SCLC has a much worse biological behavior than non-SCLC, and the disease develops and metastasizes rapidly. Although SCLC is highly sensitive to radiotherapy and chemotherapy, the maintenance time is short, and most patients die within 2 years. About 70%–80% of patients with limited disease and almost all of those with extensive-stage disease develop progression or recurrence after several months. The original chemotherapy regimen also demonstrated ineffective. The response to second-line chemotherapy is highly relevant to the time from the beginning to the recurrence time after the first-line chemotherapy; the second-line treatment response rate is often less than 10% if this is less than 3 months, and often higher than 25% if it is more than 3 months. However, the evidence base concerning the value of second-line chemotherapy for relapsed SCLC is limited, and the role of targeted therapy in SCLC has not been confirmed. Therefore, there is an urgent need to identify an effective treatment for patients with refractory SCLC but otherwise good performance status.
The EP regimen is the first-line chemotherapy most commonly used for E-SCLC. The response rate for EP is 60%–80%, and the median patient survival was 8–10 months. Irinotecan is one of the S-phase cell cycle-specific drugs. It is metabolized to its active form, 7-ethyl-10-hydroxycamptothecin (SN-38), by carboxylesterase in the liver. SN-38 then exerts its cytotoxic effect by inhibiting topoisomerase I, which is required for DNA replication, thereby damaging single-stranded DNA and blocking DNA replication, resulting in inhibition of cell division and death of tumor cells.13 The IP protocol of irinotecan and platinum drugs has been explored in SCLC. JCOG-9511, a Phase III trial of IP and EP in E-SCLC patients, showed that IP significantly prolonged survival compared with EP (12.8 months versus 9.4 months, P=0.002) in a first time.8 This trial was terminated early because the IP group showed significant survival and safety benefits in the interim analysis. Schmittel et al and Hermes et al also reported that the IP scheme can improve OS and PFS in patients with E-SCLC.9,10However, subsequent major studies conducted to confirm the superiority of IP did not yield positive results.14,15 In addition, a recent meta-analysis found that OS may be better with IP than with EP.7Differences in treatment outcomes between Asian and Western populations and the small patient population included were the main explanations put forward for the failure to observe a survival difference in JCOG-9511.
As a special pathological type, progress in the treatment of SCLC has been slow in the past few decades.16 With the exception of IP and EP, emerging chemotherapy drugs, including targeted therapy and immune therapy, have not lived up to their initial promise in the treatment of SCLC.17,18
Although IP and EP are both effective chemotherapy regimens for E-SCLC, there has been little research on the advantages and disadvantages of the sequential order of these therapies. EP and IP scheme in sequential order in the study of E-SCLC show that the two different sequential orders all showed better curative effect. The median survival time for the two groups was 15.4 months and 15.7 months, respectively, ie, higher than in JCOG-9511, and also higher than in the large clinical studies in the USA, Australia, and Canada, suggesting that EP and IP scheme of sequential treatment with more survival benefit. More importantly, the sequence of IP followed by EP, or the reverse order of EP followed by IP, failed to prolong survival. The short-term and long-term effects of the two groups were not significantly different, but the regimen with the least toxicity is preferred. Given some patients may not receive second-line treatment for physical or economic reasons, first-line chemotherapy is particularly important, and subsequent therapy after tumor progression may greatly influence OS.19
However, what is worth emphasizing is the adaptability of patients. For the patient first receiving the IP treatment in group A, severe lethality adverse, such as diarrhea, may make the patient fear the procedure. Intractable diarrhea may be very difficult to treat, which is demoralizing for the patient, and may adversely impact follow-up treatment method. Hematological toxicity may be easily managed using G-CSF or GM-CSF, enabling effective implementation of the treatment plan. This may explain why OS in group B was a little longer than in group A in our present study. Although no significant difference was found between the two groups, we still pay more attention to the little difference. Uridine diphosphate glucuronosyltransferase (UGT)1A1 has played an important role in the metabolism of irinotecan. Extensive research attention had paid to the correlation between UGT1A1 gene polymorphisms and irinotecan-related delayed diarrhea and neutropenia, and since 2005 the US Food and Drug Administration has required that testing for UGT1A1*28 as a risk factor for severe adverse events be included on the irinotecan label.20 In routine clinical practice, analysis of UGT1A1 polymorphism should be recommended to guide the use of irinotecan.21