Commentary (Chen/Gaspar): Brain Metastases in Small Cell Lung Cancer

It is well known that the prognosis for patients with brain metastases from small cell lung cancer (SCLC) is very poor, with median survivals in the range of 3 to 14 months.[1-3] As pointed out by Quan et al, brain metastasis is an important issue, given that approximately 60% of SCLC patients will develop brain metastases sometime in the course of their disease. Quan et al set out to write an article on the treatment of brain metastases from SCLC, but they often have to refer to the results of studies of brain metastases from other sites. Unfortunately, many studies specifically exclude SCLC-related brain metastases, and therefore, advances in their treatment have been few.

Treatment of Brain Metastases From SCLC

One of the primary reasons that patients with SCLC brain metastases are rarely entered into research protocols is likely that 60% to 90% of these patients have simultaneous progression at extracranial sites.[4] Does whole brain radiation therapy (WBRT) benefit patients with widespread metastatic disease? How many patients with SCLC brain metastases are treated with chemotherapy alone? This information would be difficult for those of us in radiation oncology to know.

Quan et al refer to the phase III study by the European Organization for Research and Treatment of Cancer (EORTC).[3] This study randomized patients with newly diagnosed SCLC brain metastases to treatment with a single chemotherapy agent, teniposide (Vumon), with or without concurrent WBRT. The intracranial response rate was significantly higher in the combined-modality arm (57% vs 22%, P < .001).

Although the time to progression in the brain was also significantly longer in the combined-modality group, this did not translate into prolongation of overall survival. The median survival was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm (P = .087). The majority of patients failed at extracranial sites, possibly negating any survival advantage that might have been the result of the improved intracranial control with combined WBRT and chemotherapy.[3] Quan et al state that the EORTC study demonstrated that "chemotherapy does not seem to alter outcomes."

Another interpretation of the EORTC study is that WBRT is not warranted, given that there was no improvement in either symptoms or survival as compared to patients treated with teniposide alone. Postmus et al actually conclude that the EORTC study shows that "clearly more effective chemotherapy regimens are needed to improve these poor results." It is possible that many patients, particularly those with marginal performance status and widespread metastatic disease, are treated with chemotherapy alone or supportive care.

Value of Prevention: PCI

As Quan et al point out, prevention may be more gratifying than treating established SCLC brain metastases. A meta-analysis has demonstrated that prophylactic cranial irradiation (PCI) is effective in decreasing brain metastases, with a modest increase in disease-free and overall survival among patients with limited SCLC in complete remission following initial chemoradiation.[5,6] Although it is generally agreed that PCI is standard of care for limited SCLC patients with a complete response to chemoradiation, there is reason to believe that there is only moderate enthusiasm in recommending it for individual patients.

Ludbrook et al[7] found that only 23.5 % of patients with limited SCLC referred to a Canadian cancer center received PCI. In the Canadian experience, PCI was more commonly given to younger patients than older patients. This Canadian retrospective review determined that 15% of patients with limited SCLC developed brain metastases as the sole site of first relapse. Similarly, a patterns-ofcare survey of randomly selected institutions in the United States found that during the years 1992 to 1997, PCI was given to only 23% of such patients.[8] The patterns-of-care survey will be repeated in the near future to determine how much impact the meta-analysis has had on the diffusion of PCI into radiation oncology practice.

It is possible that medical and radiation oncologists have subliminal concerns regarding the risk of PCIinduced leukoencephalopathy and cognitive decline. Although PCI can potentially induce leukoencephalopathy resulting in a decline of neurocognitive function and quality of life, it can be argued that a decline is more likely to occur in the scenario where brain metastases occur when no PCI was given.[9,10]

Prospective randomized studies have not yet demonstrated a signifi- cant difference in neurocognitive function and quality of life between patients treated or not treated with PCI.[5,11] However, neurocognitive function has been a primary end point in very few studies. Given that patients with limited SCLC have a 3-year survival rate of approximately 20%, the risk of PCI-induced cognitive decline is overshadowed by the risk of death due to uncontrolled brain metastases.

The optimal PCI dose and dose fractionation have yet to be determined. A trial conducted by the Radiation Therapy Oncology Group (RTOG 0212) randomizes patients with limited SCLC following a complete response to initial therapy to one of three PCI treatment regimens- ie, 25 Gy in 2.5-Gy daily fractions, 36 Gy in daily 2-Gy fractions, or 36 Gy in twice-daily fractions of 1.5 Gy. Patients are stratified by age (≤ 60 vs > 60 years) as well as time from completion of chemotherapy. Neurocognitive data are being collected prospectively. RTOG 0212 study is a companion study to an international randomized hyperfractionation PCI study. These large phase III studies should help clarify the questions regarding PCI radiation dose, fractionation, and its subsequent neurocognitive toxicity in the setting of limited SCLC.

Conclusions

Many issues still need to be addressed in the management of brain metastasis and in the prevention of brain metastasis in SCLC patients. Physicians should discuss the treatment options and controversies with patients and their families. Patients should be encouraged to participate in clinical studies. Off study, it is reasonable for good performance status patients with brain metastases from SCLC to be treated with WBRT to a total dose of 30 Gy given in 10 or 12 once-daily fractions of 2.5 to 3.0 Gy. For patients with limited SCLC in complete remission following initial therapy, a total PCI dose of 25 to 30 Gy given in 12 to 15 oncedaily fractions of 2.0 to 2.5 Gy appears reasonable, pending the results of the important ongoing phase III studies.

Disclosures:

The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

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