Treatment of patients with poor prognosis anaplastic germ cell tumours (AGCT) of the testis and other sites

Between 1977 and 1986, 170 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovin), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979 we have been able to compensate for adverse prognostic factors. Since then each patient has received a minimum of three courses of POMB and 139 patients have completed therapy with an overall survival of 89%, and for those patients who had not received prior radiotherapy the survival is 92%. By increasing the number of courses of POMB, the initial serum concentrations of human chorionic gonadotrophin (hCG greater than 50,000 IU/I) and/or alpha-fetoprotein (AFP greater than 500 kU/l) have ceased to be poor prognostic variables. Neither stage at presentation nor the volume of metastatic disease is a major adverse prognostic variable using this chemotherapy.     

Treatment of disseminated germ cell tumours of the testis

Between 1979 and 1987 64 men with non-seminomatous germ cell tumours of the testis were treated with chemotherapy. Nearly half of these patients had large volume disease. The most frequently used combinations were VAB-6 and POMB/ACE. Chemotherapy lasted 3.9 months for small volume disease and 5.5 months for large volume disease. Seven patients (11%) underwent resection of residual masses; viable malignancy was found in only 1 of these. Relapse occurred in 6 complete responders, 3 of whom were salvaged with further chemotherapy. Fifty-three patients are presently alive and have received no treatment for periods of 5 to 86 months. Life table analysis forecasts a survival of 81%. Adverse prognostic factors have been recognised and include high initial serum concentrations of beta-human chorionic gonadotrophin (beta-HCG) and alpha fetoprotein (AFP), large volume disease and prior irradiation. Although the survival time of patients with advanced disease has improved in recent years, it remains considerably below that of patients who present with less advanced disease. Such patients should be treated aggressively from the outset in order to obtain maximum benefit from chemotherapy. Selected cases also require adjunctive surgery.     

Fertility after chemotherapy for male and female germ cell tumours

Gonadal function was assessed in fifty-nine men and thirty-one women who had successfully completed chemotherapy with the POMB/ACE regimen for germ cell tumours. Seventeen (81%) of the twenty-one men who had not received paraaortic radiotherapy, whose original tumour bulk was less than 5 cm and whose duration of chemotherapy was less than 6 months, recovered spermatogenesis compared with twelve (32%) of thirty-eight patients who had either larger tumour masses or longer courses of chemotherapy, or both. All but one of the seventeen women in whom menstruation could have been expected to recur are now menstruating. This study suggests that the great majority of patients treated with POMB/ACE chemotherapy for germ cell tumours will recover fertility.     

Prognosis following chemotherapy for metastatic malignant teratoma

A multiple regression analysis was performed of factors affecting the prognosis of 93 patients with metastatic malignant teratoma treated at the Royal Marsden Hospital between 1979 and 1981. In a subgroup of 53 patients, where exact tumour bulk could be calculated from sequential CT scan slices, a correlation was seen between tumour marker level and volume of metastatic disease. On analysis of the risk of relapse after initial chemotherapy, the independent adverse influence was detected of serum AFP greater than 500 micrograms/l and of bulky disease defined by clinical staging. An adverse influence of high serum HCG levels was not seen, probably due to the small number of patients in this series with this presenting feature.     

Chemotherapy for poor risk germ cell tumours. An independent evaluation of the POMB/ACE regime

We have evaluated the 7-drug, alternating, high-dose cisplatin regime for germ cell tumours, designated POMB/ACE, in 55 patients with advanced malignant teratomas and 5 patients with bulky metastatic seminomas. All of the latter and 5 of the teratoma patients had relapsed following radiotherapy, chemotherapy or both. The previously untreated teratoma patients included 13 whose tumours were extragonadal. The primary testicular tumour patients comprised 16 with large and 21 with very large volume metastases according to the Medical Research Council criteria. POMB/ACE is effective therapy for poor risk patients with germ cell tumours (including those with the most advanced disease, i.e. hepatic and cerebral metastases) and prolonged treatment after marker normality seems unnecessary. It is a complex regime with significant toxicity and cannot be recommended for the treatment of patients with germ cell tumours who have an excellent prognosis with simpler, shorter and less toxic treatment.     

