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Since the advent of cisplatin-based chemotherapy in the 1970s, a majority of metastatic testicular cancer patients have been cured with chemotherapy and surgery. The high curability of testicular cancer, along with the young age of afflicted patients, can result in patients living for many years after the chemotherapy. Thus, the assessment of late effects of chemotherapy is clinically important in testicular cancer patients. This article summarizes the literature regarding the long-term side effects, and reviews approaches to the amelioration of these side effects.

Purpose: Recently, high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue has been developed for poor risk testicular germ cell cancer. In this study, we investigated the optimum timing for harvesting PBSCs with the use of bleomycin + etoposide + cisplatin (BEP) chemotherapy, which is a well known first-line regimen for the testicular cancer., Material and Method: Peripheral blood CD34-positive cell ratios were measured during a total of 10 courses of BEP chemotherapy in 6 patients with metastatic germ cell cancer between 1996 and 1998. We performed 4 apheresis in 3 patients during this period. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was administrated from the day on which the neutrophil count decreased less than 1,000/microliter., Results: The peripheral blood CD34-positive cell ratios became maximum (3.0-24.6%; average 10.0%) on the day 18 to 21 (median day 19) of BEP chemotherapy with rhG-CSF administration. The maximum ratios of peripheral blood CD34 positive cells were achieved when the number of leukocyte were 6,880-23,600/microliter and exceeded 6,000/microliter after the 18th day of BEP chemotherapy. The average number of collected CD34 positive cells was 9.5 x 10(6)/kg at a single apheresis, and 12.6 x 10(6)/kg per patient., Conclusion: Efficient hematopoietic progenitor cells were mobilized by BEP chemotherapy with rhG-CSF administration of first-line setting. Our results suggest that the optimum timing of PBSCs harvest is the day when the numbers of leukocyte exceed 6,000/microliter after the 18th day of BEP chemotherapy and the following day.

Granulocyte-Colony Stimulating Factor (G-CSF) was administered to patients with bladder cancer, ureteral cancer and testicular cancer following chemotherapy. Chemotherapy included 23 courses of M-VAC (Methotrexate, Vinblastine, Adriamycin, Cisplatin) therapy to patients with bladder cancer or ureteral cancer and 10 courses of EP (Etoposide, Cisplatin) therapy to patients with testicular cancer. During M-VAC chemotherapy, about a half of the patients experienced leukopenia below 3000/mm3 until the 11th day. Leukopenia failed to improve promptly when G-CSF was started after leukocytes decreased below 3000/mm3. On the other hand, 5-days of prophylactic administrations of G-CSF from the 9th day of M-VAC therapy were able to increase leukocytes promptly. In EP chemotherapy against testicular tumor, G-CSF was started on the 9th day and continued for 5 days. Leukocytes increased immediately and the average duration of leukopenia below 3000/mm3 was only 1.2 day. These results indicate that a short term of prophylactic administration of G-CSF following these chemotherapies is able to accelerate a recovery from leukopenia and decrease a risk of bacterial infection. G-CSF is proposed to be enrolled in the treatment of urological cancer for the improvement of safety and the outcome of therapy.

A 66-year-old man visited our hospital with a history of a slowly growing left scrotal contents for the past 5 years. Serum beta-human chorionic gonadotropin and lactate dehydrogenase was greatly elevated. The resected mass was 26 cm x 16 cm x 13 cm in size, 2,258 g in weight. It arose from left testis and grew to the left inguinal region. Histologically it was pure seminoma.

The clinical value of serum ferritin level in patients with testicular cancer was studied. Seven cases of seminoma and nine cases of non-seminoma from 1983 to 1989 were evaluated. The serum levels of ferritin, human chorionic gonadotropin (beta-HCG), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) were estimated before and after treatment. Abnormally high values of serum ferritin before treatment were noted in 4/7 (57%) in seminoma, 3/9 (33%) in non-seminoma and 7/16 (44%) in total. The total rate showing abnormally high values of serum ferritin was lower than that of beta-HCG and LDH. Meanwhile it was the same as that of AFP and higher than that of CEA. Changes in the serum ferritin level did not always correspond with the clinical course. In 3 out of 6 tumor free patients, higher levels of serum ferritin before treatment became normal after treatment. In one patient with a high level of serum ferritin before treatment, the level of serum ferritin remained higher and retroperitoneal lymph node metastasis developed after treatment. In 9 cases with normal serum ferritin level, 7 showed the normal range of ferritin level throughout the treatment course. These findings suggests that in some patients with testicular cancer, the serum ferritin level might serve as a tumor marker indicating the efficacy of the treatment and the tumor recurrence.

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.

