Treatment outcome of patients with brain metastases from malignant germ cell tumors

BACKGROUND: Multiinstitutional experience with the management of cerebral metastases from malignant germ cell tumors (MGCT) is presented. METHODS: Clinical data regarding brain metastases from MGCT at diagnosis (Group 1 [56 patients]) or after cisplatin-based chemotherapy (Group 2 [83 patients]) were collected retrospectively. All patients in Group 1 received "conventional" cisplatin-based chemotherapy supplemented by cerebral radiotherapy (36 patients) and/or neurosurgery (10 patients). In the patients in Group 2 cerebral metastases were detected a median of 9 months after the initiation of chemotherapy. Thirty-five patients received chemotherapy, 59 patients received radiotherapy, and 25 patients underwent neurosurgery. RESULTS: The 5-year cause specific survival rate in Group 1 was 45% (95% confidence interval [CI], 31-59%). Neurosurgery and the absence of extracerebral, nonpulmonary visceral disease, but not cerebral radiotherapy, were independent predictors of good prognosis. The 5-year cause specific survival rate in Group 2 was 12% (95% CI, 4-20%), but was 39% among patients with an isolated brain recurrence (24 patients). Radiotherapy, but not chemotherapy, represented an independent predictor of good prognosis together with brain metastases at first recurrence and the absence of extracerebral recurrence. CONCLUSIONS: Among patients with brain metastases at the time of diagnosis of an MGCT, cisplatin-based chemotherapy resulted in a 5-year cause specific survival rate of 45%, with cerebral radiotherapy having limited impact. The 5-year cause specific survival rate for all patients with brain metastases after cisplatin-based chemotherapy was 12%, but increased to 39% in patients with an isolated brain recurrence. Cerebral radiotherapy (and neurosurgery) represent essential treatment modalities for patients in whom brain metastases are diagnosed after induction chemotherapy.     

Decompression of epidural metastases from germ cell tumors with chemotherapy

Summary Epidural cord compression from germ cell tumor metastases is not common. Treatment usually requires high dose corticosteroids with radiation therapy and/or surgical decompression. Three patients with epidural germ cell tumor metastases were treated with cisplatin-based chemotherapy and all three had complete neurologic recovery. Systemic chemotherapy should be considered as initial therapy with corticosteroids for epidural cord compression from metastatic germ cell tumor.Abbreviations DOX Doxorubicin - CYC Cyclophosphamide - CDDP Cisplatin - BLEO Bleomycin - VBL Vinblastine - ETO Etoposide - IFOS Ifosfamide - PROC Procarbazine - VINC Vincristine - ACT D Actinomycin D. Adapted from Friedman [16]     

Treatment of recurrent germ cell tumors

Treatment of recurrent germ cell tumors is a complex undertaking. There are a number of clinical scenarios that can mimic relapse and, as such, a great deal of experience with management of germ cell tumors is required to recognize these rare but important situations that simulate recurrence. If recurrence is proven, standard chemotherapy with cisplatin, ifosfamide, and etoposide can result in approximately 30% of patients being long-term, disease-free survivors. Emerging technologies, e.g., high-dose chemotherapy and new drugs, may augment our current ability to salvage this patient population. Desperation surgery offers an additional opportunity for selected patients with localized chemotherapy-resistant relapse or those patients with late relapse of germ cell tumor.     

Treatment of brain metastases in uncommon tumors

Melanoma spreads to the CNS with an incidence of 4 to 20%. Metastases from cancer of the colorectal and genitourinary tract, as well as sarcoma, are less frequent (1%). Surgery should be considered for single brain metastases in patients with controllable disease. Stereotactic needle biopsy may still be worthwhile to confirm diagnosis, and also in patients whose tumors are considered unresectable. Whole-brain radiotherapy is the treatment of choice for most brain metastases, since more than 70% of patients have multiple metastases at the time of diagnosis. Radiosurgery is particularly useful for patients unable to tolerate surgery and for patients with lesions inaccessible to surgery. Chemotherapy could be useful in patients with asymptomatic brain metastases and uncontrolled extracranial disease, depending on performance status and previous chemotherapy received.     

