Payne, Miranda MA, BM, BCh, MRCP*; Bradbury, Penny FRACP, MD†; Lang, Bethan BSc, PhD‡; Vincent, Angela FRCPath‡; Han, Cheng MBBS, MSc*; Newsom-Davis, John MD, FRS§; Talbot, Denis BSc, MBChB, MA, PhD, FRCP*
Lung cancer is the single greatest cause of death from malignancy in both men and women1 with approximately 13% of cases classified as small cell lung cancer (SCLC)2 and increasing numbers of women affected. Although the incidence of SCLC is reducing in the western world as a result of reduced rates of tobacco consumption, the disease remains a significant global health problem.
SCLC is believed to be of neuroendocrine origin and is associated with high mitotic rate and early metastastis. The Lambert Eaton myasthenic syndrome (LEMS) is the most common paraneoplastic disorder associated with SCLC with a prevalence of approximately 3% (0–6%).3–7 Around 70% of patients with a diagnosis of LEMS have cancer, almost always SCLC.5 The clinical syndrome can include a range of debilitating symptoms related to motor and autonomic function. The most common symptoms are of progressive limb weakness and autonomic dysfunction such as a dry mouth, constipation, or impaired sexual function. Symptoms associated with this syndrome impact greatly on quality of life, and their development may predate diagnosis of any underlying malignancy, making the disease a useful marker for the tumor. Moreover, pharmacological treatment of the neurologic symptoms can improve quality of life.
The pathogenesis of LEMS is characterized by the down-regulation of presynaptic voltage-gated calcium channels (VGCCs) at the neuromuscular junction because of binding by divalent IgG autoantibodies targeted against the extracellular P/Q-type VGCCs8 that account for more than 95% of the functioning receptors at the neuromuscular junction. This results in a reduction of calcium dependent release of acetylcholine. It is presumed that the ectopic expression of neuronal antigens by SCLC induces antibody production,9,10 and that these antibodies then target the VGCCs at the neuromuscular junction. Measurement of VGCC antibodies forms the basis of the serological test for LEMS.11 Although VGCC antibodies are present in up to 95% of patients with the syndrome,12,13 other autoantibodies have also been demonstrated to be associated with SCLC-related LEMS.14 Similarly, VGCC are expressed in the cerebellum and patients with SCLC, with or without LEMS, may also have cerebellar dysfunction.15
In an unselected series of patients with SCLC, 5% had a positive titer of VGCC antibodies,16 although the frequency of neurologic symptoms in this series is not known. It has been postulated that the presence of the antibodies may confer a survival advantage by an immune mediated effect on the tumor,5,17,18 but it remains unclear whether patients with the clinical syndrome of LEMS have a better prognosis. Management of LEMS primarily involves treatment of the underlying malignancy. Additionally, 3,4-diaminopyridine can be employed to increase the duration of the action potential at the neuromuscular junction, hence increasing acetylcholine release.
Elevation of serum anti-VGCC antibodies is not exclusive to patients with clinical LEMS, as a proportion of patients with SCLC without LEMS have increased antibody titers.15 It is, therefore, essential to confirm the diagnosis by clinical examination and electrophysiological testing. We define subclinical LEMS as the presence of a positive titer of VGCC antibodies in the absence of symptoms and clinical signs specific to LEMS. This study is a prospective evaluation of the incidence of clinical and subclinical LEMS in an unselected cohort of patients with pathologically confirmed SCLC. We have also determined whether the presence of P/Q-type VGCC antibodies is associated with an improved prognosis in this group of patients.
PATIENTS AND METHODS
All adult patients presenting to the University of Oxford Medical Oncology Department with SCLC were considered eligible for this study. Inclusion criteria were histologic or cytologic confirmation of SCLC, no prior administration of systemic treatment of SCLC, and the ability to give informed consent and complete the symptom questionnaire. Patients were excluded if they were known to have Hepatitis B, C, or human immunodeficiency virus infection. Written informed consent had to be obtained from all patients before enrolment. The study was conducted over a period of 10 years with the approval of the Central Oxford Research Ethics Committee (OxREC CO2.292) and performed to the standards of Good Clinical Practice. Patients were managed according to institutional policy. This included combination chemotherapy, typically cisplatin and etoposide, radiotherapy as appropriate, and symptom control.
Before treatment, patients completed a symptom questionnaire (Table 1). This was based on previous studies that had defined the common neurologic symptoms observed in LEMS.5,19 Patients were then examined, using a set protocol, for clinical diagnostic signs of LEMS by medically qualified members of the team responsible for their ongoing clinical care (Table 2).