In 113 patients with testicular germ cell tumor, the authors determined human chorionic gonadotropin (hCG) and the free beta subunit levels in sera by differential quantitation using homologous hCG-beta radioimmunoassay (RIA) and hCG enzyme immunoassay (EIA), respectively. In 59 patients with seminoma, intact hCG was positive in 6 patients (10.1%), whereas free hCG-beta was positive in 23 patients (39.0%). Syncytiotrophoblastic giant cells were detected in 4 cases out of 6 patients with positive intact hCG seminoma. Seventeen cases (28.8%) revealed positive free hCG-beta only without elevation of intact hCG. In 54 patients with nonseminoma, both intact hCG and free hCG-beta were positive in 36 cases (66%). In some cases, hCG-beta/hCG ratio increased up to 275% when recurrence of tumor developed. Molecular heterogeneity of hCG is closely related to proliferation and differentiation of hCG producing cells. The differential quantitation of intact hCG and hCG-beta using these two assays is valuable for clinical detection of molecular heterogeneity of hCG in testicular tumor.

A 52 year-old male with advanced testicular seminoma (stage II N4) underwent right radical orchiectomy, followed by chemotherapy with vinblastine, bleomycin and cis-platinum. This resulted a partial response and he was well for 24 months after the operation. Serial monitoring of serum HCG and HCG-beta has been done, using three kinds of double antibody radioimmunoassays. A substance with immunological similarity to free HCG-beta was detected in sera and tumor extract. The serum level of this substance was reduced in parallel with the cytoreduction of metastasis by chemotherapy. A rational therapeutic approach to advanced seminoma and its serum marker are discussed briefly.

Tumor marker for tumors in urology has been widely used to testicular and prostatic tumors. A part of testicular tumor produces alpha-fetoprotein (AFP) and HCG, thus these markers can not be used for early detection of disease. However, they are very useful in typing testicular tumor, and in monitoring a course of disease which produces them. beta-HCG seems to be more specific than HCG. In case of prostatic cancer, prostatic acid phosphatase (PAP) assayed immunochemically is sensitive and specific marker. Prostate antigen seems to be another excellent marker for this tumor, and this is well correlated with PAP. In reactivated case, tissue polypeptide antigen was elevated, suggesting use of this marker.

The patient was a 29 years old male. He was attended to our hospital with a chief complaint of a right scrotal mass on August 20, 1983. Based on the diagnosis of testicular neoplasm, orchiectomy was performed on September 7, 1983. After surgery, the patients, HCG and alpha-fetoprotein (AFP) values of still remained high. Pathological diagnosis was mixed tumor (choriocarcinoma, Embryonal carcinoma, and malignant cystic teratoma). From September 22, VAB-4 combination therapy was performed and complete remission was obtained without severe side effects. The patient was in good health with normal HCG and AFP values on January 20, 1984.

The outcome of clinical therapy of adult nonseminomatous testis tumor presenting with negative human chorionic gonadotropin (hCG) at our hospital is reported. Of 45 nonseminoma, 28 cases showed negative hCG and they had no chorionic element. Embryonal carcinoma was found in 14 cases (50%), teratoma in 5 cases (17.9%), and teratomatous mixed tumor in 9 cases (32.1%). The 5 year actuarial survivals were 94% for stage I disease, 40% for stage II and 16.6% for stage III. Prophylactic irradiation was given to the patient with stage I disease and no relapse occurred in the irradiated area, but later, neoplasms had spread by vascular dissemination in 3 cases (17.6%). In the treatment of stage II disease, radiotherapy has proved unsatisfactory and retroperitoneal lymph nodes dissection was a choice of modality. Of 11 patients with lung metastasis including vascular dissemination from stage II and III disease, 3 cases (27.3%) were cured by localized radiotherapy and chemotherapy of the pre-VAB regimen era.

The most common type of testicular tumor is the germ cell tumor, which shows peculiar histological and biological features. The histopathology of germ cell tumors of the testis is illustrated here according to the WHO classification except for extremely rare polyembryoma and teratoma with malignant transformation. The tumors are divided roughly into 2 groups, one histological type including seminoma, spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma, and more than one histological type including many possible combinations of one histological type. Seminoma and spermatocytic seminoma show some similar features to the germ cell line, while embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma show differentiation toward a variety of structures appearing at any stage of embryogenesis instead of the original testicular tissue. The histology of the metastatic disease may or may not be the same as that of the primary lesion. The reasons for the occurrence of histological differences between primary and metastatic tumors is discussed. Two major tumor markers of the germ cell tumor, HCG and AFP, are analyzed using immunohistochemical procedure, and the significance of immunostaining for these markers in clinicopathological study is stressed.

