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Journal of Cancer Research and Therapeutics, Vol. 2, No. 1, January-March, 2006, pp. 5-13 Review Article Brain metastasis-Evidence based management Biswas G, Bhagwat R, Khurana R, Menon H, Prasad N, Parikh PM Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai400 012, India. Correspondence Address: Purvish Parikh, Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India-400 012, Email: purvish@rediffmail.com drgbiswas@yahoo.com Code Number: cr06002 Abstract Advances in cancer management have resulted in a significant increase in median survival of number of diseases. Consequently we are seeing more patients living long enough to develop symptomatic brain metastases. The management of such patients will be discussed here. The most important definitive investigation is contrast enhanced MRI scan of brain. Management consists of supportive care and disease directed treatment. Surgical resection remains the gold standard for the treatment of solitary brain metastases. Whole brain radiotherapy is considered standard treatment for all patients with brain metastases. The role of chemotherapy was limited in the past. Recently several new agents have been identified as potentially useful. Preliminary results indicate that drugs like temozolomide and topotecan have antitumor activity against the brain metastases as well as the primary systemic malignancies. The goal of multimodality treatment for brain metastases is to palliate local symptoms and prevent consequences of neurological involvement.Keywords: Brain Metastasis, Management, Temozolomide Introduction Brain metastasis is the most common intracranial tumor in adults. In the Caucasian population, approximately 100,000 patients have symptomatic intracranial metastases annually; a number that is six times more than the 17,000 patients with malignant primary brain tumors. Some autopsy reports indicate a 25% incidence of brain metastasis in patients who die of cancer.[1] The American Cancer Society estimates that 170,000 cancer patients develop cerebral metastases each year in the United States[2] and many of these patients harbor two or more metastases. Most patients develop involvement of the brain late during the course of metastatic cancer. In some types of cancers, brain metastases may occasionally be the first presenting feature. Patients with lung cancer, breast ca and melanoma have a greater propensity for the same.[3],[4] Pathophysiology For metastatic cells to reach the brain, the primary tumor usually gets access to the circulation either by invading the venules or lymph channels. Before reaching the brain such circulating tumor cells necessarily pass through the right side of the heart and the first capillary bed they encounter, is the lung. Accordingly, patients with symptomatic brain metastasis usually have involvement of the lung (primary tumors or metastases). Factors influencing intracranial metastases:[5] 1) In the resting state, the brain receives 15%-20% of the body′s blood flow. This high volume making it likely that circulating tumor cells will have greater chance of reaching the brain. 2) Tumor cells from certain primaries find the brain an appropriate place for metastatic colony formation and growth. This is one of the reasons that the probability of brain metastases varies among tumor types. In adults, the commonest primary tumor is lung, followed by breast, skin and colon [Table - 1].[6] In the younger age groups, sarcomas (osteogenic and Ewing′s) and germ cell tumors are more common.[6] Renal, colon and breast carcinomas generally produce single metastases whereas malignant melanoma and lung generally produce multiple secondary lesions.[6] 3) The site distribution of brain metastases is also determined by the size of the region and its vasculature. Hence, about 85% of brain metastases are found in the cerebral hemispheres- in the watershed area between middle and posterior cerebral arteries. Approximately 10%-15% of metastases are found in the cerebellum and only about 3% of metastases are found in the brainstem. Renal-cell, gastrointestinal and pelvic cancers tend to metastasize to the infratentorial area, whereas breast carcinoma is commonly found in the posterior pituitary. Clinical features The signs and symptoms of brain metastasis are related to the involved brain area [Table - 2].[7] Most patients presents with headache or focal neurological deficits. Common focal symptoms include muscle weakness, gait disturbances, visual field defects and aphasia. Symptoms usually evolve over a few weeks. However, hemorrhage into the metastases can result in a more dramatic presentation. Such propensity to bleed is commonly seen with tumors like malignant melanoma, thyroid ca, renal cell ca and choriocarcinoma. Diagnosis Proper pretreatment evaluation is important in determining the optimum treatment strategy for patients with multiple brain metastases [Table - 3]. For brain metastases, the term 'solitary' indicates the absence of extracranial metastatic disease, whereas the term 'single' merely indicates the presence of one brain metastasis with no implication as to the status of extracranial disease.