The combination of the biologic lapatinib (Tykerb) and capecitabine (Xeloda) chemotherapy appears to shrink brain metastases from HER2-positive breast cancer without need for radiation, a phase II trial showed.

Two-thirds of patients saw their previously-untreated brain lesions shrink by at least half with the treatment regimen, Thomas Bachelot, MD, of the Centre Léon Bérard in Lyon, France, and colleagues found in the LANDSCAPE trial.

The median time to whole-brain radiotherapy (WBRT) was 8.3 months, the group reported online in the Lancet Oncology.

“Traditionally, most of these women receive WBRT which can impair cognitive function. Delaying such a treatment for those patients is potentially a big advance, which is particularly relevant for a population with short overall survival,” Bachelot noted in a press release.

The efficacy of lapatinib and capecitabine was similar to whole-brain radiotherapy, noted Rupert Bartsch, MD, and Matthias Preusser, MD, both of the Medical University of Vienna, in an accompanying commentary.

The primary systemic strategy “might already be a valid treatment option” in this population with minimal clinical symptoms and good performance status, they suggested.

However, they cautioned about limitations of the treatment and the study.

Serious adverse events weren’t uncommon with lapatinib plus capecitabine — 49% of the women faced grade 3 or 4 adverse events, most commonly diarrhea and hand-foot syndrome.

Side effects were “manageable,” however, compared with those of brain radiation, which include delayed side effects of cerebellar dysfunction and cataracts, according to the researchers. Only four of the women discontinued treatment because of adverse effects.

But the group provided no data on neurocognitive function in the open-label, single-arm study of 45 patients.

“Furthermore, more than 40% of all patients did not present with neurological symptoms at baseline, which raises the question of whether screening for brain metastases was done and raises doubts about the feasibility of extrapolation of their findings to the general population of patients with symptomatic brain metastases,” Bartsch and Preusser pointed out.

“More than 95% of all patients presented with Eastern Cooperative Oncology Group performance status of 0–2, which is better than would be expected in an unselected population of patients with brain metastases.”

Nevertheless, it’s clear that a phase III study is warranted, they agreed with the researchers, who said they are planning such a trial.

The brain metastasis response was “much higher than we expected” and greater than the 27% to 50% response rates seen with whole-brain radiotherapy alone in prior studies, Bachelot’s group noted.

For the primary endpoint, 29 of the 44 evaluable patients had an objective CNS response marked by at least 50% volume reduction of brain metastases, all partial responses.

Notably, nine of the women (20%) got a CNS volumetric reduction of 80% or greater. Median time to CNS progression was 5.5 months.

The researchers cautioned that direct comparison cannot be made between these results and those of whole-brain radiation alone or other regimens, such as monotherapy.

The study was funded by GlaxoSmithKline-France and UNICANCER.

Bachelot and another co-author reported consultant or advisory roles at GlaxoSmithKline-France and research funding by GlaxoSmithKline-France. A third author declared research funding by GlaxoSmithKline-France.

Bartsch and Preusser reported having no conflicts of interest to disclose.

Primary source: The Lancet Oncology
Source reference:
Bachelot T, et al “Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study” Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70432-1.

Additional source: The Lancet Oncology
Source reference:
Bartsch R, Preusser M “Primary systemic treatment of breast-cancer brain metastases” Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70449-7.

Assistant Professor, Radiation Oncology, McGill University

It was decades after the introduction of the first concept of stereotactic radiosurgery (SRS) at the Karolinska Institute¹ that stereotactic irradiation began to see widespread use in the treatment of brain tumors. Despite many technical changes since the 1950s, radiosurgery remains a radiotherapy technique characterized by accurate delivery of high doses of radiation in a single session to small, stereotactically defined targets with sharp dose fall-off outside the targeted volume. Such a treatment appears ideally suited to parenchymal brain metastases—tumors geographically well delimited with minimal infiltration into the adjacent brain.² Unfortunately, such metastases are a common occurrence, representing approximately 250,000 cases per year in the US alone.³ Thus, even if only a fraction of these patients are referred for SRS, the management of brain metastases invariably represents a significant fraction of the workload of a radiosurgery practice. Until recently most reports supporting the use of SRS were retrospective case series. This has changed with the publication of randomized trials characterizing the benefits of SRS in the management of newly diagnosed brain oligometastases.

