Combination of radiation and PVB chemotherapy for intracranial malignant germ cell tumor

Intracranial malignant germ cell tumors such as embryonal carcinoma, endodermal sinus tumor, and choriocarcinoma are neoplasms of poor prognosis in the pediatric age group. Recently evidences of effectiveness of combination chemotherapy using cisplatin, vinblastine, and bleomycin (PVB therapy) have been reported. The authors experienced two cases with these tumors treated with radiation therapy and PVB therapy. PVB therapy was performed along with irradiation in hoping the effect of radiation sensitizer of cisplatin. Both patients showed no signs of tumor recurrence and no re-elevation of tumor makers even in the cerebrospinal fluid after more than ten months from the onset. Cisplatin has radiation sensitizing effect besides antitumor activity, but its permeability through the blood-CSF barrier is very poor. Also true is that germ cell tumors often disseminate in the cerebrospinal fluid. From these points, combination of irradiation and chemotherapy using cisplatin seems reasonable, though the superiority of this radiochemotherapy to simple PVB therapy can not be concluded from the present experience. Side effects of this combination therapy were the same as PVB therapy alone and tolerable.     

Early changes in serum alpha-fetoprotein after chemotherapy in advanced testicular tumors]

The serum levels of alpha-fetoprotein (AFP) are known to undergo acute changes (paradoxical elevation) after effective chemotherapies for testicular germ cell tumors. In order to understand the clinical significance, the changes of the serum AFP levels after PVB therapy for testicular germ cell tumors were analyzed, and their relationship to the treatment effects was investigated in this retrospective study. Thirty-one patients with testicular germ cell tumors (11 with stage I, 7 with stage II, and 13 with stage III) which had been treated by PVB therapy were evaluated. The measurement of the serum AFP levels was performed by radioimmunoassay on Day 1 (the initiation day of the PVB therapy), thereafter on Day 8 and Day 22. The half-life (t1/2) or doubling time (t2) of the serum AFP were calculated. In patients with stage I disease, the serum AFP levels declined nearly according to its biological half-life between Day 1 and Day 22 after termination of chemotherapy (t1/2 = 6.2 days). In patients with stage II or III disease, the changes of the serum AFP levels were not consistent with the treatment results between Day 1 and Day 8. Namely, complete responders revealed a prolonged decline of the serum AFP levels (t1/2 = 63.0 days), partial responders a transient rise of the serum AFP levels (t2 = 49.5 days) and non-responders a sudden rise of the serum AFP levels (t2 = 9.9 days). On the contrary, the serum AFP levels changed in accordance with the treatment effects between Day 8 and Day 22. Early changes of the serum AFP levels were seen in patients with stage II or III disease between Day 1 and Day 8 after chemotherapy. It was indicated that the measurements of the serum AFP levels during this period were not useful for the evaluation of the treatment effects in these patients. Furthermore, it was suggested that the early changes of the serum AFP levels possibly correlate with the poor response. The mechanism of the early changes of the serum AFP was also discussed.     

Chemotherapy of disseminated germ cell testicular tumors with cis-diamminedichloroplatinum and other drugs

The effect of single CDDP therapy and PVB therapy was examined in 7 cases of stage III germ cell testicular tumors with measurable metastases. The mean age of the patients was 30.6 years old, and their histological types of primary sites were seminoma in 3 cases, embryonal carcinoma in 2, immature teratoma in 1 case and embryonal carcinoma + teratoma in 1 case. In 1 case of seminoma, 375 mg of CDDP was administered. In 1 case of embryonal carcinoma + teratoma, 100 mg of CDDP and then 2 courses of PVB therapy were performed, and 3 courses of PVB therapy were given in all other cases. Three cases showed complete response, 2 cases partial response and 2 cases no change. Pulmonary metastatic nodules were extirpated after the PVB therapy in 1 of the cases showing no change, and the histological examination of these nodules was found to be mature teratoma. As a result, the effectiveness of the chemotherapy alone was 71.4%, and that of chemotherapy + surgical operation was 85.7%. Significance of intensive chemotherapy and necessity of extirpation of residual metastatic nodules after intensive chemotherapy in the management of advanced germ cell testicular tumors are stressed.     

