Brain Metastases in Locally Advanced Nonsmall Cell Lung Carcinoma after Multimodality Treatment

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1 605 Brain Metastases in Locally Advanced Nonsmall Cell Lung Carcinoma after Multimodality Treatment Risk Factors Analysis Giovanni Luca Ceresoli, M.D. 1 Michele Reni, M.D. 1 Giuseppe Chiesa, M.D. 2 Angelo Carretta, M.D. 2 Stefano Schipani, M.D. 1 Paolo Passoni, M.D. 1 Angelo Bolognesi, M.D. 1 Piero Zannini, M.D. 2 Eugenio Villa, M.D. 1 1 Department of Radiochemotherapy, IRCCS San Raffaele, Milan, Italy. 2 Department of Thoracic Surgery, IRCCS San Raffaele, Milan, Italy. BACKGROUND. Brain metastases (BM) are frequent sites of initial failure in patients with locally advanced nonsmall cell lung cancer (LAD-NSCLC) undergoing multimodality treatments (MMT). New treatment and follow-up strategies are needed to reduce the risk of BM and to diagnose them early enough for effective treatment. METHODS. The incidence rate of BM as the first site of recurrence in 112 patients with LAD-NSCLC treated with the same MMT protocol was calculated. The influence of patient, disease, and treatment-related factors on the incidence of BM and on the time-to-brain recurrence (TBR) was analyzed. RESULTS. BM as the first site of failure was observed in 25 cases (22% of the study population and 29% of all recurrences). In 18 of those cases, the brain was the exclusive site of recurrence. Median TBR was 9 months. The 2-year actuarial incidence of BM was 29%. Central nervous system (CNS) recurrence was more common in patients younger than 60 years (P 0.006) and in whom bulky ( 2 cm) mediastinal lymph nodes were present (P 0.02). TBR was influenced by age (P 0.004) and by bulky lymph node disease (P 0.003). Multivariate analysis confirmed the prognostic role of age, whereas the presence of clinical bulky mediastinal lymph nodes was of borderline significance. CONCLUSIONS. Our study confirmed a high rate of BM in patients with LAD-NSCLC submitted to MMT. Most of these CNS recurrences were isolated and occurred within 2 years of initial diagnosis. Age younger than 60 years was associated with an increased risk of BM and reduced TBR, whereas the presence of clinical bulky mediastinal lymph nodes was of borderline significance. Although our data require further validation in future studies, our results suggest that additional trials on prophylactic cranial irradiation and on intensive radiologic follow-up should focus on these high-risk populations. Cancer 2002;95: American Cancer Society. DOI /cncr KEYWORDS: brain metastases, nonsmall cell lung cancer, locally advanced, multimodality treatment. Presented at the 25th Conference of the European Society for Medical Oncology, Hamburg, Germany, October 13 17, Address for reprints: Giovanni Luca Ceresoli, M.D., Department of Radiochemotherapy, IRCCS San Raffaele, Via Olgettina, Milan, Italy; Fax: ; ceresoli. giovanni@hsr.it Received October 23, 2001; revision received February 13, 2002; accepted March 11, Patients with locally advanced nonsmall cell lung cancer (LAD- NSCLC) account for approximately one third of all NSCLC patients. Multimodality treatment (MMT) with the inclusion of chemotherapy is being used increasingly as a new standard of care for these patients. Several Phase II and III trials have shown the superiority of MMT over local therapy alone. 1 A small, but significant, survival benefit has been demonstrated. 1,2 However, the majority of patients still die of recurrent disease. In addition to locoregional recurrences, LAD-NSCLC patients have a very high rate of distant metastases. Of these, brain metastases (BM) are the most frequent types of initial 2002 American Cancer Society

2 606 CANCER August 1, 2002 / Volume 95 / Number 3 failure in several multimodality trials Therefore, new treatment and/or follow-up strategies are needed to reduce the risk of BM or to diagnose them early enough for effective treatment. In this study, we evaluated the influence of patient, disease, and treatment-related factors on the incidence of BM and on the time-to-brain recurrence (TBR). This analysis was performed on a group of patients with LAD-NSCLC who had been treated prospectively with the same protocol of MMT. 13,14 The aim of our study was to define a subset of patients at a particularly high risk of central nervous system (CNS) recurrence, on whom a policy of early detection or new treatment strategies should be focused more intently. PATIENTS AND METHODS Patients with a