[9] Single brain metastases constitute up to 50% of all brain metastases presentations. CT or MRI establishes the diagnosis of brain metastases. MRI is the superior test and should be performed whenever feasible in any patient being evaluated for metastatic brain disease. A high-quality, contrast-enhanced MR scan should be obtained to define the number of metastatic nodules and to look for evidence of leptomeningeal disease. If MRI is unavailable, CT is adequate to exclude brain metastases in most patients, but it can miss small lesions or tumors located in the posterior fossa. PET scans have a sensitivity of only 75% and a specificity of 83% for identification of cerebral metastases. Therefore, they are less accurate than MRI, which remains the gold standard.[10] On CT or MRI, most brain metastases are enhancing lesions surrounded by edema, which extends into the white matter. Unlike primary brain tumors, metastatic lesions rarely involve the corpus callosum or cross the midline. The radiographic appearance of brain metastases is nonspecific and may mimic other processes, such as infection. Therefore, the CT or MR scan must always be interpreted within the context of the clinical picture of the individual patient, particularly since cancer patients are vulnerable to opportunistic CNS infections or may develop second primaries, which can include primary brain tumors.[10] Treatment modalities [Table - 4] 1. Medical Management Vasogenic edema secondary to metastasis typically responds to treatment with corticosteroids. For initial symptom control, dexamethasone is administered at loading dose of 10-20mg followed by doses of 4mg four times a day.[12] This usually results in rapid reduction of the edema and symptom control. Side effects associated with corticosteroids include myopathy, hyperglycemia, edema, weight gain, vascular necrosis and psychosis. All cancer patients on prolonged corticosteroids should receive prophylactic therapy for pneumocystis carini pneumonia [9]. Steroids should be tapered as early as possible (decreasing the dose every three days, as tolerated) to minimize side effects. Anticonvulsants are indicated for all patients who develop a seizure. Prophylactic anticonvulsants have not been shown to be beneficial except in metastasis to motor cortex, synchronous brain metastases and leptomeningeal metastasis.[9] Prophylactic use has the potential to complicate patient management by increasing the risk of medication related side effects and drug interactions.[13] It is recommended to use non-hepatic-enzyme inducing anticonvulsants such as lamotrigine, levetiracetam and gabapentin to control seizures, as these do not increase the clearance of chemotherapeutic agents via the cytochrome P450 isoenzyme CYP3A system. Vigilance for less common complications of brain metastasis, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is critical. 2. Radiotherapy Whole brain Radiotherapy (WBRT) WBRT is considered standard treatment for the patients with brain metastases. WBRT was first described nearly 50 years ago by Chao et al.[14] It may prevent or delay the progression of neurologic deficits, restore function and decrease steroid dependency. A dose of 20Gy in 5 fractions or 30Gy in 10 fractions is recommended.[15],[16] Accelerated hyperfractionated regimens delivering up to 70.4 Gy focal radiation offer no additional benefit relative to the conventional schedule.[17],[18] Data suggests that early whole brain radiotherapy improves neurological control. But there is no clear survival benefit, with average survival 3-4 months in about 50% of the patients from brain metastases.[19],[20] As a result, many practitioners are inclined to defer WBRT until the disease in the brain becomes symptomatic. Patients with low KPS scores and progressive systemic disease often receive WBRT alone. In patients with high KPS scores and systemic disease under control, WBRT is often considered if there are new or recurrent lesions following resection or radiosurgery.[21] The acute toxicities of WBRT include headache, nausea, vomiting, ear blockade, mild-to-moderate fatigue, temporary hair loss and skin hyperpigmentation. Radiation Sensitization for Brain Metastases a) RSR 13 (Efaproxiral) is an allosteric modifier of hemoglobin that decreases the affinity of hemoglobin binding to oxygen, permitting greater oxygenation of hypoxic tumor cells, to enhance radiation cell killing.[25] A randomized, phase III study of WBRT with or without efaproxiral[26] involving 538 patients did not demonstrate significant increase in median survival in the combined arm. A subset analysis of 115 breast cancer patients (20% of the study population) suggested a possible survival advantage.[26] b) Motexafin gadolinium is the first of a new class of drugs known as texaphyrins, which are porphyrin-like macrocyclic compounds that forms complex with large metal cations.[27] MRI studies have shown that motexafin gadolinium is selectively retained in tumor cells.