Newly Diagnosed Brain Metastases

Patients with newly diagnosed brain metastases have poor local control after whole-brain radiation (WBRT). Even when intra-cranial disease is limited, neurological death occurs in approximately one-third of patients. These facts underlie the investigation of SRS as an addition to WBRT. In a small trial limited to patients with 2–4 metastases—all ≤25mm in mean diameter— Kondziolka et al. randomized patients to WBRT alone (30Gy in 12 fractions) or WBRT with SRS.⁴ The trial was closed prematurely when the primary end-point—local control—was achieved after the first 27 patients were enrolled. Local control was 0% at one year in the control arm, well below what is expected. Overall survival was not different between the two arms (median

7.5 months for WBRT and 11.0 months for WBRT plus SRS) and there was no information regarding treatment toxicity or quality of life. In a second small and, as yet, unpublished trial, Chougule et al. randomized patients to three treatment strategies: WBRT (30Gy in 10 fractions), WBRT plus SRS, and SRS alone.⁵ Patients were eligible if they had ≤3 metastases, tumor volume ≤30cc, and a life expectancy of three months. Ninety-six patients received the allocated treatment and were part of the analysis. Approximately half of the

David Roberge, MD, is an Assistant Professor of Radiation Oncology at McGill University. In the late 1980s the McGill team was pioneering in developing linear accelerator-based radiosurgery in North America. This team is well known for the development of dynamic stereotactic radiosurgery, as well as for early work on fractionated stereotactic radiotherapy. They continue to be prominent in multi-institutional trials of radiosurgery. Dr Roberge’s own clinical and academic interests include intra­and extra-cranial stereotactic irradiation. Radiosurgery is a prominent subject of his book chapters, scientific papers, and visiting professorships. Sponsored by Schering Canada, he is the principal investigator of a phase I trial of chemosensitized radiosurgery for recurrent brain metastases.

patients underwent resection of a large symptomatic lesion prior to randomization. In looking specifically at the issue of adding SRS to WBRT, local control was improved from 62 to 91%, but median overall survival was unchanged (five months for the combination and nine months for WBRT alone). In what is to be the definitive trial of SRS as a focal boost to WBRT, the Radiation Therapy Oncology Group (RTOG) accrued patients in a trial of WBRT (37.5Gy in 15 fractions) versus WBRT followed by SRS (RTOG 95-08).⁶ From 1999 to 2001, 333 patients were randomized. Eligible patients had 1–3 metastases (the largest ≤4cm), were not surgical candidates, and had a Karnofsky Performance Status score of ≥70. The primary end-point of the trial was overall survival with a planned analysis for patients with a single lesion. Overall, the trial did not find a significant advantage in overall survival

(6.5 versus 5.7 months, p=0.13), but did show an improvement in survival for patients with a single lesion (6.5 versus 4.9 months, p=0.04). The less likely a patient is to die from extra-cranial disease, the more he or she is expected to benefit from aggressive central nervous system (CNS)-directed therapy. This was shown in various subgroup analyses. For example, young patients (age <65) having controlled primary tumors and no other metastases had a median survival of 11.6 months with WBRT plus SRS versus

9.6 months for WBRT. The trial also confirmed that SRS can be performed safely, only adding 3% grade III–IV acute and late toxicity.

Recurrent Brain Metastases

Patients with recurrent or progressive brain metastases have limited treatment options. Although there is no high-level evidence supporting the use of radiosurgery in these patients, retrospective series of selected patients report median overall survival times similar to those expected for patients treated at initial presentation (6–10 months).^7,8 Most patients in these series have been treated for 1–3 metastases, but patterns of practice vary widely. For reasons including patient and physician preference, it is unlikely that the benefit of radiosurgery in this setting will ever be tested in a randomized trial.

