Prophylactic cranial irradiation for patients with limited stage small cell lung cancer

INTRODUCTION — The natural history of small cell lung cancer (SCLC) is one of rapid proliferation and early dissemination. This affects both the staging system and the therapeutic approach, which are different from those used for non-small cell lung cancer (NSCLC).

Patients with SCLC are divided into those with limited versus extensive stage disease. Limited stage disease is defined as disease confined to one hemithorax, ie, disease which can be included in a "tolerable" radiation field. About one-third of patients present with clinically determined "limited disease," although many of these patients probably already have subclinical metastatic disease.

Chemotherapy is the mainstay of treatment for patients with SCLC because of the proclivity for early dissemination. Considerable effort is being devoted to the development of more efficacious chemotherapy strategies to control systemic disease.

In addition to chemotherapy, there is a significant role for radiotherapy in the treatment of SCLC. Local tumor progression occurs in up to 80 percent of patients with limited stage disease treated with chemotherapy alone. This high recurrence rate can be significantly reduced by the addition of thoracic radiation therapy. In addition, there may be a role for prophylactic cranial irradiation (PCI) in selected patients to prevent intracranial relapse.

This topic review will describe the role of PCI in the treatment of limited stage SCLC. The role of thoracic radiation therapy for decreasing local recurrence of disease is addressed separately

BRAIN METASTASIS IN SCLC — There is a significant rate of "brain failures," ie, cerebral metastases, following systemic treatment for SCLC. As an example, one report found a 38 percent crude rate of cerebral metastases among 48 patients who achieved a complete response to systemic therapy, but received no PCI. The central nervous system (CNS) was the first and isolated site of failure for 17 percent of such patients. In addition, the authors stated that the rate of CNS failure approached 100 percent for patients who survived two years.

The high rate of CNS failures is attributed to the fact that most chemotherapeutic agents do not adequately penetrate the blood-brain barrier. The brain is therefore a "sanctuary site," similar to that observed in leukemia.

REGIMENS USING PROPHYLACTIC CRANIAL IRRADIATION — Based on the natural history of SCLC described above, PCI has been proposed as a potential means to improve the rates of CNS control and survival. Ten randomized trials have been performed to assess the role of PCI. Eligibility criteria (ie, limited versus extensive disease, complete versus no response to chemotherapy) and treatments varied substantially among these studies. The doses delivered ranged from 20 to 40 Gy, with fraction sizes of 2.0 to 4.0 Gy per day.

Seven of the 10 trials showed a statistically significant decrease in the frequency of brain metastases for patients who received PCI. An overview which included all but one of these trials reported that patients who received PCI had far fewer clinically detected brain metastases than those who did not (6 versus 22 percent).

Effect on survival — No prospective randomized trial has demonstrated a significant survival advantage for patients treated with PCI. However, the subgroup of patients most likely to benefit from PCI has not been well studied (patients with limited stage disease who achieve a complete response to systemic therapy). It is therefore possible that PCI confers a survival benefit for these patients.

The most recent randomized trial was appropriately limited to SCLC patients who had achieved a complete response to chemotherapy. Similar to previous studies, treatment with PCI led to a significant decrease in the rate of overall and isolated brain metastases, but there was no significant two-year survival advantage (29 versus 21 percent, p = 0.14).

However, the same authors more recently presented detailed data from a meta-analysis of 987 patients in complete remission who received PCI between 1977 and 1995 in 7 randomized trials. The relative risk of death in the PCI group compared to the control group was 0.84 (p = 0.01) corresponding to a reduction in mortality of 16 percent in favor of PCI and to a 5.4 percent increase in the 3 year survival rate from 15.3 to 20.7 percent.

TOXICITY OF PROPHYLACTIC CRANIAL IRRADIATION — Toxicity of this therapy is an important factor that must be considered. Acute toxicities of PCI include scalp erythema, fatigue, and alopecia, all of which are usually self-limited. (

Long-term toxicities are difficult to assess and quantify, but include potentially devastating neurologic and intellectual disabilities. The likelihood of such deficits appears to be increased with the use of concurrent chemotherapy or large fraction sizes (3.0 to 4.0 Gy)  Therefore, if PCI is given:

  bullet It should be given sequentially (not concurrently) with chemotherapy.
  bullet The total dose should be in the range of 30 to 36 Gy.
  bullet Daily fraction sizes should not exceed 2.0 Gy.

Despite its potential for toxicity, a report using Q-TWiST (quality time without symptoms and toxicity) methodology concluded that PCI is a cost-effective treatment that improves quality of life-adjusted survival for patients with SCLC who have achieved a complete remission with chemotherapy with or without radiation therapy.

RECOMMENDATIONS — Since the data pertaining to the relative risks and benefits of PCI are not clear, the use of PCI for any given patient should be individualized. For patients who present with limited stage disease and achieve a complete response or near complete response to chemotherapy, it is reasonable to offer the option of PCI after a discussion of the risks and benefits of treatment. One meta analysis shows small increase in survival.