Again, given the location of GCTs and the high postsurgical morbidity, the risks and benefits of surgery must be considered in light of the excellent response to irradiation and chemotherapy in germinoma patients. Based on the retrospective study of Sawamura et al, no further benefit was found in performing a resection of any kind-partial or complete-beyond treatment with irradiation and chemotherapy.[4] Unlike germinomas, the role of radical resection in NGGCTs is unclear, with no definitive studies having been conducted. It is possible that radical resection may increase survival rates in NGGCT. Current studies have supported the use of delayed resective surgery, or "second-look" surgery, if residual radiographic abnormalities are seen after chemotherapy and tumor markers have normalized. In this case, the residual lesion is likely to be teratoma or necrosis/fibrosis devoid of tumor. If it is a mature teratoma, surgery may be curative. These patients are then spared any further radiation therapy by performing the "secondlook" surgery. If immature teratoma is present, then local-field irradiation is initiated without further chemotherapy.[ 3,5,6] In patients whose tumor markers have not normalized, the pathology from "second-look" surgery was also often consistent with either fibrosis or teratoma. However, the risk of subsequent recurrence or progression of disease was significant. Therefore, "second-look" surgery was not supported in cases with any elevation of tumor markers, as the surgery did not improve outcome or allow for a change in therapy.[3] Germinomas
- Radiation Therapy-Germinomas are extremely radiosensitive. Five-year overall survival rates of over 90% are seen with radiation therapy alone. Traditionally, patients were treated with 50 Gy of radiation to the primary tumor site. Additionally, prophylactic craniospinal axis irradiation was given to patients secondary to the concern about CSF seeding, in light of previous reports of approximately 10% of patients with germinomas having CSF dissemination.[7] Given the concern about the effects of irradiation on the pediatric population, multiple studies have been conducted to examine the efficacy of reduced volume and dosage of irradiation in the treatment of intracranial germinomas. It has been established through multiple retrospective investigtaions that survival outcome is not affected by a decrease in the local irradiation dose, from traditional doses of 50 to 60 Gy, to doses of approximately 40 Gy.[8-10] In February 2001, Shibamoto et al evaluated lower-dose irradiation in the treatment of germinomas based on tumor volume-based irradiation doses, and found all doses to be effective with no increased risk of local failure. This study examined 38 patients with intracranial germinomas, all treated with irradiation administered locally and to the craniospinal axis, for prophylaxis without adjuvant chemotherapy. Intracranial germinomas 4 cm or less in diameter were cured with doses of 40 to 45 Gy. A dose of 36 Gy was used for germinomas after total removal, 40 Gy for tumors less than 2.5 cm, 45 Gy for 2.5- to 4-cm tumors, and 50 Gy for tumors greater than 4 cm. All doses were effective without risk of local failure, with 10-year overall and relapse-free survival rates of 95% and 91%, respectively.[10] In the prospective, multicenter Maligue Keimzelltümoren (MAKEI) 83/86/89 trials, intracranial germinomas were treated with reduced-dose irradiation.[8] In these trials, the craniospinal axis dose was reduced to 30 Gy with a local boost of 15 Gy. The overall 5-year survival rate was 94%, and the relapse-free survival rate was 91%, which are comparable to survival rates with higher radiation doses.
