Topotecan

Like irinotecan, topotecan is a semi-synthetic derivative of campothecin, an alkaloid extracted from the fruits and leaves of the Chinese tree of fortune . Topotecan is used as a cytostatic drug in chemotherapy. It inhibits the enzyme topoisomerase I(topoisomerase I inhibitor).

Type I topoisomerases relax the DNA, transform a superhelical DNA into a relaxed DNA by reversibly cleaving one strand of duplex DNA. This creates the prerequisite for the reading, i.e. transcription of the DNA. After successful DNA replication, the DNA gap is closed again. Type I topisomerase always reversibly cleaves only one strand of DNA. Topoisomerase inhibitors I allow DNA cleavage, stabilise the topoisomerase-DNA complex and prevent the enzyme from closing the cleavage site again. This leads to the breakage of the DNA strand and the cell is driven into apoptosis. Topotecan as topoisomerase inhibitor I develops the strongest antineoplastic activity in the S phase (Brogden RN et al. 1998).

Remark: Type II topoisomerases are ATP-dependent. They are able to separate both DNA strands.

In the Federal Republic of Germany, topotecan is approved for the treatment of metastatic ovarian cancer after failure of primary or subsequent therapy.

Furthermore

• In patients with relapsed small cell lung cancer (SCLC) who are not suitable for retreatment with the treatment regimen used in primary therapy.
• In combination with cisplatin, topotecan is indicated for the treatment of patients with cervical cancer in recurrence after radiotherapy and patients with stage IVB disease. Patients who had previously received cisplatin require a longer treatment-free interval to justify treatment with this combination.

Positive reports exist on monotherapeutic (and combined) use of topotecan in retinoblastoma (Schaiquevich P et al 2014).

More recent uses involve topotecan enriched in liposomes (Saraf S et al. 2016) such its use in neuroblastoma (Chernov L et al. 2017). Its topical use also appears to be successful in carcinoma of the skin (Venâncio JH et al. 2017).

Topotecan is contraindicated during lactation. Although it is not known whether topotecan passes into breast milk in humans, it is advisable to stop breastfeeding before starting therapy.

Fertility: No effects on male or female fertility have been observed in reproductive toxicology studies in rats. However, topotecan, like other cytotoxic drugs, has a genotoxic effect, so effects on fertility, including male fertility, cannot be excluded.

Ovarian and small cell lung cancer.

• Initial Dose: The recommended dose of topotecan is 1.5 mg/m2 body surface area per day, administered as a 30-minute intravenous infusion for five consecutive days. If well tolerated, treatment may be continued until disease progression is achieved
• Dosage for follow-up treatments: Further administration of topotecan should not be given until the neutrophil count is > 1 x 109/l, the platelet count is 100 x 109/l, and the hemoglobin level is > 9 g/dL (after transfusion, if necessary). Standard oncologic practice for maintaining neutrophil counts in neutropenia is either to administer topotecan with other drugs (e.g., G-CSF) or to reduce the dose.

Cervical Cancer

• Initial Dose: The recommended dose of topotecan is 0.75 mg/m2/day, administered as a 30-minute intravenous infusion on days 1, 2, and 3. Cisplatin is administered as an intravenous infusion at a dose of 50 mg/m2/day on day 1 after the topotecan dose. This treatment regimen is repeated every 21 days for six treatment cycles or until disease progression.

Adverse reactions are listed below by system organ class and absolute frequency (all reported events) (seeMedDRA below). Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), occasional (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare(< 1/10,000), and not known (frequency cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity (information taken from European Medicines Agency marketing authorization protocol).

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The most common adverse reactions are hematologic in nature such as:

Severe neutropenia (Grade 4 - neutrophil count <0.5 x 109/l) was described in 32% of patients (in 13% of cycles), severe thrombocytopenia (Grade 4 - platelet count <10 x 109/l) in 6% of patients, moderate to severe anemia (Grades 3 and 4 - Hb 8.0 g/dL) in 25% of patients.

The most commonly reported non-hematologic adverse events were gastrointestinal, including nausea (52%), vomiting (32%), diarrhea (18%), constipation (9%), and mucositis (14%).

The frequencies of severe cases (3rd or 4th degree) of nausea, vomiting, diarrhea, and mucositis were 4, 3, 2, and 1%, respectively.

Infections and parasitic diseases

• Very common: Infections
• Frequent: sepsis (deaths from sepsis have been reported in patients treated with topotecan).

Blood and lymphatic system disorders

• Very common: febrile neutropenia, neutropenia, thrombocytopenia, anemia, leukopenia
• Frequent: Pancytopenia
• Not known: Severe bleeding (associated with thrombocytopenia)

Immune system disorders

• Frequent: Hypersensitivity reactions including exanthema.
• Rare: Anaphylactic reaction, angioedema, urticaria.

Metabolic and nutritional disorders

• Very common: anorexia (this can be severe).

Respiratory, thoracic and mediastinal disorders

• Rare: interstitial lung disease (some cases with fatal outcome).

Gastrointestinal disorders

• Very common: Nausea, vomiting and diarrhea (all of which may be severe), constipation,
• Abdominal pain, mucositis,
• Not known: Gastrointestinal perforation, Neutropenic colitis including fatal neutropenic colitis have been described as a complication of topotecan-induced neutropenia.

Liver and Biliary Diseases

• Common: hyperbilirubinemia

Skin and subcutaneous tissue disorders

• Very common: Hair loss
• Frequent: Pruritus

General disorders and complaints at the site of administration

• Very common: fever, asthenia, fatigue
• Frequently: malaise
• Very rarely: Extravasation damage
• Not known: Mucositis

A chemically related compound is irinotecan, also a topoisomerase I inhibitor.

1. Brogden RN et al (1998) Topotecan. A review of its potential in advanced ovarian cancer. Drugs, 56: 709-23
2. Chernov L et al (2017) Optimization of liposomal topotecan for use in treating neuroblastoma. Cancer Med 6:1240-1254.
3. Dennis MJ et al (1997) an overview of the clinical pharmacology of topotecan. Semin Oncol 24(1 Suppl 5): 5-12
4. European Medicines Agency: http://www.ema.europa.eu/
5. Hackbarth M et al (2008) Chemotherapy-induced dermatological toxicity: frequencies and impact on quality of life in women's cancers. Results of a prospective study. Support Care Cancer 16:267-273.
6. Saraf S et al (2016) Topotecan Liposomes: A Visit from a Molecular to a Therapeutic Platform. Crit Rev Ther Drug Carrier Syst 33:401-432.
7. Schaiquevich P et al (2014) Ocular pharmacology of topotecan and its activity in retinoblastoma. Retina 34:1719-1727.
8. Venâncio JH et al (2017) Topotecan-loaded lipid nanoparticles as a viable tool for the topical treatment of skin cancers. J Pharm Pharmacol 69:1318-1326.