BEP (bleomycin, etoposide, cisplatinum) chemotherapy as an induction therapy of advanced extragonadal germ cell tumor]

Five patients with advanced extragonadal germ cell tumor (EGGCT) were treated with cisplatinum + vinblastine + bleomycin (BVP) or cisplatinum + etoposide + bleomycin (BEP) chemotherapy as an induction therapy. All patients had high levels of tumor markers and multiple distant metastasis in poor nutritious conditions. Two patients given BVP therapy died 6 and 9 months after the chemotherapy. By contrast, three patients given BEP therapy achieved complete remission and were surviving longer than one year without any evidences of disease. Granulocytopenic fever was seen soon after the first course of BEP therapy. Prophylactic granulocyte-colony stimulating factor (G-CSF) treatment, enabled two of them to receive full dose chemotherapy without any fever attacks. In conclusion, BEP chemotherapy is effective to EGGCT as well as far advanced testicular tumors and G-CSF treatment is useful for achievement of induction chemotherapy to advanced germ cell tumors.     

Treatment of thymic tumor]

The treatment of thymoma, thymic cancer and thymic germ cell tumor was reviewed in the literature. The major treatment of thymoma is surgery with or without radiation. The chemotherapy for the thymoma is now investigated in the world. CDDP, ADM, VCR, CPA or BLM are usually used, but the most effective combination of these drugs is not known. Thymic cancer is a rarer and more malignant disease than thymoma. Though the postoperative treatment is investigated as well as thymoma, only a few successful cases by chemotherapy have been reported. Chemotherapy (PVB, VAB-6, PEB) for testicular germ cell tumor is also effective for thymic germ cell tumor including seminoma. Though the combination therapy of radiation and surgery has been popular, chemotherapy will be used more frequently for seminoma in future.     

Early and long-term toxicity in the management of advanced germ cell testicular tumors

47 patients with advanced germ cell testicular tumors were treated with combination chemotherapy, cis-platinum, vinblastine and bleomycin (PVB). All patients were reexamined on average 2.5 years after the end of treatment. Persistent mild long-term toxicity affecting the lungs, kidneys and peripheral nerve system was found in about one third of the patients. In addition, 32 patients who had received radiation therapy of seminoma were reexamined. Objective long-term toxicity was rare. However, possible damage to chromosomes and spermatogenesis has to be kept in mind.     

Brain metastasis from nonseminomatous germ cell tumors of the testis: case report and review of the role of surgery

The prognosis for patients with nonseminomatous germ cell tumor of the testis is good, even when extensive metastatic disease is present, because this tumor is very sensitive to chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). If a metastasis occurs in the brain, however, the prognosis is poor because the blood-brain barrier limits the entrance of these drugs into the brain and creates a sanctuary for tumor. The current treatment for a brain metastasis is either standard PVB chemotherapy plus whole brain radiation therapy or a rigorous chemotheraputic regimen that penetrates the blood-brain barrier better than PVB. Surgery is seldom used for brain metastasis, largely because of the poor results with surgical debulking in noncentral nervous system disease. This is the report of a patient with disseminated nonseminomatous germ cell tumor and multiple large brain metastases, who was treated with surgery, PVB, and whole brain radiation therapy and cured. Evidence is presented to support a role for surgical debulking in patients with large brain metastasis.     

A case of advanced seminoma treated effectively with single agent carboplatin therapy]

Cisplatin has played a major role in the treatment of germ cell tumors. However, it causes renal damage, severe nausea and vomiting. It is also neurotoxic and ototoxic. Carboplatin is an analog of cisplatin which, does not cause renal damage at therapeutic doses. It is not neurotoxic or ototoxic and it produces less gastrointestinal toxicity than cisplatin. We used carboplatin alone as an initial chemotherapy in a 36-year-old man with stage IIB seminoma. Following left radical orchiectomy the patient received 4 courses of carboplatin chemotherapy. After the first course of chemotherapy, tumor markers (LDH, beta-HCG) returned to the normal range. After 4 courses, the size of the retroperitoneal metastases was significantly reduced. The toxicity of 4 courses of carboplatin chemotherapy was generally milder than that of cisplatin-based combination chemotherapies such as PVB or VAB-6. There were no episodes of septicemia, thrombocytopenic bleeding or renal deterioration. The patient did not suffer from alopecia, neuropathy, symptomatic hearing loss, severe nausea or vomiting. Nine months after the completion of carboplatin chemotherapy, the patient remains well and free from disease progression. This case strongly suggests that single agent carboplatin therapy could be an effective and less-toxic treatment for advanced seminoma.     

