Seminars in Oncology
Volume 32, Issue 3 , Pages 293-298, June 2005

Prophylactic Cranial Irradiation With Combined Modality Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer

  • L. Chinsoo Cho

      Affiliations

    • Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Moncrief Radiation Oncology Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, TX
    • Corresponding Author InformationAddress reprint requests to L. Chinsoo Cho, MD, MS, Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Moncrief Radiation Oncology Center, 5801 Forest Park Rd, Dallas, TX 75390-9183
    • ,
  • Jonathan E. Dowell

      Affiliations

    • Division of Hematology Oncology, UT Southwestern Medical Center at Dallas, Harold C. Simmons Comprehensive Cancer Center, Dallas, TX
    • ,
  • Dan Garwood

      Affiliations

    • Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Moncrief Radiation Oncology Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, TX
    • ,
  • Ann Spangler

      Affiliations

    • Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Moncrief Radiation Oncology Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, TX
    • ,
  • Hak Choy

      Affiliations

    • Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Moncrief Radiation Oncology Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, TX

Article Outline

Central nervous system (CNS) metastasis is a significant problem for many patients with non-small cell lung cancer (NSCLC). The earlier data reported a high incidence of CNS metastasis in patients with locally advanced NSCLC who were treated with radiotherapy alone. However, poor control of both thoracic and extracranial systemic disease dominated the results of the early trials. The risk for CNS metastasis as the first site of failure remains a significant concern for patients who have completed modern combined modality therapy. With improvements in the treatment of thoracic and systemic disease, there is renewed interest in prophylactic cranial irradiation (PCI). The results from the Radiation Therapy Oncology Group (RTOG) trial of PCI to prevent CNS relapse in patients with locally advanced NSCLC are anticipated.

 

In 2005, it is estimated that there will be 73,020 deaths among women and 90,490 deaths among men due to lung cancer in the United States. It is the leading cause of cancer-related deaths and it accounts for 13% of new cancer cases and 29% of cancer deaths per year in the United States.1 The 5-year survival rate for lung cancers was approximately 15% from 1974 through 19952 and most cures have been related to the surgical treatment of patients presenting with stage I and II cancers. However, only about 35% of all non-small cell lung cancer (NSCLC) patients present with locally advanced disease that is not amenable to surgical therapy but which is potentially curable.3 Patients with clinical stage IIIA disease on presentation have a 5-year survival rate of 10% to 15% overall. However, this survival figure falls to 2% to 5% when there is grossly visible disease in the mediastinum on a chest x-ray.4 The principal forms of treatment for patients with stage III NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Chemotherapy combined with thoracic radiotherapy improves survival for patients with locally advanced NSCLC,5, 6, 7 but systemic relapse, including brain metastasis, remains a major problem. Improvements in staging and therapy have refocused attention on the critical issue of central nervous system (CNS) failure in patients with NSCLC. There is a rising concern over the rate of brain relapse in patients with locally advanced NSCLC who seemingly have been successfully treated with a combined modality regimen.

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CNS Metastases in NSCLC 

CNS metastasis is a common and devastating problem for patients with NSCLC, with reported incidences of up to 54%.8, 9, 10, 11, 12, 13, 14, 15, 16, 17 The median survival of patients diagnosed with brain metastasis in NSCLC is less than 1 year.18, 19, 20 Tumor control after a diagnosis of gross brain metastasis is less than 20% when radiation is given as 36 Gy in 12 daily treatments.19 Although the tumor control rates of the initial gross metastatic sites in the brain are higher with surgery or stereotactic radiosurgery, subsequent metastases in other areas of the brain are common.19, 21, 22 There have been multiple risk factors associated with increased rates of CNS metastases in patients with NSCLC. Some of these factors include age,23 stage of NSCLC on presentation,24 gender,25 and time interval from the original treatment.26 Initially, the Radiation Therapy Oncology Group (RTOG) studies incorporating radiotherapy alone to the thorax found a significant risk for brain metastasis if the patients had adenocarcinomas or large cell carcinomas.27, 28 However, subsequent studies that incorporated a combined modality regimen of chemotherapy, thoracic radiotherapy with or without surgery, found that all histologies including squamous cell carcinomas presented significant risk for brain metastasis.29, 30, 31, 32 Histology may be important in determining which NSCLC patients are at risk for early (<16 weeks after treatment) CNS relapse.33, 34, 35 A recent review of the Southwest Oncology Group (SWOG) trials by Gaspar et al showed that histology may be a significant predictor for early brain relapse but it is not a significant predictor for brain metastases that occur more than 16 weeks after the conclusion of treatment.35 Multiple reports have demonstrated the efficacy of systemic therapy in reducing the rate of metastases except for those involving the CNS.17, 34 The sequence of combined modality therapy has yielded conflicting results in respect to the rate of brain metastasis. In a phase III trial that compared sequential versus concurrent chemoradiotherapy, Furuse et al36 noted that up to17% (Table 1) of the patients experienced brain metastases as the first site of relapse after concurrent chemoradiotherapy. Nine percent of patients in the sequential chemotherapy arm (mitomycin, vindesine, cisplatin) followed by the thoracic radiotherapy arm (56 Gy in 2-Gy fractions) experienced brain metastasis (P = .018). However, a retrospective analysis by Robnett et al24 reported that concurrent chemoradiotherapy was associated with a lower rate of brain metastasis. In this analysis, 15% of the patients treated concurrently experienced brain metastasis versus 27% of the patients who were treated sequentially (P < .03). Table 1 indicates the risk of CNS metastasis in NSCLC.

