Management Of Brain Metastases Research Articles

Stereotactic radiosurgery in the management of brain metastases from primary thyroid cancers

Patients with metastatic well-differentiated thyroid cancer have a generally favorable long-term outcome although multi-organ involvement is a known marker of poor prognosis. Brain metastases are rare, occurring in less than 1% of patients with thyroid cancer. Few patients have been managed with stereotactic radiosurgery (SRS). A retrospective database of 5,067 patients treated for brain metastases between 1985 and 2007 was generated from 11 institutions. Thyroid cancer patients were identified in this database and, when possible, additional information was obtained from further chart review. Patients were excluded if they had incomplete treatment or follow-up information. Two validated prognostic indices, Graded prognostic Assessment (GPA) and Recursive Partitioning Analysis (RPA), were calculated for each patient. The overall survival times were calculated by the Kaplan-Meier method. Twenty-three thyroid cancer patients were identified (51% male, 48% female). Median age was 63 years (range 20-81). Pathology of the primary thyroid disease was available for twelve patients; the majority were diagnosed with differentiated thyroid cancer (n = 9 papillary, n = 2 Hürthle cell; 92%) and one had medullary subtype (8%). Median time from diagnosis of primary disease to brain metastasis was 41.8 months (range 0-516). Fifteen (65%) patients underwent SRS as part of their initial treatment with a median number of lesions treated of 1.5 (range 1-9). The median follow-up time for living patients was 35.2 months. Overall median survival time was 20.8 months (40% alive at last follow-up) and 37.4 months for SRS-treated patients (P = NS). A poor Karnofsky performance status was predictive of worse outcome (P = 0.001). GPA and RPA did not provide additional prognostic information. In conclusion, patients treated with SRS for brain metastases from primary thyroid cancer have a favorable prognosis with an expected median survival greater than 3 years. It is unclear as to whether current prognostic indices are relevant to this patient population.

Outcomes of Stereotactic Radiosurgery in the Management of Brain Metastasis in Patients with HER2 Positive Metastatic Breast Cancer.

Abstract Background:We present single institution experience on the effect of Her 2 status on results of Gamma knife radiosurgery (SRS) for brain metastases (BM) as to local control, pattern of relapse and survival.Material and Methods:From 2004 to 2008, 65 patients with metastatic breast cancer (MBC) were treated with GK-SRS at our center, 52 had documented Her 2 status. We performed analysis based on Her 2 status of the original tumor defined as positive by 3+ DAKO or FISH. SRS was delivered using cobalt leksell GKS to a median dose of 20Gy (range 16-20 Gy) at 50% isodose line. Responses were evaluated by gadolinium enhanced MRI. We analyzed the data as to: objective response (OR) defined as radiologic response or stable disease, and local progression –free survival (PFS) defined as freedom from progression of treated BM, appearance of new brain metastases and/or leptomeningeal progression, as well as overall survival (OS) measured from the time of SRS .ResultsTwenty-eight patients were identified as HER2 positive (Group A) and 24 patients were HER2 negative (Group B). Median time to develop BM in group A was 60 months (4 -240 months) versus 48 months (4-156) in group B. Median follow-up was 12 months (1-48) from the time of onset of BM. 66% patients in group A and 82% patients in group B have no more than 2 BM at the time of SRS.In group A, OR was 78.6% (22 pts)and 21.4%(6 pts) had progressive disease (PD) where as in group B the OR was 83% (20 pts) and 17%(4 pts) had PD. Median time to local recurrence of the treated lesion in group A was 13 months (95% CI 5.84 to 20.15) compared to 8 months (95%CI 6.75 to 9.25) in group B. Local PFS at 1 year for Group A vs. B was: control of the treated lesions 69% versus 41.2% respectively, p= 0.97 by log rank test; and development of new BM 67% compared to 86% (p=0.2).Out of all CNS relapses, almost a quarter of patients in both groups received second SRS whereas 25% patients in group A and 31% patients in group B received whole brain irradiation respectively. Interestingly, 28% (9 pts) failed as leptomeningeal disease following SRS, 7 of them with Her 2 positive tumors. Leptomeningeal relapses were seen both as only pattern of recurrence (4 pts) or associated with other types of CNS progression: local re-growth or new BM (5pts).ConclusionsSRS provides high rate of objective response and local control for BM from both Her 2 positive and Her 2 negative breast cancer. No statistically significant difference in local PFS was seen. More frequent pattern of relapse as leptomeningeal disease was seen in Her 2 positive after SRS. Evaluation of novel systemic targeted therapies in conjunction with local therapies is needed for effective management of BM from breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6152.

