Search

We retrospectively analyzed the outcome of 67 patients with breast (n=24), ovarian (n=11) or testicular cancer (n=32) treated for relapse after high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) transplantation. Treatment, survival and toxicity were analyzed. Patients with breast, ovarian or testicular cancer received a mean of 5.9 (range 1-24), 5.1 (1-13) and 4.6 (1-13) regimens for relapse after HDC. Overall response at the end of the observation period was 20.8% for patients with breast cancer (three complete (CR) and two partial responses (PR)), 45.5% (one CR, four PR) for ovarian and 9.4% (three PR) for testicular cancer patients. The mean overall-survival (OAS) from first relapse was 28 (range 3-44), 17 (2-24) and 10 (1-28) months, respectively. Leukocytopenia grade 3/4 occurred in 27-63% of patients, and thrombocytopenia grade 3/4 was observed in 58-88%, respectively. Nonhematological grade 3/4 toxicities were below 20%. In conclusion, patients with relapse after HDC usually have a poor outcome but long-term survivors are observed. Hematological toxicity is common, while other severe side effects are less frequent.

Background: Because of the increasing number of long-term survivors of metastatic testicular germ-cell cancer, a general concern has been secondary morbidities, especially cardiovascular risk factors., Patients and Methods: Thirty-two patients treated with cisplatin- and doxorubicin-containing chemotherapy > or = 13 years before the time of analyses were evaluated for neuro-, oto-, pulmonary-, vascular- and gonadal toxicity including evaluation of myocardial damage and cardiovascular risk factors and analysis of microcirculation., Results: Thirty percent of the patients showed abnormal left ventricle function. Elevated follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in 75% of patients were often associated with low testosterone levels. Elevated total cholesterol levels were found in 82% and higher triglyceride levels in 44% of patients, most of them were overweight. About 25% of the patients developed diastolic arterial hypertension after chemotherapy. Reduced hearing was confirmed in 23% of patients, especially at frequencies higher than 3000 Hz. Moreover, 53% of patients presented transient evoked otoacoustic emissions. In 38% of patients non-symptomatic neuropathy was detected, in 28% symptomatic neuropathy, and in 6% disabling polyneuropathy. In 80% of patients with neuropathic symptoms additional morphological and functional abnormalities were found by nailfold capillary videomicroscopy, compared to only 57% of the patients without neuropathic symptoms., Conclusions: Patients cured by cisplatin-based chemotherapy for metastatic testicular cancer have to be cognizant of their unfavorable cardiovascular risk profile, that might be a greater risk than developing a relapse or second malignancy.

To extend the results of conventional cytogenetic analysis of testicular germ cell tumors (TGCTs), we applied the new molecular cytogenetic method of comparative genomic hybridization (CGH), which enables the detection of chromosomal imbalances without the need for dividing cells. DNA from II TGCTs was studied by CGH. In all tumors examined, gain of 12p, mostly of the whole p arm, could be demonstrated. However, in three tumors, an amplification of 12p material restricted to the chromosomal bands 12p11.2-p12.1 was found. Further fluorescence in situ hybridization (FISH) analysis using a yeast artificial chromosome (YAC) that was previously mapped to that region revealed multiple copies of that chromosomal segment in interphase nuclei of these tumors. This finding is an important clue to the localization of candidate protooncogenes at 12p involved in TGCTs. Gains of small chromosomal regions at 2p, 4q, 6p, and 19p were also detected recurrently. Furthermore, gains of chromosomes 8, 14, 21, and X as well as loss of chromosome 13 were frequent findings. In conclusion, CGH provides new insights into genetic alterations of TGCTs. By using CGH, chromosomal subregions could be identified that may harbor genes involved in the pathogenesis of this malignancy.

