The recent wave of clinical trials examining the role of maintenance chemotherapy for advanced NSCLC hasagain placed a spotlight on the benefits of second-line chemotherapy for this disease. Somewhat unexpectedly, these studies have revealed widely varying rates of second-line chemotherapy administration. In some studies, the likelihood of patients randomized to observation after first-line chemotherapy receiving chemotherapy at the time of progression is below 20%,1
raising the possibility that broader use of second-line therapies could mitigate some of the benefit attributed to a maintenance approach. The study of immediate (i.e., maintenance) or delayed docetaxel following 4 cycles of first-line therapy provides a prime example of this scenario; overall survival for patients who received immediate docetaxel and for the two-thirds of patients randomized to delayed docetaxel who ultimately received the assigned treatment was identical.4
The current study, which employs a contemporary, diverse, and unselected population, offers further insight into the real-world experience of second-line NSCLC treatment. In this cohort, 67% of individuals who had not progressed after receiving 4 cycles of first-line chemotherapy (i.e., those patients considered candidates for maintenance chemotherapy) ultimately received second-line treatment. While this rate itself is noteworthy for matching those reported in numerous maintenance therapy clinical trials,2,4,10
it must also be placed into context. Our population likely includes many individuals who, eitherdue to performance status, adherence to medical care, or comorbidities, would not be candidates for clinical trials. This study also examines second-line chemotherapy patterns among the larger population of all patients with advanced NSCLC receiving first-line treatment. Compared to the maintenance chemotherapy-eligible cohort, patients who—either because of disease progression, intolerable toxicities, or non-adherence—did not receive 4 cycles of first-line chemotherapy were substantially less likely to receive second-line chemotherapy (OR 0.26).
This and earlier studies raise numerous questions. Why is there such variation in rates of second-line chemotherapy administration? What are the reasons patients do not receive second-line therapy? Why does the rate of second-line chemotherapy use in our series of unselected patients treated in a relatively uncontrolled setting match or exceed that of several prospective, randomized clinical trials? While there are no precise explanations, features of these clinical trials may have contributed to these observations. One study—in which disease progression was cited as the predominant reason why one-third of patients in the non-maintenance arm did not receive second-line chemotherapy—employed a relatively long (three-month) inter-scan interval in the non-maintenance arm, during which symptomatic progression and associated clinical decline may have hindered administration of second-line therapy.4
Another study—conducted in over 80 centers in 20 countries, throughout which second-line practice patterns could vary considerably—left the administration and selection of post-progression treatment to the discretion of the investigator rather than mandating second-line therapy for patients in the non-maintenance arm.10
A third study included a high proportion of patients with poor performance status(>80% ECOG 2).1
We found the following variables to be associated with receipt of second-line chemotherapy: insurance type, number of cycles of first-line chemotherapy, and receipt of palliative radiation therapy prior to first-line chemotherapy administration. In a previous study of a similar patient cohort, we found that older patients with advanced NSCLC were less likely to receive first-line
presumably because older individuals tend to be more frail and have more medical comorbidities. It seems logical that age would not be associated with receipt of second-line
chemotherapy in the same population because those older patients not fit for chemotherapy have already been selected out of the present study cohort. These observations echo those of a subset analysis of the phase III trial of second-line pemetrexed versus docetaxel, in which elderly patient participation was similar to rates observed in the first-line setting.19
By contrast, we found insurance type to predict receipt of both first-line18
and second-line treatment. While reasons for this ongoing association throughout the entire disease course are not evident from either study, it seems possible that insurance type—a surrogate marker of socioeconomic status—could be associated not only with performance status and comorbidities, but also with treatment preferences and adherence to medical care, factors that continue to impact populations well beyond first-line chemotherapy. Year of diagnosis was not associated with second-line chemotherapy administration, although we had expected to see an increase after 2004, when results of phase III trials of second-line erlotinib and pemetrexed, as well as second-line docetaxel quality of life data, were presented.8–9,20
Our use of pre-chemotherapy palliative radiation therapy as a predictive variable also merits comment. We selected this unconventional metric as a potential marker of disease burden and severity. It represents a diverse group of patients, including those with brain metastases; clinically significant hemoptysis or airway compromise; and refractory pain, neurologic sequelae, or skeletal instability from bony metastases. It is possible that these patients represent a population at subsequent risk for a more symptomatic, complex clinical course. It follows that these patients are substantially less likely to receive second-line chemotherapy (OR 0.53 in this study). It seems less likely that pre-chemotherapy palliative radiation therapy itself—either via the delay in initiation of systemic therapy or through radiation-associated toxicities—accounts for the reduced rate of second-line chemotherapy administration.
Both the number of cycles of first-line chemotherapy and the receipt of second-line chemotherapy were independently associated with overall survival. While no conclusions about the effect of these treatment factors on clinical endpoints can be drawn from this observational, non-randomized trial, these findings may provide insight into overall outcomes. We selected a cut-off of 4 cycles of first-line chemotherapy because this number implies clinical effect (as radiographic studies assessing response to therapy are typically performed every 2 cycles), acceptable toxicity profile, and patient adherence to treatment. Among patients who ultimately received second-line chemotherapy, median survival was 17.9 months for those who received 4 or more cycles of first-line chemotherapy, compared to 8.7 months for those who received fewer than 4 cycles of first-line chemotherapy. These findings echo those of earlier studies, in which response to first-line chemotherapy was an independent predictor of receipt of second-line chemotherapy11
and overall survival.21
Limitations of this study include its retrospective nature, its single academic center setting, and relatively small sample size. Despite the retrospective design, disease and treatment follow-up data were available until patient death for over 95% of the cohort. Due to the geographical setting and variety of UT Southwestern-affiliated clinical facilities, our patient cohort is racially and socioeconomically diverse. Nonetheless, certain patient populations, such as East Asians, are under-represented. Furthermore, the physicians caring for these individuals are predominantly academic thoracic oncologists, who may be more likely to employ second-line chemotherapy than are other practitioners. That stated, the ability of these physicians to deliver second-line chemotherapy to two-thirds of this largely socioeconomically challenged cohort suggests that it may be feasible in most other U.S. settings as well. Finally, reasons why second-line chemotherapy was not administered were not available.
In conclusion, in this unselected, diverse cohort of patients with advanced NSCLC, approximately 50% of patients who received first-line chemotherapy eventually received second-line chemotherapy. Limiting the analysis to those individuals whose disease did not progress after 4–6 cycles of first-line chemotherapy—the population eligible for maintenance chemotherapy—the rate rises to 67%, a figure that meets or exceeds those of numerous recent clinical trials. Markers of socioeconomic status, symptom burden, and response to and tolerance of first-line chemotherapy were associated with receipt of second-line chemotherapy. Maintenance chemotherapy trials have highlighted critical economic and quality of life issues. The cost per life-year gained from maintenance pemetrexed exceeds $120,000.22
While approved maintenance agents such as pemetrexed and erlotinib are generally well tolerated, there is clearly a subset of patients who maintain prolonged disease control after first-line chemotherapy with no subsequent treatment—and who then successfully receive second-line therapy at the time of progression. It follows that identifying those patients least likely to receive second-line chemotherapy might guide the selective use of maintenance chemotherapy, thereby limiting both costs and toxicities. Based on the findings in the present study, socioeconomically disadvantaged patients and patients with greater symptom burden—manifest by the need for pre-chemotherapy palliative radiation therapy—may represent such a target population.