Controversies

Surgery versus Radiosurgery

Now that randomized studies support a survival advantage to adding either surgery or radiosurgery to WBRT in the treatment of solitary brain metastases, clinicians and patients must often choose between the two modalities. In some cases the choice is obvious: SRS is preferred for lesions in eloquent or surgically inaccessible areas while surgery is chosen for lesions too large for SRS (>4cm) or in patients lacking a pathological diagnosis. For other cases, the advantages and disadvantages of the two modalities are weighed in the context of the individual patient. Surgery offers immediate relief of mass effect, reduced steroid use, and a pathological diagnosis. On the other hand,radiosurgery is a non-invasive outpatient procedure without risk for leptomeningeal tumor seeding. There have been unsuccessful attempts to obtain class I evidence to guide us in cases for which both treatments are reasonable. At this time patients are still being enrolled in a phase III trial.

Whole-brain Radiotherapy

“Suddenly a solitary horseman appeared on the horizon, then another, then another, and then six. In a few moments a whole crowd of horsemen swooped down upon him.” Stephen Leacock lived a stone’s throw from the Montreal General Hospital and authored this passage without suspecting that it would apply to the subject of oligometastases.⁹ As with the horsemen, brain metastases are unrelenting, and truly cured patients are a rarity. If they are afforded a long enough reprieve from their extra-cranial disease, approximately 80% of patients treated without WBRT will have progressive intra-cranial disease. It has now been demonstrated in two trials that WBRT can decrease the occurrence of new brain metastases. In the three-arm trial of Chougule et al., the development of new brain metastases was halved by the use of WBRT (19–23 versus 43%).⁵ In a second recently published multicenter trial, 132 patients were randomized to SRS versus WBRT (30Gy in 10 fractions) plus SRS.¹⁰ The use of WBRT decreased the one-year rate of brain tumor recurrence from 76.4 to 46.8% (p<0.001), but did not improve overall survival (38.5 versus 28.4% at one year, for WBRT plus SRS and SRS, respectively (p=0.42). A third, smaller trial failed to complete accrual. This Trans-Tasman Radiation Oncology Group trial randomized patients post-surgery or -radiosurgery to WBRT (30–36Gy) versus observation. Despite a large difference in CNS relapse (30 versus 78%), this was not statistically significant as only 19 patients were enrolled. With only 20–30% of oligometastatic patients suffering a neurological death, current published trials are all underpowered to detect any survival advantage that could reasonably be expected to result from even a 50% decrease in new brain metastases. After an initial failed effort by the American College of Surgeons Oncology Group (ACOSOG), two groups—the European Organization for Research and Treatment of Cancer (EORTC) and the North Central Cancer Treatment Group (NCCTG)—are currently taking up this issue with larger projected sample sizes (340 and 528 patients). At this time, what can be asserted with confidence is that WBRT significantly reduces the risk of developing new metastases. Despite regular imaging, patients in whom WBRT is withheld will most commonly have symptomatic recurrences. They have a five-fold risk of needing salvage treatment and not all patients will be amenable to second-line focal therapy.¹¹ Whether these risks are offset by the—mostly unquantified—toxicities of WBRT is a matter of hot debate.

Management of ‘Radio-resistant’ Tumors

With few exceptions, in the absence of histology-specific interventions, treatment of brain metastases tends to be decided with little concern as to the nature of the primary tumor. As an example, RTOG 95-08 was open to all primary tumors with the exception of hematological malignancies.⁶ Despite generally broad eligibility criteria, two-thirds of patients in most trials have non-small-cell lung cancer (NSCLC). Thus, expanding the conclusions of current trials to less common histologies might not be appropriate. In a review of 189 patients treated with SRS for ‘radioresistant’ tumors, the one-year actuarial local control was 52%.¹² In keeping with other published series, the local control in this group was better for renal cell carcinoma and worse for patients with melanoma or sarcoma. The role of WBRT is undefined in these patients. Although new brain metastases are common, good evidence that they can be prevented by WBRT is lacking.