The chemotherapy of disseminated testicular cancer is subject to continuous change and further improvement. Because of the high efficacy, with a curability over 90% for patients with good prognostic criteria, ongoing trials investigate how far the toxicity can be reduced without a negative impact on the cure rate. Besides the standard protocols for good risk (PEB x 3; PE x 4) the substitution of cisplatinum by carboplatinum (CEB) or bleomycin by vinblastine (VPV;CEV) is currently being tested in prospective randomized trials. In patients with poor prognostic criteria, e.g. advanced disease according to the Indiana classification, the cure rate is only 50-60% with standard PEB x 4. The substitution of bleomycin by ifosfamide (PEI) seems to improve this result significantly, whereas dose escalation of platinum to double dose alone is not effective. A major advance can be expected from the early introduction of very high dose chemotherapy, within the first weeks of induction chemotherapy either by administration of megadose chemotherapy as a single cycle or by administration of sequential intermediate-dose cycles, using haematopoietic growth factors and peripheral blood progenitor cells. These types of dose-intensive regimens will be compared with standard PEB or PEI in prospective randomized trials in poor risk nonseminomatous germ cell tumours in first-line treatment as well as for salvage chemotherapy. For seminoma, however, due to the high platinum sensitivity the possibility of a carboplatinum single-agent chemotherapy for good risk seminoma patients is currently being investigated in prospective trials. The development of these new treatment strategies needs even more intense cooperation and joint effort from specialists in urology, surgery, radiotherapy, haematology, and medical oncology.

Retroperitoneal lymphadenectomy was performed in 462 patients with testicular cancer. A total of 142 patients with advanced non-seminomatous germ cell tumours underwent retroperitoneal lymphadenectomy following cisplatin-based polychemotherapy. After inductive chemotherapy all of the patients described (108/142) showed seroconversion of tumour markers. Histology following RLA revealed vital tumour in 41% and teratoma in 12%. It was not possible to distinguish preoperatively between non-malignant residual tissue and vital tumour. In addition, sonography, computed tomography, and the tumour marker results did not correlate significantly with the intraoperative histopathological findings. Although histopathological confirmed complete remission was achieved in 47% of the patients with chemotherapy alone, subsequent retroperitoneal lymphadenectomy remains mandatory in cases with residual retroperitoneal lesions and pathological partial remission.

Thirty-four patients with stage IIC (unresectable, retroperitoneal tumor mass (RTM) greater than 5 cm), stage IVC (minimal lung metastases less than 10 cm3 and RTM greater than 5 cm) and IVD (lung metastases greater than 10 cm3 and RTM greater than 5 cm), who had not received previous chemotherapy, were treated with cisplatin (40 mg/m2, on days 2-4), ifosfamide (5 g/m2, on days 1 and 5) and bleomycin (30 mg, on days 1, 8, 15) (PIB), every 21 days. Twenty of the 34 patients (59%) achieved a complete remission (CR). Furthermore, five patients (15%) showed no evidence of disease (NED) after surgical removal of residual tumor masses (NED rate of 74%). A tumor marker-negative partial remission (PR) occurred in 3/34 patients (9%), and a tumor marker-positive PR in another 3/34 patients (9%). Three patients did not respond to this regimen. At a median follow-up period of 38 months (range, 15-47 months), 26/34 patients (76%) were alive, 21 (62%) of them without evidence of disease and three with a stable tumor marker-negative remission. Major toxicity consisted of myelosuppression, neurotoxicity and nephrotoxicity. Chemotherapy-related mortality occurred in two patients (one septicemia and one bleomycin-induced lung fibrosis). In conclusion, PIB is an effective induction regimen in patients with high-risk NSTC. However, controlled clinical trials are necessary to prove the superiority of dose intensification schedules.

We present the case of a 39-year-old man with Klinefelter's syndrome and a metastatic Leydig cell carcinoma in whom autonomous cortisol production induced by the interstitial cell tumor was found. Apart from the Cushing's syndrome the endocrine activity of the tumor was demonstrated by the secretion of estradiol, estrone, alkaline phosphatase, and testosterone. This is, to our knowledge, the first description of a Cushing's syndrome not caused via ACTH production but directly induced by ectopic steroid production. While being resistent to chemotherapy and radiation, the tumor responded favorably to treatment with o,p'-DDD. The reduction of tumor size was accompanied by a continuous decrease of serum markers. The etiology of the tumor is discussed in the light of the hormonal derangement caused by the genetic abnormality of Klinefelter's syndrome.