Treatment of brain metastases in uncommon tumors

Melanoma spreads to the CNS with an incidence of 4 to 20%. Metastases from cancer of the colorectal and genitourinary tract, as well as sarcoma, are less frequent (1%). Surgery should be considered for single brain metastases in patients with controllable disease. Stereotactic needle biopsy may still be worthwhile to confirm diagnosis, and also in patients whose tumors are considered unresectable. Whole-brain radiotherapy is the treatment of choice for most brain metastases, since more than 70% of patients have multiple metastases at the time of diagnosis. Radiosurgery is particularly useful for patients unable to tolerate surgery and for patients with lesions inaccessible to surgery. Chemotherapy could be useful in patients with asymptomatic brain metastases and uncontrolled extracranial disease, depending on performance status and previous chemotherapy received.     

Treatment of malignant germ cell tumors.

In an unselected group of 278 patients with germ cell tumors, disease-free status was obtained in 97% by a treatment program including a surveillance-only strategy for stage I testicular cancer, and low-or high-dose cisplatinum-etoposide treatment for patients with more extensive disease. The overall follow-up period was a median of 40 months (range 20-62 months). At present 100% of patients with stage I disease, 91% with stage II disease, 86% with stage III disease, 75% with extragonadal germ cell tumors, and 3 of 3 patients with germ cell tumors in the ovary are alive and without disease. Among 36 patients treated with high-dose cisplatinum and etoposide there were six toxic deaths, four of them in patients with residual malignant disease. Three patients died of progressive disease. There were no toxic deaths among 54 patients with disseminated disease but without poor prognostic features who were treated with low-dose cisplatinum-etoposide; six of these patients died of progressive disease. It is concluded: 1) that surveillance is a feasible and reasonable strategy for patients with stage I disease; 2) that excellent survival results can be achieved with standard-dose cisplatinum-etoposide in patients with disseminated disease and a favorable prognostic profile; and 3) that disease-free status can be obtained in nearly all patients with poor prognostic features at the expense of significant toxicity. Standardized criteria for selection of patients with poor prognoses are needed. Randomized trials should be carried out to define the role of high-intensity treatment and, finally, measures to decrease or prevent serious toxicity should be explored.     

Involvement of the gastrointestinal tract by metastases from germ cell tumors of the testis

Six cases of metastatic germ cell tumors of the testis involving the gastrointestinal (GI) tract are reported. Three cases were primary seminomas, and three were nonseminomatous. All six cases involved the upper GI tract, three occurring at presentation and three at relapse, with a disease-free interval of 3 months to 10 years. Isolated GI involvement did not occur. The presumed mode of spread was by haematogenous dissemination in three and direct extension from paraaortic lymph nodes in three. Symptoms suggestive of involvement were severe abdominal pain secondary to high intestinal obstruction or mucosal ulceration, severe lumbar pain, and symptoms of anemia as a result of clinically evident or occult blood loss. Four patients were now disease-free after chemotherapy, one died of an unrelated illness, and one patient was receiving treatment for relapsing disease.     

Neurological complications of malignant germ cell tumors of testis: biology of brain metastases (I).

Central nervous system metastases are a common complication of disseminated germ cell tumors of the testis. They occurred in 16% of 242 patients treated and in 25% of the patients who died in our VAB chemotherapy series. Pulmonary metastases preceded or coincided with the development of brain metastases. The frequency of brain metastases differed with the histology of the primary tumor. They occurred in 13% of pure embryonal carcinomas, 18% of mixed tumors containing embryonal or choriocarcinoma elements, and 83% of pure choriocarcinomas. Embryonal carcinoma and choriocarcinoma were the principle histologies found in brain metastases. Characteristically, pure choriocarcinoma deposits in the brain were multiple (8/9) and cerebellar involvement was common (5/9). Pure embryonal carcinoma CNS metastases were typically single (6/8) or very few and cerebellar involvement was not observed. The interval from the diagnosis of malignancy to the diagnosis of brain metastases was longer for embryonal carcinoma than for pure choriocarcinoma (23 mos. vs. 6.5 mos.). Survival following the diagnosis of brain metastases was poor. There was a tendency toward longer survival for histologically pure embryonal carcinoma deposits in the brain than for the pure choriocarcinomas (6.5 mos. vs. 1 mo.).     