Serum for analysis of P/Q-type VGCC antibodies was taken before the start of treatment. The VGCC radioimmunoassay was performed by immunoprecipitation of iodine-125-omega-conotoxin MVIIC bound to VGCCs extracted from human cerebellum as previously described.11,15,16 Antibody titer was expressed as picomoles of 125I-conotoxin binding sites precipitated per liter of serum (pM). Antibody titers were considered positive if ≥50 pM (mean titer +3SD above mean for healthy controls, n = 30). This assay has a high sensitivity (85%) and specificity for VGCCs antibodies11 and is used for the routine diagnosis of LEMS.
Diagnosis of LEMS on the grounds of symptom evaluation and physical examination was confirmed by neuro-electrophysiological assessment based on the presence of small compound muscle action potentials and enhanced muscle response following high-frequency stimulation.20
Multivariate regression was used to determine the relationship between clinical symptoms and anti-VGCC titer. Cox regression analysis was used to evaluate survival. Survival was determined from date of histologic diagnosis to the date of death (data last examined 2008). In 2 × 2 tables, Fisher's exact test was used to test the relationship of stage and serum VGCC antibody level.
Sixty-three unselected patients were recruited to this single center study, all of who met the trial entry criteria. Forty-six (73%) were men and 54 (86%) had extensive stage disease. Median age at recruitment was 67 years (range, 43–80 years).
Elevation of Serum VGCC Antibodies
Of sixty-three patients, fifty-eight had serum VGCC antibodies within the range of the controls (less than 50 pM/l). Five patients (8%) had elevation of the VGCC antibodies (≥50 pM/l) with levels ranging from 69 to 1553 pM/l. These results are summarized in Table 3. The positive results were confirmed on repeat testing. There was no statistical correlation of extent of disease with elevation of serum VGCC antibodies (Fisher's exact test, p = 1.00).
Incidence of Neurologic Symptoms
Neurologic symptoms in patients without clinical signs of LEMS and before commencing cytotoxic therapy were common. Of the 63 patients, 34 (54%) reported at least one neurologic symptom of which the most common was a dry mouth (26%). Twenty-three percent experienced constipation and 12.5% described arm and leg weakness. However, symptoms specific to LEMS, such as leg and trunk weakness exacerbated by prolonged exercise, were infrequent. Results are summarized in Tables 1 and 2.
Incidence of LEMS
Only two patients (one man) had LEMS diagnosed on clinical grounds and subsequently confirmed by serological and electrophysiological testing. The first was a 75-year-old man whom at the time of his histologic diagnosis of extensive stage SCLC reported malaise and leg weakness of several months duration. His completed study questionnaire confirmed difficulty in walking, leg weakness, and impotence. Neurologic examination demonstrated a rolling gait and proximal muscle weakness of the lower limbs. A computed tomography scan of the brain demonstrated no evidence of metastatic disease. The diagnosis of LEMS was suspected on clinical grounds and confirmed within a month by a neurologist (J.N.-D.) and following demonstration of high titers of serum VGCC antibodies (1553 pM) and typical neurophysiological findings. Dry mouth and a mild ataxia were also noted at this stage. He also had the syndrome of inappropriate antidiuretic hormone secretion that was managed successfully by fluid restriction and demeclocycline. The neurologic symptoms particularly his gait disturbance, improved with 3,4-diaminopyridine (20 mg qds orally). Following first-line chemotherapy (four cycles of adriamycin, cyclophosphamide, and etoposide because of poor performance status), he achieved a radiologic partial response. Neurologic symptoms recurred 12 months later when tumor progression was confirmed. Second-line chemotherapy (four cycles of cisplatin and etoposide) was associated with an improvement in LEMS-related symptoms for several months. Death was 23.5 months after histologic diagnosis.
The second confirmed case of LEMS was in a female patient aged 75 years with extensive stage SCLC. On completion of the structured study questionnaire before chemotherapy, she confirmed difficulty in walking and leg and arm weakness. Neurologic examination at this stage was normal, but serum VGCC antibody titer was elevated (337 pM). First-line chemotherapy (six cycles of adriamycin, cyclophosphamide, and etoposide in view of her performance status) resulted in partial response. The patient relapsed subsequently and received six cycles of topotecan. Two months after completion of second-line treatment she developed, for the first time, signs of LEMS confirmed on clinical and neuro-physiological grounds (J.N.-D.); the patient described malaise, blurred vision, and began to use elbow crutches to help her walk. Examination also demonstrated ataxia, a high-stepping gait and mild nystagmus, consistent with cerebellar involvement. A computed tomography scan of the brain showed no evidence of metastatic disease. Serum VGCC antibody titer remained elevated at 204 pM. Treatment was with 3,4-diaminopyridine (20 mg qds orally) and alternate-day prednisolone. The neurologic symptoms remained prominent until her death 2 months later, 15.5 months after histologic diagnosis of SCLC.
Three patients (5%) with mildly elevated levels of VGCC antibodies at diagnosis had no clinical or electrophysiological evidence of LEMS. These patients, who were all followed until death, did not subsequently develop any clinical evidence suggestive of LEMS (time from diagnosis to death was 5, 7.5, and 29 months).
