Weekly Topotecan for Recurrent Small Cell Lung Cancer-a Retrospective Anatolian Medical Oncology Group Study

AIM
To evaluate efficacy and tolerability of topotecan treatment for recurrent small cell lung carcinoma.


PATIENTS AND METHODS
A total of 62 patients were evaluated retrospectively. Statistical analysis was performed using GraphPad Instat (version 3.05).


RESULTS
Fifty five patients (89%) were male and 7 (11%) were female. Median age was 56.7 ± 9.3 (34-75). Forty eight of patients (80%) were extensive stage (ES) at the time of diagnosis. Fifty of the patients (80.6 Medical Oncology Clinic) were given median 5.36 cycles of cisplatin-etoposide (2-8 cycles). Time to recurrence was 15.6 ± 6.13 weeks in patients with limited stage (LS) and 6.3 ± 3.82 weeks in extensive stage (ES) (p<0.0001). Overall survival was 14.0 ± 6.08 months in ES and 17.9 ± 6.88 months in LS. The difference between two groups was statistically meaningful (p=0.0447). The overall survival of the patients was 14.8 ± 6.43 months (4.5-40 months). In terms of survival, there was no difference between males and females (p=0.1171). In 17 (27%) patients who were refractory to topotecan or in whom progression occurred other chemotherapies were used.


CONCLUSION
Small cell lung cancer is chemosensitive, but recurrences occur in short time. Other chemotherapy regimens are used in progression. Topotecan is one of them. Patients who were young and in whom recurrences occur late had given better response to topotecan. Because of the retrospective nature of the study, we couldn't reach the records exactly and consequently, rate and duration of response couldn't be calculated. In recurrent SCLC topotecan is one of the treatment choices. But both hematological and non hematological side effects should be taken into consideration.

In spite of high response rates to chemotherapy, recurrences occur around 95% of patients especially in the first year (Huisman et al., 1999;Chua et al., 2004).Once recurrence occurs, prognosis is poor with a median survival around 2-4 months (Niederle et al., 2008).Response rate to chemotherapy regimens in recurrent disease is around 20% (Huisman et al., 1999).If disease is non-responsive to first line chemotherapy, or if recurrence occurs in first 60 days following the treatment, it is accepted as refractory to chemotherapy.The cases which recur after 60 days [some authors accepts 90 days (Chua et al., 2004;Hoschek et al., 2007)] are accepted as chemo-sensitive (Niederle et al., 2008).In chemo-sensitive patients, response rates to paclitaxel, topotecan and irinotecan rises to 40% (Wolf et al., 2004).With topotecan, in patients with ES, response rate of 63% and median survival time of 9.3 months were achieved (Hoschek et al., 2007).

Materials and Methods
Records of 62 patients in 9 ATOD centres were evaluated retrospectively.Results are expressed as the mean ±SD or percentage.Statistical analysis was performed using GraphPad Instat (version 3.05).For comparisons of the differences between mean values of two groups, the unpaired Student's t test was used.All statistical tests and p values were two-sided, and p<0.05 was considered statistically significant.
In Table 1 the characteristics of the patients according to centers were given.There was no relation between median age and TTP, number of CT cycles, survival and the stage.Fifty of the patients (80%) had taken median 5.36 cycles (2-8 cycles) of cisplatin + etoposide combination.
The records of the patients who had given weekly topotecan (2.5 mg/m 2 /week) were evaluated retrospectively.Median 6.97±4.33weekly topotecan were given.Between males (6.8±4.3 weeks) and females (8.2±4.6 weeks) there were no difference in terms of duration of topotecan (p=0.396).Median number of topotecan was 7.06±4.64weeks in ES and 6.64±3.15weeks in LS (p=0.7523).
Two of the patients had inappropriate SIADH at the time of diagnosis, and symptom control had achieved in them after topotecan CT.At the time of diagnosis the most frequent site of metastasis was liver.The sites of metastasis are given in Table 2.
Tobacco history couldn't be found in all the files, but it was positive in all the patients who had been asked.Similar results were valid both for weight loss and LDH levels.Weight loss was found in majority of patients.LDH records were found in 11 file, of them 6 were increased.Median overall survival was 14.84±6.43months (4.5-40 months).There was no difference between males (14.38±6.54months) and females (18.43±4.24) in terms of overall survival (p=0.1171).But difference was statistically significant between the patients who were staged as LS (13.96±6.08 months) and ES (17.86±6.88months) at the time of diagnosis (p=0.0447).
Median time to recurrence was 6.26±3.59(2-16) weeks in overall, and statistically different in patients who were LS (15.6±6.13) at the time of diagnosis and in the patients who were ES (6.3±3.82)(p<0.0001).No significant relationship was found between age with survival (p=0.15), and age with recurrence (p=0,095).There was a significant relationship between time to recurrence and overall survival (p=0.002).The patients in whom recurrence occurred late had lived longer.Time from recurrence to death was found longer in young patients (p=0,014).
There was no significant relationship between age and time to recurrence, CT cycles given, overall survival and the disease stage at the time of diagnosis.Median time from recurrence to death was 5.82±4.4months in overall, 5.98±4.56months in males and 4.71±3.04months in females (p=0.479).Median time from recurrence to death was 5.07±3.97months in patients with ES at the time of diagnosis and 8.58±4.96months in LS (p=0.079).After the recurrence, time to death was 6.89±3.59months in LS and 5.2±4.18months in ES (p=0.28).There was a significant relationship between time to second recurrence and overall survival (p=0,002).
In 17 patients (%27) because of unresponsiveness to topotecan or progression under treatment, other chemotherapy regimens were tried.Three of the patients are still alive (32, 19 and 20 months).
Toxicities due to topotecan treatment are given in Table 3.

Discussion
In a study comparing best supportive care and topotecan use in recurrent SCLC, topotecan was found to be related with better quality of life and increased survival (Hoschek et al., 2007).
In EQ-5D life quality questionnaire, in which 68 patients (96%) in topotecan and 65 patients in best supportive care group had completed questionnaire, symptom control was found better in topotecan group (O'Brien et al., 2006).In another study, response rate to topotecan was 39% in 48 chemonaive patients and 17% in 362 patients who had taken chemotherapy before (Murren et al., 2005).
Because of the retrospective nature of the study, we couldn't reach the records exactly, therefore; response rate and duration couldn't be calculated.In a meta-analysis of 24 studies, response rate to second line chemotherapy in SCLC was reported as around 20% (Huisman et al., 1999).In a phase III study topotecan and CAV regimen in 211 patients with SCLC who had relapsed at least 60 days after completion of first-line therapy were evaluated.Response rate was 24.3% in topotecan group and 18.3% in CAV group.Survival analysis was similar in two groups (median survival 25.0 weeks for topotecan and 24.7 weeks for CAV, 1-year survival rate was around 14%).Side effects were less in topotecan group.Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<0.001).Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<0.001 for both) (Pawel et al., 1999).In a phase II study in 170 patients with recurrent SCLC 1.25 mg/m 2 x 5 days topotecan was given and toxicity was found less (Huber et al., 2000).
In phase II studies response rates to chemotherapy was around 24% in chemosensitive patients and only around 10% in chemoresistant patients.Median overall survival was 5-7 months (Perez et al., 1996;Ardizzoni et al., 1997).In a phase III study comparing best supportive care and topotecan in recurrent SCLC grade 3/4 neutropenia was seen in 61%, thrombocytopenia in 38%, anemia in 25% of the patients (O'Brien et al., 2006).In our study grade 3/4 toxicities for neutropenia, thrombocytopenia and anemia was 12.5%, 14.2% and 14.2% respectively.
In a meta-analysis of 5 studies of second line chemotherapy, Gars et al reported that in older age group (70 or older), efficacy and tolerability of topotecan was comparable with younger age group (Garst et al., 2005).SCLC responds chemotherapy well, but recurrence in a short time was common.In our patients, second line topotecan was given 6.97±4.33weeks in median.Survival was found better in patients who were in LS than ES at the time of diagnosis (p=0.0447).
In our study time to recurrence was 15.6±6.13weeks in the patients who were LS at the time of diagnosis and only 6.3±3.82 in whom were ES (p<0.0001).Time from recurrence to death was 6.89±3.59months in LS and 5.2±4.18months in ES (p=0.28).A strong relationship between time to recurrence and survival was determined (p=0,002).Patients who recurred late had lived more.More and more younger the patients, time from recurrence to death was longer (p=0,014).Overall survival was found better in patients who were LS at the time of diagnosis (17.86±6.88months) than the patients who were in ES (13.96±6.08)(p=0.0447).In two of our patients with SIADH symptom control was achieved with topotecan chemotherapy.
In literature, topotecan is recommended in the second line chemotherapy of SCLC, and in first line, as a single agent, in the patients whose performance status are poor (O'Brien et al., 2006;Hoschek et al., 2007).
In conclusion, topotecan is one of the choices in recurrent SCLC especially in patients with good performance status.Response rates to topotecan are better in patients who are young, who are LS at the time of diagnosis or in whom recurrence occurred late.High toxicity rates should be kept in mind.

Table 1 . Patient Characteristics According to Centres
*LS: limited stage, ES: extensive stage, Gr: grade, CT: chemotherapy