Table 1. Central Nervous System Metastasis in Locally Advanced NSCLC
Study (First author)NStageMedian Survival (mo)CNS RelapseCNS as the Site of First Failure
Furuse865III169–19%8–17%
Cox341765II, IIIA/BN/A14–21%8–16%
Robnett16150II, IIIA/B14.530%19%
Law1742IIIA/B or IV3631%16%
Sun3288IIIA/BN/A33%17%
Andre33267III (cN2)N/A22%15%
25%⁎
Kumar3074IIIA (pN2)1543%†N/A
Gandara3783IIIB26N/A33%
Gaspar35422IIIA/BN/A26.50%(20% isolated relapse)

Abbreviation: N/A, not available; cN2, clinically determined N2 nodal status; pN2, pathologically determined N2 nodal status.

⁎ Twenty-five percent of patients who relapsed.

† Forty-three percent of patients who relapsed after resection.

Combined modality treatment consisting of chemotherapy and thoracic radiotherapy appears to have had an impact on the survival of patients with stage III NSCLC in North America during the past 25 years. Videtic et al5 noted that the 5-year survivals of patients with stage III NSCLC listed in the Surveillance, Epidemiology, and End Results (SEER) database have increased over the past 25 years. The median survival increased from 10.2 months for the 1973–74 period to 16.7 months for the 1997–98 period for patients with regional disease. The 5-year survival rate of these patients increased from 10% to 18% (P = .001 for trend). Combined modality therapy trials have reported improvement in median survival of stage III NSCLC patients when compared to radiotherapy alone. Additionally, some IIIB NSCLC patients appear to have promising median survivals after undergoing modern combined modality therapy. Gandara et al37 reported the results of the SWOG 9504 trial, which treated 83 stage IIIB NSCLC patients with concurrent chemotherapy (cisplatin/etoposide) and thoracic radiotherapy (61 Gy) followed by docetaxel consolidation. In this trial, the brain was the site of first failure in 33% of the patients and isolated brain metastases occurred in 18% of patients. The median survival in the SWOG 9504 trial was 26 months. Gaspar et al35 reported a retrospective review of the SWOG database of stage IIIA/B NSCLC patients who underwent combined modality therapy on four SWOG protocols (S8805, S9019, S9416, and S9504). Among a total of 422 patients enrolled on the SWOG trials, 20% experienced isolated brain metastasis after primary therapy. Forty-six percent of the patients who had brain as the site of first relapse developed brain metastasis within 16 weeks of completion of therapy. The RTOG also showed that NSCLC patients with locally advanced disease with the longest survival are at significant risk for developing CNS metastases.26, 34 Improvements in the treatment of locally advanced NSCLC with combination chemotherapy, radiotherapy, and surgery have shown that CNS metastases remains a major site of relapse, with up to 33% of patients experiencing CNS metastases as the first site of relapse.10, 38 Similarly, the Lung Cancer Study Group (LCSG) reported that 21% of patients developed brain metastasis after undergoing neoadjuvant chemoradiotherapy followed by surgery for stage III NSCLC.39 Martini et al also reported that 28.5% of patients developed isolated brain metastasis after undergoing chemotherapy (cisplatin, vindesine or vinblastine, and mitomycin) followed by surgery.31

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Prophylactic Cranial Irradiation: Nonrandomized Data 

