Cytarabine

證據等級: L5

預測適應症: 10 個

Cytarabine: From Acute Leukaemia to Small Cell Lung Carcinoma

One-Sentence Summary

Cytarabine (Ara-C) is a pyrimidine nucleoside analogue that has long served as a cornerstone of acute leukaemia chemotherapy (AML and ALL). The TxGNN model predicts it may be effective for Small Cell Lung Carcinoma (SCLC), with 3 clinical trials (all indirect background evidence) and 20 publications — including historical Phase II studies and case series — currently supporting this direction. The overall evidence base is observational and largely historical (1978–1997), with no modern randomised SCLC-specific trials identified.

Quick Overview

Item	Content
Original Indication	Acute leukaemia (AML / ALL)
Predicted New Indication	Small Cell Lung Carcinoma
TxGNN Prediction Score	99.78%
Evidence Level	L3
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Hold (Research Question)

Why is This Prediction Reasonable?

Detailed mechanism of action data is not currently available in the Evidence Pack. Based on established pharmacology, cytarabine is a pyrimidine nucleoside analogue that undergoes intracellular phosphorylation to its active triphosphate form (Ara-CTP), which competitively inhibits DNA polymerase-α and incorporates into replicating DNA strands, causing chain termination. Because this mechanism is tightly coupled to S-phase DNA synthesis, it is theoretically most active against rapidly proliferating cell populations.

Small cell lung carcinoma is among the fastest-dividing solid tumours known, with a very short tumour doubling time and initial high sensitivity to chemotherapy — biological features it shares with haematological malignancies. Early clinical investigations from 1979 to 1997 explored cytarabine-containing combination regimens in SCLC, including CAV + Ara-C (cyclophosphamide, doxorubicin, vincristine plus cytarabine) and VP-16 + infusional Ara-C in relapsed disease. Modest but documented antitumour activity was observed in these studies, providing a biological rationale for the TxGNN prediction.

An additional mechanistic pathway relevant to SCLC is cytarabine’s established role in central nervous system (CNS) prophylaxis and leptomeningeal disease management via intrathecal administration. SCLC has an exceptionally high propensity for CNS dissemination, and intrathecal cytarabine is a recognised component of leptomeningeal carcinomatosis treatment across solid tumour types, including SCLC.

Clinical Trial Evidence

Important note: No clinical trials directly evaluating cytarabine as a primary agent in SCLC were identified. The three registered trials below provide indirect background context for intrathecal chemotherapy in lung cancer CNS disease and are not direct evidence of cytarabine efficacy in SCLC.

Trial Number	Phase	Status	Enrolment	Key Findings
NCT03101579	Phase 1	Completed	13	Intrathecal pemetrexed for recurrent leptomeningeal metastasis from NSCLC; cytarabine cited as a standard intrathecal agent in the background rationale; provides safety context for intrathecal CNS chemotherapy in lung cancer
NCT03507244	Phase 1/2	Completed	34	Intrathecal pemetrexed combined with involved-field radiotherapy for leptomeningeal metastasis from solid tumours; confirms feasibility of intrathecal chemotherapy routes relevant to SCLC CNS disease
NCT00863512	Phase 3	Terminated	34	Adjuvant chemotherapy (vinorelbine, cisplatin, gemcitabine, pemetrexed) versus observation in surgically resected early-stage NSCLC; terminated early with minimal enrolment; not cytarabine-specific and not SCLC

Literature Evidence

PMID	Year	Type	Journal	Key Findings
9363869	1997	RCT	J Clin Oncol	Randomised trial of chemotherapy + radiotherapy ± warfarin in limited-stage SCLC (CALGB); cytarabine-containing regimen used; warfarin addition did not improve outcomes; highest-quality trial in this evidence set
232239	1979	Retrospective Clinical Study	Med Pediatr Oncol	20 previously untreated SCLC patients; cytosine arabinoside 20 mg/m² q12h (days 5–9) combined with cyclophosphamide + doxorubicin; 3,000 rads to primary tumour and whole brain in cycle 1; documented regimen feasibility
6095640	1984	Clinical Study	Am J Clin Oncol	Ara-C 100 mg/m²/day continuous infusion in SCLC: no responses in 10 heavily pre-treated patients; added to CAV in 25 extensive-stage patients with severe toxicity; important negative result in monotherapy setting
2841844	1988	Clinical Study	Am J Clin Oncol	VP-16 + infusional Ara-C (45 mg/m²/day ×72 h) in 17 relapsed/refractory SCLC patients; documents combination activity in platinum-refractory disease context
6264785	1981	Case Series	Am J Med	60 SCLC patients; intensive chemotherapy without prophylactic cranial irradiation; 78% CR+PR rate; meningeal/cerebral metastases as key complications; documents SCLC CNS dissemination patterns and role for intrathecal Ara-C
2992752	1985	Preclinical	Cancer	Five human SCLC cell lines grown as 3D spheroid models; cytarabine and other chemotherapeutic agents tested for activity; quantified cell killing in SCLC spheroids, providing in vitro efficacy data
28223673	2017	Case Report	Gan To Kagaku Ryoho	65-year-old man with Stage IV SCLC; meningeal carcinomatosis following systemic chemotherapy and whole-brain irradiation; multidisciplinary approach including intrathecal cytarabine; demonstrates real-world use in SCLC CNS progression
2156598	1990	Phase II Trial	Cancer	High-dose cytarabine (3 g/m²) + cisplatin in 37 chemo-naive advanced NSCLC patients; 14% overall response rate; Grade IV myelosuppression in 32%; provides important toxicity benchmarking for high-dose Ara-C in lung cancer
2157307	1990	Phase II Trial	Tumori	Cytarabine + cisplatin + vindesine in 32 advanced NSCLC patients; 18% response rate; establishes cytarabine pharmacological activity in lung cancer histologies
348088	1978	Review	Antibiotics Chemother	Ara-C analogue review; discusses cytidine deaminase resistance strategies; AAFC (anhydro-ara-5-fluorocytidine) shown active against SCLC in Phase II; provides pharmacological context for Ara-C class activity in lung malignancies