Management of malignant pineal germ cell tumors with residual mature teratoma

OBJECTIVE: The treatment of intracranial mixed germ cell tumors presents a unique challenge, since eradication of malignant tumor by radiation and/or chemotherapy may spare the benign tumor component. We reviewed our surgical experience with residual malignant pineal germ cell tumors after neoadjuvant therapy. METHODS: Between 1987 and 1997, 16 patients with malignant intracranial germ cell tumors were treated at the Mayo Clinic with a protocol of neoadjuvant chemotherapy and radiation therapy. After the diagnosis was confirmed by histopathological examination, all patients were treated with four cycles of etoposide and cisplatin as well as external beam radiation therapy (range, 3030-5940 cGy). Six patients had an incomplete response to therapy, as demonstrated by observation of residual tumor on magnetic resonance imaging scans. Initial pathology in these six patients was germinoma in four and combinations of yolk sac tumor, embryonal carcinoma, malignant teratoma, and germinoma in two. Two patients had synchronous pineal and suprasellar tumors, with leptomeningeal dissemination. Tumor markers were elevated in four of the six patients at presentation. RESULTS: All patients with residual pineal tumors underwent surgical resection via an infratentorial, supracerebellar approach. Pathological examination revealed mature teratoma in five patients and amorphous debris in one patient. No patient had recurrent malignancy. Significant neurological morbidity occurred in one patient, with no mortality. At a mean follow-up of 23 months, no recurrence on magnetic resonance imaging has been documented. CONCLUSION: Residual pineal tumor occurring after treatment of malignant intracranial germ cell tumor with neoadjuvant therapy is likely to be mature teratoma. Operative resection of these benign recurrences is safe and effective.     

Five cases of primary intracranial germ cell tumor treated by combination chemotherapy with cisplatin

Five cases of non-germinoma germ cell tumor which received combination chemotherapy with cisplatin were studied to elucidate the efficacy of chemotherapy. The patients' ages ranged from 7 to 24 years old. Three of the patients were male and two were female. Locations of the tumors were suprasellar in three cases, pineal in one case and basal ganglia in the other. Three of the 5 tumors were histologically verified as yolk sac tumors, embryonal carcinoma and HCG_producing germinoma. Two were histologically unverified HCG-producing tumors. Following the reception of PVB therapy (cisplatin, vincristine and bleomycin) by all the patients, three of the HCG-producing tumors showed complete remission and two of AFP producing tumors demonstrated partial remission, and progressive healing process, respectively. Renal dysfunction in two case, leukopenia in two cases and lung fibrosis in one cae were noted as side effects. Two cases were treated only with cisplatin because ling fibrosis due to administration of bleomycin was intractable and harmful. Also the time when irradiation. It seemed better to administer chemotherapeutic agents prior to or during irradiation on account of the fact that, after radiotherapy, there is reduced blood flow in the tumor region. Also, CDDP acts as a radiosensitizer. Therefore, individual administration of cisplatin during irradiation was recommended for the initial chemotherapy against the case of non-germinoma germ cell tumors, in which an intractable side effect might be expected.     

Successful combination chemotherapy (cisplatinum, vinblastine, and bleomycin) in the treatment of medulloblastoma disseminated by cerebrospinal fluid: case report

A case of successful combination chemotherapy using cisplatinum, vinblastine, and bleomycin (PVB therapy) to treat medulloblastoma disseminated by cerebrospinal fluid is presented. In this case, a locally recurrent tumor and several disseminated tumors were seen to decrease in size on CT examinations. Pain in the lower extremities and urinary incontinence improved during three courses of PVB therapy administered during a period of 9 weeks. These results suggest that combination PVB therapy may offer one of the treatments of choice for recurrent or disseminated medulloblastoma.     

Cisplatin, Vincristine, Methotrexate, Peplomycin, Etoposide (COMPE) Therapy for Disseminated Germ Cell Testicular Tumors

Background The advent of cisplatin rendered disseminated testicular germ cell tumor an often curable malignant disease. Patients with a heavy metastatic burden, however, remain poor risks; furthermore, many patients experience nausea or other adverse events. This paper reports a trial of a cisplatin-based (COMPE) combination chemotherapy regimen based on synchronization theory.
Methods Twenty patients with disseminated germ cell testicular tumors were treated with COMPE; any residual tumor mass was surgically resected.
Results Seventeen patients (85%) achieved complete remission by chemotherapy. The actuarial overall and cause-specific 3-year survival rates were 89% and 94%, respectively. In the subset of 16 "good-risk" patients, all remain alive after a median follow-up of 43 months. Complications were quite tolerable, with nephrotoxicity in particular being extremely mild.
Conclusion COMPE is an effective chemotherapy regimen in patients with disseminated germ cell testicular tumors. Complications arising from this therapy are mild.     