The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

QuestionShould patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? Target population These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. Recommendations Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS ± WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below. Question Does surgical resection in addition to WBRT improve outcomes when compared with WBRT alone? Target population This recommendation applies to adults with a newly diagnosed single brain metastasis amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.

The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

Should whole brain radiation therapy (WBRT) be used as the sole therapy in patients with newly-diagnosed, surgically accessible, single brain metastases, compared with WBRT plus surgical resection, and in what clinical settings? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases. If WBRT is used, is there an optimal dosing/fractionation schedule? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Level 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. (i.e., 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy10). If WBRT is used, what impact does tumor histopathology have on treatment outcomes? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology.The following question is fully addressed in the surgery guideline paper within this series by Kalkanis et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of WBRT in the management of brain metastases, this recommendation has been included below. Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection. Recommendation Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone.

The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

QuestionDo steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? Comparisons include: (1) steroid therapy versus none. (2) comparison of different doses of steroid therapy. Target population These recommendations apply to adults diagnosed with brain metastases. Recommendations Steroid therapy versus no steroid therapy Asymptomatic brain metastases patients without mass effect Insufficient evidence exists to make a treatment recommendation for this clinical scenario. Brain metastases patients with mild symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4–8 mg/day of dexamethasone be considered. Brain metastases patients with moderate to severe symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/day or more be considered. Choice of Steroid Level 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. Duration of Corticosteroid Administration Level 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period, or longer in symptomatic patients, based upon an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy.Given the very limited number of studies (two) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. Please see “Discussion” and “Summary” section for additional details.

The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics.

QuestionWhat evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors? Target population These recommendations apply to adults with brain metastases. Recommendations New radiation sensitizers Level 2 A subgroup analysis of a large prospective randomized controlled trial (RCT) suggested a prolongation of time to neurological progression with the early use of motexafin-gadolinium (MGd). Nonetheless this was not borne out in the overall study population and therefore an unequivocal recommendation to use the currently available radiation sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be provided. Interstitial modalities There is no evidence to support the routine use of new or existing interstitial radiation, interstitial chemotherapy and or other interstitial modalities outside of approved clinical trials. New chemotherapeutic agents Level 2 Treatment of melanoma brain metastases with whole brain radiation therapy and temozolomide is reasonable based on one class II study. Level 3 Depending on individual circumstances there may be patients who benefit from the use of temozolomide or fotemustine in the therapy of their brain metastases. Molecular targeted agents Level 3 The use of epidermal growth factor receptor inhibitors may be of use in the management of brain metastases from non-small cell lung carcinoma.

The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

QuestionDo prophylactic anticonvulsants decrease the risk of seizure in patients with metastatic brain tumors compared with no treatment? Target population These recommendations apply to adults with solid brain metastases who have not experienced a seizure due to their metastatic brain disease. Recommendation Level 3 For adults with brain metastases who have not experienced a seizure due to their metastatic brain disease, routine prophylactic use of anticonvulsants is not recommended.Only a single underpowered randomized controlled trial (RCT), which did not detect a difference in seizure occurrence, provides evidence for decision-making purposes.

Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma

Innovation in the management of brain metastases is needed. We evaluated the addition of compartmental intrathecal antibody-based radioimmunotherapy (cRIT) in patients with recurrent metastatic central nervous system (CNS) neuroblastoma following surgery, craniospinal irradiation, and chemotherapy. Twenty one patients treated for recurrent neuroblastoma metastatic to the CNS, received a cRIT-containing salvage regimen incorporating intrathecal (131)I-monoclonal antibodies (MoAbs) targeting GD2 or B7H3 following surgery and radiation. Most patients also received outpatient craniospinal irradiation, 3F8/GMCSF immunotherapy, 13-cis-retinoic acid and oral temozolomide for systemic control. Seventeen of 21 cRIT-salvage patients are alive 7-74 months (median 33 months) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. One patient died of infection at 22 months with no evidence of disease at autopsy, and one of lung and bone marrow metastases at 15 months, and one of progressive bone marrow disease at 30 months. The cRIT-salvage regimen was well tolerated, notable for myelosuppression minimized by stem cell support (n = 5), and biochemical hypothyroidism (n = 5). One patient with a 7-year history of metastatic neuroblastoma is in remission from MLL-associated secondary leukemia. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life.

