanced disease to excise residual masses, which in onefifth of cases will show evidence of residual malignancy. In a proportion of patients, testicular cancer develops on a background of long-standing infertility, whereas in many men there is temporary oligospermia, despite a previous history of fertility. The majority of patients with prior evidence of spermatogenesis recover this function following chemotherapy and there is no evidence that children fathered by such patients have an increased risk of malformation. Despite physician optimism and excellent prospects for cure, significant psycho-social morbidity is associated with the diagnosis and treatment of testicular cancer. Factors contributing to this are being identified and will lead, hopefully, to the minimisation of such problems by appropriate intervention. Key words: Testicular cancer, chemotherapy, surveillance, surgery, fertility, psycho-social sequelae. ciable. A major disadvantage was the high level of associated toxicity, particularly marrow suppression resulting in neutropenic sepsis. Following the discovery by Rosenberg et al. (51), of the growth inhibitory properties of platinum complexes and the demonstration of the activity of cisplatin in patients with testicular germ cell tumours (IS), the widely used combination of cisplatin, vinblastine and bleomycin (PVB) was developed by Einhorn and his colleagues (6). By the late 1970s, it was established that PVB could cure approximately 70 % of patients with metastatic testicular cancer. Since that time, new drugs such as etoposide and carboplatin have been introduced into clinical practice and prognostic sub-groups identified, enabling chemotherapy to be designed in relation to defined risk factors. Although a minority of patients with bulky metastases and high serum markers still fail on currently available chemotherapy, the overall cure rate for metastatic testicular tumours is now of the order of 90%. Pathological classification Of the various pathological systems in use, the criteria described by the testicular tumour panel of Great Britain (Pugh, 1976), is generally employed in the UK. This is summarised below with the corresponding American terminology indicated in parenthesis. Prior to the mid 1970s, the majority of young men with metastatic testicular cancer died of uncontrolled malignancy, although by 1970 it had become clear that single agent chemotherapy could cure a small proportion of patients. The first effective drug combination for testicular cancer, a schedule employing high dose vinblastine and intravenous bleomycin given by infusion (VB), was developed by Samuels and his colleagues (53). Although this proved to be effective for eradicating small volume metastases, the failure rate for bulky disease was appre- Non-seminomatous germ cell tumours (malignant teratoma) a) TD-Teratoma differentiated (teratoma). A teratoma which histologically is composed of fully differentiated tissue, such as cartilage, bone, muscle or squamous columnar or glandular epithelium. b) MTZ-Malignant teratoma intermediate (teratocarcinoma). The appearances of teratocarcinoma are intermediate in type between differentiated and undifferentiated teratoma, comprising incompletely differentiated tissues and elements having the histological characteristics 439

3 440 MICHAEL PECKHAM of malignancy; some mature tissue or organised structures are recognised. c) MTU-Malignant teratoma undifferentiated (embryonal carcinoma). A malignant tumour without mature or organoid elements, with a variable appearance ranging from a solid sheet of cells to an adenocarcinomatous pattern. d) MTT-Malignant teratorna trophoblastic (choriocarcinoma). A malignant teratoma of the general type of either MTI or MTU, but distinguished from them by containing true trophoblastic elements, that is syncytial cell mass and malignant cytotrophoblast. Choriocarcinoma and MTT differ since MTT may, in addition to trophoblastic elements, contain undifferentiated teratoma whereas choriocarcinoma is composed solely of trophoblastic tissue. Seminoma Classical seminoma accounts for approximately 95 % of seminomas. The tumour itself is often well demarkated and rather uniform in appearance with occasional yellow areas and necrosis. The tumour is composed of fairly uniform, round or polygonal cells with clear or finely granular cytoplasm containing glycogen and lipid. Multinucleated tumour giant cells which may resemble syncytiotrophoblast are identified in a minority of cases. These giant cells can be shown to contain human chorionic gonadotrophin by immunoperoxidase staining techniques. The presence of stroma and lymphatic infiltration is a relatively common feature. Anaplastic seminoma is characterised by increased cellular pleomorphism and 3 or more mitotic figures per high power field. Spermatocytic seminoma occurs in older men and the majority of cases with seminoma in patients over seventy are of this type. The tumours which are often mucoid and sometimes cystic in appearance composed of sheets of cells showing mark variation in size; the cytoplasm is more dense and unlike classical seminoma contains no glycogen. Multinucleated giant cells are commonly present and mitoses are usually numerous. Of 3196 tumours analysed by the testicular tumour panel between 1958 and 1973, 39.5% were seminomas, 31.7% teratomas and 13.5% combined tumours (50). Testicular cancer manifests itself with differing histology at different ages. In infancy (peak age 2 years), approximately 70 % of tumours are embryonal carcinomas or differentiated teratomas whereas in young adults (peak age years), malignant teratomas and seminomas predominate. In a series of 1058 consecutive patients registered with the Danish Testicular Cancer Study Group between 1976 and 1980, the median age at presentation for seminomas was 40.5 years, almost 10 years later than that for nonseminomatous tumours (31.7 years) (55). In men over the age of 50 years, malignant lymphomas and spermatocytic seminomas become progressively more common and in old age constitute the majority of testicular tumours. Epidemiology and aetiology Testicular cancer is presently the most common malignancy in men aged with registrations more than twice that of Hodgkin s disease. A white male in the UK has an approximately 1 in 500 risk of developing testicular cancer by the age of 50 (4). The incidence of testicular cancer has been increasing over the past 30 years in the US, UK, Denmark and other developed countries. Registrations reported to the National Cancer Registry increased from 2.1 per , population in 1962, to 3.8 per in The registration rate recorded in the Danish Testicular Cancer Study Group has more than doubled between 1943 and 1947 (55). In England and Wales, increases in registration rates have been most dramatic in young adults with an approximate doubling between 1963 and 1981 in men between 15 and 44. Although geographical comparisons are complicated by differences in level of medical services and diagnostic facilities, it is clear that substantial differences do occur from one part of the world to another, with the highest rates in North American whites, Scandinavia (with the exception of Finland), other Western European countries, including the United Kingdom and the lowest rates in Asians, Africans, Puerto Ricans and North American blacks. Thus the incidence rate per ranges from 6.7 in Denmark, to 0.5 in Puerto Rico and 0.2 in Senegal. There is also an apparent association with social class (56), with a gradient from social classes 1 and 2 to social classes 4 and 5 (27). The reasons for the increasing incidence of testicular cancer and the wide geographical variation in incidence are unknown. Approximately 10% of patients with testicular cancer have a history of testicular maldescent which may or may not have been corrected in childhood by orchiopexy. A male with cryptorchism has an increased risk of developing testicular cancer, probably about 35 times compared to the normal population. The risk is 6 times greater for intra-abdominal tests than for incompletely descended testes lying at a lower level. In patients with bilateral maldescent who develop a tumour in one testis, approximately 25 % will go on to develop a contralateral tumour. In patients with unilateral maldescent, the risk of developing a tumour in the normally descended contralateral testis is also increased compared with normally descended testes; one in five of the testicular tumours which develop in cryptorchid patients can be expected to occur in the contralateral normally situated testis. It is not known why testicular maldescent is associated with an increased risk of testicular malignancy but it is probable that it is not maldescent per se but an underlying abnormality influencing both ectopia and tumour formation.

