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Prophylactic cranial irradiation for patients with small cell lung cancer

Prophylactic cranial irradiation for patients with small cell lung cancer
Literature review current through: Jan 2024.
This topic last updated: Nov 28, 2023.

INTRODUCTION — The natural history of small cell lung cancer (SCLC) is one of rapid tumor growth and early dissemination. Because of this, the therapeutic approach is different from that used for patients with non-small cell lung cancer (NSCLC).

Although the Tumor, Node, Metastasis (TNM) staging system used for NSCLC is also suggested for SCLC, patients with SCLC are typically divided into those with limited-stage (LS) versus extensive-stage (ES) disease. (See "Tumor, node, metastasis (TNM) staging system for lung cancer".)

LS 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 LS disease, although many of these patients probably already have subclinical metastatic disease.

Chemotherapy is an integral component of the treatment of patients with LS-SCLC because of the high likelihood of early dissemination, including the minority of patients without mediastinal involvement who may be candidates for initial surgical resection. In addition, radiation therapy (RT) is important because local tumor progression occurs in up to 80 percent of patients with LS disease treated with chemotherapy alone [1]. (See "Limited-stage small cell lung cancer: Initial management".)

Brain metastases are a frequent problem in patients with SCLC, and brain imaging (preferably magnetic resonance imaging [MRI]) is indicated for patients who present with either LS or ES disease [2]. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

Prophylactic cranial irradiation (PCI) for patients without detectable brain metastases can decrease the frequency of subsequent intracranial relapse and improve survival for patients with SCLC. The role of PCI in the treatment of both LS- and ES-SCLC will be reviewed here.

BRAIN METASTASIS IN SCLC — There is a significant rate of occult brain metastases even in patients who are diagnosed with SCLC (small cell lung cancer) but do not have neurologic symptoms [3], and patients who have a good response of their other disease to initial treatment will often develop brain metastases as the sole site of relapse [4]. PCI has been extensively studied as a way to decrease the incidence of brain metastases following chemotherapy and to prevent the associated morbidity and mortality associated with brain metastases.

Limited-stage SCLC — For most patients with limited-stage (LS)-SCLC who achieve significant tumor regression to induction therapy or a complete response, we suggest PCI. PCI both increases overall survival and decreases the incidence of brain metastases in patients who have responded to initial treatment for LS-SCLC. The effectiveness of PCI in patients with LS-SCLC has been established by the results from numerous clinical trials. However, increasing age, neurocognitive comorbidities, and poor performance status are all associated with increased risk of neurotoxicity following PCI and, for this reason, PCI is not recommended for these patient groups. For patients not receiving PCI, we offer active brain MR surveillance for two years.

The value of PCI was established in a meta-analysis of seven randomized trials that included 987 patients who achieved a complete remission with chemotherapy and received PCI between 1977 and 1995 [5]. The incidence of brain metastases was significantly decreased with PCI (relative risk [RR] 0.46; 95% CI 0.38-0.57), and there was an absolute decrease in the three-year cumulative incidence of brain metastases (33 versus 59 percent). Furthermore, mortality was decreased with PCI (RR 0.84; 95% CI 0.73-0.97), which corresponded to an increase in the three-year survival rate from 15.3 to 20.7 percent. In this meta-analysis, 12 percent of patients in the PCI group and 17 percent of patients in the control group had extensive-stage (ES) disease. There were no differences in the relative risk of death or of brain metastases when the data were analyzed according to stage of disease.

A second meta-analysis that evaluated 1547 patients from 12 randomized trials reported almost identical findings [6]. Of note, neither brain MR nor PET staging was employed for either of these two meta-analyses.

Finally, in a meta-analysis of five retrospective studies with 1691 patients with resected SCLC, there was a statistically significant improvement of survival and reduction of brain metastases with PCI. But, for patients with Stage I disease, there was no survival benefit, and the 5-year risk of brain metastases was only 12 percent [7].