Optically-guided frameless linac-based radiosurgery for brain metastases: clinical experience

The purpose of this study was to describe our clinical experience using optically-guided linear accelerator (linac)-based frameless stereotactic radiosurgery (SRS) for the treatment of brain metastases. Sixty-five patients (204 lesions) were treated between 2005 and 2008 with frameless SRS using an optically-guided bite-block system. Patients had a median of 2 lesions (range, 1–13). Prescription dose ranged from 14 to 22 Gy (median, 18 Gy) and was given in a single fraction. Clinical and radiographic evaluation occurred every 2–4 months following treatment. At a median follow-up of 6.2 months, actuarial survival at 12 months was 40% [95% confidence interval (CI), 28–52). Of 135 lesions that were evaluable for local control (LC), 119 lesions (88%) did not show evidence of progression. Actuarial 12 month LC was 76% (95% CI, 66–86). Tumors ≤2 cm in size had a better 12 month LC rate (81% vs. 36%, P = 0.017) than those >2 cm. Adverse events occurred in three patients (5%). Optically-guided linac-based frameless SRS can produce clinical outcomes that compare favorably to frame-based techniques. As this technique is convenient to use and allows for the uncomplicated delivery of hypofractionated radiotherapy, frameless SRS will likely have an increasingly important role in the management of brain metastases.

Stereotactic Radiosurgery in the Management of Brain Metastases: An Institutional Retrospective Analysis of Survival

The objective of this study was to report our experience with stereotactic radiosurgery performed with the Gamma Knife (GK) in the treatment of patients with brain metastases and to compare survival for those treated with radiosurgery alone with survival for those treated with radiosurgery and whole-brain radiotherapy. Prospectively collected demographic and clinical characteristics and treatment and survival data on 237 patients with intracranial metastases who underwent radiosurgery with the GK between 2003 and 2007 were reviewed. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare survival by demographic and clinical characteristics and treatment. The mean age of the patient population was 56 years. The most common tumor histologies were non-small-cell lung carcinoma (34.2%) and breast cancer (13.9%). The median overall survival time was 8.5 months from the time of treatment. The median survival times for patients with one, two/three, and four or more brain metastases were 8.5, 9.4, and 6.7 months, respectively. Patients aged 65 years or greater and those aged less than 65 years had median survival times of 7.8 and 9 months, respectively (p = 0.008). The Karnofsky Performance Score (KPS) at the time of treatment was a significant predictor of survival: those patients with a KPS of 70 or less had a median survival of 2.9 months compared with 10.3 months (p = 0.034) for those with a KPS of 80 or greater. There was no statistically significant difference in survival between patients treated with radiosurgery alone and those treated with radiosurgery plus whole-brain radiotherapy. Radiosurgery with the GK is an efficacious treatment modality for brain metastases. A KPS greater than 70, histology of breast cancer, smaller tumor volume, and age less than 65 years were associated with a longer median survival in our study.

Neurosurgical Rescue of Bradycardia Induced by Intracerebral Hypertension: A Case Report and Review of the Literature

Brain metastases usually occur secondary to lung, breast, unknown primary, melanoma, and colon cancers. A growing tumor in the brain is commonly associated with edema and increased intracranial pressure (ICP). Common signs and symptoms due to increased ICP or brain edema include headache, nausea, and vomiting. One of the main treatment modalities in the management of brain metastases is whole-brain radiation. However, increased ICP may lead to acute deterioration of the neurologic status due to development of radiation-induced edema. Therefore, alternative management options should be considered for these patients to avoid complications from whole-brain radiation treatment. We discuss the case of a brain metastases patient who presented with bradycardia induced by brain edema.

Management of brain metastases: the indispensable role of surgery

Brain metastases are the most common neurological complication of systemic cancer and carry a very poor prognosis. The management of patients with brain metastases has become more important recently because of the increased incidence of these tumors and the prolonged patient survival times that have accompanied increased control of systemic cancer. In this article, we review the current perspectives on surgical treatment of brain metastases in terms of patient selection criteria, intraoperative adjuncts, whole-brain radiation therapy (WBRT) as a postoperative adjuvant, reoperation for tumor recurrence, and resection of multiple and single metastases. Achieving the best outcome in treatment of brain metastasis requires the judicious and complementary use of surgical resection along with modalities such as whole-brain radiation therapy and stereotactic radiosurgery.