- Chemotherapy and Radiation Therapy-The attempt to minimize radiation was further explored with the use of adjuvant chemotherapy. This was modeled after the successful treatment of extracranial GCTs with chemotherapy, as these tumors were found to be extremely sensitive to chemotherapy as well as radiotherapy. The chemotherapeutic agents chosen as an adjunct in CNS GCTs were the same agents that were used in the treatment of extracranial GCTs- namely, etoposide, cyclophosphamide, and the platinum-based chemotherapeutic agents. In fact the use of adjuvant chemotherapy has allowed for even further dose reductions in radiation treatment.[ 11] Allen et al initially examined the effect of neoadjuvant carboplatin in a prospective trial, with decreased local radiation of 30 Gy and craniospinal radiation of 21 Gy, and survival rates were comparable to those obtained with higher-dose radiation alone.[12] In Matsutani's review of 153 histologically verified cases of intracranial GCTs, seven patients with germinomas were given chemotherapy (carboplatin and etoposide) prior to radiation therapy at decreased doses of 30 Gy. The survival rate was 100%, without recurrence for over 7 years.[13] In 1998, both Fouladi et al[14] and Sawamura et al[15] examined the use of adjuvant platinum-based chemotherapy and etoposide, with decreased local radiation doses of 30 and 24 Gy, respectively. No prophylactic craniospinal radiation was administered. The investigators found comparable rates of survival with this strategy vs higher-dose radiation therapy alone. While a decrease in the radiation dose given locally has been supported by multiple studies, the appropriate volume of irradiation remains to be elucidated. While prophylactic craniospinal irradiation may be avoided due to the low rate of relapse in the spine,[16,17] a significant difference was seen in the rate of intracranial relapse between patients treated locally at the tumor site (with or without chemotherapy), and those treated with larger irradiation fields: 41.6% vs 11%, respectively. These findings suggest that local irradiation may not be sufficient to prevent local relapse. Several studies have evaluated the optimal volume of radiotherapy. In one such study, Sawamura et al evaluated 17 patients with germinomas treated with neoadjuvant chemotherapy followed by localized-field irradiation.[ 15] Patients were treated with EP (etoposide, cisplatin) or ICE (ifosfamide, cisplatin, etoposide) with subsequent involved-field irradiation at a dose of 24 Gy. According to research examining the effect of cranial irradiation on endocrinologic function, this is the maximal dose that can be administered without causing damage to the anterior pituitary gland.[18] At 2-year follow-up, overall and relapsefree survival rates of 100% and 94%, respectively, were realized. In conclusion, the use of adjuvant chemotherapy allowed for the reduction of dosage and volume of irradiation without compromising outcome. Another study by the SFOP utilized systemic chemotherapy and local irradiation of 40 Gy without craniospinal irradiation.[17] Fiftyseven patients were treated with neoadjuvant etoposide and carboplatin alternating with etoposide and ifosfamide, followed by local tumor irradiation with 2-cm safety margins. The estimated 3-year follow-up probability was 98% overall survival and 96.4% event-free survival, which are comparable to other survival rates with larger-volume radiation therapy. However, 4 out of 57 patients experienced a relapse within the intracranial compartment (cerebellum in one patients, third ventricle in the second, pineal area in the third, and pineal area and lateral ventricle in the last patient). The question remains: What is the optimal volume of local irradiation? It is unclear whether generous localfield irradiation encompassing the tumor site is sufficient, or inclusion of the third and lateral ventricles is necessary. Further prospective multicenter trials will be needed to evaluate treatment questions. These concerns were again noted after studies performed by Matsutani and the Japanese Pediatric Brain Tumor Study Group.[19] Patients were treated with carboplatin and etoposide or cisplatin and etoposide, followed by a 24-Gy dose of irradiation to the tumor site. The irradiation field consisted of a limited field with less than a 1-cm margin. The overall tumor- free rate after initial treatment was 92%; however, a 12% recurrence rate within 2½ years was also noted. Seven out of the nine patients relapsed outside the irradiated area. These findings support the previous suggestion that a larger field be employed in the future. While irradiation to the whole brain is unnecessary, the field may need to be larger than a limited local field. Aoyama et al examined 27 germinoma patients treated with etoposide and cisplatin (for pure germinoma) or etoposide, cisplatin, and ifosfamide (for disseminated germinoma or BHCG-secreting germinoma), followed by 24 Gy of involved-field local radiation therapy.