In regards to patients with advanced age and underlying neurocognitive comorbidities, we typically monitor such patients with MRI rather than offering PCI. The RTOG 0212 randomized phase II trial of different PCI dose schedules showed that increasing age was the most significant predictor for chronic neurotoxicity [8]. Eighty-three percent of patients >60 years old treated with PCI experienced chronic neurotoxicity compared with a rate of 56 percent for those who did not receive PCI.

Extensive-stage SCLC — PCI decreases the incidence of symptomatic brain metastases in patients with ES-SCLC who have a response to systemic chemotherapy, although its effect on overall survival is uncertain. PCI in ES-SCLC has been studied in two randomized multicenter trials:

In a phase III trial conducted by the European Organization for Research and Treatment of Cancer (EORTC), all patients initially received four to six cycles of chemotherapy [9]. At the completion of the initial chemotherapy, approximately 75 percent of patients had residual disease in the chest, and 70 percent had residual evidence of metastatic disease. Patients were not routinely imaged for the presence or absence of brain metastases after chemotherapy and prior to PCI. The primary objective of the study was the prevention of symptomatic brain metastases.

Overall, 286 patients with a response to chemotherapy as judged by the treating clinician were randomly assigned to PCI or to observation without PCI. Radiation doses and schedules ranged from 20 Gy in five fractions to 30 Gy in 12 fractions, depending upon the institution.

Patients treated with PCI had a significantly decreased incidence of symptomatic brain metastases at one year (15 versus 40 percent without PCI, hazard ratio [HR] 0.27, 95% CI 0.16-0.44). The median overall survival was increased in patients treated with PCI (6.7 versus 5.4 months, measured from randomization), and the one-year survival rate was significantly increased (27 versus 13 percent, HR 0.68 95% CI 0.52-0.88). The risk of extracranial progression did not differ significantly between the two groups (89 versus 93 percent at one year).

In a second trial that was conducted in Japan, 224 patients who had at least some response to their initial chemotherapy were randomly assigned to PCI or no PCI [10]. Prior to randomization, patients underwent magnetic resonance imaging (MRI) of the brain to rule out occult metastases. The treatment protocol required active surveillance with follow-up MRI at 3, 6, 9, 12, 18, and 24 months. Radiation therapy (RT) was given to a dose of 25 Gy in 10 fractions. The primary endpoint of this trial was overall survival. Secondary endpoints included the incidence of brain metastases and progression-free survival.

The trial was stopped prematurely for futility. Although not statistically significant, overall survival was shorter with PCI compared with no PCI (median 11.6 versus 13.7 months, HR 1.27, 95% CI 0.96-1.68). There was a statistically significant decrease in the incidence of brain metastases with PCI (33 versus 59 percent at one year).

Treatment with PCI was generally well tolerated in both trials. (See 'Toxicity' below.)

The results of these trials provide strong evidence that PCI can decrease the incidence of symptomatic brain metastases. The impact of PCI on overall survival in patients with ES-SCLC who respond to chemotherapy remains uncertain.

The impact of PCI for patients with ES-SCLC is uncertain, given the differences between these two trials [11]. Our approach is to limit consideration of PCI to patients with ES-SCLC who have a complete or very good partial response to their initial treatment and who have a good performance status. An individualized discussion should be held with such patients to evaluate the pros and cons of PCI versus observation [12]. In patients not receiving PCI, regular MRI surveillance for metastases by brain imaging should be performed.

RADIATION ADMINISTRATION

Timing and dose — PCI is not given during chemotherapy to decrease the risk of leukoencephalopathy [9,13].

Higher doses of radiation are associated with better control of brain metastases, although this benefit must be weighed against the risks of toxicity. For patients who achieve a complete response or near complete response to initial therapy, our approach is to use a total dose of 25 Gy in 2.5 Gy fractions; 30 Gy in 2 Gy fractions is also an acceptable regimen. More abbreviated courses of therapy are an option for patients with an incomplete response to initial chemotherapy. (See 'Toxicity' below.)