[28] Inside the tumor cell, it generates reactive oxygen species and oxidizes various intracellular reducing metabolites in a process known as 'futile redox cycling'.[27],[29] This leads to altered cellular metabolism, inhibition of DNA repair and promotes apoptosis.[27],[30] Tumor cells containing motexafin gadolinium may therefore be more vulnerable to the ionizing effects of radiation or the effects of chemotherapy. It has been tested in phase I to III trials in patients with brain metastases. A phase III study was conducted to determine whether motexafin gadolinium used with WBRT would improve neurologic function and survival.[31] Time to neurologic progression, time to loss of functional independence and radiologic response rates were secondary efficacy end points. The results of this study[31] suggest that motexafin gadolinium does not improve survival. Other end points, especially in NSCLC, may be improved like the median time to neurologic progression. Recent work published by the Radiotherapy oncology group (RTOG) has delineated specific prognostic categories for patients with newly diagnosed brain metastases [Table - 5].[32] Based on these criteria following treatment algorithm has been proposed. 3. Surgery The goals of surgery in the management of brain metastases are to obtain immediate symptom relief, gain local control and histological confirmation.[33] Lesions surgically accessible have made improvements in stereotactic techniques, cortical mapping and the use of ultrasonography.[34] Surgery is an important modality for patients with a single brain metastasis, particularly when favorable prognostic factors and systemic disease control are present.[35] A landmark trial demonstrated that selected patients with resectable single brain metastases randomized to undergo resection and WBRT survived longer than did those who underwent biopsies and WBRT alone[36] [Table - 6]. This randomized trial and a confirmatory trial have established surgery and postoperative irradiation as the standard approach for such patients.[37] Retrospective data from the Memorial Sloan-Kettering Cancer Center[38] and the M.D. Anderson Cancer Center[39] on the surgical management of brain metastases from breast cancer showed a median survival of approximately 16 months. The role of surgery in patients with multiple brain metastases is controversial. In a retrospective review,[40] in patients with multiple metastases who underwent resection of all their lesions, a longer survival length (median 14 months) was found as compared with those with multiple metastases not resected (median 6 months) (p = 0.003). 4. Stereotactic Radiosurgery (SRS) Stereotactic radiosurgery, in which high doses of focused radiation are delivered by a linear accelerator or by gamma knife to the brain metastases,[3] has emerged as a treatment for patients with metastatic brain disease with or without WBRT [Table - 6]. The hallmark of SRS is the rapid dose fall off at the target edges, permitting a clinically significant dose to be given to the target while a clinically insignificant dose is delivered to the surrounding normal brain.[33] The advantages of SRS include lower risk of hemorrhage, infection and tumor seeding. Surgery immediately relieves the mass effect, provides a tissue diagnosis and has no risk of radiation necrosis.[42] The effect of SRS combined with WBRT in patients harboring two to four metastases has been shown to be superior to WBRT alone[45],[46],[47] in the control of metastatic brain disease [Table - 6]. The largest and most credible randomized study to date was conducted by the RTOG [Table - 6]. In this trial, 333 patients were randomly assigned to WBRT or WBRT plus SRS. The overall trial demonstrated no significant improvement in survival. The prespecified group of patients with a single metastasis, however, experienced significant improvement in median survival (6.5 v 4.9 months; P = . 05). In this study, radiosurgery technique (ie, linear accelerator v gamma knife) had no impact on outcome. The treatment dose to the tumor margin typically is between 15 to 20 Gy and is based on tumor size, location, history of prior radiotherapy and dose overlap from the treatment of other radiosurgical metastases. 5. Chemotherapy The primary hurdle in developing chemotherapy regimens for patients with brain metastases is that the intact blood-brain barrier (BBB) is largely impermeable to most chemotherapeutic drugs. However, the microcirculation of cerebral metastases differs substantially from that of the normal blood-brain barrier. This is inferred from the leakage of gadolinium or iodinated contrast into brain metastases observed in MRI or CT scans, respectively. By the time most patients develop brain metastases, they have already been exposed to the most effective chemotherapeutic agents and the metastatic clones are relatively chemo resistant. Although BBB is disrupted in patients with brain metastases, water-soluble chemotherapy may not penetrate sufficiently to attain a therapeutic concentration. Newly diagnosed patients who are chemotherapy naive and neurologically asymptomatic may respond favorably to systemic chemotherapy. Treatment efficacy is determined by the sensitivity of tumor cells to chemotherapeutic agents and whether or not these drugs can cross the BBB. Among the various tumor types, brain metastases from small-cell lung cancer, germ cell tumors and lymphoid malignancies are perhaps the most sensitive to chemotherapy, whereas brain metastases from non-small-cell lung cancer (NSCLC) and breast cancer are somewhat less sensitive to chemotherapy.