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Radiation Therapy in the Management of Brain Metastases From Renal Cell Carcinoma

Radiation Therapy in the Management of Brain Metastases From Renal Cell Carcinoma

ABSTRACT: Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

The incidence of renal cell carcinoma (RCC) has increased for more than 2 decades. The cause of the increase is not known, but improved diagnostic techniques and early detection are suspected to be contributors.[1] According to the US census and cancer statistics, carcinoma of the kidneys affected approximately 36,160 lives in 2005,[2,3] more than 80% of whom had RCC. A third of the patients with RCC have evidence of metastases at the time of the diagnosis, and up to half of the patients treated for localized disease eventually develop a recurrence.[4] Approximately 4% to 17% of all RCC patients eventually develop brain metastases, with 50% of these suffering from multiple lesions.[5] Untreated, patients with brain metastasis from RCC have a poor prognosis and a mean survival of 3.2 months.[6] The distribution of RCC brain metastases, as with many other types of brain metastases, parallels brain weight and blood flow.[7]

Radioresistance

RCC is considered to be radioresistant. Conventional radiation therapy has not been effective in controlling this type of tumor in the curative or adjuvant settings. The lack of effectiveness may well be due to the intrinsic radioresistance of the tumor. In the linear-quadratic model, a low alpha-beta ratio implies radioresistance. Recent experiments with human cell lines of RCC have revealed a low alpha-beta ratio, ranging from 2.6 to 6.92. (Table 1).[8-10] The exact cellular mechanisms of radioresistance in RCC remain elusive, but various intranuclear and extranuclear molecular markers (including p53, BRCA1, BRCA2, HER2/neu, Bcl-2, PI-3k, ataxia telangiectasia kinase, IFG-I, HER1, HER2, VEGF, and ECF) have been shown to influence radiosensitivity for other tumor types.

On the other hand, the failure of radiation to control RCC in the curative or adjuvant setting may have more to do with the tolerance of neighboring structures to the kidney than intrinsic tumor resistance. The organs of the abdomen including the liver and small bowel have a relatively low tolerance for radiation, and thus the curative and adjuvant trials have generally been restricted to moderate radiation doses of 30 to 55 Gy.

In contrast to the curative or adjuvant setting, radiation has been effective in palliating RCC, especially in the metastatic setting.[11-13] Differences in results may be attributable to differences in radiation technique. Metastatic RCC has been treated with higher doses and more hypofractioned radiation including stereotactic radiosurgery, whereas curative cases have used lower total doses and conventional fractionations. RCC may be more responsive to radiation at higher doses or in a hypofractionated form (including stereotactic radiosurgery). Systemic treatments may also have synergistic effects with radiation.

Whole-Brain Radiotherapy

Survival

Whole-brain radiation therapy (WBRT) has been the community standard for treating brain metastases from many types of cancers. In general, the median survival time for patients with brain metastases treated with steroids alone is about 2 months. WBRT can increase median survival by 1 to 4 months for most tumor types.[14] The percentage of patients responding to WBRT varies greatly from study to study, with response rates of 50% to 70% generally reported.[15] WBRT alone results in median survivals of 7.1, 4.2, and 2.3 months for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class I, II, and III, respectively, in patients with brain metastases from nonradioresistant tumors.[16]

Despite the reports of radioresistance, retrospective studies suggest that WBRT is an effective treatment modality for patients with brain metastases from RCC. Patients with untreated brain metastases from RCC have a median survival of 3 to 4 months.[6] In three retrospective series, patients with brain metastases from RCC treated with WBRT had slightly improved overall survivals of 3.0 to 7.0 months (Table 2).[17-19] Moreover, WBRT provided up to 60% local control (control at the sites of radiographically apparent disease), with only 8% of distant brain failure (incidence of new brain lesions away from initial sites of disease).[18] Reports of median survivals according to RTOG RPA classes further support the effectiveness of WBRT for metastatic RCC (Table 3). The median survival in patients with brain metastases from RCC treated with WBRT is 8.5, 3, and 0.6 months for classes I, II, and III, respectively.

Dose-Response Effect

The role of dose escalation and/or hyperfractionation in WBRT for non-RCC brain metastases is controversial. The RTOG has conducted two randomized studies that demonstrated comparable results for different fractionation schedules—40 Gy in 15 or 20 fractions, 30 Gy in 10 or 15 fractions, and 20 Gy in 5 fractions.[20,21] In these randomized trials, there was no difference in neurologic function, duration of improvement, time to progression, or survival.

These results were recently challenged by Epstein and colleagues, who reported superior survival times and improved neurologic function in patients with solitary brain metastases using whole-brain doses of 32 Gy administered in 1.6 Gy fractions twice daily, followed by boost doses to 48, 54, 64, and 70 Gy.[22] Survivals increased with increasing doses, from 4.9 months with 48 Gy to 8.2 months with 70 Gy. Nieder et al found that patients who received WBRT with 30 Gy in 10 fractions had half the response rate of the group receiving 40 to 60 Gy in 20 to 30 fractions but no survival benefits.[23] These retrospective studies suggest that there may be a dose-response effect at higher doses, which is not evident at lower doses such as the ones used in the randomized RTOG trials.

Although there is some evidence that dose-escalation or hyperfractionation may improve response rates and survival in patients with non-RCC metastases, such data are scant in RCC. A retrospective study of RCC patients by Cannady and colleagues found that patients who receive more than 30 Gy had significantly longer survival than patients who received 30 Gy or less. This result, however, was confounded by the fact that patients who received higher doses also had better prognostic factors such as Karnofsky performance status and RPA class. Thus, it remains unclear whether a change in dose or fractionation has an impact on the treatment of RCC brain metastases.

WBRT continues to be the treatment of choice for patients with a single brain metastasis not amenable to surgery or radiosurgery, for patients with poorly controlled systemic disease and thus a relatively short life expectancy, and for patients with multiple brain metastases whose metastases are too numerous for stereotactic radiosurgery or surgery. The most commonly reported dose for WBRT in RCC is 30 Gy in 10 fractions. In practice, the dose and fraction size of WBRT should be individualized to take into consideration the status of systemic or extracranial disease as well as performance status. While higher fractional dose as well as total dose may increase the chance of complications, non-RCC research suggests that increased doses may improve quality of life and survival. Dose escalation in RCC should be explored especially in combination with other therapeutic modalities such as surgery, radiosurgery, and systemic therapy (eg, molecular targeted therapy).

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