Treatment of seventy-eight patients with testicular tumors

Seventy-eight patients with testicular tumors were treated in our clinic between April, 1972 and October, 1990. The average age of patients with seminoma (37.5 yrs) was higher than that (24.5 yrs) of those with non-seminomatous germ cell tumor (NSGCT). Histopathologically, 34 patients had seminoma and 36 patients had NSGCT. The remaining 8 patients had non-germinal cell tumors. The 5-year survival rate was 76.7%, 90.3% and 75.8% for all patients, seminoma group and NSGCT group, respectively. As for seminoma group, the 5-year survival rate was 100%, 50.0% and 33.3% for Stage I, Stage IIb and Stage III, respectively. The survival rate of Stage IIb and Stage III in seminoma group were lower than Stage I statistically. In NSGCT group, the 5-year survival rate was 100% for Stage I and 26.7% for Stage III, between the two groups there was significant difference. The higher serum LDH and HCG levels, the lower the survival rate in NSGCT. Serum AFP, beta-HCG levels and ESR were unrelated to the survival rate. The survival rate for the patients treated by the chemotherapy including CDDP was compared to those treated by the other therapy in germ cell tumor (greater than or equal to Stage IIb). The survival rate of CDDP group was higher than the others (p less than 0.01).     

The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988.

The United Kingdom Children's Cancer Study Group (UKCCSG) malignant germ cell tumour (MGCT) studies were undertaken to establish standard protocols of investigation, staging, and treatment. The efficacy of new drug combinations and the value of serial measurements of serum alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG) were evaluated. Following the initial surgery, staging of the tumour was performed using a variety of investigative approaches. In stage 1 testicular tumours, orchidectomy was performed. In more advanced tumours, and in stage 1 tumours that failed to show the expected decline in AFP or recurred, chemotherapy was used after appropriate surgery. Seventy-three boys, under 14 years of age, with testicular MGCTs have been entered into the UKCCSG studies since 1979. Serum AFP was measured preoperatively, or within 2 weeks of operation, in 70 boys. It was unequivocally elevated in 69. Monitoring by serial AFP measurement proved valuable in assessing response and in early detection of recurrence. HCG was measured in 46 boys, and was raised in three. Sixty-seven (91%) of the tumours were yolk sac (Teilum) tumours, four were immature teratoma, and two were mixed MGCTs. The only non-AFP producing tumour was an immature polydermal teratoma in a 1-year-old boy. Serum HCG was raised in three boys with yolk sac tumours, one with a mixed teratoma, and one 14-year-old boy who had a mixed MGCT. The results of treatment were assessed on April 1, 1989 (median time from diagnosis, 3 years 4 months). Seventy-one boys were alive, 48 of whom had been cured by orchidectomy alone. The remaining 25 patients received chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic resection for 28 patients with small hepatocellular carcinoma.

Twenty-eight patients with hepatocellular carcinoma (HCC) of not larger than 5 cm diameter were surgically treated during the 12 years from 1977 to 1988, twenty-five of them since 1983. Half of the patients were admitted for check up because of elevated serum AFP and were high risk subjects. Serum HBsAg were positive in 24 (85.7%). Serum AFP was less than 10 ng/ml in 2 (7.1%) and greater than or equal to 200 ng/ml in 14 (50%). Coexistent liver cirrhosis was found in 21 (75%). Local resection or partial hepatectomy played a major surgical role in small HCC, especially in the presence of cirrhosis and tumor in right liver. The cumulative survival rates for the 28 patients treated by hepatic resection at 1, 2 and 5 years were 60.6, 42.5 and 42.5 percent. The survival rate of patients with tumor size not larger than 3 cm diameter is not better than those with tumor size between 3 cm and 5 cm. The small HCC patients with AFP less than or equal to 200 ng/ml had better survival than those with AFP greater than 200 ng/ml.     

