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However, if these lesions remain unrepaired, they can lead to cytotoxicity and ultimately apoptosis [26,27] .
At its earliest stages, temozolomide was used in treating refractory astrocytoma and glioblastoma
[26]
multiforme .
[26]
In SCLC, several studies suggested that TMZ can be useful. Pietanza et al. performed a phase II study on
64 patients where 48 had sensitive disease (defined as having relapse or progression > = 60 days after first
2
line chemotherapy) and 16 had refractory disease. Patients received oral TMZ 75 mg/m daily for 21 days
during a 28-day cycle. The study reported an ORR of 23% (95%CI: 12%-37%) in the sensitive group and
13% (95%CI: 2%-38%) in the refractory group. Patients who had methylated MGMT experienced a higher
response compared to patients with unmethylated MGMT (38% vs. 7%, P = 0.08). Interestingly, patients
[26]
with brain metastasis had an ORR of 38% (95%CI: 14%-68%) . Another study showed that TMZ can also
be effective and tolerable using a regime of 200 mg/m daily for 5 days in 28-day cycles for patients with
2
[28]
relapsed SCLC . The most common toxicities reported with temozolomide were fatigue, gastrointestinal
symptoms, and hematologic toxicities (most commonly lymphopenia) .
[26]
Etoposide
Etoposide has been used in treatment of SCLC for a long time. The use of etoposide in the second line
setting has also been studied in patients who had received IV etoposide. A phase II trial showed that oral
2
etoposide 50 mg/m daily for 21 days can lead to an ORR of 45.5% (95%CI: 27%-65%), median duration of
response of 4 months (1.5-9.5 months), and median survival of 3.5 months (1-15 months) . Another phase
[29]
[30]
II trial showed a response rate of 23% . The most common observed toxicities were myelosuppression and
[29]
alopecia .
Vinorelbine
Vinorelbine is a semisynthetic vinca alkaloid which acts through binding to microtubular proteins,
[31]
preventing tubulin polymerization . There are data that suggest efficacy of vinorelbine in the setting
of SCLC. A phase II study was conducted on 26 patients with history of recurrent SCLC, who received
2
vinorelbine 30 mg/m weekly, having shown a partial response rate of 16% (95%CI: 4%-36%) whereas 28%
[31]
of the patients had stable disease . Leukopenia was the major associated toxicity with vinorelbine as it
occurred in 80% of the patients. Other common toxicities included anemia, gastrointestinal symptoms,
[31]
and drug related fever . Recently, a study in Poland showed that combining vinorelbine and cisplatin with
electroporation (EP) was associated with increased anticancer activity due to the exposure of the cells to
[32]
high intensity electric pulses, allowing the usage of lower doses of drugs .

Bendamustine
Bendamustine is an alkylating agent that has been commonly used in different lymphoproliferative
disorders. The clinical benefit of bendamustine in SCLC was demonstrated initially in a phase II clinical
trial that was conducted in Europe. In this study, Schmittel and his colleagues enrolled 21 patients with
[33]
SCLC who had a relapse ≥ 2 months after completion of first line therapy. Twenty-one patients received
bendamustine at a dose of 120 mg/m in the first two days every 3 weeks. The study showed a response rate
2
of 29% with a median survival of 7 months.

Subsequently, another phase II study was conducted in North America for patients with relapsed SCLC
where patients received 120 mg/m on the first 2 days of a 21-day cycle. This study subdivided the
2
population to a sensitive disease group; defined as stable or responsive disease to a platinum containing
therapy for at least 90 days, or resistant disease group. A total of 50 patients participated with a response
rate of 26% (95%CI: 13.3%-39.5%). The response rate was higher in the sensitive disease group compared to
the resistant disease group(33% vs. 17%). The overall clinical benefit (complete response + partial response
+ stable disease) rate was 67%. The median OS was 4.8 months (95%CI: 3.8-6.3 months) which was also