histologically confirmed diagnosis of LAD-NSCLC who had been referred to our institution between January 1991 and June 1998 and treated with the same MMT protocol were included in this analysis. The planned treatment consisted of two or three courses of chemotherapy according to the MVP schedule 3 : cisplatin 120 mg/m 2 on Days 1, 29, 71; mitomycin C 8 mg/m 2 on Days 1, 29, 71; vinblastin 4 mg/m 2 on Day 1, 2 mg/m 2 on Day 8, and 4.5 mg/m 2 on Days 15 and 22, then administered every other week. Response was evaluated after two courses. The third course was administered only to patients who had a major response and no severe toxicity. At the end of chemotherapy, the patients were evaluated for resection. If unresectable, they were treated with radical radiation therapy (60 70 Gy). If resectable, they underwent surgery and postoperative radiotherapy (50 56 Gy). Patients were analyzed on an intent-to-treat basis. Therefore, the completion of planned treatment was not required for inclusion in the analysis. Baseline evaluations included medical history, physical examination, complete blood cell count and biochemical profile, chest X-ray, computed tomography (CT) scans of the chest and abdomen, and whole bone scan. Routine CT scans, magnetic resonance image scans of the brain, or both were obtained before initiation of treatment. All patients gave informed consent before beginning therapy. Entry criteria of the trial included patients with Stage IIIA and IIIB according to the 1986 version of the TNM staging system. 15 Subjects with T3N0 disease, at that time classified as IIIA, were included in this treatment group in instances of large tumor volumes (maximum diameter 5 cm). Mediastinoscopy was not performed routinely, but only in selected cases. It was not required if the patient had a documented T3 tumor, or a very significant case of mediastinal lymph node disease evidenced at CT scan. In the current analysis, we retrospectively examined several potential predictive factors with the aim to define a subset of patients at a particularly high risk of CNS recurrence. Stage was analyzed taking into account the new version (1997) of TNM classification. 16 Patients with T3N0 disease were therefore grouped in the IIB subset. Patients received a follow-up physical examination and a CT scan of the chest and abdomen every 4 months during the first 2 years after MMT, then twice a year for the following 2 years, and yearly thereafter. Additional imaging studies were performed as necessary. In particular, posttreatment brain scanning was only performed in the event of new neurologic symptoms or signs. The incidence rate of BM as the first site of recurrence was calculated. Patients with disease progression in sites other than the CNS and patients who died of any cause were censored for actuarial BM rate at the date of failure or death. TBR was defined as the period from the first day of MMT of lung disease to the date of first radiologic evidence of CNS recurrence or last follow-up. Survival was calculated from the first day of therapy until death or last follow-up. All causes of death were regarded as events for the purpose of survival analysis. Survival curves were generated using the Kaplan Meier method. Patients with BM were analyzed using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classes. 17 The incidence of BM as the first recurrence was evaluated with the following variables: patient-related factors (age, gender, Eastern Cooperative Oncology Group performance status [PS], and weight loss); disease-related factors (stage, histology, lymph node status, presence of bulky [ 2 cm] mediastinal lymph nodes, tumor size, white blood cell count, hemoglobin level, platelet count, and serum lactate dehydrogenase [LDH] value); and treatment-related factors (response to chemotherapy, surgery). All parameters were analyzed as categorical variables. The hemogram and LDH data were dichotomized into normal and abnormal values according to standard laboratory norms. The Spearman test was used to compare percentages in subsets of patients through univariate analysis. Multivariate analysis was performed using a logistic regression model. The impact of these variables on TBR was evaluated by univariate analysis using the log rank test. The independent value of variables was assessed in multivariate analysis using the Cox proportional hazard regression model, with an estimate of hazard ratios and 95% confidence intervals. All probability values were two sided.