[20] The clinical target volume of irradiation was the gross tumor volume as assessed by magnetic resonance imaging. Followup ranged from 18 to 102 months. Recurrence of disease was seen in 1 out of 16 patients with pure germinomas, with an actuarial relapse-free 5-year survival rate of 90%. Five out of nine patients with BHCG-secreting germinomas relapsed, with an actuarial relapse-free survival rate of 44%. Consistent with previous studies, the overall relapse rate was higher after local-field irradiation. However, the authors concluded that for the treatment of pure germinomas, limited local-field irradiation is sufficient. On the other hand, the BHCG-secreting germinomas were thought to require a higher dose of radiotherapy to attain control without relapse. Other studies have evaluated the difference in prognosis and response to the treatment of pure germinomas vs BHCG-secreting germinomas, concluding that the latter may require a more intensive treatment protocol.[16] In more recent studies where a more intensive chemotherapeutic regimen was administered to BHCG-secreting germinomas, equal outcomes were noted.[17]
- Chemotherapy Only-Some investigators have attempted to treat germinomas with chemotherapy alone, without radiation therapy. In a case review of nine patients who refused radiation treatment after chemotherapy, eight of the nine showed a complete response to chemotherapy. However, four patients experienced recurrence within 1½ years of treatment.[19] In 1999, Shibamoto et al also reviewed five cases in which the patients were treated with chemotherapy alone by the primary physician and subsequently presented for salvage radiation therapy.[21] The patients were given standard doses of 40 to 45 Gy of local radiotherapy, with complete response and no recurrence after 90 months. A multicenter, prospective trial was then initiated to further evaluate the possibility of treatment with chemotherapy without concomitant radiotherapy. In the First International CNS Germ Cell Cooperative Trial, 45 patients with germinomas were treated with chemotherapy alone. The patients were given carboplatin, etoposide, and bleomycin, which produced a complete remission rate of 84%; however, 50% of the patients recurred. Most of the patients with pure germinomas who relapsed were then treated with salvage radiotherapy successfully. The investigators concluded that approximately 50% of the patients were spared radiotherapy, without deleterious effects. However, the early years of this multinational study showed a 10% mortality rate overall, including the germinoma and NGGCT patients, secondary to chemotherapeutic toxicity.[22] The risks and benefits of chemotherapeutic toxicity need to be weighed against those of irradiation. In addition to immediate toxicity from chemotherapy, including myelosuppression and increased risk of infection, late effects from chemotherapy can include infertility in males, ototoxicity, and secondary neoplasm. Therefore, controversy continues to exist regarding the treatment of germinomas with chemotherapy alone. Although chemotherapy alone does not appear to produce a benefit over combined treatment, it may be considered in younger patients, or in those with pretreatment neurocognitive deficits, for whom radiotherapeutic toxicity is of greater concern. In these circumstances, any possibility of sparing or delaying radiotherapy without adverse effect may benefit the outcome and the patient's quality of life. NGGCTs
- Radiation Therapy-Compared with germinomas, NGGCTs are relatively radioresistant and associated with a poorer outcome. Traditionally, patients with NGGCTs have been treated with at least 50 Gy of local boost and craniospinal axis irradiation, with 3-year overall survival rates of approximately 20% to 45%.[23] This wide range is attributed to variations in histology, which respond to treatment differently and carry different prognoses. In a report by Matsutani et al, patients with pure choriocarcinoma, endodermal sinus tumor, or embryonal carcinoma had a 3-year survival of 27%, patients with mixed tumors composed primarily of malignant elements had a 3-year survival of 9%, and patients with predomipredominantly germinoma or teratoma mixed with other NGGCT elements had a 3-year survival of 70%.[13] Many controversies complicate the role of irradiation in children with NGGCTs. The first such issue is craniospinal radiation. Most authors agree that low-dose craniospinal irradiation in patients who present beyond puberty is acceptable, especially in the setting of positive CSF cytology or overt metastatic spread. For patients with positive CSF cytology, doses of 20 to 24 Gy are recommended, and for patients with metastatic disease, Bamberg et al reported equivalent results with a reduction in dose from 36 to 30 Gy (and a concomitant reduction in the dose to the primary from 50 to 45 Gy). Patients with focal spinal disease visualized on magnetic resonance imaging have received a local boost of up to 50 Gy.[8] The second key issue is radiation field size for the primary tumor. Local radiation volume may vary from the inclusion of the primary tumor with a 1- to 2-cm margin to primary tumor with adjacent ventricle to whole-brain radiation. Some evidence supports whole-brain radiation. In the MAKEI, the incidence of leptomeningeal disease in patients treated with local irradiation alone was 28%, as compared with 2% for those treated with whole-brain and craniospinal irradiation.[8] However, whole-brain irradiation is associated with neurocognitive deterioration, which may be minimized with a reduction in the radiation field and the use of conformal radiation and intensity-modulated radiation therapy. Dose-response data support a dose range of 45 to 50 Gy to restricted radiation fields. Total doses of less than 45 Gy have been associated with higher relapse rates of 40% to 50%, as compared with 10% to 20% in patients receiving greater than 50 Gy. Several reports have recommended lower doses of radiation when combined with chemotherapy.[23]
