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Keywords:

  • lung carcinoma;
  • small cell lung carcinoma (SCLC);
  • neurologic complication;
  • brain metastases (BM);
  • leptomeningeal metastases;
  • paraneoplastic syndrome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Neurologic complications are an important cause of morbidity and possibly also mortality in patients with small cell lung carcinoma (SCLC). The current study was undertaken to prospectively investigate survival and the frequency of neurologic disorders in patients with SCLC.

METHODS

Between October 1980 and September 2001, 432 consecutive patients with microscopically proven SCLC were included in the current study. Patients underwent neurologic examinations on a regular basis prior to, during, and after treatment. Routine imaging of the brain (computed tomography or magnetic resonance imaging) was performed before and after systemic therapy.

RESULTS

A neurologic disorder was diagnosed in approximately 56% of the SCLC patients. In nearly half of the cases, the neurologic disorder already was present at the time of diagnosis. Brain metastases (BM) were diagnosed most frequently. Seventy-four patients (18%) had BM at the time of diagnosis; in 20 of these patients, the BM did not demonstrate clinical signs. Another 101 patients developed BM during follow-up. The 2-year cumulative risk of BM reached 49% for patients with limited disease (LD) and 65% for patients with extensive disease (ED). Patients with BM as the only site of disease dissemination were found to have a poorer survival compared with LD patients. The majority of the nonmetastatic disorders preceded the diagnosis of SCLC. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was diagnosed most frequently.

CONCLUSIONS

In this prospective study, neurologic disorders were diagnosed in greater than half of the patients with SCLC. BM were detected most frequently. Approximately 18% of the patients were found to have BM at the time of diagnosis. In approximately 33% of the cases, these BM did not cause symptoms. BM were found to have a negative effect on survival in patients with SCLC. Cancer 2004;100:801–6. © 2004 American Cancer Society.

In 2000, it was estimated that 164,100 new cases of lung carcinoma are diagnosed per year in the U.S., with 159,900 deaths from the disease reported annually.1 Of all incident cases of lung carcinoma, approximately 20–25% are reported to be small cell lung carcinoma (SCLC).2

The incidence of SCLC in the Netherlands is 15.3 (per 100,000 persons age ≥ 16 years).3 Despite new treatment regimens, survival remains poor.4 This is due in part to the neuroendocrine phenotype of SCLC, which distinguishes it from other types of lung carcinoma. These neuroendocrine properties are most likely responsible for the unique behavior of SCLC, which includes metastatic activity to the central nervous system (CNS) and the generation of paraneoplastic syndromes.5 Neurologic complications frequently are reported in patients with SCLC and are believed to contribute heavily to morbidity as well as mortality.6, 7 With a prevalence of approximately 10%, brain metastases (BM) are the most common neurologic complication diagnosed in patients with SCLC. Another 40% of patients have been reported to develop BM during follow-up.8 The probability of developing BM increases to 50–80% at 2 years from diagnosis.9

The current study was undertaken to prospectively investigate survival and the frequency of neurologic disorders in patients with SCLC. Patients were followed prospectively, and neurologic disorders were actively searched for. The current study is a continuation of a previously published study.6 Because the current study included a larger number of patients, it allowed a more detailed analysis to be performed.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

Between October 1980 and September 2001, 432 consecutive patients with microscopically and histologically proven SCLC were enrolled in the current study. Patients were diagnosed and treated at the University Hospital Maastricht (The Netherlands). Potential follow-up for each patient was at least 1 year. Patients initially were staged by a pulmonologist; physical examination, routine blood and chemistry profile, chest X-ray, computed tomography (CT) scan of the chest, and fiberoptic bronchoscopy were performed routinely. Limited disease (LD) was defined as tumor confined to one hemithorax, the mediastinum, and the ipsilateral and/or contralateral scalene and supraclavicular lymph nodes. Tumor occurring beyond these sites was defined as extensive disease (ED).

Neurologic Follow-Up

All patients were examined by a neurologist at the time of diagnosis, every 3 months during the first year, and every 6 months thereafter. Imaging of the brain was performed before and after treatment. An additional brain scan was performed when patients had survived for 12 months after the initial diagnosis of SCLC. Until 1989, CT scans were used. After 1989, CT was replaced by magnetic resonance imaging (MRI). In the case of new neurologic symptoms or signs developing, neurologic consultations and diagnostics were performed more frequently.