A case of bilateral testicular tumor

A case of bilateral germ cell tumor of the testis is reported. In 1988, a 36-year-old male presented with painless swelling of left scrotal contents. Right orchiectomy and retroperitoneal lymph node dissection for embryonal carcinoma had been performed 5 years earlier. Left orchiectomy was performed and its histological finding was seminoma and embryonal carcinoma. Evaluations including CT scan and Ga scintigraphy revealed no metastasis. Postoperatively, the patient was treated with PVB therapy. Previous reports of bilateral germ cell testicular tumor were reviewed, and the age distribution, interval, and histological classification of these cases are discussed.     

Diagnosis,staging, and clinical characteristics of the patient with mediastinal germ cell carcinoma

When an anterior mediastinal mass is found in a young male patient, mediastinal germ cell tumors should always be one of the leading diagnostic considerations. The staging evaluation and diagnostic procedures should be performed rapidly. Every patient with a mediastinal germ cell tumor should be approached with curative intent, and appropriate treatment should be initiated as soon as the brief diagnostic procedure has been completed. Currently, treatment is curative in most patients (> 80%) with pure mediastinal seminoma, even in patients with huge mediastinal tumors and evidence of distant metastases. Although the cure rate is lower for patients with nonseminomatous germ cell tumors, the overall cure rate of 35% to 40% makes these tumors one of the most effectively treated advanced cancers. Further details regarding the treatment of mediastinal germ cell tumors are presented elsewhere in this issue.     

Further practical experiences in the recognition and management of carcinoma in situ of the testis.

99 biopsies from the contralateral testis in patients with unilateral germ cell tumor were investigated using the semithin section technique. Four cases (4%) revealed a carcinoma in situ (CIS) pattern. Two patients underwent a local radiation (20 Gy), 2 patients received combination chemotherapy (cisplatin, etoposide and bleomycin; PEB). No tumor cells were found in control biopsies 4-8 months after therapy. Both biopsy specimens taken from radiated patients lacked also germ cells. In contrast, 1 patient who was treated with PEB and also another 1 presenting with a teratocarcinoma of apparently retroperitoneal origin and unilateral CIS revealed germ cells after chemotherapy. The present data suggest radiation therapy to be the first line treatment for CIS-bearing testes. In order to get informations about the distribution of CIS cells in the affected testes, one or two biopsies were additionally taken from macroscopically unsuspicious tissue surrounding various solid germ cell tumors (74 patients). 56 cases (76%) revealed CIS. Even considering the possibility of missing CIS, a screening biopsy is actually the only method for detecting early manifestations of germ cell tumors and should be performed routinely in contralateral testes of patients with germ cell tumors.     

The future of therapy for nonseminomatous germ cell tumors

This article has reviewed recent advances in understanding the molecular mechanisms of germ cell transformation, germ cell tumor differentiation, and germ cell tumor chemotherapy sensitivity and resistance. Future developments should include the following: The use of high-throughput techniques to assess tumor biology and evaluate new markers will allow more sophisticated assessment of prognosis. Future therapy will use oligonucleotide chips, perhaps specific to germ cell tumors or gene products associated with drug resistance, to assign treatment (radiation, RPLND, chemotherapy). The pathways associated with metastases and resistance will either replace or amplify the current risk algorithms and the clinician's ability to select therapy. The same high-throughput techniques will identify critical molecules and pathways, providing new specific treatment targets. Cell cycle-specific targets are an ideal focus of study, because genes abrogating normal cell cycle control and promoting germ cell tumorigenesis are increasingly identified. In germ cell tumors, CCND2 and KIT are open to study. Molecular and genetic markers of differentiation are additional resistance markers and should be a focus of study. In this context, the treatment of malignant transformation and the prediction of teratoma at metastatic sites will take on a greater importance. Over the past 2 decades, the treatment of germ cell tumors has become well-defined. Further improvement requires that investigators find new markers corresponding to tumor phenotype. This achievement will prevent unnecessary treatment in patients destined to have a favorable outcome, and will target biologically unfavorable or resistant disease for new therapy developed specifically to target the molecular or genetic defects that disrupt normal cell cycle control.     