There have been five nonrandomized trials that incorporated prophylactic cranial irradiation (PCI) into the treatment regimen for locally advanced NSCLC. Skarin et al15 reported the results of chemotherapy and radiation followed by surgery for 41 stage III NSCLC patients in 1989. The study was initiated in 1981 and closed in 1984. The treatment consisted of combination chemotherapy (cyclophasphamide, doxorubicin, cisplatin) followed by thoracic radiotherapy (30 Gy in 15 fractions). Thoracotomy was performed on 37 patients and additional radiotherapy (25 to 27 Gy in 10 to 12 fractions) was given to 27 patients. Seven patients were given PCI (36 Gy in 18 fractions). PCI reduced the rate of brain metastasis from 27% to 14%. The median survival for all patients in this study was 32 months. Rusch et al40 published the results of a SWOG phase II trial in 1989 that enrolled 73 patients with locally advanced NSCLC. Two groups of patients received neutron thoracic radiotherapy. One group of 15 patients received a PCI dose of 30Gy in 10 daily fractions, while a second group of 50 patients was given 36 Gy in18 fractions. Two cycles of combination chemotherapy were given before and after radiotherapy. No brain relapses were seen in either group of patients that received PCI. Strauss et al11 reported the results of a Cancer and Leukemia Group B (CALGB) phase II study that treated pathologically staged IIIA NSCLC patients with concurrent chemotherapy and radiotherapy followed by surgery in 1992. The thoracic radiotherapy was a split-course regimen, which consisted of 3,000 cGy in 15 fractions with concurrent chemotherapy (5-fluououracil, cisplatin, vinblastine) before surgery followed by an additional cycle of chemotherapy with concurrent thoracic radiotherapy of 3,000 cGy in 15 fractions after surgery. PCI of 3,000 cGy was scheduled after completion of thoracic radiotherapy if a patient had adenocarcinoma or large cell carcinoma. None of the 13 patients who received PCI developed subsequent brain metastasis, whereas 17% of the patients who did not receive PCI developed brain metastasis. Of the five patients who relapsed in the brain, three had brain metastasis prior to the scheduled PCI. A pretreatment computed tomography (CT) scan of the head was not required in this study and two of three early failures in the brain did not have pretreatment CT scans of the brain. The median survival in this study was 15.5 months. In another study, Albain et al9 reported the results of SWOG 8805 in 1995. There were 126 patients treated between 1988 and 1992 on this phase II study. The treatment was offered to pathologically staged IIIA and IIIB NSCLC patients. The therapy consisted of concurrent chemotherapy (cisplatin, etoposide) and thoracic radiotherapy (45 Gy in 25 daily fractions) followed by thoracotomy if there was nonprogressive disease after chemoradiotherapy. Those with unresectable or incompletely resected disease were given two additional cycles of chemotherapy and radiotherapy (total cumulative dose of 5,940 cGy). Optional PCI (36 Gy in 18 daily fractions) was given to 26 patients starting on day 8 of concurrent chemoradiotherapy. Two patients (8%) who received PCI relapsed in the brain compared to 16 of 100 (16%) patients who did not receive PCI (P = .44). The median survival was 13 months for stage IIIA patients and 17 months for stage IIIB (P = .81).

In 1999, Stutschke et al10 published the results of a trial of 75 patients with stage IIIA/IIIB NSCLC. Forty-seven patients were eligible to receive PCI of 30 Gy in 2-Gy daily fractions. CT scans of the brain and body were performed before initiation of therapy. Preoperative therapy consisted of induction chemotherapy with etoposide and cisplatin followed by twice-daily thoracic radiotherapy to a total dose of 45 Gy in 3 weeks with concurrent cisplatin and etoposide. PCI was given after the fourth cycle of chemotherapy or on day 9 of thoracic radiotherapy. Surgery was offered to those patients who had a high chance of complete resection. PCI reduced the rate of brain metastases as the first site of relapse from 30% to 8% at 4 years (P = .005) and the overall frequency of brain metastases decreased from 54% to 13% (P < .001) (Table 2).

Table 2. Prophylactic Cranial Irradiation for NSCLC: Nonrandomized Trials
Study (First author)NSCLC HistologyPCI Dose (dose/fraction)Median Survival (mo)Brain Metastasis
+PCI−PCI
Skarin15All36 Gy/183214%26%
Rusch40 (SWOG)All30 Gy/10 36 Gy/18N/A0%—
Strauss11 (CALGB)Nonsquamous30 Gy/1515.50%12%
Albain9 (SWOG)All36 Gy/18158%16%
Stuschke10All30 Gy/152013%54%