4 TESTICULAR CANCER 44 1 There is no evidence that early orchiopexy substantially reduces the risk of subsequent malignancy. In a review of 724 testicular tumour patients seen over a 10-year period from 1975 to 1984, at the Royal Marsden Hospital of whom 69 (9.5 %) had a history of cryptorchidism, 58 had had an orchiopexy or orchiectomy for maldescent. The distribution of age at orchiopexy or orchiectomy of the 58 testicular tumour patients was comparable to that expected on the basis of national rates (47). This observation suggests that age at treatment of undescended testes has little effect on the risk of subsequent testicular cancer. Comparison of the histology of testicular tissue from boys undergoing orchiopexy for maldescent with the appearance of testes from children dying as a result of road traffic accidents or sudden infant death, shows that histological abnormalities are evident by the second or third year of life in cryptorchidism (12). This evidence of early morphological change in cryptorchid testes supports the view that gonadal dysgenesis rather than ectopy per se increases the risk of malignancy. The testicular dysgenesis hypothesis receives support from observations of carcinoma in situ in infertile men. Skakkebaek (59) and Pryor et al. (49), reported an increased risk of testicular cancer ( per ) in men with testicular hypo-function. The association between carcinoma in situ of the testis and invasive testicular neoplasia was described in 1972 (58). Krabbe et al. (24), identified carcinoma in situ in 4 of 50 men with a history of testicular maldescent who agreed to testicular biopsy. The incidence of carcinoma in situ of the contralateral testis in patients developing a testicular tumour is approximately 5 % (65). In patients with unilateral testicular cancer who have a history of cryptorchidism and/or an atrophic contralateral testis, 23 % have carcinoma in situ in the remaining testis. Carcinoma in situ was identified in 3 of 12 patients with the androgen insensitivity (testicular feminisation) syndrome (31) and all 4 children with gonadal dysgenesis and a 45, XOI-46, XY mosaic karyotype had carcinoma in situ (32). Approximately 50% of men with carcinoma in sifu will develop invasive malignancy within 5 years. Anecdotal reports indicate that the evolution of carcinoma in situ into invasive testicular cancer may be protracted over 1 or even 2 decades. The most likely origin of testicular cancer is gonadal dysgenesis. Initiators may include genetic influences, the environment or lifestyle of patients during critical periods of gestation and possibly the pre-pubertal environment of the patients themselves. Promoters may include cryptorchidism and pre-natal oestrogen exposure (56). It is of interest that recent data from the Oxford Study suggests that the incidence of testicular maldescent may have increased over the past 2 decades (Chilvers, personal communication). A patient who has had one testicular tumour, is at increased risk of developing a contralateral tumour. Of 760 men attending the Royal Marsden Hospital between 1952 and 1976, 2.75% developed a tumour in the contralateral testis; in 2 instances synchronously and in the remainder at intervals from 4 months to 15 years (61). In a recent report on 2338 Danish patients, 2.7% developed a contralateral tumour (36). The overall relative risk was higher for non-seminoma than seminoma. In view of the increased risk of developing a tumour in the contralateral testis and the demonstration by testicular biopsy that 5 % of patients with one testicular tumour show carcinoma in situ in the remaining testis, the question arises as to whether all patients with testicular cancer should routinely have the remaining testis biopsied. If carcinoma in situ is identified, low dose radiotherapy (20 Gy in 10 fractions) has been reported to be effective in its elimination (65). This inevitably leads to loss of fertility but hormonal function is preserved. Attempts to preserve fertility in testicular cancer patients are of great importance and in our view routine biopsy of the contralateral testis is indicated only in patients likely to be infertile including those with maldescent or atrophic testes. If it is anticipated that fertility will be retained, clinical observation without routine biopsy is a preferable option. Presentation and diagnosis Although current chemotherapy is highly effective for metastatic disease, it is important that patients seek medical advice at the earliest possible stage, and that their condition is diagnosed promptly. In the collaborative Medical Research Council study (29) the 3-year survival figure for men with a history of less than 3 months was 81 % compared with 61 % when the history was more than 3 months (p=0.02). This difference was explained by the association of more advanced disease with a delay in diagnosis. Thus when the history was less than 6 months, 54% of patients had small volume metastases and 65% low serum marker levels compared with 39% and 51% respectively in patients with a history of longer than 6 months. It is clear that public awareness can influence the promptness with which patients seek medical advice. In results reported from the Danish Testicular Carcinoma Study, there was a significant increase between 1976 and 1980 in the proportion of seminoma patients with stage I disease at presentation. There was also a decrease in the mean maximun diameter of primary tumours at diagnosis in both seminoma and teratoma; finally the size of the primary tumour correlated with the probability of metastases (25). Testicular tumours usually present as painless swellings, however pain and tenderness at presentation are not uncommon. This feature may lead to delay with an erroneous diagnosis of inflammation. A history of trauma is fairly common; it is likely that this either draws the patient s attention to the presence of a mass or results in haernorrhage into a pre-existing mass. Occasionally pa-

5 442 MICHAEL PECKHAM tients present with metastatic germ cell malignancy without a primary tumour palpable in either testis. In a study of 18 patients presenting in this way at the Royal Marsden Hospital, it was found that the majority had very advanced disease associated with abdominal pain and systemic symptoms (48). Eight patients had an history of testicular atrophy. The diagnosis of testicular cancer in this group of patients was established by biopsy of enlarged abdominal or cervical lymph nodes, lung biopsy or by the finding of high serum marker levels. In 3 of 4 patients, in whom the testis was examined histologically following a history of atrophy or pain, there was evidence of a microscopic primary tumour. Investigation and staging History and clinical assessment are important. Backache is suggestive of involved retroperitoneal nodes and gynaecomastia usually associated with high serum concentrations of human chorionic gonadotrophium (HCG). Blood should be taken prior to orchiectomy for the estimation of alpha fetoprotein (AFPj and HCG; approximately 80 % of non-seminomatous germ cell testicular tumours produce either one or both of these markers and pre-orchiectomy information is invaluable for follow-up purposes. A history of orchiopexy should be sought. The appropriate surgical approach to orchiectomy is an inguinal incision. If a firm area is identified in the body of the testis usually associated with superficial overlying veins, the spermatic cord is divided and the testis removed. Biopsy is only necessary in patients with a solitary testicle. If the testis is explored through a scrotal incision in the first instance for inspection and the establishment of a diagnosis, provided the tunica albuginea has not been breached, there is little risk of scrotal dissemination. It is of interest that of 210 patients with clinical stage I testicular non-seminomas managed by orchiectomy and surveillance at the Royal Marsden, between 1979 and 1985, 17 % had scrotal incisions or