3 Brain Recurrence in Locally Advanced NSCLC/Ceresoli et al. 607 TABLE 1 Patient Characteristics (n 112) No. of patients (%) Gender Female 11 (10) Male 101 (90) Age (yrs) Median (range) 58 (37 72) (61) (39) ECOG performance status 0 45 (40) 1 67 (60) Weight loss No 102 (91) Yes 10 (9) Histology Squamous 62 (55) Adeno 30 (27) Large cell 6 (5) NSCLC undifferentiated 14 (13) Stage (clinical) IIB 16 (14) IIIA 48 (43) IIIB 48 (43) N-stage (clinical) N (34) N 2 62 (55) N 3 12 (11) Bulky mediastinal lymph nodes No 71 (63) Yes 41 (37) Tumor size (cm) 5 61 (54) 5 51 (46) WBC count (mm 3 ) (78) (22) Hemoglobin (g/dl) (79) (21) Platelet count (mm 3 ) (87) (13) LDH rate 1 88 (79) 1 24 (21) ECOG: Eastern Cooperative Oncology Group; NSCLC: nonsmall cell lung cancer; WBC: white blood cells; LDH: lactate dehydrogenase. RESULTS The study group consisted of 112 patients. Their main characteristics are listed in Table 1. There were 16 Stage IIB (T3N0), 48 Stage IIIA (3 T3N1, 11 T1N2, 34 T3N2), and 48 Stage IIIB patients (19 T4N0-1, 17 T4N2, 12 T1-4N3). Most patients had nonminimal mediastinal lymph node involvement. Bulky lymph nodes ( 2 cm of maximum diameter) were found in 41 patients (37%) at CT scan and 26 patients with nonbulky lymph node disease had multiple sites of involvement. All patients received two or three courses of full-dose chemotherapy, except for 4 patients in whom the treatment was stopped after one cycle due to toxicity. Overall response rate to chemotherapy was 75% (81% in Stage IIB, 79% in Stage IIIA, and 69% in Stage IIIB patients). A radiologically complete remission of disease was achieved in 7 patients (6%). Fifty patients were completely resected: resection rate was 81% for Stage IIB, 58% for Stage IIIA, and 19% for Stage IIIB patients (33% in the T4N0 subgroup). A pathologically complete remission was observed in nine patients (8% of the whole series). Ninety-four patients underwent radiotherapy, 43 as an adjuvant treatment, 51 as exclusive locoregional treatment. Radiotherapy was not delivered in 18 cases: in 11 unresectable patients for reasons of metastatic disease progression (9 patients) or poor PS after chemotherapy (2); in 7 resected patients due to poor PS after surgery (5 cases) or protocol violation (2). Median overall survival was 21 months for the entire population of the study, 24 months for Stage IIB and IIIA patients, and 17 months for Stage IIIB patients. The 3-year and 5-year survival rates were 32% and 26% for the whole group, 42% and 31% for Stage IIB patients, 42% and 33% for Stage IIIA patients, and 19% and 13% for Stage IIIB patients, respectively. Twenty-three patients are alive with a median follow-up of 63 months (range, months). Overall, 85 patients had recurrence: 26 (23% of the whole study population) had a local failure, 37 (33%) had distant metastases, and 22 (19%) had both local and distant recurrence. BM as the first site of failure was observed in 25 patients (22% of the whole study population and 29% of all recurrences), 18 with the brain as the exclusive site of recurrence. Median TBR in patients with CNS recurrence was 9 months (range, 1 47 months). Five patients experienced first recurrence in the brain after more than 1 year; only one patient developed BM after more than 2 years from the initial diagnosis of LAD-NSCLC. The 2-year actuarial incidence of BM was 29% (Fig. 1). Nine patients had a CNS recurrence with a single BM, whereas multiple BMs were observed in the other 16 cases; TBR was identical in the two groups. Treatments for BM were individualized. Single BMs were treated with radiosurgery alone (4 patients) or resection followed by whole-brain radiotherapy (WBRT; 3 patients). The majority of patients with multiple BM were submitted to WBRT (10 patients) and in selected cases to radiosurgery alone. Dose of radiation was 25 Gy on the 50% isodose for radiosurgery, 30 Gy in 10 fractions for WBRT, and Gy in patients with postoperative

4 608 CANCER August 1, 2002 / Volume 95 / Number 3 WBRT. Five patients received supportive care only after CNS recurrence. Of the 25 patients with first recurrence in the brain, 14 (56%) died of BM, 7 of thoracic progression or metastases at another site, and 4 are alive without evidence of CNS disease. Thirteen (72%) of the 18 patients with isolated BM died of CNS recurrence. Patients with RPA Class I survived longer than patients with Class II and III; median survival after brain recurrence was 22 months versus 4.5 months versus 2 months, respectively (P ). Univariate analysis of the incidence of BM in the different subsets of patients according to pretreatment and treatment-related factors (Table 2) showed that BM were more common in patients younger than 60 years (31% vs. 9%, P 0.006) and in patients with bulky mediastinal lymph nodes (34% vs. 15%, P 0.02). Patients with squamous histology had a decreased incidence of BM (16%) relative to patients with other histotypes (30%), but this did not reach statistical significance (P 0.17). No