In a prospective study 18 patients with metastasizing testicular teratomas were treated with adriamycin, bleomycin and vincristin. Sixteen could be fully evaluated: 12 in stage IV (visceral metastases), three in stage III (lymphondular involvement beyond the diaphragm) and one with advanced stage II (iliac, para-aortic and inguinal nodes). None of the patients had previously received chemotherapy. Toxic side-effects were not severe enough to prevent 12 patients from being treated on an outpatient basis. Complete remission occurred in five, with four of them still in remission two, eight, ten and eleven months later. Partial remission (50% decrease in tumour size for at least four weeks) occurred in three, with one still improving. No change was noted for 11 months in a patient with advanced pulmonary disease. Progression under therapy occurred in seven patients and in some of them there was an initial response which did not, however, meet the criteria of partial remission. The therapeutic results as well as toxicity suggest that this regime is superior to actinomycin D montherapy and various previously used combinations.

cis-Diamino-dichloro-platinum (II) (DDP, NSC-119875) is an inorganic compound with cytostatic properties which have only recently been appreciated. DDP has an action which may tentatively be described as alkylating through some, as yet unknown, metabolic product. In a phase I study the effectiveness against testicular neoplasma had been established. A prospective trial was, therefore, conducted to test the drug's efficiency in patients with disseminated non-seminomatous testicular cancer refractory to all previously used combinations of chemotherapy. In a group of 22 patients the results were: 1 CR, 14 PR, 2 NC, and 5 PD. Because of these results, DDP was made part of an induction regime for disseminated and non-seminomatous testicular tumors.

Between 1974 and 1979 a total of 344 patients with testicular teratomas were treated at the West German Tumor Center, Essen. Brain metastases were encountered in 16 patients by means of neurologic symptoms as well as scintigraphy and computerized tomography. Cerebral involvement was closely related to preexistent lung metastases (n = 162) and the risk appeared to increase with the duration of pulmonal disease amounting to about 10% (16/162) in this group. Radiotherapy was the treatment of choice and produced objective and subjective improvement in 13 of 16 cases. Thus, long-term prognosis of patients with brain metastases was mainly determined by the preexistent metastatic involvement of the lungs.

The efficacy of ifosfamide combination chemotherapy was studied in 164 patients, 94 with advanced testicular carcinoma and 70 with metastatic sarcoma. Ifosfamide was given at 40-60 mg/kg/day i.v. on five consecutive days every 3-4 weeks together with mesna prophylaxis with 8 mg/kg i.v. being used at 0, 4 and 8 h after ifosfamide administration. Of 70 sarcoma patients 57 were evaluable for response, of whom 49 had received prior chemotherapy. The overall response rate was 46% (26/57) including 3 complete (CR) and 14 partial remissions (PR). Ninety-four patients with germ cell tumours of the testis were treated. Of 16 seminoma patients 15 achieved CR or PR. Seventy-eight patients with nonseminomatous testicular cancer who had received previous chemotherapy were either treated with ifosfamide/etoposide (n = 63, remission rate: 30%) or ifosfamide/cisplatin (n = 15, CR + PR: 33%). These results indicate that ifosfamide alone or in combination is active in sarcomas, seminomas and teratomas and that further studies are warranted employing the drug in first-line regimens.

Following orchiectomy and retroperitoneal lymph node dissection (RND) 140 patients with stage II non-seminomatous testicular cancer were treated by sequential combination chemotherapy consisting of vinblastine/bleomycin and adriamycin/cis-dichlorodiammineplatinum(II) (DDP), plus/minus radiotherapy. 68 stage IIA-patients (complete RND and normal tumor-markers thereafter) received 6 courses of chemotherapy, followed by radiotherapy in 35 patients. 40 stage IIB-patients (minor residual disease after RND or elevated tumor-markers after RND) and 32 stage IIC-patients (advanced residual disease after RND) were treated by at least 12 chemotherapy courses and optional intermittent radiotherapy and/or relaparotomy. In stage IIA and IIB disease the actuarial 4-year survival rates were between 80 and 100%. These favourable results were not significantly influenced by additional radiotherapy and corresponded to the survival rates for 34 stage I-patients. For stage IIC-patients the prognosis was significantly worse with a 12% 4-year survival rate.