Australia Market Information

Cytarabine is not currently registered on the Australian Register of Therapeutic Goods (ARTG). There are no ARTG entries for this medicine.

Cytarabine may be accessed in Australia through the following alternative pathways:

Access Pathway	Details
TGA Special Access Scheme (SAS)	Category B (unapproved therapeutic goods for individual patients) or Category C (non-emergency use)
Authorised Prescriber	Specialist oncologist may apply to TGA for authorised prescriber status
Clinical Trial Supply	Available under an approved Clinical Trial Notification (CTN) or Clinical Trial Exemption (CTX)

Healthcare professionals should consult the TGA Special Access Scheme guidance at www.tga.gov.au and refer to an overseas Product Information (e.g., FDA or EMA label) for prescribing information.

Cytotoxicity

Cytarabine is a conventional cytotoxic antineoplastic agent (antimetabolite — pyrimidine nucleoside analogue) and requires full cytotoxic handling precautions.

Item	Content
Cytotoxicity Classification	Conventional cytotoxic — Antimetabolite (Pyrimidine nucleoside analogue, S-phase specific)
Myelosuppression Risk	High — Phase II lung cancer data (PMID 2156598) reported Grade IV myelosuppression in 32% and Grade III in 14%; severe toxicity also documented in SCLC patients (PMID 6095640); leucopenia, thrombocytopenia, and anaemia are expected dose-limiting toxicities
Emetogenicity Classification	Low to moderate (route and dose dependent; high-dose Ara-C regimens ≥3 g/m² carry moderate-to-high emetogenic potential)
Monitoring Items	Full Blood Count (FBC) with differential — weekly minimum during treatment; renal and liver function tests; serum electrolytes; neurological assessment (cerebellar toxicity) with high-dose regimens; ophthalmological assessment (conjunctivitis)
Handling Protection	Must comply with cytotoxic drug handling regulations per SHPA Guidelines for Handling Cytotoxic Drugs and applicable state/territory Work Health and Safety legislation; PPE (gloves, gown, eye protection) required; closed-system drug transfer devices (CSTDs) recommended for preparation and administration

Conclusion and Next Steps

Decision: Hold (Research Question)

Rationale: The existing evidence for cytarabine in SCLC is entirely historical (1978–1997), composed of small observational studies, early-phase trials, and case reports — none meeting the threshold for current regulatory or clinical repurposing standards. No modern randomised controlled trials or prospective cohort studies exist, and cytarabine is not incorporated into any current SCLC treatment guideline (standard of care: etoposide/carboplatin ± atezolizumab; lurbinectedin or topotecan in relapsed disease). A formal research question is justified, but clinical deployment is premature without additional evidence generation.

To proceed, the following is needed:

Safety assessment: Retrieve and review the complete cytarabine Product Information (PI) from TGA or a recognised overseas authority (FDA/EMA) to complete a full S1 safety evaluation; current safety data are a blocking gap
MOA confirmation: Query DrugBank API (DB00987) to formally document mechanism of action and pharmacological class for biological plausibility analysis
Systematic literature review: Conduct a comprehensive search specifically targeting cytarabine + SCLC combination regimens from the 1980s–1990s literature (including grey literature and conference abstracts) to quantify historical response rates and toxicity profiles
Comparative effectiveness assessment: Evaluate whether cytarabine offers any pharmacological advantage over current standard-of-care SCLC regimens given its toxicity profile
Expert consultation: Engage a thoracic oncologist and clinical pharmacologist to assess whether a prospective pilot study or translational SCLC cell-line investigation is scientifically warranted
Regulatory pathway mapping: If a research question is confirmed, identify appropriate TGA pathways (SAS, CTN/CTX) for any prospective Australian study

This report is generated for research purposes only and does not constitute medical advice. All drug repurposing candidates require clinical validation before therapeutic application. Healthcare professionals should refer to the TGA-approved Product Information and current clinical guidelines for prescribing decisions.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.