significant difference was observed in BM rate according to the other variables. Multivariate analysis with multiple regression confirmed the independent statistical significance of age (P 0.03), whereas the presence of bulky lymph node disease was only of borderline significance (P 0.11; Figs. 2 and Fig. 3). In univariate analysis (Table 3), TBR was shortened in patients who were younger than 60 years (P 0.004) and had bulky lymph node disease (P 0.003). Histotype was nearly significant (P 0.09). On the contrary, no statistical significance was observed for treatment-related factors such as surgical resection or response to chemotherapy. Multivariate analysis with the Cox model confirmed the independent value of age (P 0.05), whereas the presence bulky lymph node disease was nearly significant (P 0.09). FIGURE 1. Cumulative actuarial incidence of brain metastases in the whole population. DISCUSSION BM are a common type of failure in patients with NSCLC, both in early stages after treatment with complete surgical resection and in LAD stages after treatment with radiation therapy alone 21 or MMT. 8 12,22,23 The rate of BM in LAD-NSCLC patients has been estimated at between 17% and 32%, 8 12 with a median TBR in the range of months. 10,12 In most of these studies, BM were detected within 2 years of diagnosis. 8,10,12,24 The results of our study are consistent with these observations, with an overall rate of BM of 22% and a median TBR of 9 months. The 2-year actuarial incidence of BM was 29% (Fig.1). Like other authors, 3,24 we observed a late brain recurrence, almost 4 years after treatment of the primary tumor. Subgroup analysis in our series showed that certain patients are at particular risk of BM. Age was the main prognostic indicator. Two-year actuarial incidence of BM in younger patients was relevant, with a 44% risk of brain recurrence as the first site of failure (Fig. 2). TBR was significantly shorter in younger patients (13.5 months vs months in older patients, P 0.05 in multivariate analysis). Notably, median survival and median follow-up were similar in the two groups (P 0.18). Age was not reported as a risk factor for BM in other series. 10,12 The difference in our results may be due to a more aggressive course of disease in younger patients or to a difference in unknown prognostic factors between the two groups, such as biological factors. 25 Alternatively, the higher incidence of BM and the shorter TBR could be related to the fact that brain masses are more symptomatic in younger patients. 26 Posttreatment brain scanning was only performed in case of new neurologic symptoms or signs, which may explain the higher incidence of events in younger patients in our series. Further studies are needed with scheduled CNS imaging studies in nonsymptomatic patients. Lymph node bulky disease in the mediastinum was also related to an increased risk of BM, with an incidence of 34% and a 2-year actuarial rate of 61% (Fig. 3). TBR was significantly shorter in this group of patients (10 months vs for patients with no bulky lymph nodes), even though this difference lost its statistical significance when evaluated using the Cox model (P 0.09). Patients with lymph node involvement were reported to have a higher risk of developing CNS recurrence compared with those without lymph node involvement. 18,27 Mediastinal lymph node size as

5 Brain Recurrence in Locally Advanced NSCLC/Ceresoli et al. 609 TABLE 2 Incidence of Brain Metastases Rate (%) P (univariate) P (multivariate) Odds ratio (95% CI) Age (yrs) ( ) 60 9 Stage IIB 12.5 IIIA ( ) IIIB 21 Histology Nonsquamous ( ) Squamous 16 Bulky lymphnodes Yes ( ) No 15 Response to ChT Yes ( ) No 18.5 Surgical resection Yes ( ) No 20 ChT: chemotherapy; CI: confidence intervals. FIGURE 2. Cumulative actuarial incidence of brain metastases according to age (P 0.006, univariate; P 0.03, multivariate). a prognostic factor has been analyzed in only a few trials, with overall survival as the exclusive endpoint. A report 28 found no difference in survival between patients with lymph nodes smaller than 1 cm and with lymph nodes 1 2 cm in diameter, whereas patients with lymph nodes larger than 2 cm were not considered in the analysis. On the contrary, another study showed a significantly lower survival rate in patients with bulky mediastinal lymph nodes ( 2.5 cm). 29 There is a growing body of data suggesting that, in FIGURE 3. Cumulative actuarial incidence of brain metastases according to the presence of bulky ( 2 cm) mediastinal lymph nodes (P 0.02, univariate; p 0.11, multivariate). addition to the accepted TNM staging, patients with Stage IIIA-B disease should be subdivided into different risk groups according to their lymph node status. 30 Stage (IIB vs. IIIA vs. IIIB) did not affect the rate of BM or TBR in our series. The same conclusions were reported by Law et al. 10 However, in the series reported by Robnett et al., 12 Stage IIIB was associated with a higher risk of BM than Stage II-IIIA.