Radiosurgery Trends

Fractionation

To any radiobiologist, the choice of a single fraction of radiation to control an epithelial tumor is counterintuitive. Not to fractionate is to miss an opportunity to differentially spare normal tissue and allow necrotic tumors to re-oxygenate and cancer cells to redistribute into more sensitive phases of the cell cycle. These radiobiological disadvantages have been partially offset by the steep dose gradient limiting radiation exposure of healthy brains as well as the potential effect of high single doses on tumor vasculature. It remains that, to avoid toxicity, SRS doses must be decreased for metastases larger than 2cm. In these tumors, the actuarial local control is disappointing, a fact masked by reporting crude data in patients with short survival. In a series from the Cleveland clinic, one-year local control rates were 45 and 49% for lesions treated with 15 and 18Gy, respectively.¹³ Until recently, because of the need for rigid frames affixed to the patient’s skull, stereotactic accuracy had been mostly limited to single fraction treatments. Newer technologies in image-guided radiotherapy now permit SRS positioning accuracy without the use of an invasive frame.¹⁴ This allows convenient fractionation of the dose, possibly leading to better local control for lesions >2cm and making larger lesions amenable to focal radiotherapy. Another strategy made possible by new technology is the so-called concurrent boost approach, in which individual tumors are ‘boosted’ during the delivery of WBRT.¹⁵

Surgery, SRS, WBRT, and the Kitchen Sink

For patients managed with surgical resection, the surgical bed is an important site of failure—even with adjuvant WBRT. This has been an opportunity to investigate SRS as a complement or alternative to WBRT.¹⁶ When used alone, it may be more logical to fractionate the dose as, in contrast to traditional SRS, what is treated is mostly normal brain tissue.

Targeted Therapy/Chemotherapy

As targeted small molecules and blood–brain-barrier-crossing cytotoxic agents enter the therapeutic armamentarium for a growing number of malignancies, the agents will complement and even compete with radiosurgery.¹⁷ The current RTOG trial for NSCLC brain oligometastases is currently investigating two such agents: temozolomide and erlotinib. At McGill University, chemosensitization is under investigation for patients treated with SRS alone in the context of recurrent brain metastases.

Conclusions

SRS is an important tool in the management of selected patients with intra­cranial metastases. The technology is evolving and its use continues to be refined through prospective clinical trials. ■

1. Leksell L, Acta Chirurgica Scandinavia, 1951;102:316–19. 7. Davey P, et al., Br J Neurosurg, 1994;8:717–23. 13. Vogelbaum MA, et al., J Neurosurg, 2006;104:907–12.
2. Noel G, et al., Radiother Oncol, 2003;68:15–21. 8. Hoffman R, et al., Cancer J, 2001;7:121–31. 14. Nishizaki T, et al., Minim Invasive Neurosurg, 2006;49:203–9.
3. Sheehan J, et al., Surg Neurol, 2004;62:32–40. 9. Rubin P, et al., Semin Radiat Oncol, 2006;16:120–30. 15. Bauman G, et al., Am J Clin Oncol, 2007;30:38–44.
4. Kondziolka D, et al., Int J Radiat Oncol Biol Phys,1999;45:427–34. 10. Aoyama H, et al., JAMA, 2006;295:2483–91. 16. Rades D, et al., Strahlenther Onkol, 2004;180:144–47.
5. Chougule PB, et al., Int J Radiat Oncol Biol Phys, 2000;48:114. 11. Sneed PK, et al., Int J Radiat Oncol Biol Phys, 2002;53:519–26. 17. Boogerd W, et al., Cancer, 2007;109:306–12.
6. Andrews DW, et al.,, Lancet, 2004;363:1665–72. 12. Chang EL, et al., Neurosurgery, 2005;56:936–45;discussion 936–45.