Median duration from histologic diagnosis to death was 7.5 months (mean, 11.7 months; range, 1–158 months). There was no association between serum anti-P/Q-type VGCC titer and survival (p = 0.08, hazards ratio 0.999).
We report a prospective study examining the incidence of clinical and subclinical LEMS in patients with SCLC. Our study is the first to include a prospective careful clinical evaluation of all patients specifically designed to elicit physical signs of LEMS or other neurologic signs. Further tests, including electrophysiology, were performed on all patients who had relevant symptoms and signs of LEMS. Eight percent of patients with SCLC had an increased titer of serum VGCC antibodies in this cohort of 63 consecutive consenting patients. All patients with elevated serum VGCC antibodies had extensive stage disease. Our findings are consistent with the report by Wirtz et al.18 who studied 148 patients with confirmed SCLC and found a 7% incidence of elevated P/Q-type VGCC antibodies. Similarly, earlier studies found that elevated VGCC antibodies are relatively common in this patient group.15,16
In our study, only two patients had a confirmed diagnosis of LEMS according to electrophysiological criteria (3%). This is in concordance with other data,3,21 including the prospective study by Wirtz et al.18 in which clinical signs of LEMS were found in three of the 10 patients with elevated anti-VGCC antibody titers (2.7% overall), although neuro-physiological confirmation before chemotherapy was established in only one patient. The presence of VGCC antibodies without LEMS is not altogether surprising, because antibodies are thought to be stimulated by VGCCs on the tumor cells. Some patients with VGCC antibodies and SCLC have cerebellar degeneration with or without LEMS.15 Indeed, both our patients with LEMS also had mild cerebellar ataxia. It is important to recognize the possibility of both conditions because some of the gait difficulties associated with cerebellar ataxia may be compounded by the trunk and leg weakness of LEMS, and treatment of the latter with 3,4-diaminopyridine can help alleviate walking difficulties.
It is not known whether subclinical LEMS may predispose susceptible patients to future development of clinical LEMS. In our study, three patients had elevated serum anti-VGCC antibody titers but without LEMS. In these patients, who were followed until death, there was no clinical evidence of subsequent progression to LEMS. However, one of the two patients who developed LEMS confirmed by clinical and electrophysiological criteria late in her disease did not have the clinical syndrome at presentation despite positive VGCC antibodies.
There is evidence suggesting an association between the presence of antibodies against P/Q-type VGCC and improved survival,5,17,18 and it has been postulated that the development of VGCC antibodies may reflect a beneficial immune response against cancer. Although our study was small, we found no correlation between serum anti-VGCC titer and survival. The five patients with elevated VGCC antibodies we report lived between 5 and 28 months from diagnosis. Of these, the two patients who also had confirmed LEMS lived 15.5 and 23.5 months. Our data are in accordance with the prospective study conducted by Monstad et al.16 where elevated VGCC antibodies had no association with clinical outcome. The symptoms of LEMS often antedate other manifestations of malignancy and may lead to an earlier diagnosis of the underlying carcinoma than in the absence of the paraneoplastic syndrome. It has been postulated that previous work suggesting that LEMS is associated with a survival advantage in patients with SCLC may instead reflect a lead-time effect.17 This is not supported by our study.
The structured patient questionnaire was easy for the clinical team to apply, and the systematic clinical examination focused on the signs most commonly found in LEMS and ataxia. As some symptoms, such as weakness and constipation, are common in patients with cancer, it was anticipated to lead to over-reporting, and indeed, neurologic symptoms and signs were common in our patient population. The majority of patients with signs and symptoms potentially suggestive of neurologic involvement did not have elevated serum VGCC antibodies. This study was also underpowered to detect a true survival difference between patients with elevated serum VGCC antibodies and patients without. Despite these drawbacks, this prospective study confirms the low incidence of LEMS reported by other authors, adds to prior evidence that the presence of VGCC antibodies may be more common than expected and indicates that these antibodies can be a marker for SCLC in the absence of clinical LEMS.
Although not the aim of this study, the data collected here suggest that routine measurement of VGCC antibodies in patients with known SCLC without clinical LEMS has little practical application in patient management. It should be reserved for patients in whom there is already a high clinical suspicion of LEMS. Detection of elevated serum VGCC antibodies can be helpful for two reasons. Firstly, it aids accurate diagnosis of a distressing and often rapidly progressive neurologic syndrome. Secondly, it directs investigations for the most probable underlying neoplasm. It may be that future improvements in the diagnosis and care of this challenging group of patients will depend on the identification of alternative antibodies with greater predictive value.14
Supported by Cancer Research UK.
The authors are grateful to Dr. Robin Kennett, Clinical Neurophysiologist, Oxford Radcliffe Hospitals Trust, for the neuro-physiological data.
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