Case report of malignant sertoli cell tumor

Malignant sertoli cell tumor is a rare disease and only a few cases have been described previously. We report a terminal case of malignant sertoli cell tumor. A 38-year-old male visited a hospital with a complaint of swelling his left testis. He underwent high left orchiectomy. His pathologic diagnosis was suspected seminoma, and all tumor markers (LDH, HCG, AFP) were negative, and CT imaging confirmed clinical stage 1 (pT1N0M0S0). One year later, a CT scan showed a small retroperitoneum lymph node swelling. Four months later, these lesions increased to 55 x 45 x 70 mm in diameter. He received 3 courses of chemotherapy with BEP (bleomycine, etoposide, cisplatin), but, lymph node size did not change. After he underwent a CT guided lymph node biopsy, his pathologic diagnosis was viable embryonal carcinoma. He then came to our hospital. We selected CPT-11 and nedaplatin for his salvage chemotherapy, but lymph node lesions did not change. After he received 3 courses of chemotherapy, we performed retroperitoneal lymphadenectomy. His pathologic diagnosis was viable sertoli cell tumor, malignant type. After 30 days, he had multiple liver metastases ane died 27 months after orchiectomy. All tumor markers were negative in his all clinical courses.     

Tumor marker levels in post-chemotherapy cystic masses: clinical implications for patients with germ cell tumors

PURPOSE: Increased tumor markers after induction chemotherapy for patients with germ cell tumor usually represent systemic disease and consequently second line chemotherapy is instituted, while retroperitoneal lymph node dissection (RPLND) is reserved for patients with marker normalization. We report the concentration of alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in the fluid of post-chemotherapy cystic masses to evaluate this as a potential source for serum marker elevation. MATERIALS AND METHODS: From March 2002 to December 2002, 11 consecutive patients with post-chemotherapy cystic masses underwent RPLND. Following resection, aspirated fluid was analyzed for AFP and HCG. Only 5 post-chemotherapy RPLNDs were performed in patients with increased serum tumor markers, including the 3 patients in our study. Patients with increasing tumor markers and/or multifocal disease with noncystic residual masses after induction chemotherapy underwent salvage chemotherapy despite teratomatous elements in the primary tumor. RESULTS: All 11 patients had teratoma in the orchiectomy specimen and retroperitoneum, including one with malignant transformation. Cystic fluid markers were increased in all patients, 9 of 9 with HCG (range 7.0 to 6,880) and 9 of 11 with AFP (27.5 to 521.2). Two patients with an increased serum AFP before surgery (47.9 and 31.6) had cyst levels of 73.5 and 790.4 respectively. Both serum markers normalized postoperatively. One patient with increased pre-RPLND serum HCG (11.6) had a cyst level of 233. HCG continued to increase postoperatively and the patient died of disease. The remaining 10 patients remain disease free. CONCLUSION: Fluid from cystic teratoma contains variably elevated levels of HCG and AFP in all patients and appears to be independent of serum marker level or pathology. It is possible that a "slow leak" of fluid from cystic teratoma may explain elevated serum markers in selected patients with teratoma and thus may potentially avoid second line chemotherapy.     

Intensive chemotherapy in poor-prognosis nonseminomatous germ cell tumors of the testis.