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PCI: Randomized Trials 

Three published prospective randomized trials investigated the role of PCI in patients with NSCLC. One of the early studies was from the Veterans Administration Lung Group (VALG) and was reported by Cox et al12 in 1981. The study reported the results of treatment for 281 inoperable NSCLC patients enrolled between 1975 and 1978. Treatment consisted of thoracic radiotherapy alone with a dose up to 50 Gy in 25 daily fractions with or without PCI (20 Gy in 10 fractions). Six percent of patients (7/136) who received PCI relapsed in the brain compared to 13% (16/145) of patients who did not receive PCI (P = .38). The reduction in brain relapse was not significant for squamous cell histology, and the addition of PCI did not alter the median survival of patients in the study. Umsawasdi et al14 from the the M.D. Anderson Cancer Center reported the results of a randomized trial testing the role of PCI in 1984. The study included 100 patients with locally advanced NSCLC who were clinically free of lung cancer after combined modality therapy. Patients received two cycles of induction chemotherapy (cyclophasphamide, doxorubicin, cisplatin) followed by thoracic radiotherapy administered concurrently with the same chemotherapy. Patients in the PCI group received 3,000 cGy in 10 daily fractions to the whole brain. PCI reduced the incidence of brain metastasis dramatically from 27% to 4% (P = .002). However, no survival benefit was seen with PCI due to the negative impact from frequent extracranial relapses. Finally, the RTOG conducted a study that investigated the role of PCI in 187 patients with unresectable or inoperable adenocarcinoma or large cell carcinoma of the lung. Russell et al13 reported the results of the randomized study that incorporated thoracic radiotherapy with or without PCI (30 Gy in 10 daily fractions). The dose to the chest was 60 Gy in 30 treatments for patients without prior surgery and 50 Gy in 25 treatments for those who had prior thoracotomy. Eighteen patients (19%) developed brain metastasis without PCI and eight patients (9%) with PCI developed brain metastasis (P = .10). There was no survival difference seen due to the significant extracranial systemic (81%) and thoracic (61%) relapses (Table 3).

Table 3. PCI for NSCLC: Randomized Trials
StudyNPCI (Gy/No. fractions)Medial Survival (mo)Brain Metastasis
+PCI−PCI+PCI−PCI
VALG1228120 Gy/10 fractionsNANA6%13%
RTOG1318730 Gy/10 fractions8.48.19%19%
M.D. Anderson149730 Gy/10 fractions8.4N/A4%N/A
RTOG L-02141,04830 Gy/15 fractions————

Abbreviation: VALG, Veterans Administration Lung Group.

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PCI: Toxicity 

The randomized trials reported very little or no late neurologic complications from PCI for NSCLC. However, there are more data available regarding the late toxicity of PCI from small cell lung cancer (SCLC) patients who underwent PCI. In these trials of PCI for patients with SCLC, dementia was not commonly seen,41, 42, 43 but attention deficit, memory changes, and changes in visual perception were noted.41, 43, 44 Some investigators noted changes in the white matter in T2-weighted magnetic resonance images of the brain.10, 44, 45 Most of the patients exhibiting these changes did not show significant deterioration in clinical status. In addition, the changes rarely affected daily life functions.10 Recent data from prospective studies incorporating PCI in SCLC did not demonstrate a profound effect on neuropsychological function.46, 47, 48, 49 In addition, recent studies have reported that a significant portion of the patients with SCLC had cognitive dysfunction even before PCI48, 49 and these patients did not have significant changes in their neuropsychological status after PCI. This implied that the neuropsychological abnormalities seen with SCLC might have been due to either systemic therapy or SCLC itself. Le Pechoux et al50 reported follow-up data on 57 patients in a randomized PCI trial followed for more than 36 months. There was no severe late-onset neurotoxicity. However, memory loss and mood changes were felt to be more attributable to PCI. Memory loss was seen in 21% (7/33) of patients who received PCI versus 4% (1/24) of patients who did not receive PCI. Mood changes such as anxiety were seen in 18% (6/33) of the patients who received PCI versus 4% (1/24) of patients who did not receive PCI. The highest rates of toxicity have been seen when PCI was combined with concurrent chemotherapy or when a high dose per fraction was used.51 Long-term data regarding neuropsychological changes for patients with NSCLC who received PCI are limited due to multiple factors. The use of multiple regimens to treat patients with NSCLC for both the primary tumor and PCI poses significant difficulty in interpreting the toxicity data. In addition, the impact of histology and stage of disease requires prospective studies. The current RTOG L-0214 study will address multiple questions related to PCI for locally advanced NSCLC. One thousand fifty-eight patients who have non-progressive disease after receiving therapy with curative intent for stage IIIA or IIIB NSCLC will be randomized to PCI (30 Gy in 15 fractions) or observation. Patients with squamous histology will be included in the study. The study is designed to detect a 20% improvement in median survival for patients receiving PCI.

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Conclusions 

There is significant risk of CNS relapse in patients with locally advanced NSCLC. Previously conducted randomized trials have failed to demonstrate a survival advantage with PCI and it is not frequently used in the oncologic community. However, with the advancement of multimodality treatments for locally advanced NSCLC, brain relapse is a prominent site of failure after initial successful treatment. Therefore, an updated trial with a power to distinguish a 20% improvement in survival is advocated to answer many questions related to PCI in NSCLC. RTOG 0214 is an important study that will investigate the role of PCI in the modern treatment setting.

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PII: S0093-7754(05)00087-4

doi:10.1053/j.seminoncol.2005.02.017

Seminars in Oncology
Volume 32, Issue 3 , Pages 293-298, June 2005

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