Serum tumour marker regression rate following chemotherapy for malignant teratoma

The rate of fall of the serum tumour markers alphafetoprotein (AFP) and the beta sub-unit of human chorionic gonadotrophin (HCG) was analysed following platinum-based chemotherapy for metastatic non-seminomatous germ cell tumours. Of 90 evaluable patients 81% were alive and disease-free 1.5–4 yr (median 28 months) from the start of chemotherapy and 69 (77%) had remained continuously disease free. All three patients with an initial AFP half-life greater than 9 days relapsed; however, a further eight relapsing patients had an initial regression rate of serum AFP within the same range as patients remaining in remission (half-life 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 late slowing of the rate of marker fall (i.e. increasing half-life), five relapses were seen (45%), though this pattern was also observed in the context of large residual differentiated teratoma masses.     

Primary malignant mediastinal germ cell tumours: A literature review and a study of 18 cases

From 1957 to 1992, 18 cases of primary mediastinal germ cell tumours were referred to the Peter MacCallum Cancer Institute (PMCI). Six were seminomas, six were mixed germ cell tumours, two were embryonal cell carcinomas, three were teratocarcinomas and one was labelled an ‘anaplastic germ cell tumour’. Two of the 18 patients were female. For seminomas, surgical (and in one case chemotherapeutic) debulking, followed by radiotherapy produced the best results. Mediastinal doses ranged from 30 to 40 Gy. Local control was achieved in those patients receiving mediastinal radiotherapy. Four patients currently survive disease-free. The non-seminomatous germ cell tumours showed a significantly poorer survival, and only two of 12 patients remain alive in remission at 110 and 130 months after diagnosis. Survival has been updated as of November 1997. Attention is focused on the anterior position of the primary germ cell tumours in the mediastinum. A review of the literature up to and including 1997 is presented.     

Cytogenetics, ploidy and differentiation of human testicular, ovarian and extragonadal germ cell tumours

Data from cytogenetics of testicular, ovarian and extragonadal germ cell tumours indicate that the group of germ cell tumours for which Skakkebaek proposed the name gonocytoma (seminoma, dysgerminoma and germinoma) is characterized by the presence of isochromosome 12p. The (dysplastic) gonocytes from which these tumours are derived are prone to polyploidization, especially in the gonads. There is evidence that non-seminomatous germ cell tumours in the testis may evolve through a (subclinical?) gonocytoma stage by loss of chromosomes. Since gonocytomas have already acquired the i(12p) marker, evolution of non-seminomatous germ cell tumours from gonocytomas would explain the presence of i(12p) in non-seminomatous germ cell tumours of the adult testis. A similar evolution may account for the presence of i(12p) in testicular type non-seminomatous germ cell tumours occurring in the ovary and extragonadally.     

Prediction of relapse after lymph node dissection for germ cell tumours: can salvage chemotherapy be avoided?

Salvage chemotherapy has been used by some oncology centres for patients with residual malignant or immature elements in retroperitoneal lymph node dissections removed for metastatic non-seminomatous germ cell tumours. However, surveillance of these patients shows that many are cured by surgery alone. 118 retroperitoneal lymph node dissections for metastatic non-seminomatous germ cell tumours were reviewed and the morphology seen within them was quantified. 28 of these had immature or malignant elements and had been treated by surveillance before administration of further chemotherapy. The proliferation rate in these cases was assessed by immunochemistry. The proliferation index and the amount of embryonal carcinoma (EC) were both predictors of recurrence and therefore the need for further chemotherapy. Patients with greater than 25% of EC had an 84% chance of relapse and those with a Ki-67 index of greater than 50% had a 71% chance of relapse. The two tests had a positive predictive value of 83% and 71%, respectively. Patients with such a high risk of recurrence could be considered for post-operative adjuvant therapy at this point whilst others would be suitable for a watchful waiting approach.     

Single agent activity of carboplatin in patients with previously untreated non-seminomatous germ cell tumours.

The response to a single course of carboplatin has been investigated in 12 patients with previously untreated non-seminomatous testicular germ cell tumours. Patients received one course of carboplatin at a dose calculated to achieve a target area under the free carboplatin plasma concentration versus time curve (AUC) of 7 mg/ml x mins using the formula: dose (mgs) = target AUC x (GFR + 25). Response to carboplatin was assessed after a single course and treatment was then continued on the POMB/ACE schedule. Ten of 12 patients had either a greater than 50% decrease in serum HCG and/or AFP levels or a greater than 50% decrease in tumour volume after a single course of carboplatin. No patient had evidence of disease progression after carboplatin. This study demonstrates that single agent carboplatin is highly active in patients with non-seminomatous testicular germ cell tumours and thus provides evidence to justify its inclusion in chemotherapy combinations.     