[1] An objective response rate (ORR) of 82 %and a median survival time of 34 weeks[49] were reported in patients with chemosensitive brain metastases from SCLC who was treated initially with cyclophosphamide, doxorubicin, vincristine and etoposide. In patients with brain metastases from breast cancer at initial diagnosis, cisplatin and etoposide yielded a high ORR of 55% in the central nervous system (CNS), whereas response rates of 17%-59% were seen in those treated with combination chemotherapeutic regimens that included: cyclophosphamide, doxorubicin and prednisolone; cyclophosphamide, doxorubicin, prednisone, methotrexate and vincristine; methotrexate, vincristine and prednisolone; cyclophosphamide and doxorubicin; cyclophosphamide, methotrexate and 5-fluorouracil; and cyclophosphamide, doxorubicin and 5-fluorouracil. [50],[51],[52] Although the role of chemotherapy for brain metastases still remains controversial, a new generation of chemotherapeutic agents those have the ability to cross an intact or physiologically normal BBB, hold promise. a) Temozolomide (TMZ) This small molecule is a third generation alkylating agent, which is 100% bioavailable when taken orally. Because of its small size and lipophilic properties, it crosses the BBB.[53] Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite (MTIC).[54] Unlike, nitrosoureas and other alkylating agents that chemically cross-link the DNA and are associated with severe, dose limiting, cumulative hematological toxicity, TMZ is associated with generally mild, noncumulative myelosuppression.[55] Based on the favorable toxicity profile observed in early clinical trials, subsequent studies have investigated doses of 150 mg/m2/day for 5 days for patients who had previously been treated with cytotoxic chemotherapy with a planned increase to 200 mg/m2/day if no major myelosuppression was evident on day 22 of the 28-day cycle. For previously untreated patients, the initial dose is typically 200 mg/m2/day for ?5 days. The most common nonhematologic adverse events are nausea, vomiting, headache, fatigue and constipation. These events are generally mild to moderate in severity.[55] Limited response rates have been obtained in metastatic melanoma (13.5%) and NSCLC (0-8%)[56],[57],[58] [Table - 7]. In newly diagnosed brain metastases patients with progression after WBRT show ORRs between 5 and 10%.[59],[60] Several phase II trials suggest that single-agent temozolomide [Table - 7]has modest activity in patients with recurrent or progressive brain metastases. The efficacy and safety of using temozolomide concurrently with WBRT for patients with newly diagnosed brain metastases was evaluated in four recent phase II studies [Table - 8]. The largest of these trials enrolled 134 patients, 82% with lung cancer. Patients were randomly assigned to receive temozolomide (75 mg/m2/d) plus WBRT (10 fractions of 3 Gy each) or WBRT alone. In addition, patients in the combined therapy group continued to receive temozolomide (200 mg/m2 days 1 through 5 every 4 weeks for six cycles) beginning 1 month after completing WBRT. The group receiving WBRT plus temozolomide experienced a significant improvement in response rate compared with those receiving WBRT alone (53% v 33%; P =.039). Patients younger than 60 years and those with KPS more than 90 realized even greater relative benefit ( P =. 003). There was no significant difference in neurologic response. The temozolomide arm yielded a nonsignificant trend toward improved survival compared with WBRT alone (8.3 v 6.3 months; P =.179) [Table - 8]. Chemoradiation studies with temozolomide have shown encouraging results with an objective response rate in 96 %of patients versus 66% in the WBRT group[63] [Table - 8]. This impressive data is not seconded by other trials. b) Topotecan Topotecan is a semisynthetic camptothecin derivative that selectively inhibits topoisomerase I in the S phase of the cell cycle. The activity, tolerability and symptom improvement associated with topotecan has established the clinical value of topotecan as second-line therapy in patients with SCLC and ovarian cancer.[69],[70] Topotecan freely penetrates the BBB and measurable levels of topotecan and its metabolite can be detected in CSF. [71]This may be attributed to its low protein binding in serum (20% of less) relative to other campothecins.[71] The emerging data suggest that systemically administered topotecan has antitumor activity against brain metastases. The potential antitumor activity of topotecan against brain metastasis has been investigated in several studies [Table - 9]. These studies support the use of topotecan as a first line treatment for newly diagnosed brain metastases in SCLC particularly in platinum-sensitive patients. A comparison of the responses of cerebral and extracerebral lesions to topotecan treatment suggests that the responses in the former occurred more rapidly.