trans-scrota1 needle biopsy at, or prior to, the removal of the primary tumour. However, none of the 36 patients who had scrotal interference developed scrotal recurrence during surveillance and the overall relapse rate of 11 % was comparable to that observed in the series as a whole (20%). These observations suggest that the propensity of testicular cancer to spread locally is low (23). Once orchiectomy has been performed, histological examination of the tumour is carried out with immunocytochemical staining for the presence of AFP and HCG. Evidence of involvement by tumour of blood vessels and lymphatics in the testis is sought as well as extension into adjacent structures, such as the rete testis and epididymis. In a minority of patients, widespread tumour dissemination makes intensive staging unnecessary and pretreatment investigation is limited to serum marker assay, as- Stage I I1 I11 IV Table 1 The Royal Marsden Hospital Lymphogram negative, no evidence of metastases Lymphogram positive, metastases confined to abdominal nodes; Three sub-groups are recognised: A. Maximum diameter of metastases <2 cm B. Maximum diameter of metastases 2-5 cm C. Maximum diameter of metastases >5 cm Involvement of supra- and infradiaphragmatic lymph nodes. No extralymphatic metastases Abdominal status A, B, C as for Stage I1 Extralymphatic metastases. Suffixes as follows: 0- lymphogram negative; A, B, C as for Stage I1 Lung status L, ~3 metastases L2 multiple <2 cm maximum diameter L, multiple >2 cm diameter Liver status H, = liver involvement sessment of renal and hepatic function, chest radiography and full blood count. Whenever possible, however, patients should be staged as precisely as possible using noninvasive investigative methods. The object of this detailed staging procedure is definition of the extent and sites of tumour spread. Furthermore, since the volume of metastases exerts an influence on therapeutic response, this parameter is included in the clinical staging system. Investigations include computerised axial tomography (CAT) scans of lungs, liver and retroperitoneum and pelvis, full blood count, liver function tests, serum calcium, urea and electrolytes, measurement of serum AFP and HCG levels, renal function tests (EDTA or creatinine clearance), pulmonary function tests for patients receiving bleomycin and semen analysis, with banking if the sperm count is adequate and treatment is considered likely to compromise fertility. Lymphography is no longer employed in non-seminoma patients but is carried out in stage I seminoma patients entering the surveillance study (vide infra). The Royal Marsden Hospital staging classification of testicular cancer is summarised in Table I. Management of seminoma The modal age of patients with seminoma is between 35 and 40 years, and although seminomas are seen in patients in their teens they are rare in childhood. They are charactensed by exquisite radiosensitivity and, as discussed below, by a high degree of sensitivity to chemotherapy. Seminomas tend to present with early stage disease. Thus, in seminoma patients documented in Denmark between 1976 and 1980, 77% had stage I disease, 21%

6 TESTICULAR CANCER 443 stage I1 disease and only 3 % stage I11 and IV disease (25). The radiosensitivity of seminoma, and the fact that most patients either have stage I or I1 disease, has resulted in excellent survival figures, exceeding 90 % following orchiectomy and lymph node irradiation. Stage I seminoma: Radiotherapy or surveillance. The successful adoption of the surveillance policy in nonseminomatous tumours raises the possibility that a similar approach may be applicable in stage I seminoma. In favour is the probable low incidence of occult metastases in retroperitoneal lymph nodes in patients with clinical stage I disease. Maier et al. (28), in a series of stage I patients submitted to radical lymph node dissection, found that only 8 % of patients had histologically positive abdominal nodes. On the other hand, seminomas tend to grow more slowly than teratomas and the time to relapse following orchiectomy may be more protracted rendering a surveillance policy difficult to manage. Furthermore, whereas in teratomas AFP and HCG are valuable tumour markers, there is a lack of useful markers in seminoma although placental alkaline phosphatase is of more limited value. The results of radiotherapy in stage I seminoma are excellent. Among 240 patients treated at the Royal Marsden Hospital there has been no death from seminoma and the relapse rate is only 2% (11). However, the morbidity of radiotherapy, although low, is not negligible. Thus 6% of patients developed peptic ulcers following treatment and although it is difficult to be sure of the role of irradiation it seems probable that the majority were induced or exacerbated by treatment. In a comparison of surveillance and radiotherapy for stage I non-seminoma patients (receiving 40 Gy rather than 30 Gy as for seminoma) there was a significantly higher incidence of duodenal ulceration in irradiated patients (4.9 vs 0%; p=0.05) (10). In 1983 a prospective study of surveillance following orchiectomy was initiated in clinical stage I seminoma. Between February 1983 and July patients were entered into the study; with observation times of months (median 23 months) 7 (13.4%) had relapsed, (41). It is of interest that 6 of the 7 relapses were confined to the retroperitoneal lymph nodes, 2 patients having stage IIA disease and 4 stage IIB. One patient relapsed with small volume abdominal disease and limited lung metastases. The time from orchiectomy to relapse ranged from 9 to 23 months with 4 relapses appearing in the first year and 3 during the second year. On the basis of these preliminary observations surveillance for stage I seminoma can be contrasted with routine lymph node irradiation. The relapse rates are 13% and 2% respectively, with 5% of the surveillance patients receiving chemotherapy and 2% of those relapsing after radiotherapy being potential candidates for chemotherapy. Of the surveillance patients not more than 13 % on the basis of the present results would proceed to radiotherapy and therefore be at risk of post-radiation peptic ulceration or radiation-induced malignancy, whereas all irradiated patients are submitted to this small but finite risk. Clearly it is premature to arrive at a definite conclusion regarding the possible role of surveillance in stage I seminoma. Until such information is available from carefully conducted clinical investigations the routine treatment of choice should be regarded as lymph node irradiation. Stage I1 seminoma. The results of radiotherapy in stage I1 seminoma are influenced by tumour volume with relapse rates in stages IIA, IIB and IIC of lo%, 18% and 38% respectively (1). Similar findings were reported by Thomas et al. who found that the 5-year actuarial survival rate for patients with palpable abdominal disease was significantly worse than for stage I1 patients in whom an abdominal mass was not present (62 vs 84%; p<0.02). In a more recent analysis of our experience in stage I1 seminoma patients treated with radiotherapy between 1970 and 1984, 9/53 patients (17%) relapsed, 5 (9%) died of testicular cancer and 1 (2%) died of intercurrent disease (9). Supradiaphragmatic irradiation was not advantageous; of 22 patients receiving infradiaphragmatic irradiation, 3 (14%) relapsed compared with 6/31 (19%) of those who had supra- and infradiaphragmatic irradiation. In this study serum HCG levels were found to be raised prior to radiotherapy in 3/26 (1 1.5 %) stage IIA and IIB patients and 3/10 (30%) stage IIC patients. However, this did not influence the outcome of radiotherapy since 0/6 patients with raised HCG levels relapsed compared with 7/30 (23%) of those with normal levels. On the basis of these observations we continue to advocate radiotherapy for stage IIA and IIB disease, and chemotherapy for stage IIC patients. Radiotherapy for stage IIA and IIB