Indirect evidence supporting the efficacy of higher doses of radiation in reducing brain metastases comes from the initial meta-analysis that established the efficacy of PCI, in which the dose of radiation was broken down into four categories (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) [5]. A statistically significant trend for improved control of brain metastases was observed with increasing total doses of radiation. Similarly, a retrospective analysis of PCI doses demonstrated an approximately linear dose-response relationship for reduced brain metastases with increases in dose that ranged from 0 to 35 Gy in 2 Gy fractions [14].

The effect of radiation dose has been studied in two large randomized trials and neither demonstrated an advantage for doses above 25 Gy in 10 fractions:

The most extensive data on the impact of radiation dose come from a multinational phase III trial, in which 720 patients with limited-stage (LS)-SCLC and a complete response to their initial treatment were randomly assigned to PCI at a dose of either 25 Gy in 10 fractions or a dose of 36 Gy (administered either as 18 fractions of 2 Gy each or 24 fractions of 1.5 Gy given twice-daily) [15]. Among the patients randomized to the 36 Gy treatment arm, 78 percent received once daily therapy.

The two-year incidence rates of brain metastases were 23 percent for the higher radiation dose and 29 percent with the lower dose. This difference was not statistically significant (HR 0.80, 95% CI 0.57-1.11). However, the higher dose was associated with a significantly lower two-year survival rate (37 versus 42 percent, HR 1.20, 95% CI 1.00-1.44). There was no obvious explanation for the increased mortality in the group treated with higher doses of PCI.

The RTOG 0212 trial randomly assigned 265 patients with LS-SCLC and a complete response after chemotherapy and thoracic RT to PCI with either 25 Gy in 10 fractions or 36 Gy. The 36 Gy cohort was secondarily randomized to receive their radiation either in 18 fractions of 2 Gy or 1.5 Gy twice daily in 24 fractions [8]. At a median follow-up of 25 months, there was no significant difference in the incidence of brain metastases or overall survival between the treatment arms, but the study was not adequately powered to evaluate the impact of treatment on these parameters. This trial did provide important information regarding the long-term neurotoxicity of PCI. (See 'Long-term toxicity' below.)

Standard PCI versus hippocampal avoidance — Hippocampal avoidance (HA) has been evaluated in patients with SCLC receiving PCI as a means of reducing neurocognitive decline. Either standard PCI or HA (when available) are options, with either option being acceptable based on individual decision-making evaluating pros and cons.

Available data are as follows:

In a randomized trial of 150 patients with SCLC, those assigned to PCI with HA experienced a lesser decline in delayed free recall from baseline to three months compared with those receiving standard PCI (5.8 versus 23.5 percent; odds ratio 5.0, 95% CI 1.6-15.9) [16]. Other measures of cognitive function also favored the hippocampal-avoidance group. The incidence of brain metastases, overall survival, and quality of life were similar between the two groups.

However, in a previous randomized trial, patients assigned to HA experienced no differences in cognitive functioning at four months compared with those assigned to standard PCI, and had higher rates of cognitive failure over time [17].

Finally, the phase IIR/III trial NRG-CC003 found similar relapse rates with PCI, with and without HA, but discordant outcomes with neurocognitive measures. This trial randomly assigned 392 patients with SCLC to PCI with or without HA, stratified by planned memantine use. In terms of one primary endpoint, HA-PCI had non-inferior 12-month intracranial relapse rate (PCI 14.8 versus HA-PCI 14.2 percent). However, in terms of the other primary endpoint, there was no statistically significant reduction in 6-month delayed recall deterioration, as measured by a scale (PCI 30 versus HA-PCI 26 percent).

Although differences in methodology (eg, measurements of cognitive functioning, quality controls, etc) likely accounted for these discordant outcomes [18], pending further data, either standard PCI or HA are acceptable.

TOXICITY — Cranial irradiation can be associated with both acute and long-term toxicity.

Acute toxicity — Acute toxicities associated with PCI include fatigue, alopecia, scalp erythema, and to a lesser extent, headaches and low-grade nausea, all of which are usually self-limited. Fatigue and alopecia are the most prevalent short-term toxicities [13]. (See "Acute complications of cranial irradiation", section on 'Standard fractionated radiation therapy'.)