Brain metastases of malignant germ cell tumors in children and adolescents

BACKGROUND: Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival. METHODS: The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period. RESULTS: Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors. CONCLUSIONS: Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.     

Treatment of epidural spinal cord involvement from germ cell tumors with chemotherapy

BACKGROUND:

Germ cell tumors (GCTs) are chemosensitive, and epidural spinal cord compression (ESCC) from GCT may be amenable to treatment with chemotherapy (CT) only. This retrospective study compares the clinical outcome of GCT patients with ESCC treated with CT or radiotherapy (RT) + CT.

METHODS:

All patients with a histologic diagnosis of GCT from 1984 to 2009 were included in this study. Patients with ESCC were identified. Age, clinical features, histology, treatment, and outcome were analyzed.

RESULTS:

The authors identified 1734 patients with GCT, of whom 29 (1.7%) had ESCC. The median age of these 29 patients was 32 years. The ESCC was treated with CT only in 16, RT + CT in 11, and 2 patients received palliative care only. The ESCC was more extensive in the RT + CT than the CT group. Patients who received RT + CT had a higher proportion of failed prior CT regimens, a higher percentage of nonseminomatous GCT, T‐spine involvement, multilevel epidural disease, and bony vertebral metastases. Median overall survival after diagnosis of ESCC was not reached for those treated with CT alone versus 15 months for those receiving RT + CT (P = .02). There was also a significant difference in survival in patients receiving first‐line therapy (n = 15), where median overall survival was not reached in the CT group (n = 11), compared with 22 months in the RT group (n = 4) (P = .04).

CONCLUSIONS:

GCTs rarely involve the epidural compartment. Patients with ESCC who are likely to have chemosensitive disease can receive CT alone as definitive treatment. Cancer 2011. © 2010 American Cancer Society.     

Multimodality treatment of patients with liver metastases from germ cell tumors: the role of surgery

BACKGROUND: The presence of liver metastases represents an independent poor risk prognostic factor for survival in patients with germ cell tumors. METHODS: The clinical files of 37 patients who had undergone liver resection for the treatment of disseminated germ cell tumors were reviewed to define the indications for resection of residual liver metastases after chemotherapy in patients with germ cell tumors. The histologic patterns of primary tumor and residual disease were compared. The prognostic factors for survival were studied by univariate analysis. RESULTS: All but 2 of 37 patients underwent complete resection. One patient died of postoperative complications. Thirteen complications occurred in 10 patients. Twelve patients had active residual tumor, 7 patients had mature teratoma, and 18 patients had only necrosis on histologic examination. Twenty-three of 37 patients (62%) were alive with no evidence of disease after a median follow-up of 66 months (range, 31-134 months). Three prognostic factors were found to be significant in the univariate analysis for unfavorable outcome: the presence of pure embryonal carcinoma in the primary tumor, liver metastases measuring > 30 mm in greatest dimension at the time of surgery, and the presence of viable, active residual disease. CONCLUSIONS: Because it is impossible to determine the histologic pattern of residual liver masses after chemotherapy with current imaging tools and percutaneous biopsy, patient selection for liver surgery may be undertaken according to the size of residual liver masses. Patients with masses that measure < or = 10 mm in greatest dimension should be considered for close follow-up, because they have a high probability of necrosis and are at low risk for malignant disease. Male patients with masses that measure > or = 30 mm in greatest dimension represent a high-risk group of patients who are not likely to benefit from liver surgery. Only male patients with masses that measure 10-29 mm in greatest dimension and all female patients with masses that measure > 10 mm in greatest dimension should be considered for liver resection.     