[78] This may be explained by the lack of exposure of brain metastasis to prior cytotoxic agents. Responses or disease stabilization in the brain often occurred in patients with progressive extracerebral lesions suggesting that cranial and extracranial metastases may have heterogenous topotecan sensitivities. The feasibility of topotecan as a radiosensitizer has been studied in phase I and II studies. The phase I study [79]included topotecan in a dose of 1.5 mg/m2 on days 1-5 of a 21 day cycle and WBRT in a dose of 60 Gy in 30 fractions over 6 weeks and the phase II study[80] had a continuous IV infusion of topotecan in dose of 0.4-0.6 mg/m2day for 21 days in combination with WBRT. Although there was no statistically significant survival advantage over other therapies, the combination was well tolerated. c) Combination Chemotherapy The combination of a topoisomerase 1 inhibitor with an alkylating agent has demonstrated synergy in preclinical studies. Following this it was hypothesized that the combination of topotecan with temozolamide may enhance the cytotoxic activity of these two agents. A phase I study[81] using this combination demonstrated partial responses (PR) in 3 pretreated patients and stable disease (SD) in 7 of the 25 patients treated with various dosage schedules of the two drugs. In view of dose-limiting febrile neutropenia, this study recommended topotecan in a dose of 1.5 mg/m2/day along with temozolamide in a dose of 150 mg/m2 daily for 5 days for future phase II trials. d) Paclitaxel The role of paclitaxel was reported in a phase III study[82] in which 86 patients were randomly assigned to receive paclitaxel or WBRT alone.52 Grade 3/4 toxicity was higher in the paclitaxel group, but median survival was not improved. Chemotherapy may be useful in the setting of recurrent brain metastases. At recurrence, most patients have multiple lesions that are not amenable to radiotherapy or focal therapy. The majority have active and often symptomatic systemic tumor. The clinical scenario makes palliative chemotherapy an appropriate intervention. Chemotherapy currently has a limited but increasing role in the treatment of brain metastases. Though WBRT is still the standard of care, immediate (first-line) chemotherapy may be considered in patients with a chemo-sensitive primary tumour, with clinically asymptomatic brain metastases, or with only minor neurological signs and symptoms and in whom there is an indication for systemic chemotherapy for metastases elsewhere in the body. 6. Chemoradiation In-vitro studies have suggested an increased cell kill using topotecan in combination with irradiation.[83] The use of cisplatin, carmustine and etoposide with WBRT was studied in a phase II trial[84] in patients with NSCLC and SCLC. Of the 60 patients there were 35 (58%) CNS responses, of which 25 (42%) had a CR. The median survival was 7.4 months; at 18 months the survival rate was 19%. A phase III study[85] with cisplatin and vinorelbine and WBRT either sequentially or concurrently showed no difference in the overall response rates (27% in both treatment arms) or median survival time (14 weeks versus 8 weeks). The study however suggested that chemoradiation is feasible, myelosuppression being the only important toxicity. 7. Gefitinib Prognosis Once brain metastases have developed, the patient′s overall prognosis is poor, with a median survival of 4-5 months and a 1-year survival of approximately 10%. Important prognostic factors [Table - 10] for a better survival are a good performance status, absence of extracranial metastases, controlled primary tumor and age less than 65 years. When all these factors were present, the median survival time was more than 7 months, but if one of them was absent the median survival fell to around 4 months. The treatment options and related outcome has been presented in [Table - 11]. Conclusion Improvement in therapy for systemic cancer has resulted in an increase in a number of patients living long enough to develop brain metastases. Clearly, they pose a major threat to the patient′s well being and quality of life with an increased risk of developing neurological and cognitive deficits. In most patients, such metastases are diagnosed late in the disease course. Although the average prognosis for an individual with brain metastases is poor, selected patients will benefit significantly from aggressive local therapy or judicious use of chemotherapy. References
Copyright 2006 - Journal of Cancer Research and Therapeutics The following images related to this document are available:Photo images[cr06002t8.jpg] [cr06002t1.jpg] [cr06002t9.jpg] [cr06002t7.jpg] [cr06002t2.jpg] [cr06002t4.jpg] [cr06002t10.jpg] [cr06002f1.jpg] [cr06002t5.jpg] [cr06002t11.jpg] [cr06002t6.jpg] [cr06002t3.jpg] |
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