Brain metastasis is a feared complication of cancer that is associated with a significant decrease in quality of life and a dismal prognosis. The risk of developing brain metastasis has been estimated at around 25% in all cancer patients; however, this incidence has been increasing in many common cancer types, particularly breast and NSCLC. This can be explained by several factors including the inability of certain chemotherapy agents to cross an intact blood–brain barrier (BBB), as well as an inherent propensity for the development of brain metastasis observed in long-term cancer survivors.

General Considerations

Available treatment options for brain metastasis include focal (i.e. surgery and radiosurgery) and non-focal (whole-brain radiotherapy and chemotherapy) treatment modalities. In spite of numerous randomised trials, the optimal timing and patient selection for each of these treatment modalities remains contentious. This controversy seems to derive from two main issues: the first is related to the extreme heterogeneity of patients with brain metastasis, who can differ considerably in terms of prognostic characteristics such as primary cancer type, systemic disease control, brain metastasis location, number of lesions, age, performance status, and presence of cognitive or other neurologic impairment. This renders extremely difficult the task of extrapolating generic results derived from clinical trials to an individual patient. To address this issue, the Radiation Therapy Oncology Group (RTOG) proposed a classification based on a recursive partitioning analysis (RPA) of a large population of patients with brain metastasis in an effort to homogenise patient populations for clinical trials and facilitate treatment decisions. For this classification, patients are divided into three classes based on Karnofsky performance status (KPS), age and extent of systemic disease. The resulting stratification has prognostic value and has been validated in a variety of primary cancer types. Although the RPA classification may help provide general guidelines, it is not perfect, particularly because it does not take histology into consideration.

A second major source of controversy in the management of brain metastasis has been the lack of

Antonio Marcilio Padula Omuro

Attending Physician, Hôpital Pitié-Salpétrière

trials adequately designed and powered to investigate questions related to the balance between successful tumour control and long-term treatment-related neurocognitive impairment. Radiotherapy is particularly associated with an increased risk of neurotoxicity; however, it has been difficult to ascertain the magnitude of this problem, especially because it is difficult to differentiate tumour burden on neurologic function from neurotoxic effects. Moreover, assessment of neurotoxicity depends on long-term neuropsychological follow-up, which has been difficult to incorporate into large prospective studies. Results of available clinical trials and details pertaining to each treatment modality are reviewed below.

Whole-brain Radiation Therapy

Whole-brain radiation therapy (WBRT) has historically been the most important modality of treatment for brain metastases. Phase III trials have demonstrated that WBRT achieves radiographic responses and improves neurologic function in approximately 50% of patients; median survival increases to 4–6 months. Central nervous system (CNS) disease is the cause of death in approximately half of these patients, while the other half will die from systemic disease progression.

Multiple trials have tried to determine the optimal dose and schedule but to date there is little evidence to support that hyperfractionated schedules or higher doses are superior to the traditional dose of 30Gy fractionated in 10 daily sessions. WBRT has the advantage of treating microscopic disease and is consensually indicated for patients with multiple (more than three) lesions, since these are not good candidates for focal treatment. However, the use of WBRT in potential candidates for focal therapies has been controversial. There is strong evidence to support that WBRT improves local control when added to focal therapies; but a major concern is the risk of development of late-delayed neurotoxicity among long-term survivors. The incidence of such a complication has been estimated at 10% to 20%, with elderly patients at particular risk. Common symptoms of neurotoxicity are dementia, gait ataxia, and

incontinence; quality of life is profoundly affected in the presence of such a complication. Therefore, many authors recommend starting with focal modalities of treatment or reducing the dose per fraction in patients with life expectancy greater than nine months. However, others consider that the burden of tumour recurrence on neurologic dysfunction when WBRT is withheld surpasses the risk of neurotoxicity and that WBRT should therefore be indicated for all patients. In the lack of adequately powered trials incorporating neuropsychological end-points and long-term follow-up, the decision of indicating WBRT for RPA class I patients should be taken on an individual basis. In any case, WBRT remains a widely accepted option for a majority of RPA class II and III patients, since they will typically die before developing neurotoxicity.

