Year : 2009 | Volume
: 5 | Issue : 3 | Page : 161--164
Reirradiation for progressive brain metastases
Amit Bahl1, Milind Kumar2, DN Sharma2, KS Jothy Basu2, MS Jaura2, GK Rath2, PK Julka2,
1 Department of Radiation Oncology, Delhi State Cancer Institute, New Delhi, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
Delhi State Cancer Institute, New Delhi - 110 029
Brain metastases constitute one of the most common distant metastases of cancer and are increasingly being detected with better diagnostic tools. The standard of care for solitary brain metastases with the primary disease under control is surgery followed by radiotherapy. Radiotherapy is also the primary modality for the treatment of multiple brain metastases, and improves both the quality of life and survival of patient. Unfortunately, more than half of these treated patients eventually progress leading to a therapeutic dilemma. Another course of radiotherapy is a viable but underutilized option. Reirradiation resolves distressing symptoms and has shown to improve survival with minimal late neurotoxicity. Reirradiation has conventionally been done with whole brain radiotherapy, but now studies with stereotactic radiosurgery have also shown promising results. In this review, we focus on reirradiation as a treatment modality in such patients. We performed a literature search in MEDLINE (www.pubmed.org) with key words brain metastases, reirradiation, whole brain radiotherapy, stereotactic radiosurgery, interstial brachytherapy, and brain. The search was limited to the English literature and human subjects.
|How to cite this article:|
Bahl A, Kumar M, Sharma D N, Jothy Basu K S, Jaura M S, Rath G K, Julka P K. Reirradiation for progressive brain metastases.J Can Res Ther 2009;5:161-164
|How to cite this URL:|
Bahl A, Kumar M, Sharma D N, Jothy Basu K S, Jaura M S, Rath G K, Julka P K. Reirradiation for progressive brain metastases. J Can Res Ther [serial online] 2009 [cited 2019 Dec 13 ];5:161-164
Available from: http://www.cancerjournal.net/text.asp?2009/5/3/161/57120
Around 20-40% of patients diagnosed with cancer are estimated to develop brain metastases.  Detection of brain metastases has increased due to the development of sensitive imaging modalities like contrast-enhanced MRI. Cancer of the lung and breast and malignant melanoma [Table 1] are some of the common primary cancers giving rise to brain metastases but in 15% of patients, the primary site may remain unknown.  Up to 25-40% of these patients may present with solitary brain metastases, , and these may show a partial response or progression after primary treatment requiring further therapeutic intervention. The intent of treatment in patients with progressive brain metastases is usually palliative but a subgroup of such patients may benefit from an aggressive treatment approach. In cases presenting with a single brain metastasis with a controlled primary disease, surgery followed by whole-brain radiotherapy (WBRT) is the initial treatment of choice. Stereotactic radiosurgery (SRS) alone can be employed for patients with single metastases up to 4 cm in size. Patients with limited metastases (up to three) and a controlled systemic disease can also be treated with SRS followed by WBRT.  Brain metastases presenting as multiple lesions (more than three in number) are associated with a poor median survival of 3-6 months. WBRT is the conventional therapy for such patients. WBRT is also preferred in cases with an uncontrolled primary with a solitary brain metastasis. However, majority of these patients are undertreated because of their perceived poor prognosis and limited life span. Radiotherapy has shown to improve the neurological symptoms and thus has a direct bearing on the quality of life of such patients. There have been suggestions that it also increases the duration of survival. , Unfortunately, more than half of the patients who are treated for brain metastases, eventually show progressive disease. These patients remain a difficult group to treat. Only a minority of such patients (3-10%) receive further treatment. Reirradiation in such patients can be attempted with WBRT, partial brain irradiation, SRS, fractionated stereotactic radiotherapy, or brachytherapy. The tolerance dose for the whole brain to a single course of radiotherapy is 45 Gy in 2-Gy daily fractions.  Reirradiation should be done keeping in mind the previous radiotherapy doses and the risk-benefit ratio. The advent of highly conformal radiotherapy techniques mandates a new look at reirradiation as a viable therapeutic option. Decisions regarding reirradiation in such patients can be guided by several patient- and treatment-related parameters which we have tried to analyze in this review.