Treatment

Initial treatment was comprised of combination chemotherapy using cyclophosphamide, doxorubicin, and etoposide. This combination was repeated at 3–4-week intervals, with a maximum of 5 courses. The actual number of courses depended on the clinical condition of the patient. Local radiotherapy occasionally was applied to the primary tumor after chemotherapy; no strict indication criteria were established for this treatment. Response after initial treatment was measured using standard criteria. Complete remission (CR) was defined as the total clinical and radiologic resolution of the disease. A reduction of at least 50% of all measurable lesions was regarded as a partial remission (PR). The remainder of responses were regarded as no response (stable disease or progressive disease).

Patients in CR were eligible for prophylactic cranial irradiation (PCI). Until 1986, both patients with LD and those with ED could opt for PCI. After 1986, only patients with LD could do so. Between 1990–1997, PCI was excluded from the treatment protocol. PCI was administered to the entire brain after the completion of the chemotherapy. The total dose was 30 grays (Gy), administered as either 3 Gy given 4 times a week or 2 Gy given 5 times a week. Clinically manifest BM were treated with whole brain radiotherapy with fractions of 3 Gy given 4 times a week, also up to 30 Gy in total dose. In the case of cerebral edema, patients received corticosteroid medication.

Patients with leptomeningeal metastases were treated with intrathecal methotrexate, systemic chemotherapy, or local radiotherapy at symptomatic sites. Therapy for epidural or intramedullar spinal metastases was comprised of radiotherapy combined with corticosteroids.

Patient characteristics and details regarding treatment are shown in Tables 1 and 2.

Table 1. Patient Characteristics at the Time of Diagnosis and Frequency of Metastases outside the CNS
 Disease stage
Limited(%)Extensive(%)
  1. CNS: central nervous system.

Total140 292 
Men102(73)245(84)
Median age (yrs) (range)65 (32–80) 66 (39–89) 
Metastases (not in CNS)    
None136(97)20(7)
Bone  144(49)
Liver  148(51)
Mediastinum  62(21)
Other4(3)115(39)
Table 2. Treatment and Response
 Disease stage
Limited(%)Extensive(%)Total(%)
  • CR: complete remission; PR: partial remission; SD: stable disease; PD: progressive disease.

  • a

    Patients died before evaluation of result.

Chemotherapy      
 Yes127(94)239(86)366(88)
 No8(6)40(14)48(12)
 Unknown2 2 4 
 Dead3 11 14 
  Total140 292 432 
Response      
 CR68(56)66(30)134(39)
 PR33(27)88(40)121(35)
 SD11(9)18(8)29(8)
 PD9(7)50(23)59(17)
 Unknowna6 17 23 
  Total127 239 366 
Radiotherapy to the brain25 65 90 
Prophylactic cranial irradiation35 10 45 

Statistical Analysis

Survival curves were estimated using the Kaplan–Meier method. Differences between survival curves were tested with the log-rank test. A P value < 0.05 was considered to be statistically significant. Survival was calculated from the date of diagnosis of SCLC. BM-free survival time was calculated from the date of the diagnosis of SCLC to the date of the diagnosis of BM, and patients were censored from the moment they died.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 432 patients were included, 292 of whom (68%) were staged as having ED. Table 3 shows the neurologic disorders apparent at the time of diagnosis. Disorders that were diagnosed within 4 weeks after the diagnosis of SCLC was made were considered to be present at the time of the initial diagnosis of SCLC. Seventy-four patients (18%) were found to have BM at the time of diagnosis (synchronous); in 20 patients, these BM did not appear to cause clinical signs (asymptomatic). In 11 patients, BM were found at the time of autopsy, during which SCLC was diagnosed as well. Forty-five patients did not undergo a brain scan because their clinical condition was too poor and/or they died shortly after the diagnosis of SCLC was made. For another five patients, we were unable to ascertain data regarding diagnostic procedures. Other neurologic metastatic disorders were found in 17 patients. One patient had both leptomeningeal metastases and epidural metastases. Of all nonmetastatic disorders, syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) was found most frequently.

