Peter MacCallum Cancer Centre East Melbourne, Vic
Fifteen years ago, the development of brain metastases was regarded as such a negative prognostic event that for most patients it meant the cessation of active systemic management, and many were discouraged from having even palliative radiotherapy, which was the standard treatment approach at that time. Death quickly ensued, with untreated patients having a median survival of only four weeks. However, the intervening years have seen a number of clinical trials and developments in all modalities of oncology that have made this earlier view outmoded. Today the trend is to adopt a much more active approach to the treatment of patients with brain metastases, and to individualise treatment based on a number of patient and disease-related factors. The aims of this approach are to reduce neurological morbidity and mortality in patients with brain metastases, and thus improve both their quality of life and ultimately their survival.
Whole brain radiotherapy (WBRT) remains the most appropriate treatment for the majority of patients with brain metastases. Around two-thirds of patients have multiple metastases at diagnosis, thus rendering surgery not an option in most cases. Radiotherapy increases the median survival to four to six months, and reduces the proportion of patients who die of progressive neurological complications to less than 50%, ie many patients succumb to their systemic disease rather than their brain disease.1 The optimal radiation schedule, however, is still open to question. The Radiation Therapy Oncology Group (RTOG) has performed a number of randomised trials of different regimens of WBRT, ranging from 20Gray (Gy) in 5 fractions to 50Gy in 20 fractions, without any obvious difference in efficacy.2 Thus most radiation oncologists will opt for a short schedule – 20Gy in 5 fractions, or 30Gy in 10 fractions being the most commonly used.
A number of studies have attempted to improve the efficacy of WBRT by the addition of radiation sensitisers such as RSR13 and motexafin gadolinium, or concurrent chemotherapy. The combination of WBRT and radiation sensitisers appears to result in minor gains in survival and/or time to neurological progression in very specific sub-populations of patients with brain metastases,3 and studies are ongoing. Concurrent chemotherapy trials have suffered from difficulties with accrual, but significant benefit with older chemotherapy agents such as carboplatin has not been clearly established.4However, newer agents may be more successful in this setting. Phase I/II studies of Topotecan in combination with WBRT have demonstrated encouraging early results.5There also has been a phase II randomised trial showing a significant improvement in survival and time to neurological progression in patients treated with concurrent and adjuvant temozolomide and WBRT 40Gy compared with WBRT alone.6 Larger randomised studies will be necessary to confirm the results of these smaller studies.
One area of increasing interest is that of prophylactic cranial irradiation (PCI). Meta-analysis has now confirmed this as not only reducing the incidence of brain recurrence in patients with small-cell lung cancer who achieve a complete response of their primary disease by over 50% (relative risk 0.46), but also has demonstrated increased survival in PCI-treated patients (16% reduction in risk of death, with a 5.4% increase in three-year survival).7 PCI for non-small cell lung cancer (NSCLC) has not been so successful; however, with better staging, particularly PET scanning, and more effective primary treatment, the role of PCI in selected patients is being re-evaluated, with several randomised studies in progress.
One of the major concerns with WBRT has been the potential for late toxicity. Although most patients with brain metastases treated with WBRT do not survive 12 months, there is a significant tail on the survival curve, and early reports suggested a worrying incidence of long-term dementia in patients who survived more than 12 months. Recent trials, however, indicate a much lower risk of long-term toxicity. Tests of neurocognitive function in patients treated with PCI do not demonstrate any excess of long-term impairment compared with the non-PCI group.8 Fractionation may be important, and it is probably best to avoid fraction sizes greater than 3Gy in patients with better prognosis disease.
But what defines “better prognosis disease”? Although the RTOG trials did not show an advantage to any specific radiation schedule, they did allow the identification of subgroups with different prognoses. This recursive partitioning analysis (RPA) assigned patients to one of three groups. RPA class1 patients had Karnofsky scores of > 70, age < 65 years, controlled primary disease and no extracranial metastases. RPA class 3 patients had Karnofsky scores of < 70, with or without other unfavourable factors. RPA class 2 included all other patients. Survival in the three groups, 1, 2, and 3, was 7.1 months, 4.2 months, and 2.3 months respectively. The RPA class can thus be used as a guide to the aggressiveness of the treatment approach.9
The landmark surgical study was performed by Patchell, who randomised 48 patients with single brain metastases to either surgery plus WBRT or WBRT alone.10 The radiation dose for both groups was 36Gy in 12 daily fractions. There was a statistically significant increase in survival for the surgical group (40 weeks vs 15 weeks). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence were significantly longer in the surgical resection group.