Based on combination chemotherapy with vinblastine, bleomycin, cisplatin, ifosfamide, etoposide and adriamycin--these appear to be the most active agents--complete remissions between 60 and 70% of all patients with disseminated testicular teratomas appear realistic. Extent of disease, distribution and localization of metastases, patterns of specific markers such as alpha fetoprotein and beta-HCG, and the general condition of the patient at initiation of therapy determine the final prognosis. It appears most important that induction chemotherapy needs to be as intensive as possible: individualized doses and short intervals should be used initially despite some toxicity associated with this approach. In regional disease, four to six courses of adjuvant chemotherapy after lymphadenectomy have yielded cure rates as high as 95% (Stage II A) and 70% (Stage II B), respectively.

Forty-two patients with disseminated nonseminomatous testicular cancer were randomly entered to receive a two-armed chemotherapy regimen with mandatory crossover, consisting of either vinblastine-bleomycin or doxorubicin-cis-dichlorodiammineplatinum(II) (DDP) as initial therapy. Forty of these patients received at least four courses and were considered evaluable. Twenty-five of these patients received vinblastine-bleomycin and 15 received doxorubicin-DDP as initial treatment. The overall remission rate was 88%, with a complete remission rate of 68%. Thirty-two patients remain alive and 20 (50%) remain disease-free at 3+ to 18+ months, with a median duration of complete remissions of 9+ months. The response rate was not affected by prior chemotherapy or radiotherapy. Either treatment arm proved equally effective. However, response with doxorubicin-DDP therapy occurred in nine of 19 treatment courses when vinblastine-bleomycin therapy had failed, while response with vinblastine-bleomycin therapy occurred in only two of 11 treatment courses when doxorubicin-DDP therapy had failed. Thus, different patterns of cross-resistance between these alternative regimens may exist.

In early stages of the disease the prognosis of testicular cancer has been improved mainly by the introduction of radical surgical procedures. Cytostatic treatment of metastasising testicular cancers has only been of limited value. Actinomycin D has been shown to be one of the most potent agents in malignant teratomas. Own results are presented for 21 eligible patients who received actinomycin D alone. One complete remission and 4-partial remissions were achieved giving an overall response rate of 19%. This precentage seems to be low compared to similar data in the current literature. The result may be explained by the selection of the patients with a high percentage showing far advanced disease before therapy was initiated. However, comparing the data presented with those from our own study on combination chemotherapy and with the more recent results in the literature, single agent chemotherapy does not seem to be the method of choice in metastasising testicular cancer. Improvement of the results by the integration of combination chemotherapy, hormonal therapy and irradiation will have to be based on prospective, controlled studies.

Sequential chemotherapy with vinblastin and bleomycin, as well as adriamycin and cis-platin, was administered to 29 patients with disseminated malignant testicular teratoma. In order to intensify the induction phase, the intervals between drug administrations were individually shortened, with the next course of treatment following directly after the phase of critical leucocyte depression. This method was pursued over four courses of chemotherapy without dose reduction, followed by courses of chemotherapy in a conventional three-weekly rhythm. A response was obtained in 28 patients, 18 of them achieving complete remission. Taking into consideration unfavourable prognostic factors in the treatment group, this result is better than after the same chemotherapy at three-weekly intervals. Induction treatment adapted to leucocyte response carries with it the risk of higher toxicity, but this would seem to be acceptable in view of the improved long-term prognosis. This or similar intensification of the first treatment phase, for a long time used with leukaemias, could also be considered in the management of various chemotherapy-sensitive solid tumours, especially in younger patients.

