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into limited-stage disease (LS-SCLC), which shows confined growth, or extensive-stage disease (ES-
SCLC) which is associated with metastasis. It is estimated that approximately 60% of SCLC patients present
with extensive-stage disease at the time of initial diagnosis. The most common sites of spread include
[4,5]
contralateral lung, adrenal glands, brain, liver, bones, and bone marrow .
[3,5]
SCLC is highly responsive to chemotherapy . The standard first-line treatment of LS-SCLC includes
concurrent chemotherapy (cisplatin-etoposide) and radiation, while ES-SCLC is treated with a combination
chemotherapy (platinum-etoposide) and an immune checkpoint inhibitor. For long time, the treatment
[5]
of ES-SCLC consisted of platinum agents and etoposide . This was changed recently due to results
from IMpower-133 and CASPIAN studies, both of which demonstrated improved survival by adding
[6,7]
atezolizumab and durvalumab, respectively, to platinum and etoposide .

Despite being responsive to chemotherapy, most SCLC patients will experience tumor relapse within a few
[8,9]
months, making management of these patients challenging . If the relapse occurs within 3 months of
[9]
treatment, the disease is called refractory or resistant, and the response to further treatment is < 10% . If
the relapse occurs after 3 months, the expected response to further treatment is 25%. Options for patients
with refractory or relapsed disease are limited and patients with relapsed or refractory disease have a
median survival of 8-9 months [9,10] .

The treatment of refractory/relapsed SCLC has been an active area in research given the dismal prognosis
and the poor outcome. Chemotherapy remains the cornerstone of treatment, but recently newer agents
including immunotherapy are being studied, with promising results. In this review, we will discuss the
current agents that are used in relapsed or refractory SCLC.

TREATMENT OPTIONS OF RELAPSED/REFRACTORY SMALL CELL LUNG CANCER
Chemotherapy
Topotecan
Topotecan is a semisynthetic water-soluble analog of camptothecin which acts as an inhibitor of the nuclear
enzyme topoisomerase I, leading to DNA damage [11,12] . For a long time, it was the only drug that was
approved by the Food and Drug Administration (FDA) for relapsed small cell lung cancer.

One of the earliest studies of topotecan in SCLC was conducted by the European Organization for
Research and Treatment of Cancer . This study was a phase II trial which included 92 patients (47
[11]
patients who were refractory to first-line treatment, and 45 patients had disease relapse after 3 months of
stopping chemotherapy). In both arms, patients received intravenous (IV) topotecan at 1.5 mg/m for five
2
consecutive days every 3 weeks. Topotecan demonstrated an overall response rate (ORR) of 6.4% (95%CI:
1.3%-17.6%) in patients who failed first-line treatment, and 37.8% (95%CI: 23.8%-53.5%) in patients who
had disease relapse after 3 months of finishing chemotherapy treatment. The overall response in both
groups was 21.7%. The overall median duration of response was 7.6 months (95%CI: 5.1-12.2 months), the
median time to progression was 2.8 months (95%CI: 2.2-3.9 months), and the overall survival (OS) was
5.4 months (95%CI: 4.8-6.3 months). This study showed that topotecan had good activity in SCLC,
[11]
specifically in patients who responded to initial chemotherapy .

[12]
von Pawel et al. conducted a randomized phase III trial comparing topotecan to Cyclophosphamide,
Doxorubicin, and Vincristine (CAV). In this study a total of 211 patients were recruited (107 treated with
2
topotecan and 104 treated with CAV). Patients in the topotecan arm received IV topotecan 1.5 mg/m daily
for five consecutive days every 3 weeks. The ORR of topotecan was 24.3% compared to 18.3% in the CAV arm.
The median time to progression and median survival were similar in both arms (13.3 weeks vs. 12.3 weeks,
and 25 weeks vs. 24.7 weeks, respectively). Despite the similarity in outcomes, this study showed that