Pediatric germ cell tumors

Pediatric germ cell tumors are a diverse group of neoplasms with variable clinical behaviors, depending upon the age and site of presentation. Most result from sporadic mutations, although environmental exposures and other genetic aberrations may play a role. Platinum-based chemotherapy has dramatically improved the event-free and overall survival outcomes of pediatric patients with malignant germ cell tumors over the past two decades. Prognosis is dependent on tumor stage and location. Patients with gonadal germ cell tumors have at least a 95% 5-year survival for early stage disease and at least a 85% 5-year survival for advanced stages. In general, extragonadal germ cell tumors carry a poorer prognosis with mediastinal location having the worst outcomes (70% 4-year survival). Current trials are focused on maintaining similar excellent outcomes while reducing morbidity by reducing the dose and duration of chemotherapy. Cytogenetic research studies have found chromosomal aberrations specific to some of these tumors that may serve as prognosticators and even direct therapy.     

Intracranial germ cell tumors

Intracranial germ cell tumors are a heterogeneous group of lesions which occur in children and adults. Within the classification of intracranial germ cell tumors, there are a variety of different tumor types which carry different prognoses. The diagnosis of an intracranial germ cell tumor usually requires histological information, but a subgroup of tumors will secrete specific tumor markers, including alpha-fetoprotein and beta-human chorionic gonadotropin, which may obviate the need for surgical intervention. The management of intracranial germ cell tumors in both children and adults remains unsettled. Germinomas have a good prognosis, as over 90% of patients can be effectively treated with radiation therapy. The dose and volume of radiation therapy needed for disease control is not well established, and controversy exists concerning the need for whole brain or craniospinal radiation therapy for localized tumors. Germinomas are also chemosensitive and recent reports suggest that the dose and volume of radiation therapy required for disease control can be lessened with the addition of adjuvant chemotherapy. The outcome for patients with nongerminomatous germ cell tumors is less favorable. Radiation therapy alone will result in disease control in 40%-60% of patients. The addition of chemotherapy to radiation therapy may improve the rate of survival.     

Testicular germ cell tumors

PURPOSE OF REVIEW: Preclinical and clinical developments in germ cell tumors over the past year are summarized. RECENT FINDINGS: Attenuations in the rising incidence of testicular germ cell tumors are beginning to be observed in certain European populations. Additional data on predisposing factors related to race, estrogenic exposure, cryptorchidism, and infertility are becoming available. Significant work on the genetic and molecular alterations in tissue specimens and cell culture models of germ cell tumors continues. Additional treatment strategies for advanced stages of the disease are being evaluated. Cardiovascular and metabolic consequences of therapies in long-term testicular germ cell tumor survivors are being further clarified. Late relapses of successfully treated patients are also being increasingly recognized. SUMMARY: More effective treatments for intermediate risk, poor risk, and recurrent germ cell tumors need to be developed, while long-term toxicities of therapies need to be further modified. Given these challenges, active research on these fronts continues and remains a priority.     

Pediatric germ cell tumors

Malignant germ cell tumors are relatively uncommon, accounting for approximately 3% of all childhood malignancies. Occurring with an incidence of approximately 4 per million among children less than 15 years of age, they account for approximately 225 new cases per year in the United States. Germ cell tumors occur in both gonadal and extragonadal sites, with extragonadal and testicular tumors predominating in children less than 3 years of age and with the gonads being the main location of tumors during and after puberty. They occur more frequently in girls than boys. Germ cell tumors are interesting for several reasons: (1) abnormal migration of primordial germ cells account for many of the childhood germ cell tumors; (2) markers exist to allow evaluation of the extent of resection and the development of recurrence for many of the tumors; and (3) the introduction of platinum-based chemotherapy has markedly improved the survival rate for germ cell tumors, as well as the salvage rate for recurrent or metastatic disease.