Forty-one patients with poor-prognosis nonseminomatous germ cell tumors (NSGCT) of the testis were treated between 1980 and 1989. This group was defined by the presence of one of the following features: multiple large lung metastases, bone, liver or brain metastases, abdominal mass greater than 10 cm, abdominal mass greater than 5 cm with high serum concentration of the tumor markers [alpha-fetoprotein (alpha FP) greater than 500 kU/l or beta-subunit of human chorionic gonadotropin (beta HCG) greater than 1,000 IU/l) or very high serum tumor marker concentrations (alpha FP greater than 5,000 kU/l or beta HCG greater than 10,000 IU/l). The first 21 patients were treated with cisplatin, vinblastine, bleomycin (PVB) chemotherapy and the following 20 with an intense, alternating 6-drug chemotherapy consisting of cisplatin, bleomycin, vincristine, methotrexate, etoposide and ifosfamide (BOMP/EPI). Surgery of residual masses was performed when tumor markers were negative. Fifteen patients (71.4%) in the PVB group and 18 patients (85%) in the BOMP/EPI group remained disease-free at a median follow-up of 67 and 41 months, respectively. None of the resected masses in the BOMP/EPI group contained malignant disease whereas viable carcinoma was found in 5 of 14 (26.4%) patients in the PVB group. The toxicity of the BOMP/EPI regimen was severe but tolerable. Intensive chemotherapy regimen seems to be useful in this subset of patients, but randomised prospective trials comparing these with standard chemotherapy are necessary.     

Malignant germ cell tumors in the mediastinum

Mediastinal germ cell tumors are divided into seminomas and non-seminomatous germ cell tumors. The former is a radiosensitive tumor that can be successfully treated by surgery and radiation. The latter is much more malignant than the former, however, the therapy has been making remarkable progress owing to CDDP. Nevertheless, the median survival time of patients with mediastinal involvement is 14 months, much lower than that seen in patients with testicular involvement. From our 12 patients and a review of the literature, we drew the following conclusions. If malignant germ cell tumors are suspected among anterior mediastinal tumors affecting male patients of around 20 years old, tumor markers such as AFP and HCG must be investigated and then, tissue histology should be diagnosed from specimens obtained by mediastinoscopy or anterior mediastinotomy. In the case of NSGCT, or AFP and/or hCG producing seminoma, the first choice is the chemotherapy including CDDP. Seminomas, that do not produce either AFP or HCG, can be treated by surgery and radiation. If the patients have tumor markers such as AFP and/or HCG, these are very useful to evaluate the efficacy of the therapy. When the efficacy of chemotherapy reaches the maximum, adjuvant surgery may be indicated. Chemotherapy should be continued, when malignant tissues are present in the resected mass.     

A case of mediastinal yolk sac tumor successfully treated with chemotherapy and surgery

A 28-year-old man was admitted due to increasing respiratory symptoms. X-ray examination of the chest showed a tumor mass in the anterior mediastinum with possible invasion into the chest wall and upper lobe of right lung. No tumor was found in the testis. Serum alpha-fetoprotein (AFP) concentration was 6400 ng/ml. Serum levels of CEA and HCG were within normal limits. Percutaneous biopsy of the tumor strongly suggested yolk sac tumor with an evidence of AFP by an immunoenzyme labelling technique. The serum AFP rapidly decreased after two courses of combination chemotherapy. En bloc resection of the tumor was successfully performed and third chemotherapy was added. Mediastinal yolk sac tumors should be treated with combination chemotherapy and surgical resection.     

合并肝硬化中晚期肝癌TACE治疗后血清AFP检测的意义

目的 探讨合并肝硬化的中晚期肝癌患者血清AFP水平对经肝动脉化疗栓塞术（TACE）治疗预后的意义.方法 收集250例TACE术后的中晚期肝癌合并肝硬化患者的血清,采用放射免疫法测定患者血清AFP的水平.将测定的结果分成AFP升高组（＞20 μg/L,n＝165）例和正常组（＜20 μg/L,n＝85）,并对肝癌患者进行随访（1周～65个月,中位时间21.5个月）.用Kaplan-Meier生存曲线分析患者生存率,评估AFP水平及相关因素对中晚期肝癌患者预后的意义.结果 AFP升高组的1、2、5年生存率为57%、48%、5.1%,AFP正常组为37%、46%、12%.AFP升高组的1年生存率明显高于AFP正常组（P＜0.05）,AFP升高组5年生存率明显低于AFP正常组（P＜0.05）.结论 对于中晚期肝癌的患者,血清AFP水平高者较血清AFP水平低者短期预后好,但远期预后差.     