BEP (bleomycin, etoposide, cisplatin) therapy for testicular tumors]

We describe our experience with BEP (bleomycin, etoposide, cisplatin) therapy as chemotherapy for testicular tumors in 11 patients. Eight were non-seminomatous testicular cancer patients and 3 were seminoma patients. Three of 8 non-seminomatous testicular cancer patients had no evident metastasis and BEP therapy was performed for prophylaxis of recurrence. Other 5 non-seminomatous testicular cancer patients and 3 seminoma patients had metastatic lesions and BEP therapy was performed to cure these metastatic lesions. Ten of our 11 patients are living and disease-free. One non-seminomatous testicular cancer patient who had brain, lung, eye and bladder metastases and had an extremely elevated human chorionic gonadotropin (hCG) level responded only partially and died later due to disease progression. Side effects in most patients were nausea, vomiting, alopecia and leucopenia and all these side effects were reversible. Neuromuscular toxicity such as paresthesia or abdominal cramp that is sometimes encountered in PVB (cisplatin, vinblastine, bleomycin) therapy was not seen in our patients. Our results support the concept that BEP therapy is better than PVB therapy as an initial chemotherapy for testicular tumors.     

Hat die Systemtherapie von Lymphknotenmetastasen einen kurativen Wert?

Can systemic treatment for lymph node metastasis be given with curative intention? The answer to this question depends on the tumor entity. Therefore we want to give an overview about the role of systemic therapy in the curative treatment of locally advanced urological cancers, such as germ cell tumors, urothelial, renal cell, and prostate cancer. In the case of germ cell tumors cure can be achieved by platinum-based polychemotherapy without any additional treatment modality. This is also true for high-risk germ cell tumors, in which complete remissions and long-term survival are observed following polychemotherapy. In contrast, the role for chemotherapy in locally advanced urothelial cancers so far seems to be confined to (neo-)adjuvant treatment in concert with surgery. Further clinical trials are warranted to standardize and optimize this strategy. So far, renal cell cancer can only be cured by surgery. Cytokines and novel targeted therapies provide a therapeutic option in advanced renal cell cancers. A possible role of the latter modality in adjuvant treatment following resection of high-risk renal cell cancer is currently being tested in randomized trials. The same is true for hormone ablation therapy in locally advanced prostate cancer. In summary, as of today medical therapy can provide cure in advanced germ cell cancers. Its role in all other urological cancers is confined to palliative treatment of non-resectable disease. A possible contribution in the (neo-)adjuvant setting is presently a matter of clinical research.     

Pathology of germ cell tumors of the testis.

Testicular germ cell tumors form a complex group of interrelated entities. Problems of nomenclature remain, but there does appear to be a close agreement between the major classifications in use. The identification of clinically useful markers for certain germ cell testicular tumors has provided a major impetus in this field. Information gained from the study of these markers has promoted an understanding of the histogenesis of germ cell tumors, has improved standard nomenclature, and has stimulated progress in patient care. Radioimmunoassay techniques are now frequently used to measure beta-human chorionic gonadotrophin and alpha-fetoprotein levels in evaluating the clinical course of patients with nonseminomatous germ cell tumors of the testis. It is hoped that the use of these markers will permit earlier detection of tumor recurrence, prompt treatment, and an improved survival rate. The knowledge of the production of alpha-fetoprotein by the human yolk sac has further refined tumor classification. It is against this general background that we have outlined the standard pathology of germ cell tumors of the testis.     

Treatment of nonseminomatous testicular tumor with liver metastases

Therapeutic course of 2 cases of nonseminomatous testicular tumor with liver metastasis is reported. One case had mixed tumors including embryonal carcinoma, choriocarcinoma and yolk sac carcinoma, and was positive pulmonary metastasis already at the initial examination. In the other case having mixed tumors of embryonal carcinoma and choriocarcinoma, metastasis to the supraclavicular lymph node was detected at the initial examination. In both cases liver metastasis occurred after complete response could be obtained by treatment chiefly consisting of PVB therapy. For liver metastasis four-drug combination treatment using cisplatin, vinblastine, adriamycin and actinomycin D was performed with partial response. However, this patient eventually died. The other case received VAB-6 therapy with complete response for liver metastasis. It is advisable to consider other modalities therapy in addition to conventional chemotherapy in cases of testicular tumor with liver metastasis since the prognosis is poor in these cases.