Management of brain metastases from ovarian and endometrial carcinoma with stereotactic radiosurgery

Metastases to the brain from ovarian and endometrial carcinoma are uncommon and to the authors' knowledge consensus regarding optimal management is lacking. Stereotactic radiosurgery (SRS) has proven useful for the treatment of many benign and malignant brain tumors. In the current study, the authors evaluated outcomes after SRS in patients with ovarian and endometrial carcinoma. Twenty-seven patients with brain metastases underwent gamma-knife SRS. Six patients had endometrial carcinoma, whereas 21 patients had ovarian carcinoma. Eighteen patients also received whole-brain radiotherapy. A total of 68 tumors were treated with gamma-knife SRS. At the time of last follow-up, 1 patient was still alive and 26 had died. The median survival was 7 months after the initial diagnosis of brain metastasis and 5 months after SRS. The 1-year survival rate after radiosurgery was 15% and that from the diagnosis of brain metastases was 22%. On final imaging, all tumors were controlled without further growth. Two patients (7.4%) developed new or progressive neurologic deficits after SRS. SRS is an acceptable choice for the treatment of brain metastases resulting from ovarian and endometrial carcinoma, and provides local tumor control with limited morbidity. Careful patient selection is warranted in the setting of patients with uncontrolled systemic disease in whom a limited survival benefit is expected.

Neuropsychological testing and biomarkers in the management of brain metastases

Prognosis for patients with brain metastasis remains poor. Whole brain radiation therapy is the conventional treatment option; it can improve neurological symptoms, prevent and improve tumor associated neurocognitive decline, and prevents death from neurologic causes. In addition to whole brain radiation therapy, stereotactic radiosurgery, neurosurgery and chemotherapy also are used in the management of brain metastases. Radiosensitizers are now currently being investigated as potential treatment options. All of these treatment modalities carry a risk of central nervous system (CNS) toxicity that can lead to neurocognitive impairment in long term survivors. Neuropsychological testing and biomarkers are potential ways of measuring and better understanding CNS toxicity. These tools may help optimize current therapies and develop new treatments for these patients. This article will review the current management of brain metastases, summarize the data on the CNS effects associated with brain metastases and whole brain radiation therapy in these patients, discuss the use of neuropsychological tests as outcome measures in clinical trials evaluating treatments for brain metastases, and give an overview of the potential of biomarker development in brain metastases research.

Successful management of brain metastasis from malignant germ cell tumours with standard induction chemotherapy

Because of possible long-term toxicity, cranial radiotherapy (RT) was withheld as part of standard treatment for brain metastasis (BM) from non-seminomatous germ cell tumours (NSGCT). This study evaluates this change in management in our institute. Twenty-two consecutive patients with BM from NSGCT were analysed. Ten patients presented with BM at initial diagnosis (group 1), two patients developed BM at extra-cranial complete remission (CR) (group 2), and ten patients during treatment of the primary tumour without achieving CR (group 3). All patients received cisplatin-based induction chemotherapy. In group 1, three patients with a single metastasis and three patients with multiple BM underwent craniotomy. Five patients received chemotherapy and whole brain RT (WBRT), and five patients received chemotherapy without WBRT. In group 2, both patients underwent craniotomy for a relapse with multiple BM. One patient received additional high-dose (HD) chemotherapy with WBRT, and the other HD chemotherapy without WBRT. In group 3, one patient underwent craniotomy, seven patients received WBRT, and four patients additional HD chemotherapy. In group 1, five of ten patients (50%) achieved CR (follow-up 49-245 months), in four of those five without WBRT. In group 2, both patients achieved CR (follow-up 146 and 211 months). In group 3, one of ten patients (10%) achieved CR after HD chemotherapy and WBRT (follow-up 107 months). It is concluded that cure in patients with BM from NSGCT can be achieved with standard induction chemotherapy without WBRT.

Experimental treatment of brain metastases

The rapid development of targeted therapies capable of entering the brain and the emerging technology of nano shells armed with cytotoxins reflects promising progress in the treatment of brain metastasis. The management of brain metastases is complicated by a number of major problems. The histological, molecular, biologic and immunologic nature of the various tumour types metastasizing to the brain differs significantly. As a consequence, the sensitivity towards various cytotoxic drugs or other treatment options varies substantially. Only few drugs are usually considered capable of penetrating the blood/brain and the brain/liquor barriers. Thus, the availability of a drug with adequate molecular size and pharmacokinetics within the compartments of the central nervous system determine the usage of cytotoxic drugs rather than the sensitivity of a specific tumour type to a specific drug. Recently, however, progress has been made in the development of more efficient types of therapy against brain metastases.