Materials and Methods
We performed a literature search in MEDLINE ( www.pubmed.org ) using key words brain metastases, reirradiation, whole brain radiotherapy, stereotactic radiosurgery, interstitial brachytherapy, and brain. The search was limited to the English literature and human subjects.
Reirradiation using Whole-Brain Radiotherapy
Reirradiation by WBRT involves delivery of a homogenous dose of radiation to the entire brain by using parallel, opposed skull portals. It has been the most common technique of treating the brain parenchyma in the setting of cerebral metatstases. The aim of such treatment is palliation of the patients' symptoms to improve their quality of life. Appropriate patient selection is thus very important in order to derive any benefit from reirradiation as the overall prognosis of these patients continues to be poor. Various prognostic factors can guide clinical decision making in such patients. It has been seen that patients with a primary disease in the breast generally respond better than those with non-small-cell or small-cell lung cancer with a median survival after reirradiation of 4.7, 3.6, and 3 months, respectively.  Response to the first course of radiotherapy is also important as it has been seen that responders fare well to retreatment as compared to nonesponders.  Patients having a Karnofsky performance status (KPS) of more than 70, age less than 60 years, no evidence of extracranial metastases constitute a favorable subset where such treatment should be tried.  In one of the largest published series, Wong et al. identified the absence of extracranial metastases and solitary brain lesions as the only two favoable prognostic factors.  An 18-month survival rate of 11% versus 0% was seen in patients without extracranial metastses compared to those with extracranial metastases (P = 0.025). A median survival of 5.8 months was seen in patients with solitary brain metastases compared to 3.5 months in those with multiple metastases (P = 0.03). No guidelines are available on the time interval between the two courses of treatment. A median interval of 6.3-10 months has been reported in different series. ,,
Some authors take the progression of the disease within 4 months as a contraindication for further radiation.  The dose of radiotherapy used in the first course of radiation has varied from 20 Gy to 50.4 Gy. The commonly used schedules for reirradiation include 25-30 Gy in 10-15 fractions and 20 Gy in 5, 8, or 10 fractions. , A reirradiation dose greater than 20 Gy has been associated with a better response than lower doses.  Concerns about treatment-related acute toxicity appear to be largely unfounded as a majority of large series have not reported any treatment interruptions. Most of these patients also receive concomitant steroid therapy which can improve their tolerance to the treatment. Delayed neurological toxicity should also not be an issue in these patients as the detrimental effects of disease progression far outweigh the late effects of the treatment. Survival reported after reirradiation varied from 0.25 to 72 months. ,, An improvement in quality of life with a symptomatic relief has been documented in majority of patients.
Reirradiation by Stereotactic Radiosurgery
SRS is another technique used in the treatment of brain tumors. SRS involves delivery of a single dose of radiation to the tumor-bearing area sparing the normal surrounding brain tissue. Loefller et al. first described the use of radiosurgery in treating recurrant brain metastases.  SRS is restricted for small-sized tumors usually less than 4 cm in size. Previously treated patients presenting with solitary brain metastases with the primary disease under control are most suitable for such treatment. However, up to four metastatic lesions have been reported to be treated by radiosurgery.  No definite time interval has been described between the primary radiation and reirradiation using SRS. However, an interval longer than 14 months between previous whole-brain radiotherapy and radiosurgery was associated with a longer survival.  Different dose schedules have been used with doses ranging from 9 to 35 Gy. The RTOG 90-05 protocol established the maximum tolerated doses of reirradiation in patients with brain metastases and primary brain tumors. Doses of 24 Gy, 18 Gy, and 15 Gy were used for tumors ≤20 mm, 21-30 mm, and 31-40 mm. Larger tumor size was associated with higher neurotoxicity.  Stereotactic treatments are usually delivered by a Leksell gamma knife or a linear accelerator. Encouraging 1-year local control rates ranging from 77 to 97% have been reported in different studies. , A median survival time for patients of 7.5 months was seen in the RTOG protocol.  Acute complications of treatment like transient headache, nausea, vomiting, seizures, and alopecia are seen but are well managed by conservative measures. Some of the other prognostic factors identified for radiosurgery treatments include KPS, recursive partitioning analysis (RPA) class, and score index for radiosurgery (SIR). 