Importantly, the one-month mortality was four percent in each group, indicating that there was no additional mortality resulting from surgery. A subsequent Dutch study using a different radiation schedule (40Gy in 20 fractions) showed a similar survival advantage to the surgical arm, with a trend toward longer duration of functional independence in these patients.11 A negative Canadian study has been criticised because of probable selection bias leading to poor results in its surgical arm compared with the other two studies, and its results thus largely disregarded.12
The two positive studies established the role of surgery in the treatment of patients with a single brain metastasis. Two further questions were then posed. The first was whether surgery would be beneficial for patients with more than one brain metastasis. To date there remains no definite evidence to support a survival advantage for surgery over WBRT in this situation. However, surgery may be considered in patients with multiple metastases in specific situations, eg a dominant lesion responsible for most of the patient’s symptoms (large posterior fossa metastasis, metastasis with large area of associated oedema), or residual/recurrent symptomatic lesion following radiotherapy. Neurological morbidity, if not survival, can be considerably improved by this approach. The more controversial question remains whether patients with a single metastasis which has been resected benefit from the addition of radiotherapy. The one randomised study looking at this question showed a marked reduction in the incidence of in-brain recurrence both at the index site and elsewhere in the brain, and in neurological mortality.13 However, no survival advantage could be demonstrated. This has been interpreted by some as a reason to defer radiotherapy, with avoidance of neurological morbidity being cited as a major benefit; however, the toxicity of WBRT is generally modest, and should be balanced against the documented reduction in neurocognitive functioning that results from recurrent brain metastases. WBRT given at the time of recurrence may not improve this, even with objective response to treatment. Despite the negative study results, Patchell remains convinced there is a strong argument in favour of adjuvant WBRT following focal therapy.
There is a small subgroup of patients whose solitary brain metastasis is either the presenting symptom of their malignancy, or is found on initial staging. Several small retrospective series support a radical surgical approach at both sites in such patients, including a local study of 20 patients which reported a zero mortality rate with this approach, and a median survival of 12 months.14
Radiosurgery is a radiotherapeutic technique that delivers high dose, highly conformal, small field radiotherapy to brain lesions that might otherwise be treated surgically. Although there are many retrospective reports of its efficacy in the treatment of brain metastases,15 there is a paucity of randomised data. The largest randomised study is the RTOG 95-08, which compared WBRT 37.5Gy plus radiosurgery to WBRT alone in patients with up to three brain metastases. Patients with single metastases treated with radiosurgery plus WBRT had a significantly longer survival than those treated with WBRT alone (6.5 months vs 4.9 months), but in those with two or three metastases there was no significant difference in either survival or local failure rates. There was no significant difference in the cause of death for either group.16
Comparison of the results of radiosurgery plus WBRT for single brain metastases appear to be similar to those of surgery plus WBRT, although no direct randomised comparison has been undertaken to date. A current randomised Trans-Tasman Radiation Oncology Group (TROG) study hopes to answer this question definitively. In the interim it is reasonable to offer radiosurgery as an alternative to surgery in patients with single metastases less than 3cm in diameter not demonstrating significant mass effect. Radiosurgery may also be considered for patients treated surgically, where there is known or suspected small volume residual disease, although there is no published data to support this approach at present.
The long-held view that chemotherapy was unlikely to be successful for brain metastases because of the blood-brain barrier has been challenged by newer agents that are achieving significant response rates. The current view is that brain metastases themselves cause disruption of the blood-brain barrier, and that the lack of response to chemotherapy in the past related more to ineffective agents given as second- or third-line therapy. Despite this optimism, most of the supporting evidence for chemotherapy remains anecdotal, with a paucity of clinical trial data. Temozolomide and Topotecan are the most promising agents, with small phase II trials having response rates of 30-40%, including patients previously irradiated.17,18 Larger clinical trials are needed to confirm these findings, and also to investigate newer molecular-based therapeutics,19 alone and in combination with currently available treatment options, to determine the optimal application of chemotherapy to metastatic brain tumours.
It may be reasonable to consider chemotherapy as first-line treatment for patients with brain metastases causing little or no neurological morbidity, and who have an indication for systemic chemotherapy for metastases elsewhere in the body. However, if unnecessary neurological morbidity is to be avoided, such patients need to be carefully monitored, and other treatment modalities introduced promptly if there is not good early evidence of response.
There is no one-size-fits-all treatment for patients with brain metastases. A treatment plan based on careful consideration of individual patient, disease and treatment parameters will maximise the outcome for the patient, in both survival and quality of life. Such decisions are best made in a multidisciplinary clinic by clinicians experienced in the management of patients with brain metastases. Patients should be treated on clinical trials where possible. Regular monitoring post-treatment will enable any further appropriate interventions to be offered in a timely fashion.
3. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21:2529-36.
4. Guerrieri M, Wong K, Ryan G, et al. A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung Cancer. In press 2004.
7. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476-84.
8. Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997;33:1752-8.
9. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745-51.
15. Auchter R, Lamond JP, Alexander E, et al. A multi-institutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys. 1996;35:27-35.
16. Sperduto PW, Scott C, Andrews D, et al. A phase III trial comparing whole brain irradiation alone versus whole brain irradiation plus stereotactic radiosurgery for patients with one to three brain metastases. Int J Radiat Oncol Biol Phys. 2002;51(2 Suppl):S3.
17. Korfel A, Oehm C, von Pawel J, et al. Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. A multicentre phase II study. Eur J Cancer. 2002;38:1724-9.
19. Cappuzzo F, Ardizzoni A, Soto-Parra H, et al. Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC). Lung Cancer. 2003;41:227-31.