Optimal treatment of clinical stage I yolk sac tumor of the testis in children

Thirty-four children with malignant germ cell tumors of the testis were seen at the Institut Gustave-Roussy from 1970 through 1980, after orchiectomy alone. The tumor was classified according the WHO classification (immature teratoma, embryonal carcinoma, choriocarcinoma, yolk sac tumor). Twenty-four of the 34 children had a stage I yolk sac tumor (YST) defined as a tumor completely removed by the inguinal approach, without clinical node involvement and/or metastases. No lymphadenectomy was performed. All the patients had an alphafetoprotein (AFP) determination before or after orchiectomy. For those (23/24) with an elevated level of AFP the clinical stage I was assigned if the AFP decreased regularly to normal values by 3 months after orchiectomy. Twelve patients received systemic chemotherapy every 3 months [methotrexate, actinomycin D, cyclophosphamide (Cytoxan)]; 12 did not receive any treatment after orchiectomy. An AFP evaluation was assayed for all of these regularly. The 3-year survival rate was 96% and the 3-year relapse-free survival rate was 84%, with no difference found between the two groups receiving or not receiving systemic chemotherapy. This series confirms the advisability of a conservative approach for clinical stage I YST, employing orchiectomy and evaluation including AFP determinations. Ten percent to 20% of patients will suffer a relapse, which can be demonstrated by an increasing level of AFP, and these children can be treated at this time. With this approach, 80% of patients having clinical stage I YST can be treated by orchiectomy alone and will not suffer any sequelae or complication of either lymphadenectomy or chemotherapy. For the few who do relapse, treatment at the time of relapse is curative for the majority. This approach requires absolute adherence to a strict follow-up program.     

Recognizing abnormal marker results that do not reflect disease in patients with germ cell tumors

PURPOSE: The judicious use of serum alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase is key to appropriate management of patients with germ cell tumors. Elevated AFP and/or HCG generally indicate active disease. We describe patients with germ cell tumors who had elevated serum AFP and/or HCG but no active disease, despite careful repeat evaluation. MATERIALS AND METHODS: Histories of 6 cases of germ cell tumors that remained in remission despite abnormal serum AFP and/or HCG were reviewed. RESULTS: Markers were only modestly elevated, remained constant or spontaneously normalized during repeat measurements, and there was no other clinical or radiographic evidence of disease. Patients were treated conservatively with physical examination, radiological tests and repeat marker assays, with no relapse to date. CONCLUSIONS: Stable, low increases in serum AFP and HCG may not represent active disease. Careful repeat evaluation will determine whether the markers increase. If no change is noted after appropriate studies have been reviewed by an experienced practitioner to exclude active disease from diagnosis, then consideration should be given to managing such cases with close surveillance to avoid unnecessary chemotherapy.     

Detection of AFP and HCG in metastatic testicular cancer after treatment with chemotherapy or radiation therapy

We used an indirect immunoperoxidase technique to detect alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in tissue sections of nine metastatic germ cell tumors excised after treatment with chemotherapy or radiation therapy, and correlated the results with the serum levels of AFP and HCG. In all but 1 case yolk sac tumor (YST) was the only histologic type that reacted for AFP (AFP+) and syncytiotrophoblasts (STB) were the only histologic type that reacted for HCG (HCG+). Among 5 cases with normalization of the serum AFP before surgery, 3 were associated with YST-/AFP-, 1 with YST+/AFP+, and 1 with YST+/AFP- metastases; and among 4 cases with normalization of the serum HCG all were associated with STB-/HCG- metastases. Among 3 cases with persistent elevation of the serum AFP, 1 was associated with YST+/AFP+, 1 with YST+/AFP-, and 1 with YST-/AFP- metastases; and of 2 cases with persistent elevation of the serum HCG, 1 was associated with STB-/HCG- and 1 with STB+/HCG+ metastases. These data suggest that marker normalization in the face of persistent tumor results primarily from eradication of YST and STB, but also from treatment-induced inhibition of AFP and HCG synthesis or secretion.     