Reirradiation of Brain Metastases with Interstitial Brachytherapy
Interstitial brachytherapy involves the placement of radiation sources within the tumor bed intraoperatively. Encouraging results using iodine-125 brachytherapy have been seen in recent studies. Huang et al. reported a median survival of 7.3 months in recurrent brain metastases treated by surgery and interstitial brachytherapy alone.  Another study has shown a 1-year local control rate of 96% using brachytherapy alone with surgery in single brain metastases. These studies have suggested that surgery and interstitial brachytherapy alone without external beam radiotherapy can be used to treat brain metastases. This can help in lowering treatment related morbidities t.  In a study by Schulder et al.,  permanent low-activity iodine-125 implants were done in 13 patients who underwent gross total resection of the metastatic lesion. Patients with a recurrent tumor with a volume too large to permit radiosurgery, and a KPS of 70 or higher were chosen for the treatment. The mean implant dose was 83 Gy. A median survival in their study was 9 months (range 2 weeks to 9 years). Clinical and radiographic local control was obtained in nine patients. The results were encouraging apart from two patients who died of acute, postoperative complications within a month of implantation. These results demonstrate that permanent 125 I implants can result in good survival and quality of life, and occasionally yield long-term survival. There may be a role of implantation with 125 I seeds in patients with large, recurrent metastatic tumors that are being tackled surgically. A major impediment in this procedure is the lack of availability of permanent iodine sources in developing countries like ours.
In another study by Prados et al.,  14 patients with progressive brain metastases were treated with a temporary implant with iodine-125 sources with a stereotactic technique. They used high-activity iodine-125 sources (10-40 mCi). The median MTD (peripheral minimum tumor dose) used was 4971 cGy. Nine of these patients had received prior WBRT and were treated for the recurrence at an interval of 4-16 months after WBRT. The median survival reported was 80 weeks. Heros et al.  reported on three patients with recurrent brain metastases treated with iridium-192 implants and documented a long-term survival in the two patients. The various dose schedules used in reirradiation are summarized in [Table 2].
Newer Techniques of Radiation Delivery
Highly conformal radiation delivery techniques like3DCRT and intensity-modulated radiotherapy (IMRT) can deliver high doses of radiation to the tumor-bearing area while sparing the surrounding normal tissue. IMRT has been evaluated in treating gliomas and has been found to be useful for reducing treatment-related toxicity.  These modalities are noninvasive compared to interstitial brachytherapy and can be extremely useful for addressing the concerns of treatment-related toxicity. The application of conformal techniques in reirradiation of brain tumors has not been studied and is an area which needs further studied. Newer chemotherapeutic agents like temozolamide have proved to be useful in the primary management of glioblastomas.  Their role in recurrent brain metastases needs to be evaluated. Combination treatment using conformal radiotherapy and newer chemotherapy agents may also help improve treatment results.
A subset of patients with recurrent brain metastasis can benefit from reirradiation. These include solitary brain metastases with no extra cranial disease. Patients with a KPS >70, age <65 years, who have shown good response to the first course of radiotherapy are those with the best prognosis in such situations. Patients with primary cancer in breast with brain metastases is another subset of patients who can be suitable for such treatment. Further investigations to explore favourable prognostic groups for such treatment are warranted in light of advances in radiation delivery methods. The current body of evidence supports re-irradiation in cases of progressive brain metastases in the subgroup of patients mentioned above.
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