- Combined Chemotherapy and Radiation Therapy-The addition of chemotherapy to the treatment of children with CNS NGGCT has been reported to be associated with overall survival rates of up to 60%. Robertson et al reported on 18 patients who were treated with radiation and three or four cycles of cisplatin and etoposide. Their study demonstrated a 4- year event-free survival of 67% and overall survival of 74%. All patients received more than 50 Gy of involvedfield radiation, and six received additional whole-brain or craniospinal irradiation. Survival after recurrence was brief.[24] Balmaceda et al reported on the First International Central Nervous System Germ Cell Tumor Study. Twenty-six patients had NGGCTs. Patients were initially treated with four cycles of carboplatin, etoposide, and bleomycin. Patients who achieved a complete remission received two more cycles of chemotherapy. For patients who did not achieve complete remission, radiation was given either before or after two more cycles of the same chemotherapy but with the addition of cyclophosphamide. Second- look surgery was strongly recommended if less than a complete remission was achieved. Twenty-one patients achieved a complete remission after four cycles of induction chemotherapy. However, 50% of the patients progressed or relapsed, and only 6 of those 13 were alive and without disease at the time of the report. The investigators observed a 10% rate of toxic deaths, and the overall survival rate for patients with NGGCTs was 62%.[22] Kellie et al reported on the Second International CNS GCT Cooperative Trial. Patients were treated with combinations of cisplatin, etoposide, cyclophosphamide, bleomycin, and carboplatin. With a median follow-up of approximately 6½ years, 14 out of 20 patients were alive at between 38+ and 86+ months from diagnosis. Five patients received treatment with chemotherapy alone, and three received local irradiation after four cycles of chemotherapy in violation of the protocol. In addition, 6 of the 12 patients who progressed or relapsed were salvaged with more chemotherapy and irradiation. Only 1 of 20 patients died of toxicity, and the overall survival rate was 75%.[25] Although the First and Second International studies showed a higher rate of recurrence with chemotherapy alone, approximately half of the patients with NGGCTs were salvaged with the addition of irradiation and more chemotherapy. This is encouraging for very young patients, in whom radiation therapy may ideally be avoided or delayed.
Pure CNS teratomas occur primarily in neonates with a female predominance. Complete resection is the therapy of choice. In patients with immature teratoma, chemotherapy has been reported to be useful.[26] The value of additional irradiation is unclear. Patients with incompletely resected teratoma have a 10% risk of recurrence, and those with immature teratoma, a 20% risk irrespective of previous chemotherapy.[27] However, a significant proportion of CNS germinomas or NGGCTs have components of immature or mature teratoma that may remain following eradication of the more malignant elements, requiring surgical intervention alone (for mature teratoma) or with the addition of focal irradiation (for immature teratoma).[3] Relapse
Many investigators have shown that while more than 90% of relapses occur at the primary site of the tumor, 30% are combined with leptomeningeal spread. The outcome of relapsed patients, particularly those with NGGCTs, is bleak. Salvage therapy has included surgery, craniospinal irradiation, and a focal boost with and without high-dose chemotherapy and stem cell rescue. In patients with germinoma who have not received radiation therapy in the past, the benefit of craniospinal and focal irradiation is clear. Merchant et al reported on eight patients who relapsed after treatment with chemotherapy alone for primary CNS germinoma. Patients were then treated with high-dose cyclophosphamide followed by craniospinal irradiation (25.2 to 36 Gy) and a boost to the site of recurrent disease (45 Gy). All patients were alive at a median follow-up of 32 months folfollowing treatment.[28] For patients who relapse after receiving irradiation as part of primary therapy, it is recommended that they be treated with surgery, if possible, followed by myeloablative chemotherapy and stem cell rescue. Modak et al reported on 21 patients with recurrent or progressive CNS germ cell tumors who underwent treatment with thiotepa-based high-dose chemotherapy with autologous hematopoietic stem cell rescue. Half of the patients received consolidation therapy with radiation. Seven of the nine patients with germinoma were disease-free at a median time of 48 months after high-dose chemotherapy. On the other hand, 4 of the 12 patients with NGGCT were diseasefree at a median of 33 months after high-dose chemotherapy.[29] Other investigators have reported similar results with high-dose chemotherapy regimens in this setting.[30]