Combined polychemotherapy and radiotherapy in advanced inoperable squamous cell carcinoma of the head and neck

Between August 1979 and August 1984, 46 untreated, inoperable patients with advanced squamous cell carcinoma of the head and neck were submitted to a combined modality of treatment based on four courses of polychemotherapy (vincristine, bleomycin, and methotrexate), rotated with three courses of radiotherapy, 20 Gy each. Forty-six patients entered the study: 45 were evaluable for their response to the treatment and 46 for toxicity effects. We observed 26 complete responses (57.7%) and 14 partial responses (31.1%); overall actuarial survival was 28% at 55 months. Mucositis occurred in 11 patients, 3 patients suffered from nausea and vomiting, 2 patients developed fever, and 1 had a platelet count of 50,000/mm3. One toxic death occurred: one patient developed an acute renal failure related to Methotrexate.     

肝动脉、门静脉栓塞化疗治疗不可切除的原发性肝癌

目的：探讨肝动脉、门静脉双管栓塞化疗对不可切除的原发性肝癌的治疗作用。方法：对19例不可切除的原发性肝癌患者采用手术方法向肝动脉、门静脉植入皮下埋藏式投药泵,术中即开始经肝动脉投药泵栓塞化疗,术后7－10d在X线监测下经门静脉投药泵栓塞化疗,以后定期经两投药泵栓塞化疗,术后观AFP的变化、Bus或CT检查并与同期3次以上的32例HACE进行比较。结果：双栓化疗组17例术后1月AFP均下降、3月下降为正常8例,84．2％的肿瘤缩小,6月、9月、12月、24月生存率分别为89．5％、78．9％、68．4％、31．6％,中位生存期17．1月,其中2例进行了二期手术切除。HACE组术后1月AFP下降10例、3月后下降21例,46．9％的肿瘤缩小,6月、9月、12月、24月生存率分别为71．9％、53．1％、31．3％,中位生存期11．2月、12月、24月生存率组间比较P＜0．01;两组均无异位栓塞。结论：皮下埋藏式投药泵肝动脉、门静脉双插管栓塞化疗术后给药途径简单、方便、疗效好、并发症少,是治疗不可切除的肝癌有效方法之一。     

Abdominal metastasis of a pineal region tumor through ventriculoperitoneal shunt. Case report]

An 18-year-old male was admitted with headache, nausea, and vomiting. Computed tomography (CT) revealed an enhanced tumor of the pineal region and hydrocephalus. The tumor was partially resected via a parieto-occipital craniectomy. The histological diagnosis was germinoma. No serum tumor markers such as alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were detectable. A ventriculo-peritoneal (V-P) shunt was emplaced and radiation therapy (whole brain 59 Gy) given. The tumor and the hydrocephalus regressed completely and he returned to work. Six years later, he experienced constipation and general fatigue. CT and echotomography of the abdomen showed a large peritoneal tumor and ascites. Laboratory investigation demonstrated serum levels of AFP 7640 ng/ml and HCG 150 IU/l, and high ascitic levels of AFP 12,890 ng/ml and HCG 1030 IU/l. AFP and HCG levels regressed after combined chemotherapy. However, he died due to leukopenia and pneumonia. Autopsy found no metastasis of tumor cells to the central nervous system. The peritoneal cavity contained hemorrhagic fluid and a large tumor 4100 g in weight. The tip of the V-P shunt tube was in front of the tumor. No neoplasm was found in the testis, retroperitoneal cavity, thymus, and other organs. The microscopic appearance of the peritoneal tumor was different to the first pineal tumor. The neoplasm was confirmed as a mixed germ cell tumor with teratoma components and suspected to be a metastasis of the pineal tumor through the V-P shunt system.