Commentary (Bunn/Witta/Kavanagh): Brain Metastases in Small Cell Lung Cancer

Quan and colleagues have provided an important and timely review on the treatment of brain metastases in patients with small cell lung cancer (SCLC). We certainly agree with the comments and views of the authors, but wish to emphasize several aspects of central nervous system (CNS) metastases in SCLC patients.

Magnitude of the Problem

First, the authors underestimate somewhat the magnitude of the problem. A recent study of 432 consecutive SCLC patients found brain metastases at diagnosis in 18% (asymptomatic in 20 of 74) and in another 23% of patients during follow- up.[1] The 2-year cumulative risk of brain metastases was 49% for limited- stage and 65% for extensive-stage disease. In another recent study, magnetic resonance imaging (MRI) exams in asymptomatic patients found unsuspected brain metastases in 17 of 112 newly diagnosed SCLC patients (15%).[2] Clearly, all SCLC patients should have a brain MRI as part of their initial evaluation.

Second, CNS metastases to the brain are frequently associated with metastases to other portions of the CNS including the leptomeninges,[ 3,4] vertebral bodies with spinal cord compression,[5,6] and/or intramedullary spinal cord.[7] SCLC patients with brain metastases should be examined carefully for lesions in these other regions.

We agree that patients with any CNS involvement should be treated immediately with dexamethasone in the doses indicated. For patients who do not respond and/or who develop worsening symptoms during irradiation, the dose of dexamethasone can be doubled progressively to a maximum of 96 mg/d.

Role of Whole Brain Radiotherapy

Patients who initially present with brain metastases and patients who relapse in the brain after initial therapy could be treated with (1) whole brain radiotherapy (WBRT) followed by chemotherapy; (2) WBRT with concurrent chemotherapy; (3) chemotherapy followed by WBRT at the completion of chemotherapy, or (4) chemotherapy alone with WBRT only at time of progression. There are few randomized trials to determine whether one of these approaches is superior, but there are clinical features that should be considered. The response rates to WBRT are higher than response rates to chemotherapy at either the initial presentation or at relapse. Thus, symptomatic patients should be treated with WBRT first, followed by chemotherapy.

WBRT can interfere with the blood-brain barrier, allowing more chemotherapy into the normal brain. Dementia and other neurologic sequelae of therapy are probably more likely in patients with long survival who had been treated with both WBRT and chemotherapy simultaneously than with chemotherapy after WBRT. Thus, asymptomatic patients may be treated with chemotherapy first, followed by WBRT.

One group studied the outcome of 30 patients with extensive SCLC (with the brain as the single site of metastases at initial diagnosis), after cisplatin- based chemotherapy and concomitant WBRT consisting of 3,600 to 4,800 cGy. Twenty-two patients also received thoracic radiation therapy.[8] The overall response rate was 80%, and the median survival of the entire group was 14 months. The outcome of these patients was similar to that of patients with limited-stage disease.

A randomized trial reported by the European Organization for Research and Treatment of Cancer (EORTC) showed that teniposide (Vumon) plus WBRT was superior to teniposide alone with respect to response rate and time to progression in the brain.[9] Thus, the option of delaying WBRT until relapse is probably not warranted.

Effects on Neurocognitive Function

Possible adverse effects on neurocognitive function are an important concern whenever WBRT is administered for the treatment of brain metastases, but results from a recent large prospective randomized study provide insight into the frequency of baseline impairment and the most common etiology of functional decline after treatment. In a study involving over 400 patients with brain metastases from a variety of solid tumors excluding SCLC, patients underwent pre- and posttreatment neurocognitive testing of memory, fine motor speed, executive function, and global neurocognitive impairment using an assortment of validated instruments.[10]

At baseline, over 90% of patients had a measurable abnormality in neurocognitive function detected on one or more tests, and over 40% had an impairment detected in four or more tests. Baseline neurocognitive test abnormalities were tightly correlated with the volume of the indicator lesion at baseline, and multivariate analysis indicated that lesion volume was the only predictor of global neurocognitive impairment at baseline. Likewise, decline in neurocognitive function observed 2 months after WBRT also closely correlated with indicator lesion volume. Patients with radiographic evidence of progressive disease had far greater functional decline than patients with partial response, and only patients with a partial response demonstrated improvement on any of the tests used. Thus, it appears that the burden of metastatic disease in the brain-and not the treatment administered-is the dominant influence on neurocognitive function, at least in the first few months after treatment.

Other Areas of Agreement

As the authors point out, brain metastases in SCLC are rarely solitary. However, we agree that patients with solitary metastases should be considered for surgical resection followed by WBRT when the tumor is easily accessible, or stereotactic radiosurgery followed by WBRT when it is not.

The authors are also correct in that SCLC patients with brain metastases should be included in trials evaluating new approaches. Unfortunately, it is unlikely that the poor survival of these patients will be reversed until we have more effective systemic therapies.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Seute T, Leffers P, ten Velde GP, et al: Neurologic disorders in 432 consecutive patients with small cell lung carcinoma. Cancer 100:801-806, 2004.
2. Hochstenbag MM, Twijnstra A, Wilmink JT, et al: Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis. J Neurooncol 48:243-248, 2000.
3. Rosen ST, Aisner J, Makuch RW, et al: Carcinomatous leptomeningitis in small cell lung cancer: A clinicopathologic review of the National Cancer Institute experience. Medicine (Baltimore) 61:45-53, 1982.
4. Bunn PA Jr, Nugent JL, Matthews MJ: Central nervous system metastases in small cell bronchogenic carcinoma. Semin Oncol 5:314- 322, 1978.
5. Pedersen AG, Bach F, Melgaard B: Frequency, diagnosis, and prognosis of spinal cord compression in small cell bronchogenic carcinoma. A review of 817 consecutive patients. Cancer 55:1818-1822, 1985.
6. Goldman JM, Ash CM, Souhami RL, et al: Spinal cord compression in small cell lung cancer: A retrospective study of 610 patients. Br J Cancer 59:591-593, 1989.
7. Murphy KC, Feld R, Evans WK, et al: Intramedullary spinal cord metastases from small cell carcinoma of the lung. J Clin Oncol 1:99-106, 1983.
8. Kochhar R, Frytak S, Edward GS: Survival of patients with extensive small-cell lung cancer who have only brain metastases at initial diagnosis. Am J Clin Oncol 20:125-127, 1997.
9. Postmus PE, Haaxma-Reiche H, Smit EF, et al: Treatment of brain metastases of smallcell lung cancer: Comparing teniposide and teniposide with whole-brain radiotherapy-a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 18:3400-3408, 2000.
10. Meyers CA, Smith JA, Bezjak A, et al: Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: Results of a randomized phase III trial. J Clin Oncol 22:157-165, 2004.