The addition of radiosensitisors is an emerging strategy of treatment for improving the efficacy of WBRT. After several negative trials utilising a variety of new radiosensitisors, a recent phase III study comparing WBRT with and without motexafin gadolinium (MGd) in RPA class I and II patients has suggested that this drug may benefit patients with lung cancer in terms of time to neurologic progression. However, survival benefit was not seen in any histology and, to date, US Food and Drug Administration (FDA) approval has not been granted to this drug. More importantly, that trial has demonstrated the feasibility of incorporating neurocognitive outcomes in the design, which in fact can be even more relevant than survival end-points in such population; moreover, these results suggested that different histologies should be studied separately. Other trials on radiosensitisors are under way.

Surgery

The role of surgical resection in the management of brain metastases has also been extensively debated. Well-accepted indications for surgery include lesions with extensive mass effects that need to be evacuated, and the necessity of obtaining tissue for diagnostic confirmation. Other indications for surgery are more controversial. As demonstrated in two randomised trials, surgical resection for the treatment of single lesions prior to WBRT achieves longer median survival and functional independence than WBRT alone. Patients younger than 65 years, with a KPS of more than 70 and controlled systemic disease, seem to benefit most. A third trial did not find any differences but their population included more patients with a lower KPS and active systemic disease. Taken together, these results suggest that surgery is a suitable option for patients with a single resectable lesion whose systemic disease is under control. The decision to add WBRT for these patients should be individualised and should follow the principles described above. One study comparing surgery alone versus surgery plus WBRT demonstrated that tumour recurrence and death due to neurological causes was lower in the group subsequently treated with WBRT, validating the concept that WBRT improves local control. However, overall survival and duration of functional independence was similar in both groups, reflecting the morbidity and mortality related to systemic disease progression even when local control is achieved. These results have been interpreted in both ways, particularly because there is no sufficient data on the development of neurotoxicity in long-term survivors. Focal external beam radiation to surgical bed is another strategy under investigation for improving local control after surgery and might be a useful tool particularly for those patients in whom surgical resection was incomplete. There are no randomised trials looking at the role of surgery in patients with more than one lesion. Retrospective series from centres with good surgical experience have suggested that resection of up to three lesions in selected patients is feasible, safe and may yield results similar to patients with single lesions. However, such an approach should be limited to selected patients, particularly for those situations when surgery is necessary to decrease mass effect.

Stereotatic Radiosurgery

Stereotatic radiosurgery (SRS) is a technique for delivering highly focal external irradiation to a clearly defined small target, allowing the use of high doses of radiation without damaging adjacent normal tissue. Gamma-rays (gamma knife), high energy X-rays (linear accelerator) and proton beams are different techniques utilised that seem to achieve comparable results. SRS is a relatively non-invasive method, does not require hospitalisation and allows the treatment of surgically inaccessible lesions. It is also effective for those tumours known to be relatively radioresistant such as melanoma, renal cell carcinoma and sarcoma. The main limitation is that it can only be used for treating lesions under 4cm in diameter. Late complications occur in 10% of patients, including symptomatic radionecrosis that requires treatment with steroids and, rarely, surgical resection.

As with surgery, there has been some controversy over the role of adding SRS to WBRT. A prospective phase III trial conducted by the RTOG enrolled 333 patients with one to three newly diagnosed brain metastases to receive WBRT either with or without SRS. Although a survival benefit was clearly demonstrated only in patients with a single lesion (median overall survival (OS) of 6.5 versus 4.9 months; p=0.03), patients in the WBRT+SRS arm were significantly more likely to have a stable or improved KPS compared with the WBRT alone group (stable or improved KPS at six months of 43% versus 27%, respectively). RPA class 1 and favourable histological status were predictors of

survival on multivariate analysis. These results suggest that the addition of SRS to WBRT seems to be beneficial to all patients who are candidates for SRS. However, whether SRS can substitute WBRT as initial treatment in this population remains unclear, since no prospective studies are available. One retrospective study with 569 patients with newly diagnosed metastases demonstrated that SRS alone provided a survival similar to SRS plus WBRT, suggesting that focal treatment without WBRT could be a reasonable initial approach in selected patients. The role of SRS compared with surgery is even less clear. The RTOG is conducting a randomised prospective trial directly comparing these treatment modalities, but accrual has been very slow due to a strong preference of patients for one modality or the other. Retrospective experience has demonstrated no major differences between these two modalities, but available studies have several limitations. Therefore, to date, SRS should be seen as an alternative to surgery in those patients most likely to benefit from focal control, particularly RPA class I patients who have controlled systemic disease and up to three lesions; it would be the procedure of choice over surgery for those with lesions in surgically inaccessible areas or those with other contraindications to surgery.

Chemotherapy

The role of chemotherapy in treating brain metastasis is limited, and response seems to vary according to the type of primary tumour. The rationale for its use would be the possibility of treating both primary tumour and metastases. However, many patients with brain metastasis have already failed first-line chemotherapy and have limited therapeutic options; moreover, it has been observed that brain lesions respond less frequently to chemotherapy compared with the primary tumour. This seems to be explained by intrinsic properties of the metastatic lesion, conferring chemoresistance, as well as the presence of the BBB. It is accepted that the BBB is disrupted in the metastatic lesion. However, it is difficult to assess whether this is enough to allow water-soluble agents to achieve therapeutic concentrations within the affected region. Nevertheless, there are examples of water-soluble agents causing regression of brain metastases, and selecting agents known to have activity against the primary cancer type is key.

Metastases resulting from certain types of chemosen­sitive tumours are more likely to respond to chemotherapy, particularly SCLC, but also testicular, NSCLC, breast and melanoma. Chemo-naïve and RPA class I patients also seem to exhibit a better response to chemotherapy. For example, response rates for newly diagnosed, untreated SCLC seem to be around 70% to 80% with chemotherapy alone, while for previously treated patients the response is 40%. Therefore, chemotherapy may be considered the first line of treatment for chemo-naïve SCLC patients. For all other situations, WBRT or focal therapies are considered standard treatment and chemotherapy should be reserved as a salvage strategy in the event of recurrence.

Recurrent Brain Metastasis

The treatment of recurrences should take into consideration the present status of both systemic and CNS disease, as well as previous treatments. If the patient has been treated with focal modalities, and continues to have controlled systemic disease, the first step would be to assess whether the patient is still a candidate for focal therapy. Surgery would be indicated for those with extensive mass effect and could be considered for palliation. Lesions previously resected may benefit from radiosurgery. If these options are not feasible or if the patient has progressive systemic disease, WBRT should be considered. Re-irradiation with WBRT may be used with palliative intent, particularly if prior treatment occurred more than one year earlier. Chemotherapy is an option to be considered for chemosensitive tumours, with drugs appropriate for those types of tumours. Two studies using temozolomide for recurrent metastasis from solid tumours have demonstrated some efficacy and it may be an interesting option, particularly for patients with NSCLC. Other drugs are being tested as single agents or in combination.

Conclusions

Successful treatment of brain metastasis relies on the adequate control of CNS disease as well as systemic tumours. Despite major advances in strategies for focal control, patients continue to die, either from brain recurrence or systemic disease progression. On­going clinical trials will help to optimise the use of available treatment modalities but the key seems to be the development of new treatment strategies that address both systemic and CNS disease; the mechanisms of chemoresistance in brain metastases need to be further clarified. For the time being, patients and family should be made aware of potential risks and benefits of available treatment options. ■

Acknowledgement

The author thanks Dr Jean-Yves Delattre for reviewing the manuscript.

A version of this article containing references can be found in the Reference Section on the website supporting this briefing (www.touchoncologicaldisease.com).