should be confined to the infradiaphragmatic lymph node areas to avoid the complications of chemotherapy in patients who have received infra- and supradiaphragmatic irradiation. As described below, carboplatin appears to be highly effective as a single agent in the management of seminoma; if further experience substantiates the role of the new platinum analogue then it may prove to be a less toxic and simpler option for the treatment of stage IIA and IIB disease. Chemotherapy of advanced seminoma. It is now established that seminoma is extremely sensitive to chemotherapy, and excellent survival figures are achieved using some of the drug combinations currently employed to treat advanced testicular non-seminomas. Recent data shows that platinum analogues, employed as single agents, are also highly active in advanced seminoma, which raises doubts about the contributions of other drugs. Samuels & Logothetis (541, using Bleo-Comf and vinblastine and bleomycin (VB), reported that these were relatively ineffective in the management of seminoma with 0/7 patients treated with VB surviving. Since approximately 50% of patients with metastatic teratoma are cured with VB, it appears that the spectrum of drug sensitivity in seminoma differs substantially from that observed in non-seminomatous turnours. In a series of 44

7 444 MICHAEL PECKHAM patients treated at the Royal Marsden Hospital with cisplatin-containing combination chemotherapy or carboplatin (JM8) as a single agent, 40 (91 %) are alive and diseasefree at 12 to 73 months (median 36 months) (42). It is of interest that the complete remission rate at 1 month following completion of chemotherapy was only 32%. This is explained by the fact that residual masses, particularly in patients with initially bulky disease, are common in seminoma. These masses regress spontaneously and slowly over months or even years. Limited surgical data show that residual masses are densely fibrotic, adherent and almost invariably histologically negative. For this reason surgery is not advocated, although patients should be monitored carefully. The possible value of radiotherapy to initially involved sites of disease following completion of chemotherapy for advanced seminoma has not been investigated in a prospective randomised study, although our experience suggests that irradiation may not be contributory. Thus, of 15 patients treated with chemotherapy followed by radiotherapy, 1 has relapsed, compared with 1 of 16 patients managed by chemotherapy alone. More recent data indicates that carboplatin is highly active as a single agent in the treatment of advanced seminoma (42). Thus, of 14 untreated seminoma patients, 13 (93%) were free from active disease at 7 to 38 months (median 12 months) following chemotherapy. Of 11 patients who have been observed for a minimum of 1 year, 10 are disease-free. In a recent update of this experience in 34 patients receiving carboplatin as a single agent and followed for a minimum period of one year following chemotherapy, 6 relapsed of whom 5 were salvaged with combination chemotherapy. At the time of reporting (16) 33 of 34 patients were alive and disease-free. Placental alkaline phosphatase as a marker in seminoma Placental alkaline phosphatase, an isoenzyme of the alkaline phosphatase group of enzymes, is normally synthesised in the placental synoytiotrophoblast after the 12th week of pregnancy when it is shed into the maternal circulation. In testicular tumours, raised serum levels of placental alkaline phosphatase have been associated particularly with seminomatous components (20, 21, 26, 68). In a study from this unit serum samples from 62 patients with seminoma were assayed for placental alkaline phosphatase-like activity using the monoclonal antibody H17E2 in order to evaluate its usefulness as a serum marker (18). Sixteen of 46 patients considered to be in remission had elevated placental alkaline phosphatase levels, giving a false positive rate of 35%. Unfortunately smokers may have elevated levels of the enzyme and 15 of the false positive results were probably attributable to concomitant smoking. In 7 patients where sequential assays were camed out to monitor evolution of disease there was a good correlation between clinical response and serum marker concentration. Management of non-seminomatous germ cell tumours Surveillance after orchiectomy for clinical stage I. A range of clinical approaches have proved highly successful in curing patients with stage I testicular cancer. These include lymph node dissection and deferred chemotherapy (S), lymph node dissection and adjuvant chemotherapy (60) and radiotherapy with deferred chemotherapy (46). Analysis of historical data suggested that sub-clinical metastatic disease is present in only 20-30% of patients with clinical stage I non-seminomatous tumours, and given the effectiveness of chemotherapy in patients with small volume metastases it was felt appropriate to investigate a policy of surveillance following orchiectomy, the endpoint of the investigation being curability and the avoidance of unnecessary treatment. Surveillance was introduced at the Royal Marsden Hospital in Eligibility criteria included a normal CT scan of the thorax and the abdomen, a normal lymphogram, histological verification of non-seminomatous germ cell malignancy and normal serum markers prior to orchiectomy or a rapid fall of serum marker levels to normal values following removal of the primary tumour. Pathological review of the primary tumour included assessment of vascular and lymphatic permeation as well as local extension of the tumour into adjacent structures and immunocytochemical staining for HCG and AFP. Transscrotal biopsy, scrotal orchiectomy or prior orchiopexy, were not contraindications to surveillance. The surveillance protocol for patients confirmed to have stage I disease clinically, includes out-patient visits with physical examination, chest radiogram and assay of serum tumour markers every month for the first year, every 2 months for the second year, every 3 months for the third year, and every 4 months for the fourth year. Initially, CT scans of the thorax and the abdomen were performed on alternate visits for the first 2 years but subsequently CT scans have been performed less frequently with 4 scans during the first year and a further scan at the end of the second year. The major objective of the surveillance study, was to establish the cure potential of orchiectomy alone and to see whether a group of patients could be identified where the relapse probability following orchiectomy was sufficiently high to warrant immediate chemotherapy. Results have been reported in a series of publications (38-41). The results of surveillance are shown in Table 2 which summarizes data on 132 patients followed from 12 to 84 months (median 43 months) from orchiectomy. Thirty-five patients (27 %) relapsed. All relapsing patients were treated with combination chemotherapy using bleomycin, etoposide and cisplatin (38, 40). Thirty-four (97%) are alive and disease-free with one patient dying in remission from complications of renal failure. Thirty-one (90 %) relapses occurred within the first year after orchiectomy ; the time to relapse is shown in Fig. 1. Relapse was revealed by rising serum marker levels in 26 (74%) of pa-

8 TESTICULAR CANCER 445 Table 2 Surveillance after orchiectomy for clinical stage I testicular germ-cell tumours. Outcome in patients followed for a minimum of 1 year (The Royal Marsden Hospital, ) History No. of No. of Per- Observation time after pats. relapses centage orchiectomy in months (median) MTI (teratocarcinoma) (43) MTU (embryonal carcinoma) (42) MTT (59) Seminoma, raised AFP , 58, 75 Differentiated teratoma 5 0-1&59 (54) Total (43) ~r--l--r--r ~ irnc nficr orchiilccloniy (months) Fig. 1. Surveillance for stage I testicular non-seminoma: time to relapse after orchiectomy (The Royal Marsden Hospital, ). tients. The pattern of relapse was as follows: 17 patients (47 %) relapsed in abdominal nodes, 4 (13 %) had abdominal and lung metastases, 6 (17 %) had lung metastases and 8 (23%) had elevated serum marker levels as the only evidence of disease. Of 35 relapsing patients 26 (74 %) had elevated serum levels of either AFP or HCG but 9 (26%) had normal serum marker levels. In the latter group, relapse was proven histologically in 5 patients and in 4 it was obvious on consequential scans. Overall of the 132 patients, only 8 had metastases resected for diagnostic purposes either before or after chemotherapy. As indicated the eventual aim of the surveillance study was to identify prognostic factors permitting the immediate delivery of chemotherapy for high risk patients. A multiple regression analysis of prognostic factors was carried out on 126 patients entered into the surveillance study between 1979 and 1985 (19). As discussed below, it is becoming clear that less toxic chemotherapy can be developed for patients with metastatic testicular cancer using fewer drugs or less toxic drugs, such as carboplatin. In the future alternative and less toxic therapy is likely to be the treatment of choice for stage I patients at high risk of harbouring subclinical metastases. The prognostic significance of 13 clinical, histopathological and biochemical factors, was analysed: vascular and lymphatic invasion within the primary tumour, histology and involvement of the epididymis and rete testis were significantly associated with an increased risk of relapse. Multiple regression analysis showed that only histology and lymphatic invasion were significant independent prognostic factors. The relapse rates ranged from 6 out of 15 (12%) in teratocarcinoma patients without lymphatic invasion to 7 out of 9 (78%) of embryonal carcinoma patients with lymphatic invasion (Table 3). Subsequently a multi-centre study of prognostic factors has been camed out by the Medical Research Council Testicular Tumour Working Party in 259 patients with stage I non-seminomatous tumours treated by orchiectomy alone (8). In this study 4 features independently predicted relapse: invasion of testicular veins, invasion of testicular lymphatics, absence of yolk sac elements, and the presence of undifferentiated malignancy. On the basis of these observations, and index, based on the number of risk features observed has been established, which permits the identification of a high risk sub-group with a 42% relapse-free rate at 2 years. A study has been initiated by the Medical Research Council Working Party of postorchiectomy chemotherapy (2 cycles of bleomycin, etoposide and cisplatin) in high risk patients with clinical stage I testicular non-seminoma. In conclusion, experience since 1979 has amply demonstrated the feasibility of a surveillance policy in clinical stage I disease. Node dissection and radiation therapy are avoided and more than 70 % of patients require no further

9 446 MICHAEL PECKHAM treatment. A quarter of the patient population subsequently manifest metastases, in most instances within the first year of follow-up. Early detection of relapse and the institution of appropriate chemotherapy results in a virtually 100 % survival figure. Post-orchiectomy chemotherapy is highly likely to eradicate occult metastases in high risk patients. Stage IIA and IIB. It is agreed that chemotherapy is the treatment of choice for patients with bulky stage I1 (IIC) non-seminomatous tumours and those with stage 111 and IV disease. There remains some controversy regarding the management of patients with stage IIA and IIB disease. In the United States radical lymph node dissection is the preferred initial treatment. The argument advanced for retaining such a policy hinges on the avoidance of chemotherapy in patients cured by surgery. Approximately half the patients with histologically positive lymph nodes relapse of which half are cured by lymph node dissection. Thus approximately 50% of patients managed by surgery alone eventually require chemotherapy and those who do not are subjected to the stresses of a major surgical procedure including the risk of ejaculatory failure. A policy employing initial chemotherapy without surgery is equally effective. Thus of 50 stage IIA and IIB patients treated at the Royal Marsden Hospital between 1977 and 1984, 49 (98 %) are alive without evidence of disease (42) (Table 4). The only treatment failure occurred in a patient treated with etoposide and cisplatinum (EP), a combination which a phase I1 study suggested was inferior to bleomycin, etoposide and cisplatinum (BEP) (43). All 30 stage IIA and IIB patients treated with BEP are alive without evidence of disease. In this study only 9/50 (18 %) patients required surgery for excision of residual masses. Clearly, equivalent results can be obtained in stage IIA and IIB patients employing widely different treatment methods, and the choice between them depends upon relative toxicities and to some extent upon patterns of established practice. Chemotherapy for advanced tumours. The development of effective chemotherapy for testicular cancer has been the most dramatic advance in oncology over the past decade. The introduction of the combination of vinblastine and bleomycin by Samuels and his colleagues was an important milestone (53). The VB-3 regimen employing vinblastine 6 mg/kg with bleomycin as a continuous 5-day intravenous infusion of 30 mg/day resulted in a complete remission rate of 53 % (52). However, although effective, this combination was associated with considerable toxicity; 13% of patients developed septicaemia and 4.5% died as a result of chemotherapy complications. The demonstration of the activity of cisplatinum in testicular cancer (15) led to its incorporation into a schedule with VB by Einhorn and his colleagues (6). Cisplatinurn, vinblastine and bleomycin (PVB) was evaluated between 1974 and 1976 in 47 patients of whom 27 were long-term disease-free survivors. The major toxicity of Table 3 Influence of histology and presence or absence of lymphatic invasion in patients observed after urchiectomy for stage I testicular non-seminoma (number relapsingltotal patients) Lymphatic invasion within primary tumour Histology No Yes MTI 6/50 (12%) 4/10 (40%) MTU 11/31 (33%) 119 (78%) Table 4 Clinical stage I1 testicular non-seminomas. Outcome of treatment by substage (The Royal Marsden Hospital ) Stage No. of Alive Alive Dead of Dead of pats. NED* with tumour complications disease of treatment IIA 20 19" (95%) 1 IIB 30 30*(100%) IIC 37 28' (76%) Total (90%) 5 3 * NED = No evidence of disease a). Observation time IIA 7-56 months (median 28) b). Observation time IIB 8-74 months (median 29) c). Observation time IIC months (median 52) the original study, which used vinblastine 0.4 mg/kg, was myelosuppression. Between 1976 and 1978 a randomised trial showed that a regimen employing vinblastine 0.3 mg/kg was less toxic but equally effective; furthermore the addition of adriamycin did not improve treatment results (7). The PVB combination cures approximately 75% of patients and until recently was the most widely used form of chemotherapy for patients with metastatic malignant teratoma. Following the demonstration of the activity of etoposide as a single agent this drug was substituted for vinblastine and a combination of bleomycin, etoposide and cisplatinum (BEP) evaluated as first line treatment (40). Our experience with BEP indicated that this is as effective as PVB but less toxic. More recently Williams et al. (70) have reported the results of a randomised clinical trial, comparing PVB with BEP. The myelosuppressive effect of the two regimens was comparable but BEP was substantially less toxic in terms of paresthesia, abdominal cramps and myalgia. Overall the complete remission rate was not significantly different being 74% for PVB and 83% for BEP. However, in patients with bulky disease results, both in terms of complete response rate and survival, were significantly better for BEP than PVB.

10 TESTICULAR CANCER 447 Table 5 Chemotherapy for metastatic non-seminomatous testicular cancer (The Royal Marsden Hospital ) Total no. of Alive Alive with Dead of Dead of patients progressive tumour intercurrent tumour disease (83 %) 8 (2.5%) 42 (13%) 12 (3.8%) Table 6 Chemotherapy for metastatic non-seminomatous testicular cancer. Deaths of intercurrent disease (The Royal Marsden Hospital ) Total no. of patients Total deaths from Cause of death of intercurrent disease intercurrent Arterial Post- Late Chemotherapy disease disease operative radiation damage _I < (3.8%) By chemotherapy regimen (for abbreviations see text) VB 3 BEP 1 BEVIP 1 PVB 1 PVB + JVB 1 BOP 2 > 80 :- h 70i CT 3 cn 60 LL so 1 m 0 g 20 st lo I I I 0 I Fig. 2. Actuarial survival cure for 320 patients with metastatic testicular teratoma treated at The Royal Marsden Hospital Between 1976 and 1985, 320 patients with metastatic testicular cancer received chemotherapy on the Testicular Tumour Unit at the Royal Marsden Hospital. (Table 5). The median observation time for the whole group is 39 months and the actuarial survival at 5 years is 81 % (Fig. 2); 266 out of 320 (83 %) of patients are presently alive and I disease-free. Of the patients 13% died of uncontrolled malignancy and 3.8 % of intercurrent disease, the majority resulting from chemotherapy. Table 6 shows the causes of death from intercurrent disease. Nine of 12 intercurrent deaths were attributable to chemotherapy; 6 of the 9 drugrelated deaths were in patients receiving intensive schedules. Of 148 patients treated with BEP, there was only 1 drug-related death. Fig. 3 shows the time to relapse after the start of chemotherapy; more than 90% of relapses occurred within the first year. Relapse after first-line chemotherapy carries a poor prognosis; of 69% relapsing patients, 19 (28 %) are disease-free with a median observation time of 31 months after the diagnosis of relapse. As discussed below the outcome of treatment is strongly influenced by the volume of metastases and serum marker concentrations. Tumour volume and the concentration of serum AFP and HCG, are idependently highly significant prognostic indicators. In a multi-centre study, carried out by the Medical Research Council Testicular Tumour Working Party, a multivariate analysis of prognostic variables was carried out on 458 patients (29). This study confirmed that tumour volume and serum marker concentrations are independent prognostic variables which, when combined, allow prognostic sub-groups to be defined more precisely. The findings of the MRC study, summarised in Table 7, provide a conceptual basis for individualising chemotherapy in relation to risk factors. This aspect of management

11 448 MICHAEL PECKHAM - 0 bu Table 7 Prognostic factors in advanced non-seminomaious germ-cell testicular tumours. 3-year survival rates according to volume of metastases and serum marker sfatus (summary of data from MRC Report, 1985) Subgroup based Serum No. of Percentage 3-year size of marker patients survival metastases RIonihs Iflei ctieiiiotiici.\jq Fig. 3. Time to relapse after first-line chemotherapy for metastatic non-seminomatous testicular cancer (The Royal Marsden Hospital ). is discussed in further detail below. The outcome of treatment in the Royal Marsden series, in relation to type of chemotherapy, is shown in Table 8. Chemotherapy in relation to risk factors. As shown in Table 9, patients with small metastases, regardless of marker status, and those with large volume metastases and low marker concentrations, all have a very high cure probability. Conversely, patients with very large volume disease and high serum marker concentrations, constitute a high risk group. Patients with large metastases and high serum marker concentrations, or very large metastases and low serum marker concentrations, constitute an intermediate group in which approximately 75 % of patients are cured. In patients with low risk disease, it is appropriate to attempt to develop low toxicity chemotherapy which is equally effective at eradicating turnour. On the other hand, in patients at high risk, more effective chemotherapy is required and, although toxicity is a relevant issue, improved anti-tumour effect is the most important requirement. Lower toxicity chemotherapy. The main approaches to the development of less toxic chemotherapy can be summarised in Table 10. Etoposide and cisplatin has been compared in a randomised study with bleomycin, etoposide and cisplatin by the EORTC (62). The results of this study, which are summarised in Table 11, show no significant difference between the 2 chemotherapeutic approaches, although, as shown in Table 12, there is a significant reduction in toxicity. Preliminary data suggests that in low risk patients, carboplatin may be substituted for cisplatin without loss of anti-tumour effect but with an absence of nephrotoxicity and improved patient tolerance. As described above, carboplatin is highly active as a single agent in advanced seminoma. Following the demonstration of its activity in non-seminomatous germ cell tumour xenografts, a phase I1 study of the drug in cornbination with etoposide and bleomycin was initiated, the preliminary results of which were encouraging (42). In an Small Low I80 91 High Large Low High Very large Low High Table 8 Chemotherapy of metastatic non-seminomatous tesiicular cancer. Disease-free survival by chemotherapy schedule (The Royal Marsden Hospital ) VB (64%) PVB (79%) BEP/CEB (83%) Total (81%) V = vinblastin B = bleomycin P = cis-platin C = carboplatin E = etoposide Table 9 Chemotherapy for metastatic non-seminomatous iesticular cancer. Disease-free survival by chemoiherapy schedule, turnour volume and serum marker status (The Royal Marsden Hospital ) Chemo- Volume Serum marker therapy category concentration VB PVB BEP/CEB Small Large Very large Small Large Very large Small Large Very large Low 717 (100%) 5/6 (83 %) 2/5 15/15 (100%) 16/17 (94%) 1 /2 96/101 (95%) 23/25 (92%) 8/11 (73%) High 2f 2 4/6 (67 %) 1/7 (14%) 5/5 (100%) (63%) 3/8 (38%) 23/26 (88%) 15/22 (68 %) 22/39 (56%) Table 10 Good prognosis metastatic iesticular non-seminoma. Approaches to the development of low ioxicity chemoiherapy Dose reduction Reduction of number of cycles Fewer drugs Less toxic drugs

12 TESTICULAR CANCER 449 Table 11 *EP US. BEP in low risk metastatic testicular teratoma. (Stoter et al. (61)) Treatment Total Complete Positive Relapse Death of Progression Deaths no. of remission* histology uncontrolled after patients disease progression BEP / / (94 %) (21 %) (1.4%) (4 %) EP / I (95 %) (4 %) (5.6%) (10%) p=o.15 p=o.31 p=o. 11 p=0.28 * scan, marker, histology E = etoposide P = cis-platin B = bleomycin Table 12 *EP us. BEP in low risk metastatic testicular teratoma. (Stoter et al. (61)) Treatment Neutropenia Thrombo- Skin Toxicity (<2500) cytopenia (<76000) BEP 49 % 31 % 36 % EP 28 % 19 % 4% *E = etoposide P = cis-platin B = bleornycin Table 13 Development of more effective chemotherapy for high risk testicular non-seminoma Dose escalation Rapid cycling of drugs Multiple drugs New drugs update of this experience, in 47 patients there were 2 relapses and 3 patients had histologically positive resected nodes. All 5 were salvaged with cisplatin containing chemotherapy and there have been no cancer deaths (Horwich. personal communication). High risk patients. Several approaches, directed at improving treatment results in high risk patients, are being explored. These fall into 4 main categories: the use of multi-drug combinations, regimens employing existing drugs in higher doses, the investigation of new drugs, and approaches employing known drugs in more rapidly cycled schedules (Table 13). The first approach has been emplored at the Memorial Hospital (VAB 6) (67), and the Charing Cross Hospital (POMB-ACE) (33, 34). In the latter report 14/16 had liver involvement at presentation and 6/7 patients had brain metastases. The overall survival rate for patients treated between 1979 and 1985 was 89% and for the 100 patients who had not received radiotherapy, 92%. High dose cisplatin therapy has been explored (37). Cisplatin was employed at twice the usual dose and administered with hypertonic saline to minimise the risk of nephrotoxicity. Preliminary data from a trial comparing PVB with etoposide, vinblastine, bleomycin and high dose cisplatin in high risk patients, suggested an advantage for the high dose regimen. However, the latter regimen contained etoposide in addition to high dose cisplatin so that interpretation of the results is difficult. Encouraging results in high risk patients using a rapid cycling regimen have also been reported by WETTLAUFER et al. (69). Of 6 patients with liver involvement or central nervous system metastases, 5 were disease-free with a minimum follow-up of 18 months. The latter series of patients was treated with bleomycin, vincristine and cisplatin employing a weekly schedule which during the first 4 weeks involved alternating 5-day cisplatin infusions with 5-day bleomycin infusions. A similar schedule has been employed at the Royal Marsden Hospital and preliminary results are encouraging. Twenty-nine high risk patients with metastatic testicular teratoma received such rapidly cycled chemotherapy; 27 of these were evaluable with a follow-up of 5-27 months (medium 18) and 90% have remained continuously relapse-free (A. Horwich, personal communication). Fortunately only a small proportion of patients fall into the high risk category and even this number is reducing due to increasing patient and physician awareness of the importance of early diagnosis. Use of markers in the management. The serum tumour markers alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG) are of proven value in the diagnosis and management of non-seminomatous germ cell tumours, one or both of these markers being elevated in approximately 80 % of patients with metastatic disease. Alphafetoprotein has a molecular weight of and is the major serum protein of the human foetus. It has been found in the serum of patients with hepatocellular carcinoma and subsequently in a high percentage of patients with testicular teratoma.

13 450 MICHAEL PECKHAM Human chorionic gonadotrophin is a hormone of molecular weight secreted by the syncytiotrophoblastic cells of the normal placenta, It contains 2 dissimilar subunits designated alpha and beta. The amino acid sequence of the alpha sub-unit is very similar to that of some other human glycoprotein hormones, such as luteinising hormone. However, differences in amino acid sequences of the beta chains confer specificity. A radioimmunoassay has been developed which is specific for the beta chain of HCG. Raised serum levels of this marker occur in gestational trophoblastic tumours and a high proportion of germ cell tumours. As indicated above, raised serum levels of AFP and/or HCG prior to orchiectomy (approximately 80% of stage I patients) are not per se prognostic indicators. Thus in the surveillance study, patients with elevated serum AFP and/ or HCG levels prior to removal of the primary turnour appear to show a similar natural history to those with normal serum marker levels. However, the rate at which the serum marker concentration diminishes is extremely important. The rate of clearance of markers from the serum of patients can be expressed in terms of the apparent half-life (AHL). Metabolic studies, supported by marker analysis following orchiectomy in stage I disease, have demonstrated an AHL of 4 to 6 days for AFP and 1 to 2 days for HCG. Protracted or incomplete clearance after orchiectomy in surveillance patients is strongly suggestive of the presence of occult metastases. In patients with proven metastatic tumour, serum marker concentration and tumour volume are independent prognostic variables. In the surveillance of stage I patients and monitoring treatment outcome in advanced disease serum AFP and HCG are invaluable markers. However, it is important to realise that patients who have had raised markers initially may relapse without showing raised levels of either marker. Conversely, initially marker negative patients may show elevated serum AFP and/or HCG concentrations at relapse The rate of fall of AFP and HCG during chemotherapy has been investigated in a study of 90 patients treated with cisplatinum-containing chemotherapy (17). Rates of fall slower than 4 to 6 days for AFP and 1 to 2 days for HCG may well reflect balance between marker clearance and marker production by viable tumour cells and thus the AHL following chemotherapy may be an index of the success of treatment. The study analysed the prognostic significance of the initial rate and subsequent pattern of fall of AFP and HCG following chemotherapy. The rate of fall of serum tumour markers in response to the first course of chemotherapy was assessed by comparing the level on day 21 with the level before chemotherapy on day 1 and expressing the rate of fall in terms of the apparent half-life in days. It was found that all 3 patients with initial AFP half-lives greater than 9 days relapsed; however, a further 9 relapsing patients had an initial regression rate of Table 14 Resection of residual masses ajier chemotherapy for advunced testicular cancer Histology No. of Alive Relapsed Dead pats. Fibrosishecrosis (9%) 2 Differentiated teratoma (16%) 9 Residual Cancer (59%) 15 Unpublished data from W. F. Hendry (The Royal Marsden Hospital) serum AFP within the same range as patients remaining in remission (half-lives 6-9 days). The HCG regression rate did not discriminate between patients remaining well or those who relapsed after chemotherapy. In 11 examples of a pattern of slowing of the rate of marker fall (i.e. increasing half-time), 5 relapses were seen (45%), though this pattern was also observed in the context of large residual differentiated teratoma masses. From this study it was concluded that with known effective chemotherapy regimens and previously untreated patients the initial rate of tumour marker fall only rarely had prognostic significance but that an increasing marker AHL was an early indicator of relapse in 5/11 instances where this pattern was seen. In patients being considered for surgical excision of residual masses after chemotherapy, raised serum marker levels are of serious prognostic significance and the majority of patients in this category are not salvaged. For this reason every attempt should be made to secure normalisation of AFP and HCG levels prior to exploration. On the other hand normal marker levels do not metin that