Long-term toxicity — Long-term toxicity, especially delayed neurocognitive impairment, is a potential concern, particularly for patients with limited-stage (LS)-SCLC. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.)

Long-term toxicities are difficult to assess and quantify, and the data pertaining to these are limited. Potentially devastating neurologic and intellectual disabilities were seen with earlier treatment techniques that used concurrent chemotherapy, large fraction sizes (3.0 to 4.0 Gy), and/or a high total dose, all of which have been shown to be associated with severe late neurotoxicity [19-21]. Less devastating but significant impairment in cognitive functioning was also demonstrated in a CALGB study following simultaneous treatment with chemotherapy, thoracic radiation, and PCI [22].

The likelihood of severe deficits appears to be minimal with modern techniques for PCI:

Two early randomized trials that evaluated PCI included neurotoxicity as an outcome [4,23]. In the first, patients underwent neuropsychological examination and computed tomography brain scans, which were repeated regularly during follow-up after randomization to either PCI or to no PCI [4]. No significant differences were observed in neuropsychological function. In the other, cognitive functioning and quality of life were assessed both before and after treatment with PCI or control [23]. Although significant abnormalities were present prior to randomization, neither study demonstrated adverse effects attributable to PCI.

The RTOG 0212 trial randomly assigned 265 patients with LS-SCLC and a complete response after chemotherapy and thoracic RT to PCI with either 25 Gy in 10 fractions or 36 Gy. The 36 Gy cohort was secondarily randomized to receive their radiation either in 18 fractions of 2 Gy or twice daily in 24 fractions [8]. Detailed neurocognitive and quality of life assessments were carried out on the study population. Baseline assessment prior to PCI identified abnormalities in multiple parameters including language, visual and spatial scanning, attention, sequencing, and speed. Further neurologic impairment was observed at the 12 month assessment, but chronic neurotoxicity was significantly less frequent in patients treated with 25 Gy compared with 36 Gy (60 versus 85 and 89 percent, respectively, p = 0.02).

As treatment for SCLC becomes more successful, the potential for long-term neurotoxicity due to PCI will be more relevant. Research efforts to minimize the neurotoxicity of PCI have included twice daily fractionation (1.5 Gy twice-daily to 30 to 36 Gy), hippocampal-sparing whole brain radiotherapy, and the use of alternative systemic agents [24-26].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Small cell lung cancer (The Basics)")

Beyond the Basics topics (see "Patient education: Small cell lung cancer treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Prophylactic cranial irradiation in limited stage small cell lung cancer – For patients with limited stage (LS) small cell lung cancer (SCLC) who achieve a complete response to their initial treatment, prophylactic cranial irradiation (PCI) can decrease the incidence of brain metastases and prolong survival. Using modern techniques, this can be achieved with a tolerable level of acute and delayed neurotoxicity. (See 'Limited-stage SCLC' above and 'Radiation administration' above.)

For good performance status patients with LS-SCLC who achieve a complete response to induction therapy, we suggest PCI (Grade 2B). For patients with LS-SCLC with evidence of significant tumor regression but less than a complete response at the completion of chemotherapy, we also suggest PCI (Grade 2C). However, MR surveillance is a reasonable alternative, particularly for those with stage I cancers. (See 'Limited-stage SCLC' above.)

For those receiving PCI, either standard treatment or hippocampal avoidance are acceptable based on shared decision-making.

Options in extensive-stage SCLC – For good performance status patients with extensive-stage SCLC who have had a complete or very good partial response to their initial chemotherapy, both PCI and observation with regular brain MRI surveillance are acceptable options. An individualized discussion should be held with such patients to evaluate the risks and benefits of each approach. PCI decreases the incidence of brain metastases, although its impact on overall survival remains uncertain. (See 'Extensive-stage SCLC' above.)

Radiation administration – For patients who achieve a complete response to initial therapy, our approach is to use a total dose of 25 Gy in 2.5 Gy fractions; 30 Gy in 2 Gy fractions is also an acceptable regimen. More abbreviated courses of therapy are an option for patients with an incomplete response to initial chemotherapy. (See 'Radiation administration' above.)

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References

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