Response to chemotherapy and survival was retrospectively analyzed in 28 patients with bulky retroperitoneal and disseminated seminoma treated between 1977 and 1983. The median age was 41 years (range: 23-52). All patients had histological evidence of pure testicular seminoma, however, 14 patients revealed moderate increases of human beta-chorionic gonadotropin levels. Prior radiotherapy had been given to 9/28 (32%) patients. Treatment consisted of at least four courses of simultaneous or sequentially alternating therapy with cisplatin, vinblastine, bleomycin plus/minus adriamycin (PVB +/- A), administration of ifosfamide or combination therapy with ifosfamide/cisplatin (IFS/DDP) or ifosfamide/etoposide (IFS/ETP). Twenty-five of 28 patients (89%) achieved a complete (CR), and 3/28 patients a partial remission. Relapse occurred in 1/8 CR patients after adjuvant postchemotherapeutic irradiation, and in 1/11 patients without any further radiotherapy. So far, 23/28 patients (82%) are free of disease after a median follow-up of 28+ (14+----82+) months. Marked myelosuppression was observed in previously irradiated patients, mainly after PVB +/- A therapy. In two patients, transient nephrotoxicity developed after PVB and IFS/DDP, respectively. After PVB +/- A chemotherapy, three patients revealed polyneuropathy, paralytic subileus and bleomycin-induced pneumonitis, respectively. In conclusion, the present series suggests a high probability of continuous CR in even bulky retroperitoneal and widespread metastatic seminoma. So far, no definite conclusions can be made on the therapeutic superiority of one of the different chemotherapeutic regimens used. However, this preliminary experience suggests that the combination of ifosfamide and etoposide or cisplatin may prove less toxic than sequentially alternating or simultaneous PVB +/- A chemotherapy.

The value of sequential alternating chemotherapy was analyzed retrospectively in 180 patients with disseminated, non-seminomatous testicular cancer. Response rates of adriamycin/cisplatin--(combination A) and bleomycin/vinblastine (combination B)--combination chemotherapy were evaluated separately with respect to tumor histology and tumor stages. Tumor response was achieved in 151 of 180 patients (84%) who were evaluable for adriamycin/cisplatin chemotherapy. Out of those, 91 of 117 patients (78%) pretreated with combination B and 60 of 63 patients (95%) without prior chemotherapy responded. Irrespective of pretreatment tumor response was observed in 131 of 157 patients (84%) evaluable for treatment with bleomycin/vinblastine. Resistance to combination A was 2.5 fold higher in embryonal carcinomas (class II of Dixon and Moore) than in choriocarcinomas (class V). Bleomycin/vinblastine-therapy failed more frequently in choriocarcinomas as compared to other histological categories (22% vs. 14%). This report also includes an analysis of treatment failures in different tumor stages. Both regimens were more frequently ineffective in tumor stages with a large tumor burden (stages II C and IV D). Patterns of cross-resistance were evaluated for both regimens. Response to adriamycin/cisplatin occurred in 18/26 patients (69%), when combination B had failed, and response to bleomycin/vinblastine was achieved in 14/24 patients (58%) when adriamycin/cisplatin had failed. In patients not responding to either regimen the treatment failure was already recognized after the first chemotherapeutic course in 93% of these cases.

74 patients with disseminated non-seminomatous testicular cancer were randomly entered on a prospective sequential combination chemotherapy regimen with mandatory crossover, consisting of either vinblastine/bleomycin or adriamycin/cis-dichlorodiammineplatinum (II) (DDP) as initial therapy. Independent of the randomization the overall remission rate in 71 evaluable patients was 89% including 54% complete remissions. 35% of the patients remained disease-free at 2+ to 28+ months with a median of 12 months. By additional surgical removal of residual pulmonary metastases in two patients the complete remission rate was increased to 40/71 (56%), and the number of patients with no evidence of disease to 27/71 (38%). According to the life-table method the two-years survival rates were 63% for complete responders and 29% for all other patients, which was significantly lower. 53 patients (75%) were alive at 3 to 28 months with a median of 9 months. Additional advanced abdominal disease, initially elevated beta-HCG and LDH and extension of pulmonary disease were of significant negative influence on the prognosis. The evaluation of single chemotherapy courses revealed equal efficacy of both combinations. However, response to adriamycin/DDP occurred in 46% of the courses, when vinblastine/bleomycin had failed, while response to vinblastine/bleomycin occurred only in 21% of the courses when adriamycin/DDP had failed. Thus different patterns of cross-resistance between these alternative regimens may exist.

Copyright of Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)