Table 3. Neurologic Disorders at Date of Diagnosis of SCLC
 Limited “disease”Extensive “disease”Total(%)
  1. SCLC: small cell lung carcinoma; CNS: central nervous system; SIADH: syndrome of inappropriate antidiuretic hormone secretion.

No. of patients140292432 
Metastatic disorders    
Brain metastases    
No brain metastases140168308(71)
Symptomatic brain metastases 4343(10)
Asymptomatic brain metastases 2020(5)
Brain metastases at autopsy 1111(3)
Unknown055-
No brain scan performed04545(10)
Other metastases (CNS) (n = 18 patients)   (4)
Leptomeningeal metastases 88 
Epidural metastases 99 
Intramedular metastases 11 
Nonmetastatic disorders (n = 37 patients)   (9)
SIADH22224 
Polyneuropathy112 
Lambert–Eaton myasthenic syndrome347 
Subacute cerebellar degeneration101 
Limbic encephalitis123 

The denominators in Table 4 account for all patients with LD or ED who were alive 4 weeks after diagnosis, minus those patients already diagnosed with the specific neurologic disorder involved. A total of 45 patients (10%) died within 4 weeks of the diagnosis of SCLC. As described in Table 4, 101 patients developed symptomatic BM during follow-up (metachronous). In 59 patients, it remains unknown whether they developed symptomatic BM, in part because they did not undergo a second brain scan because of their poor clinical condition or early death.

Table 4. Lifetime Incidence of Neurologic Disorders Developing During Follow-Up
 Limited diseaseab(%)Extensive diseaseab(%)
  • SIADH: syndrome of inappropriate antidiuretic hormone secretion.

  • a

    Stage of disease at the time of the initial diagnosis of small cell lung carcinoma.

  • b

    The denominator accounts for all patients in this stage of disease who were alive after 4 weeks, minus those patients already diagnosed with the respective neurologic disorder.

Metastatic disorders    
Symptomatic brain metastases38/136(28)63/127(50)
Leptomeningeal metastases11/136(8)18/243(7)
Epidural metastases2/136(1)13/242(5)
Intramedular metastases1/136(1)3/250(1)
Nonmetastatic disorders    
SIADH6/134(4)0/229(0)
Polyneuropathy2/135(1)3/250(1)
Lambert–Eaton myasthenic syndrome3/133(2)0/247(0)
Subacute cerebellar degeneration0/135(0)0/250(0)
Limbic encephalitis0/135(0)0/249(0)

Twenty-nine patients developed leptomeningeal metastases during follow-up and 8 cases were detected at the time of diagnosis. In 23 patients with leptomeningeal metastases, BM were present as well (62%).

The majority of nonmetastatic disorders preceded the diagnosis of SCLC. SIADH was diagnosed most frequently, followed by the Lambert–Eaton myasthenic syndrome.

The median survival time in the current study group (n = 421) was 8.5 months (range, 0–154 months). The median survival of those patients treated with chemotherapy (n = 127) was 9.2 months (range, 0–154 months). As expected, survival in the patients with ED was shorter than that in the patients with LD (P < 0.0005) (Fig. 1). The median survival for patients with ED (n = 284) was 7.2 months (range, 0–124 months), whereas that for patients with LD (n = 137) was 11.9 months (range, 0–154 months). As shown in Figure 2, patients with BM only (patients with ED in whom the brain was the only site of disease dissemination) had a poorer survival than patients with LD (P < 0.0005). Patients with BM only (n = 20) had a median survival of 6.1 months (range, 0–32 months).

thumbnail image

Figure 1. Kaplan–Meier curves showing survival after the date of diagnosis of small cell lung carcinoma (SCLC) in patients with limited disease (LD) and extensive disease (ED). The asterisk (*) indicates all patients minus those patients diagnosed with SCLC at autopsy.

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thumbnail image

Figure 2. Kaplan–Meier survival curves showing survival from the date of diagnosis of small cell lung carcinoma of patients with extensive disease (ED), patients with brain metastases (BM) only, and patients with limited disease (LD).

