Pharmaceutical ApprovalManufacturer: GlaxoSmithKline, Philadelphia, PA

Indication: A combination of topotecan and cisplatin is now available for the treatment of advanced (stage 4B) recurrent or persistent carcinomas of the cervix that are not amenable to curative treatment with surgery or radiation.

Drug Class: Hycamtin, a semisynthetic derivative of camp-tothecin, is an antitumor drug with topoisomerase I-inhibitory activity. Its chemical name is (S)-10-[(dimethyl amino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b] quinoline-3,14-(4H,12H)-dione monohydrochloride.
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Cisplatin belongs to the group of medications known as alkylating agents. Cisplatin interferes with the growth of cancer cells, which are eventually destroyed. Because the growth of normal body cells may be affected by cisplatin, other effects also occur.

Uniqueness of Drug: Topoisomerase I relieves torsional strain in DNA by inducing reversible single-stranded breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these breaks.

The cytotoxicity of topotecan is thought to be a result of double-stranded DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA.

Mammalian cells cannot efficiently repair these double-stranded breaks. The combination of topotecan and cisplatin is more effective than either agent alone in advanced stage 4B cervical cancer.

Boxed Warning: Topotecan HCl for Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
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Therapy with topotecan should not be given to patients with baseline neutrophil counts below 1,500 cells/mm3. To monitor the occurrence of bone marrow suppression, (primarily neutropenia), which may be severe and result in infection and death, health care providers should perform frequent peripheral blood cell counts for all patients receiving topotecan.

Cisplatin can cause a decrease in the number of blood cells in the bone marrow. The physician orders tests before, during, and after treatment to see whether the drug is affecting the blood cells.

Cisplatin can also lead to a severe form of kidney impairment and hearing loss. If patients experience loss of balance, ringing in the ears, trouble hearing, painful urination, or red urine, they should call their doctor immediately. Patients should be advised to keep all of their doctor and laboratory appointments. Laboratory tests are ordered to check the response to cisplatin.

Warnings: Bone marrow suppression (primarily neu-tropenia) is the dose-limiting toxicity of topotecan. Neutro-penia is not cumulative over time. The following myelo-suppression data are based on:

  • the combined experience of 879 patients with metastatic ovarian cancer or small-cell lung cancer who were treated with topotecan monotherapy at a dose of 1.5 mg/m2 per day for five days
  • the experience of 140 patients with cervical cancer who randomly received topotecan 0.75 mg/m2 per day on days one, two, and three, plus cisplatin 50 mg/m2 on day one.

Neutropenia:

  • Ovarian and small-cell lung cancer experience: Grade 4 neutropenia (below 500 cells/mm3) was most common during the first course of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of seven days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia affected 23% of patients, and sepsis was fatal in 1%.
  • Cervical cancer experience: Grade 3 and 4 neutropenia affected 26% and 48% of patients, respectively.

Thrombocytopenia:

  • Ovarian and small cell lung cancer experience: Grade 4 thrombocytopenia (less than 25,000/mm3) occurred in 27% of patients and in 9% of courses. The median duration was five days, and the median platelet nadir was 15 days. Platelet transfusions were given to 15% of patients in 4% of courses.
  • Cervical cancer experience: Grade 3 and 4 thrombo-cytopenia affected 26% and 7% of patients, respectively.

Anemia:

  • Ovarian and small-cell lung cancer experience. Grade 3 and 4 anemia (less than 8 g/dl) occurred in 37% of patients and in 14% of courses. The median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses.
  • Cervical cancer experience: Grade 3 and 4 anemia affected 34% and 6% of patients, respectively.

Dosage and Administration: The following dosing schedule is appropriate. cisplatin 50 mg/m2 every three weeks or cis-platin 50 mg/m2 on day one and topotecan 0.75 mg/m2 IV over 30 minutes for three consecutive days every three weeks.

Commentary: Although the death rate from cervical cancer has been dropping steadily since the introduction of the Pap test, the disease is still deadly. The American Cancer Society estimates that 3,700 American women will die of cervical cancer in 2006. Although chemotherapy cannot cure this cancer, it can prolong life and often improve its quality. The new drug combination is a small step along the road to longer and better survival. tadacip

Women receiving the topotecan/cisplatin combination lived longer (on average, 9.4 months) than those who received only cisplatin (6.5 months). The combination resulted in more adverse effects (lower blood counts, nausea, and vomiting); however, when the women were asked to assess their quality of life, there was no difference between the two groups.

In summary, adding topotecan to cisplatin lengthened survival in women with advanced cancer of the cervix, although the benefit was small.