An analysis of surveillance for stage I combined teratoma--seminoma of the testis.

We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance (530 in total) post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma (P = 0.01, log-rank test, chi-square test P = 0.001). The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome.     

Germ cell tumours in uncorrected cryptorchid testis at Institute Rotary Cancer Hospital, New Delhi.

Twenty-four out of 164 (14%) adult patients with primary germ cell tumours of testis seen over the last 6 years at the Institute Rotary Cancer Hospital (IRCH) of the All India Institute of Medical Sciences (AIIMS), New Delhi, were found to have cryptorchidism. Only one patient had undergone correction. As a result the testes were intra-abdominal in the vast majority, and patients presented late. Twenty-two patients presented with stage IIb or more advanced disease. Twelve patients had seminoma and the others had mixed or non-seminomatous germ cell tumour (NSGCT), i.e. 50% each. The earlier patients were managed by initial resection followed by radiation and/or chemotherapy. As experience grew the seven patients who presented late were given initial chemotherapy followed by resection in those with residual tumours. The probability of overall survival was 0.65 at 36 months and, was not significantly different from survival in 114 patients with tumours of normally descended testis. Early orchipexy facilitates the detection, but whether it reduces the incidence of tumours is controversial. Uncorrected cryptorchidism is now rarely seen in the West, but in India and many other developing countries tumours of uncorrected cryptorchid testes continue to be seen.     

BOP/VIP--a new platinum-intensive chemotherapy regimen for poor prognosis germ cell tumours.

Ninety-one patients with poor prognosis non-seminomatous germ cell tumours (NSGCT) were treated with an initial intensive chemotherapy schedule. Suitable patients fulfilled one or more of the following criteria: lymph node metastases greater than 10 cm diameter; liver, brain or bone metastases; serum HCG level greater than 50,000 IU/L; and extragonadal primary tumours. Treatment consisted of 3 cycles of bleomycin, vincristine and cisplatin (BOP) administered at 10 day intervals, followed by 3 cycles of etoposide, ifosfamide and cisplatin (VIP) at 21 day intervals. A total of 64 patients (70%) achieved a complete remission. This comprised 46 patients who received BOP/VIP only, and 18 patients who received additional chemotherapy after BOP/VIP. Of these 64 patients, 51 underwent complete surgical resection of residual masses, including 11 in whom there was evidence of teratoma with cellular atypia or non-germ cell cancer in the resected tissue. A further 9 patients had persisting unresected radiological masses in the presence of marker complete remission. The overall response rate was 80%. Currently 57 patients (63%) remain alive and free from disease progression. The median follow-up period is 90 weeks (range 24-206 weeks), with a 2 yr actuarial progression-free survival of 66% (95% c.i. 55-77%). Major toxicity was myelosuppression, occurring during the VIP arm of therapy, with a median nadir WBC of 1.1 x 10(9)/L and median platelet count of 51 x 10(9)/L. Other toxicity included peripheral neuropathy (WHO Grade 2 and 3 in 22%). We conclude that treatment results with the BOP/VIP schedule in this poor prognosis patient group are at least comparable with other schedules, and toxicity is manageable.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term follow-up of residual masses after chemotherapy in patients with non-seminomatous germ cell tumours

This retrospective study was undertaken to determine the outcome of patients with non-seminomatous germ cell tumour who achieved a serological complete response but who had residual radiologic abnormalities upon completion of primary platinum-based chemotherapy. This was an analysis of 76 consecutive patients treated at Mount Vernon Hospital between 1983 and 1997. The patients were placed into two groups based upon whether they had surgical resection (surgery group, 48 patients) or observation (observation group, 28 patients) of residual radiologic masses on completion of initial chemotherapy (to enter the surgery group, complete surgical resection must have been achieved). The primary end-points were progression-free and overall survival. The percentage of patients alive with median follow-up 66 months was 90% for the surgery group and 80% for the observation group (P = 0.53, not significant). The percentage of patients continuously disease-free was 70% in the surgery group and 80% in the observation group (P = 0.31, not significant). In the small sub-group of patients with differentiated teratoma (TD) in the primary lesion who were observed, there was no excess risk of relapse or death. Patients who achieve a serological complete response after primary chemotherapy, but are left with 相似文献   

Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer. the Indiana University experience

Two cycles of bleomycin, etoposide, and cisplatin (BEP) were evaluated as adjuvant chemotherapy for patients with pathological stage II non-seminomatous germ cell tumours. Between 1985 and 1995, 86 patients with pathological stage II non-seminomatous testicular cancer were treated with two cycles of BEP. At retroperitoneal lymph node dissection (RPLND) 49 patients (57%) had pathological stage II(A) (microscopic nodal metastases) and 37 (43%) had stage II(B) (gross nodal metastases). After RPLND, the patients received bleomycin, 30 units weekly for 8 weeks, etoposide (100 mg/m(2)) and cisplatin (20 mg/m(2)) each for 5 days every 28 days for two cycles as adjuvant chemotherapy. 4 patients were lost to follow-up. 10 patients (12%) developed granulocytopenic fever during their chemotherapy. Of the 82 evaluable patients all remained with no evidence of disease except for a single patient with a cervical nodal relapse of teratoma. This was resected and he remains disease free. Median follow-up has been 85 months (range: 42-173 months). In patients with fully resected stage II non-seminomatous germ cell tumour, two cycles of BEP were almost universally effective in preventing relapse.     

Improving the outcome of salvage treatment for non-seminomatous germ cell tumours (NSGCT)

Between 1991-96, 41 patients were treated in this unit for relapsed non-seminomatous germ cell tumours (NSGCT). Twenty-eight patients had raised markers at relapse: 17 required salvage chemotherapy and post-chemotherapy surgery, 11 only chemotherapy. In addition 9 patients received high dose chemotherapy. Overall 16/28 patients (57%) requiring chemotherapy remain alive, 14 (50%) disease free. Of the 17 patients treated with chemotherapy and surgery: 12 remain alive, 10 (59%) with no evaluable disease. Only 4/11 (36%) patients treated with chemotherapy alone remain alive, all in complete remission (CR). For relapse with raised markers, univariate analysis suggests that less than CR to induction therapy, resulting in the presence of residual disease is the most important predictor of poor outcome (P<0.001). All of the 13 patients relapsing with normal markers remain alive, having been primarily treated surgically. Overall these results indicate an improving outlook for relapsed NSGCT.     

Advanced seminoma: treatment with cis-platinum-based combination chemotherapy or carboplatin (JM8)

Between 1978 and 1983, 44 patients with advanced seminoma were treated with cis-platinum-based combination chemotherapy (39 patients) or with carboplatin (JM8), as a single agent (5 patients). Of the total group, 40 (90%) are alive and disease free. Two of the 4 patients who died relapsed as non-seminomatous germ-cell tumours. Results in previously untreated patients indicate that tumour volume is less important as a prognostic factor than in non-seminomas. Residual masses were present in almost 80% of patients 1 month after chemotherapy; such masses regress slowly and surgery is not indicated. Elective radiotherapy after chemotherapy appears to be inessential since relapse rates are comparable in irradiated (1/15) and unirradiated patients (1/16). Pretreatment serum HCG concentrations did not influence the outcome of chemotherapy. Preliminary results with JM8 suggest that it is an active single agent in the treatment of seminoma.     

Exceptional sensitivity of testicular germ cell tumour cell lines to the new anti-cancer agent, temozolomide.

Metastatic testicular germ cell tumours are cured in approximately 85% of patients using cisplatin-based combination chemotherapy. Patients who fail to respond have a poor prognosis, and there is a need for more effective treatments for cisplatin-resistant disease. In this study, it is shown that two of four cell lines derived from human non-seminomatous testicular germ cell tumours are exceptionally sensitive to temozolomide, a new imidazotetrazine which can cross the blood-brain barrier in mice. In addition, three pairs of cisplatin-resistant sublines show little cross-resistance to temozolomide. These data suggest that temozolomide might have activity against non-seminomatous testicular germ cell tumours which have relapsed following cisplatin-containing chemotherapy, and could have a role in the treatment of patients with metastatic lesions in the brain.     