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The 2-year cumulative risk of BM among patients who were free of BM at the time of SCLC diagnosis was 49% for patients with LD and 65% for patients with ED (Fig. 3).

thumbnail image

Figure 3. Kaplan–Meier survival curves showing brain metastases-free survival from the date of diagnosis of small cell lung carcinoma in patients with limited disease (LD) and those with extensive disease (ED).

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Of the SCLC patients with BM, 170 died within the study period. The causes of death are described in Table 5. In 59 patients, death was considered an immediate result of BM (intracranial hypertension). The cause of death remained unknown in 45 patients who died at home. Categorized as “other” are causes such as sepsis, dehydration, and myocardial ischemia.

Table 5. Causes of Death in SCLC Patients with Brain Metastases
 No.%
  • SCLC: small cell lung carcinoma.

  • a

    Death was not caused by brain metastases, but was not specified further.

No. of deceased patients170 
Cause of death  
Neurologic  
 Brain59(47)
Nonneurologic  
 Lung21(17)
 Liver4(3)
 Other7(6)
 Not specifieda34(27)
Unknown45 

During the period in which PCI was excluded from the treatment protocol (1990–1997), the 1-year cumulative incidence of BM after the diagnosis of SCLC was 33%. During the period in which PCI was applied, the 1-year cumulative incidence after the diagnosis of SCLC was 23%.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the current study, 240 SCLC patients (56%) were diagnosed with a neurologic disorder at some point during their disease. In nearly half of the cases, the neurologic disorder already was present at the time of diagnosis. A higher frequency of BM was observed in comparison with earlier studies (18% vs. 10%).8–10 This most likely is due at least in part to differences in the diagnostic procedures utilized in the initial staging. CT scan and later MRI were used routinely in the pretreatment evaluation in the current study, which led to the identification of asymptomatic BM.

During follow-up, another 101 patients developed symptomatic BM. The lifetime incidence was lower among patients with LD compared with patients with ED.

It has been reported that BM as such do not negatively influence the prognosis for patients with SCLC.11, 12 However, we found that patients with ED who had only BM had a poorer survival than patients with LD (Fig. 2). In addition, in nearly half of the patients with BM, the cause of death was found to be related directly to the BM (Table 5). We therefore argue that BM have an adverse effect on survival in patients with SCLC.

Comparing periods in which PCI was administered with those in which it was not administered, we found that the cumulative incidence of BM was higher during the period in which PCI was not administered. This supports the findings of other authors who have reported that PCI may decrease the incidence of BM.13, 14

Leptomeningeal metastases were diagnosed for the most part during follow-up. In total, we found 37 patients with leptomeningeal metastases, which was 9% of the total patient group in the current study. Previously reported percentages have been reported to vary from 6–18%.6, 7, 15, 16

Ten patients were found to have spinal metastases at the time of diagnosis. During follow-up, another 15 patients were diagnosed with epidural metastases and 4 patients were diagnosed with intramedullar metastases. In all patients with intramedullar metastases, BM already were present. Earlier studies also reported low frequencies of spinal metastases in patients with SCLC..6, 7, 17

Because of its neuroendocrine properties, SCLC is associated more frequently with paraneoplastic syndromes compared with other malignancies.18–21 In the current study, 9% of patients were found to have a nonmetastatic paraneoplastic disorder at the time of diagnosis of SCLC. SIADH was diagnosed in 30 patients, a frequency that is similar to the findings of other investigators.19 The results of the current study confirm earlier findings, which demonstrated that paraneoplastic syndromes frequently precede the diagnosis of SCLC.22

The median survival in the current study, which was reported to be 11.9 months in patients with LD and 7.2 months in patients with ED, is in accordance with the findings of earlier studies.4, 6, 23

Conclusions

Among the conclusions reached in the current study are: 1) at the time of diagnosis of SCLC, 18% of the patients in the current study had BM; however, these BM caused no symptoms in approximately a third of the cases; 2) contrary to reports in the literature, BM appear to have a negative effect on survival in patients with SCLC; and 3) BM are the direct cause of death in nearly half of the patients with BM.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES