Jones, Gavin Stewart
(2019)
An investigation into treatment administration and survival for people with small cell lung cancer.
PhD thesis, University of Nottingham.
Abstract
Background
Chemotherapy is the backbone of treatment for small cell lung cancer (SCLC) but this may change in the future with the emergence of immunotherapy. Current recommendations state performance status (PS) and comorbidity should be used as measures to decide whether chemotherapy is appropriate but in some circumstances this decision comes down to whether the patient is fit enough to withstand its toxicity. Thoracic radiotherapy and prophylactic cranial irradiation (PCI) are adjuncts to chemotherapy and can cause additional side effects, impacting quality of life. This is an important factor to consider as median survival is short. Furthermore, the efficacy of PCI has been questioned in extensive disease (ED-SCLC). In order to deliver effective treatment it is important that clinicians are aware of the short-term risks and long-term survival gains of these therapies so that a balanced, objective decision can be made before treatment is administered.
This thesis aims to improve the patient selection process by quantifying the factors that determine: receipt of treatment, early mortality and long term survival following chemotherapy. In addition, it sets survival benchmarks following the currently used treatments so that novel therapies can be compared in the future.
Methods
English national lung cancer audit data (NLCA) were linked with chemotherapy (SACT) and radiotherapy (RTDS) data to develop a multivariate logistic regression model in order to quantify the factors associated with receipt of treatment, early mortality and 1-year survival. A subsequent systematic review and meta-analysis of early and late survival following platinum chemotherapy was conducted. MEDLINE, EMBASE and online libraries from major lung cancer conferences were examined to identify studies from 1946 to 2017. Pooled survival estimates were calculated at 30 and 90 days, 1 year, 2 years and 5 years along with the median survival.
Results
Receipt of treatment
Approximately 60% of people diagnosed with SCLC received chemotherapy in the NLCA data. Receipt of treatment was independently associated with PS, age and the amount of comorbidities (P=<0.01 for all factors). There was significant variation in receipt of chemotherapy, radiotherapy and PCI by geographical location (P=<0.01 for all treatment modalities). There was no association between receiving chemotherapy and the stage of cancer.
Early survival
The 30-day mortality following chemotherapy for all stages of SCLC was approximately 7.8% in the NLCA data. This was associated with stage (ED-SCLC vs limited stage (LD-SCLC) adjusted OR 1.53 (95%CI 1.02-2.28)) and PS (PS2 vs PS0 adjusted OR 3.76 (95%CI 1.71-8.26)). After case-mix adjustment there was significant variation in 30-day mortality by geographical location (P=0.01). Thirty-day survival was considerably better in the meta-analysis of SCLC studies (all stages 98% (95% CI 98-99%, I266.2%, n=167)) and showed minimal variation by study factors. Neutropaenic sepsis and disease progression were the predominant causes of early death following chemotherapy. Overall ninety-day survival was 95% (95% CI 94-96%, I2=81.7%, n=166).
Late survival
When the NLCA data were examined there was a considerable difference in 1-year survival between LD-SCLC and ED-SCLC (approximately 60.6% and 26.2 % respectively). For individuals with LD-SCLC this was associated with PS, chemotherapy, receipt of radiotherapy (total dose ≥40Gy) and PCI. Whereas in ED-SCLC sex, PS, comorbidity, receipt of radiotherapy (total dose ≥30Gy) and PCI were associated. The odds of 1-year survival for individuals who received 6 cycles of chemotherapy, instead of 4, were not significantly different (6 cycles vs 4 LD-SCLC adjusted OR 0.97 (95%CI 0.48-1.97) and ED-SCLC adjusted OR 1.34 (95%CI 0.81-2.22)). One-year survival did not vary considerably across England, with the exception of one hospital network. This network had better survival and tended to give more radiotherapy and PCI. The meta-analysis including all stages of SCLC revealed a pooled 1-year survival of 54% (95%CI 51-57%, I2=93.3%, n=189). The reporting of 2 and 5-year survival were almost exclusive to LD-SCLC cohorts (41% (95%CI 38-44%, I2=78.9%, n=85) and 23% (95%CI 20-25%, I2=72.3%, n=48) respectively).
The median survival for individuals who did not receive chemotherapy in the national audit data was 251 days (95% CI 201-284 days) for LD-SCLC and 32 days (95% CI 28-36 days) for ED-SCLC. The meta-analysis of studies that administered chemotherapy revealed a median survival of 18.0 months (95% CI 17.0-19.1 months, I2=77.3%, n=110) for LD-SCLC and 9.6 months (95%CI 8.9-10.3 months, I2=95.2%, n=103) for ED-SCLC. These figures varied substantially by the year of study, cohort ethnicity, PS, receipt of radiotherapy and PCI, with the latter two factors applying to LD-SCLC only.
Conclusions
This research provides robust survival benchmarks for the currently recommended treatments of SCLC. Age, PS and the number of comorbidities influenced whether a person received chemotherapy yet PS and stage were the central factors determining prognosis. These two factors, PS and stage, could be used to estimate the risk of early death following chemotherapy and guide treatment decision-making. In addition to assessing early mortality risk, thoracic radiotherapy and PCI should be encouraged in favour of prolonging chemotherapy beyond 4 cycles as this may yield better 1-year survival. Indeed, reducing the geographical inequalities in access to these treatments may also augment outcomes. Further survival advances can be achieved with the development of novel therapies, however, these will require approval by national commissioning bodies prior to use in clinical practice. The survival benchmarks identified within this thesis can be used in the appraisal process to ensure the survival gains of novel therapies are true and are worth their cost.
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