resected tissue is invariably benign histologically. Surgical excision of residual masses following chemotherapy. Approximately 25 % of patients receiving chemotherapy for metastatic testicular non-seminomatous tumours require surgery for the excision of residual masses from the para-aortic region, chest or neck (13). As shown in Table 14, in approximately 50% of cases the excised tissue shows differentiated, mature teratoma with no evidence of undifferentiated malignancy. In the remainder, the appearances show either necrosis and fibrosis or residual cancer. Prognosis is good following the excision of masses which are necrotic or fibrotic or which show mature teratoma although it should be noted that approximately 20% of patients with apparently mature somatic tissues subsequently relapse. More than 50% of patients with residual cancer will develop further evidence of disease unless there is scope for delivering further and effective chemotherapy. As shown in Table 15, if serum AFP and/or HCG concentrations are raised at the time of surgery then the risk of subsequent relapse is high. Furthermore, if masses are incompletely excised or excised with difficulty, the risk of

14 TESTICULAR CANCER 45 1 Table 15 Resection of residual masses after chemotherapy for advanced testicular cancer. Influence of markers status at time of surgery Histology Relapse/total patients Markers normal Markers raised Fibrosidnecrosis 2/30 (7%) 1/4 (25%) Differentiated teratoma 9/72 (13%) 417 (57%) Residual cancer 5/12 (42%) 11/15 (73%) Unpublished data from W. F. Hendry (The Royal Marsden Hospital) Table 16 Resection of residual masses after chemotherapy for advanced testicular cancer. Influence of extent of surgery Histology Relapse totaupatients Complete Difficult Incomplete Fibrosishecrosis 0/28 (0%) 3/6 (50%) - Differentiated teratoma 7/68 (10 %) 2/7 (29%) 4/4 (100%) Residual cancer 8/21 (38%) 3/3 (100%) 3/3 (100%) Overall 15/117 (13%) 8/16 (50%) 7/7 (100%) Unpublished data from W. F. Hendry (The Royal Marsden Hospital) subsequent relapse is higher than in patients where a complete excision has been achieved. As shown in Table 16, if resection is difficult or judged incomplete, the risk of relapse is higher. If a bilateral node resection is carried out, the risk of subsequent loss of ejaculation is higher than is the case if a unilateral resection is carried out. (43 % compared to 9 %). The reasons why the excision of residual masses is advocated, are 3-fold. Firstly, it is not possible to be sure that all tumour tissue has been eradicated by chemotherapy and histological confirmation of the presence of residual cancer is an indication for further therapy. Secondly, the observation that the relapse rate is lower in patients who have a complete excision of residual disease, compared with those who have an incomplete excision, or an excision achieved with difficulty, suggests that surgery itself contributes to cure. Thirdly, masses of differentiated teratoma frequently become cystic; these fluid-filled cyst cavities may progressively enlarge and cause problems as space-occupying lesions. The appearance of mature teratoma is of considerable interest since it raises the possibility that chemotherapy may promote differentiation. Differentiated teratoma may contain connective tissue, cartilage, smooth muscle, bone, nervous tissue, mucus secreting epithelium, squamous epithelium, ciliated epithelium and fat. Endocrine cells associated with gastrointestinal epithelium have been described including enterochrornaffin cells; somatostatin, glucagon and pancreatic polypeptide immuno-reactive cells have also been identified as well as intestinal types of APUD cells (63). It has long been known that regression with spontaneous maturation of primary testicular tumours may occur. The phenomenon of change towards a more benign state in testicular tumour metastases has long been recognised and numerous reports describe differentiated teratoma metastases excised after chemotherapy and/or radiotherapy. However, whereas prior to recent developments in chemotherapy, evolution towards morphological differentiation was uncommon, it is now a well recognised feature. Approximately 75 % of patients from whom differentiated masses are excised after chemotherapy, have evidence of differentiation in the primary tumour initially (malignant teratoma intermediate or teratocarcinoma). Oosterhuis et al. (35) have presented data indicating a progressive increase in the proportion of patients with mature teratoma as chemotherapy has become more effective; however, this increase is largely confined to patients who have teratocarcinoma primary tumours. Induction of complete differentiation leading to mature end cells has obvious attractions as a therapeutic manoeuvre in germ cell tumours. On presently available evidence, we cannot exclude the possibility that differentiation is treatment-induced, however the data can equally well be interpreted to indicate that chemotherapy eradicates undifferentiated tumour leaving pre-existing differentiated elements in situ. Fertility after chemotherapy Fertility may be grossly impaired in patients presenting with testicular tumours; normal sperm counts (>10x106/ml) were observed in only 22% of 54 patients with seminomas, and 29% of 154 patients with teratomas or mixed tumours, presenting to the Royal Marsden Hospital between 1976 and 1983 (14). Similar observations have been made by Bracken & Smith (13), Jewett et al. (22) and Berthelsen & Skakkebaek (2). Interestingly, low sperm counts are observed in men who have previously fathered children, suggesting that depression of spermatogenesis is an acquired phenomenon accompanying the development of the tumour. We have previously documented recovery of sperm count following chemotherapy (14) and in a longitudinal study of 43 men it was found that 14 regained normal sperm counts and 28 showed spermatozoa in the sperm with counts <20x 106/ml. In fact only 3/43 men remained azoospermic. Nine of these patients had fathered healthy children at the time of reporting and of these, 8 were oligospermic and only 1 normospermic at the time of conception. In a recent analysis, 25 children fathered by men successfully treated with chemotherapy for testicular cancer were examined together with control children fathered by men in the community or stage I testicular cancer patients

15 45 2 MICHAEL PECKHAM on surveillance (57). The proportion of malformations in children in the chemotherapy group did not differ from that in children in the control group, or from incidence rates for malformations in the general population. A national study is in progress to enable larger numbers of children to be examined to exclude the risk of malformation with more confidence. Psychosocial problems There is scanty information on the psychosocial problems provoked by a diagnosis of testicular cancer and subsequent management. Since these once lethal tumours occur in young men, often with family responsibilities and at a critical stage in the evolution of their careers, it is not surprising that there is a significant psychosocial morbidity which is often missed by the busy clinician focussing on the physical aspects of the patient s illness. 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