Multimodality treatment of malignant germ cell tumours of the mediastinum

Of 15 patients with malignant germ cell tumours of the mediastinum, 9 patients had pure seminomas and 6 had non-seminomas. Resection was radical in only 4 non-seminomas, 1 of which was resected after chemotherapy; radiotherapy was delivered to all seminoma patients as sole therapy (2 patients) or as part of combined modality therapy. All patients with non-seminomatous tumours underwent chemotherapy (cisplatin-based combination). Therapy was generally well tolerated, but 1 seminoma patient died of sepsis. Chemotherapy achieved a 71% complete response rate in pure seminoma patients and a 33% complete response rate in non-seminoma patients. 53% of patients are alive and free of disease beyond 36 months from start of any treatment. Pure seminoma patients survived longer than non-seminoma patients (3 and 5 year survivals were 67% and 33%, respectively). Although cisplatin-based chemotherapy is highly effective in pure seminomas and also in non-seminomas, a better therapeutic approach is needed in non-seminomas.     

Sequential resection of residual abdominal and thoracic masses after chemotherapy for metastatic non-seminomatous germ cell tumours.

Thirty-eight patients with advanced non-seminomatous germ cell tumours (NSGCTs) underwent multiple surgical interventions (two in 33 patients, three in four patients, four in one patient) after cisplatin-based chemotherapy. All patients had normal serum tumour markers but persistent radiographic masses. The larger mass was routinely resected first. Fifteen patients (39%) had dissimilar histological findings at sequential surgical procedures, 12 of whom demonstrated less favourable pathological features during the first operation and three at the second. Patients who underwent both retroperitoneal lymph node dissection (RPLND) and lung resection showed less favourable histological features in the retroperitoneum in nine cases and in the lung in three cases. Eight of 16 patients (50%) without mature teratoma in their primary tumours showed complete necrosis/fibrosis at all surgical interventions, whereas all patients whose primary tumour was classified as malignant teratoma intermediate demonstrated mature teratoma at least at one anatomical site. As histology of post-chemotherapy residual masses cannot be extrapolated from one anatomical site to another, patients usually are properly managed by excision of all residual masses. In particular, in patients with necrosis/fibrosis at lung resection omission of RPLND is not advised.     

Post-chemotherapy surgery in advanced non-seminomatous germ-cell testicular tumours: the significance of histology with particular reference to differentiated (mature) teratoma

Of a total of 307 patients treated with chemotherapy for advanced non-seminomatous germ-cell testicular tumours between 1976 and 1983, 73 (23.8%) had masses excised after treatment. Resected tissue showed residual malignancy in 16 (22%), fibrosis and necrosis in 25 (34%) and differentiated (mature teratoma) in 32 (44%). Of the 16 patients with tumour only 7 (44%) are alive and disease-free compared with 21/25 (84%) and 27/32 (84%) for fibrosis/necrosis and differentiated teratoma respectively. In addition to histological evidence of residual tumour, elevated serum markers at the time of surgery and/or incomplete excision of residual masses were adverse prognostic features. Of 12 patients with differentiated teratoma or fibrosis who had incomplete resections or densely adherent masses excised with difficulty, 7 subsequently relapsed. The majority of differentiated teratoma patients (75%) had evidence of differentiation in their primary tumours; 88% showed cystic change in metastases and almost one-third showed an increase in the size of metastases during chemotherapy. The data suggest that post-chemotherapy surgery may have a therapeutic as well as a diagnostic role and that complete excision of residual disease should be attempted even if resection at one site has shown either fibrosis or differentiated teratoma. The significance of these findings in relation to treatment induced differentiation is discussed.     

Platinum-based chemotherapy of primary extragonadal germ cell tumours: the Hellenic Cooperative Oncology Group experience.

Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the mediastinum and retroperitoneum and have variable responses to platinum-based chemotherapy. A retrospective analysis was performed on 38 patients with EGCT treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13 nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas). Initial surgery included complete resection in 1 patient, biopsy in 27 patients and debulking surgery in 10 patients. Complete response rates with chemotherapy +/- surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12-75% NSGCT, 6 of 9-66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9 of 11-81.81% NSGCT, 5 of 5-100% seminomas). One patient who underwent complete resection of a mediastinal malignant teratoma combined, received PVB chemotherapy on an adjuvant basis and remains alive and disease-free. Three additional seminoma patients who achieved partial response after chemotherapy remain alive and disease-free following mediastinal radiotherapy. All 14 patients with extragonadal seminomas remain alive with no evidence of disease at a median follow-up of 49 months (range 7-164), giving an overall survival of 100%. Nine of 13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a median follow-up of 43.5 months (range 7-152). Nine of 11 (81.81%) patients with retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56 months (range 14-110). Complete surgical resection of residual mass was undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4 patients. Patients who had viable malignant cells in the resected specimens received two more courses of VelP chemotherapy. None of our patients had relapsed at the time of this analysis. None of our 6 patients who underwent testicular biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of the testis were found to have testicular tumour or fibrotic scar. In conclusion, this retrospective analysis showed significant responses in patients with either mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based chemotherapy +/- surgery. All patients with extragonadal seminomas remain alive with no evidence of disease, regardless of the site at presentation.     