6 610 CANCER August 1, 2002 / Volume 95 / Number 3 TABLE 3 Time-to-brain recurrence (TBR) a Median TBR (months) P (univariate) P (multivariate) Odds ratio (95% CI) Age (yrs) ( ) Stage IIIB ( ) IIB IIIA 21 Histology Nonsquamous ( ) Squamous 21 Bulky mediastinal lymphnodes Yes ( ) No 21.5 Response to ChT No ( ) Yes 22 Surgical resection No ( ) Yes 32 ChT: chemotherapy; CI: confidence intervals. a Actuarial data calculated on the whole population. BM occur more frequently in patients with nonsquamous histology treated with surgery and radiotherapy alone, 21 whereas the results are more variable in LAD-NSCLC patients treated with MMT. In at least three studies, an adenocarcinoma subtype was associated with a higher rate of CNS recurrence. 11,23,31 However, in other series, there was no significant correlation between cell type and the incidence of BM, 9,10,12,24 although a trend toward higher risk in nonsquamous tumors was often observed. 12 Our data indicated a trend toward a higher risk of CNS metastases for nonsquamous histology: the rate of BM was almost doubled (30% vs. 16%) and TBR was shorter (14 vs. 21 months), but neither of these differences was statistically significant. The addition of chemotherapy in the treatment of LAD-NSCLC has modestly improved survival rates mainly due to the reduction of distant metastases. 23,32 However, the incidence of BM has been altered little by chemotherapy. 23 The slight improvement in overall survival rates may be associated with a relatively increased rate of isolated BM. 9 12,24 Andre et al. 11 compared the patterns of recurrence in 81 NSCLC patients with clinically detectable mediastinal lymph node enlargement who had been treated with preoperative chemotherapy with the recurrence patterns of 186 comparable patients who had been treated with primary surgery. Preoperative chemotherapy decreased the risk of visceral metastases, but was associated with a higher rate of isolated BM (22% vs. 11% of patients treated with primary surgery). In our series, all the patients had received induction chemotherapy. However, the rates of BM and TBR were not influenced significantly by the response to chemotherapy. Interestingly, the median time to occurrence of BM was similar in our series and in the surgical series. 33 As reported by Robnett et al., 12 the timing of radiotherapy can influence the risk of CNS recurrence: the rate of BM was 27% in patients receiving induction chemotherapy before radiotherapy and 15% in patients who were treated with concurrent chemoradiation. The 2-year actuarial rate of BM was 39% versus 20%. The authors hypothesized that early aggressive locoregional and systemic treatment could better control regional disease, which can in turn affect the development of BM. However, the retrospective nature of the study could have resulted in an imbalance of prognostic factors in the two groups, which limits the value of these findings. Furthermore, the results contradict the reports of three randomized studies, 31,34,35 in which the BM rate after concurrent therapy was greater than or equal to the BM rate after sequential treatment. In a combined analysis of 461 patients enrolled in five RTOG trials using three chemotherapy/radiotherapy sequencing strategies, no significant difference in CNS recurrence rate was found. 36 More data on this topic are needed before any firm conclusions can be drawn. In the current analysis, patients were analyzed on an intent-to-treat basis. Radiation therapy was not considered an inde-

7 Brain Recurrence in Locally Advanced NSCLC/Ceresoli et al. 611 pendent variable because patients not undergoing radiation treatment were negatively selected (due to progressing disease or poor PS). The growing evidence of a high rate of isolated BM in LAD-NSCLC patients submitted to MMT has led to a renewed interest in prophylactic cranial irradiation (PCI) 11,12,24 as well as new strategies of follow-up observation that could increase the chances of effective and timely treatment. 10,37,38 PCI was associated with a reduction of BM rate in early trials, 27,39 42 with no improvement in survival rates. The lack of survival benefit with PCI may be due to the inclusion of patients with early disease and low risk of BM 18 or to the high rate of locoregional and distant non-cns failures reported in those studies. More recently, a significant reduction of BM as first recurrence was reported in a nonrandomized trial including patients with LAD- NSCLC who had been submitted to PCI after intensive MMT. 8,24 Other authors have suggested the use of routine scans of the brain in the follow-up examination of these patients. 10 Both strategies need to be evaluated in prospective randomized trials. The use of prophylactic chemotherapy is another interesting issue in these patients. However, the ability of drugs to cross the blood brain barrier (BBB) must be taken into account. Cisplatin has been proved to cross the BBB. A response rate of 15 30% has been reported in BM in NSCLC patients treated with cisplatin-containing regimens. 43 Temozolomide 44 is a recently developed compound achieving high concentrations in the CNS. Unfortunately, its activity in NSCLC patients is poor (response rate 10%). 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