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[34]
better in the sensitive group (5.7 months vs. 4.1 months) . The most common toxicities were fatigue,
[34]
anemia, thrombocytopenia, and different gastrointestinal symptoms .

Gemcitabine
2
A phase II study showed that treatment with gemcitabine at a dose of 1000 mg/m on day 1, day 8 and
day 15 of a four-week cycle, resulted in an overall response rate of 13% (95%CI: 6%-27%), with a median
[35]
2
survival of 17 weeks (4-84 weeks) . Interestingly, a different study tried gemcitabine 1,250 mg/m on day 1
and 8 every 3 weeks as a second line treatment of SCLC. But the results were not encouraging, as none of
[36]
the 27 patients had a response .
Amrubicin
Amrubicin is a 3rd generation anthracycline and a topoisomerase II inhibitor that has a chemical structure
similar to doxorubicin [37,38] . The first data about amrubicin in SCLC was obtained from Japan after a phase
II trial studied it in patients with untreated ES-SCLC. This study showed an overall response rate of 75.8%
[37]
(95%CI: 57.7%-88.9%) and a median survival of 11.7 months (95%CI: 9.9-15.3 months) . Later, several
studies were conducted, but the most notable one was a phase III clinical trial which compared amrubicin
to topotecan in the second line setting. This trial evaluated 637 patients who were randomized 2:1 to
2
amrubicin 40 mg/m daily for three days or topotecan 1.5 mg/m for 5 days every 3 weeks. Amrubicin was
2
associated with a better overall response rate (31.1% vs. 16.9%, P = 0.001) and median PFS (4.1 months vs.
[38]
3.5 months, P = 0.01). However, it failed to show improvement in OS which was the primary endpoint .
[9]
This drug is not recommended in the NCCN guidelines for treatment of SCLC .
Vinflunine
Vinflunine is a microtubule inhibitor that has been used in different malignancies including non-small
[39]
cell lung cancer. Spigel and colleagues performed a phase II study on 51 patients with relapsed SCLC.
2
Patients received IV vinflunine at 320 mg/m every 3 weeks. The study showed an ORR of 19.6% % (95%CI:
10-33%). The median PFS and OS were 1.6 months (95%CI: 1.3-3.9 months) and 4.9 months (95%CI: 3.2-
6.5 months) respectively. Despite being well tolerated, 5% of the patients had grade 3/4 toxicities with
neutropenia being the most common (32%). Other side effects included fatigue (16%), arthralgia (16%),
and different gastrointestinal symptoms .
[39]
Combined chemotherapy
Multiagent chemotherapy have been the standard treatment for extensive-disease SCLC for long time [40,41] .
Chemotherapy regimens like etoposide with platinum, CAV, and cyclophosphamide-doxorubicin-etoposide
(CDE) all showed reasonable response rate when used in the first line treatment. Nevertheless, the use of
combined chemotherapy is limited in the setting of recurrent/relapsed SCLC, mainly due to intolerable
[9]
[40]
toxicity at that stage . The NCCN guidelines suggest only CAV in the 2nd line setting .
One of the few studies to evaluate combined chemotherapy agents in the 2nd line setting was a phase III
trial from Japan which compared a combination of cisplatin-irinotecan-etoposide (CIE) to topotecan in
the setting of relapsed SCLC. This study revealed that CIE had a better OS (18.2 months vs. 12.5 months; P
= 0.0079). However, the toxicity was significantly higher in the CIE arm and therefore it is not commonly
[42]
used in practice .

Table 1 summarizes some of the clinical trials that evaluated different chemotherapy agents in relapsed/
refractory small cell lung cancer.

Immunotherapy
The utilization of the immune system in treating cancers has been an exciting field that is being developed
over the last years. The immune system recognizes cancer cells but, in most situations, it is not able to