Current surgical management of brain metastases

Metastatic brain tumours are among the most common surgical targets in brain surgery. Up to 40% of cancer patients develop brain metastases during the course of their disease. Lung, breast, kidney, intestine and melanoma are the most common cancers, spreading into the CNS. New techniques in neurosurgery have lead to a significant increase in survival and quality of life of patients suffering from brain metastasis. Image guidance, intraoperative ultrasound, electrophysiological cortical mapping, functional neuronavigation and awake craniotomy expanded the indication of surgery even to patients suffering from multiple metastases. Thus, appropriate selection criteria are necessary to provide benefits of surgery to the widest population of patients possible. Besides traditional criteria like age, Karnofsky performance status (KPS), number, extension, surgical accessibility, histology and status of the systemic disease, recursive partitioning analysis has led to a new preoperative classification system (RPA Classes 1–3), to select patients, having best benefit from surgical treatment.

Management of brain metastases from germ cell tumours

16076 Background: Brain metastases (BM) from germ cell tumours (GCT) are rare events for which treatment is not yet standardized. Methods: The clinical data of patients with BM from GCT treated in ...

An Update on the Treatment of CNS Metastases in Small Cell Lung Cancer

Brain metastases occur frequently and are a significant threat to the quality of life in patients with small cell lung carcinoma. The primary treatment modality has historically been whole brain radiation, which can provide a moderate extension of life and improvement in neurologic symptoms. Despite increasing interest in the use of alternative therapeutic agents-primarily chemotherapy-these have yet to be demonstrated to be superior to radiation in management of brain metastasis. Prophylactic cranial irradiation prevents or delays the occurrence of brain metastases in patients with small cell lung carcinoma. Until recently, this benefit has been thought to be primarily restricted to a minority of patients with limited stage disease. A large European trial, however, has now shown a survival benefit to the use of prophylactic cranial irradiation in patients who have any response to systemic chemotherapy. This finding should significantly shift management practices for this aggressive disease for most patients.

Response of Intracranial Metastases to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: It May All Depend on EGFR Mutations

TO THE EDITOR: We read with great interest the case description by Fekrazad and colleagues in the Journal. They describe a nonsmoking Native American woman with brain metastases from a lung adenocarcinoma who had a marked response to monotherapy with erlotinib at 150 mg/d. Although they do not provide these data, it is very likely that the patient had an activating epidermal growth factor receptor (EGFR) mutation, based on her clinical characteristics and response to the oral tyrosine kinase inhibitor (TKI) erlotinib. In the recently reported phase II trials of gefitinib 250 mg/d and erlotinib 150 mg/d for patients with the L858R and exon 19 deletion EGFR mutations, patients with CNS metastases were included. The overall response rate in these and other prospective trials of gefitinib and erlotinib exceed or equal 75% for all sites. In both instances, it seems that patients with intracranial metastases also have a similar high level of tumor responses in their CNS. The Spanish Lung Cancer Group followed the CNS response of seven chemotherapynaivepatients with an EGFR mutation given erlotinib 150 mg/d (available as part of the 2006 ASCO Annual Meeting’s slide presentation of their abstract). They reported four patients with a complete response and three with a partial response to this EGFR inhibitor: a 100% response rate of brain metastases. These results are astounding, and indicate that in a molecularly selected population with brain metastases, both gefitinib and erlotinib can achieve high response rates in a metastatic site that historically has not been sensitive to systemic chemotherapeutic agents used in non–small-cell lung cancer. Despite the striking efficacy of these EGFR inhibitors, secondary resistance is common and the brain may actually be the first site of loss of response to EGFR TKIs. Others have speculated that over time the effective dose of gefitinib in the CNS may wean to levels that are subtherapeutic to inhibit EGFR mutations. We look forward to mature results of prospective trials that evaluate the clinical benefit of EGFR TKIs in patients who have EGFR mutations with brain metastases. It is not inconceivable to think that in this patient population, oral TKIs may replace or supplement radiation therapy for management of brain metastases.