Between August, 1968 and March, 1985, we treated 27 patients with testicular seminoma. The histopathological type was typical seminoma in 23 (85%) and anaplastic seminoma in 4 (15%). Their clinical stages were classified into stage I for 17 patients (63%), 7 patients (25%) in II and 3 (12%) in III. Tumor markers, alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG-beta), were determined in 16 patients. None of them showed an elevated level of AFP, but 7 (43.8%) had elevated hCG-beta in the peripheral vein. The hCG-beta in the spermatic vein on the tumor side was elevated in 12 out of 14 patients (88.9%). The hCG-beta level in the spermatic vein on the tumor side was significantly higher than that in the peripheral vein in 10 patients with stage I seminoma. This finding suggests that the determination of hCG-beta in the spermatic vein would give us more accurate information on the production of hCG-beta in seminoma. Although the elevation of the hCG-beta level in pure seminoma has been supposed to be a poor prognostic factor, our results indicated that a mild to moderate elevation of hCG-beta in stage I seminoma did not always imply a poor clinical course, first, because none of these 10 patients, even with an elevated hCG-beta, who underwent retroperitoneal lymph node dissection (RPLND), had microscopic metastasis, and second, because none of these have had a recurrence of the disease up to now.(ABSTRACT TRUNCATED AT 250 WORDS)

During induction chemotherapy, we experienced the false elevation of the tumor marker alpha-fetoprotein (AFP) in some disseminated testicular cancer patients. We discussed the possibility of the false elevation of the tumor marker AFP and evaluated the relationship between AFP and the markers of liver damage (GOT, GPT, LDH, etc.), the elevation of which were caused by induction chemotherapy of the VAB-6 regimen. We evaluated each variable of the eleven patients with disseminated testicular cancer who had been treated in our hospital between 1979 and 1984. The elevation of each marker of liver damage was induced by the VAB-6 regimen, immediately after the end of each induction chemotherapy but not by other induction chemotherapy regimens. A statistical study confirmed that there was a close correlation between the elevation of AFP and of the markers of liver damage, that is induced frequently by the induction chemotherapy of VAB-6 regimen.

Twelve cases of testicular cancer were treated at our Department of Urology between 1984 and 1985. The mean age of the patients was 35.2 years old. Eight of them were pure seminoma in histology, other cases were non-seminomatous germ cell tumors (NSGT). Seven cases were of stage I testicular cancer, 3 cases were of stage IIA, and 2 cases were of stage IIB. Patients with stages I and IIA seminoma were given radiation to the ipsilateral iliac and bilateral paraaortic caval nodes to the crura of the diaphragma. Two patients with stage IIB seminoma were treated with PVB therapy and retroperitoneal lymph node resection. Chemotherapy containing CDDP was effective to reduce the tumor size. Two cases were of stage I NSGT, one case was treated with high orchiectomy only, and the other case was treated with chemotherapy after high orchiectomy. Chemotherapy and retroperitoneal lymph node resection were given to two patients with stage IIA NSGT. Abnormally elevated values of lactate dehydrogenase were observed in cases with a primary tumors weight larger than about 100 g. Six of the 8 cases of pure seminoma had slightly elevated beta-human chorionic gonadotropin levels. Two cases with bilateral testicular cancer were found among the 12 cases so that necessity of meticulous palpation of remaining testis was felt. Recurrent change was not observed in any of the 12 cases so that testicular cancer is considered to be an almost curable disease.

Clinical findings and results of various treatments were discussed for 30 patients with nonseminomatous testicular tumor (NSTT) who had been treated from August, 1968 to March, 1985. Radioimmunoassays were positive for AFP in 19 of the 22 evaluated patients (86.4%) and were positive in 14 of the 19 evaluated patients (73.7%). These positive rates are consistent with those reported by others. Abnormal pre-treatment level of hCG-beta did not always indicate poor clinical courses, since in patients under stage III A pre-treatment level of hCG-beta did not correlate to either treatment results or clinical courses, even in patients with bulky metastasis such as stage IIIB1, B2 or C their treatment results and clinical courses seemed to be primarily determined by the size and extent of metastasis. However, pre-treatment measurement of hCG-beta was useful to predict in primary and/or metastatic tumor the presence of choriocarcinoma element which could not be found with conventional histopathological studies. Most of our 14 patients at stage I were subjected to radical orchiectomy and retroperitoneal lymph node dissection followed by post-surgical management with radiotherapy or chemotherapy. With these treatments only one of the stage I patients had a recurrence. However, adjuvant therapy may not be necessary for them because of a low recurrence rate following retroperitoneal lymph node dissection and the high cure rate with intensive chemotherapy including CDDP for the early stage of recurrence, when a close follow-up would be possible. We treated only 2 patients at stage II A. One of these 2 patients became free of the disease by intensive chemotherapy including CDDP (24 months after the start of treatment). In stage II A, a high recurrence rate has been reported, following retroperitoneal lymph node dissection without post-surgical adjuvant chemotherapy, which indicates that these patients should be treated with adjuvant chemotherapy, including CDDP. All 4 patients in stage II B or III treated mainly by chemotherapy without CDDP died of the disease at around one year after treatment. However, the five-year survival rate was improved to 40% in 10 advanced patients with these stages who had been treated mainly with recent chemotherapy regimen including CDDP. The recent development of chemotherapy regimen including CDDP has been able to lead many patients with advanced stage to a curable status. However, the appropriate treatment for some patients with bulky and extensive metastasis remains to be established. More aggressive treatment such as cytoreductive surgery may be necessary for such patients.