Malignant Ovarian Germ Cell Tumours: A Survival and Prognostic Analysis

The medical records and histopathology of all ovarian germ cell tumours (OGCT) in a tertiary centre between 1980 and 1996 were reviewed. Response, overall survival (OS), relapse-free survival (RFS) and prognostic factors were analysed. Sixty-seven patients with OGCT were identified and treated, including 33 dysgerminomas, 18 immature teratomas, 10 endodermal sinus tumours, and 6 mixed tumours. Fifty-three patients (79%) received conservative surgery, 24 (36%) had residual disease post-primary surgery, and 43 (64%) had chemotherapy. Complete response was achieved in 62 patients (93%), 4 out of 5 patients who relapsed were successfully salvaged; OS and RFS at 5 years were 89% and 76%, respectively. Advancing stage of disease was the only significant adverse prognostic factor (p=0.0001 for OS, and 0.0003 for RFS at 5 years). Out of 44 women with the potential to conceive following treatment, there were 16 successful pregnancies. None of the children born subsequent to the chemotherapy were reported to have any congenital abnormalities. The review indicates a high cure rate in OGCT with combined surgery and chemotherapy and that conservative surgery and preservation of fertility are feasible.     

Occurrence of malignant non-germ cell components in primary mediastinal germ cell tumours.

METHODS: Thirty-five patients with primary mediastinal germ cell tumours (PMGCT) underwent primary thoracotomy in a 30-year period (1965-1994). Of the 35 patients, 12 had benign teratomas, five pure seminomas and 18 non-seminomatous germ cell tumours. RESULTS: Out of 18 non-seminomatous germ cell tumours, 14 comprised more than one malignant component. In two cases malignant teratomas had an additional malignant non-germ cell component: one a mixed sarcomatous component and the other a neuroendocrinal component. There were different methods of treatment between 1965 and 1994. All but one of patients with seminomas survived for 5 years. Among 18 patients with malignant PMGCT, all but two died within 5 years (mean survival rate was 15 months). CONCLUSIONS: When planning treatment of patients with malignant PMGCT we have to take into account the fact that malignant non-germ-cell components may occur. In this circumstances, surgical resection after initial chemotherapy is recommended.     

Testicular Germ Cell Tumours in Denmark 1976-1980 Pathology of 1058 Consecutive Cases

In the first five-year period of the Danish Testicular Carcinoma Study (DATECA) 1058 consecutive testicular germ cell tumours were examined. Of these, 554 were seminomas comprising 515 of typical type, 26 anaplastic and 13 spermatocytic; 497 were non-seminomas comprising 145 pure tumours and 352 mixed tumours of various types. Among the various subtypes of non-seminomas embryonal carcinoma (EC) was recorded in 87 per cent, endodermal sinus tumour (yolk sac tumour; EST) in 22 per cent, teratoma (T) in 55 per cent and choriocarcinoma (CC) in 17 per cent. Only very few tumours were pure EST or pure CC. Five tumours were recorded as 'others or uncertain'. The tumours were graded with regard to various histologic features. Moderate and severe necrosis, bleeding, and a large number of mitoses were significantly more frequent in non-seminomas. The presence of tumour tissue at the resection margin was also more frequent in non-seminomas. Tumours with a largest diameter of less than 2.5 cm had already caused metastases in 16 per cent of the seminomas and 29 per cent of the non-seminomas. Increasing size of the tumours was associated with increasing frequency of metastatic disease but this association was not directly proportional. Distribution of the various histologic types according to the stage of disease varied. Thus, 78 per cent of the seminomas presented in stage 1 while 54 per cent of the non-seminomas had localized disease. Anaplastic seminomas were distributed similarly to the non-seminomas while all spermatocytic seminomas, with one exception, were recorded as stage I. Of non-seminomatous subtypes pure EC was associated with the highest frequency of stage III, followed by mixed tumours containing CC components. Although the present series is large the heterogeneity of germ cell tumours demands further investigation of larger numbers to confirm some of the findings.