A Survey on New Anticancer Drugs
Dr. Wesely C.T. Shiu, MD, MRCP administration of mesna2. A very high dose of
Dr. Thomas W.T. Leung, MB ifosfamide can now be given to patient previously
Department of Clinical Oncology not responsive to low dose alkalating agent.
Chinese University of Hong Kong
In ifosfamide one chloroethyl group is shifted to
Introduction the ring nitrogen. This leads to physico-chemical
differences such as the higher water solubility of
Over the last few years there is a rapid
development of new anticancer drugs in an attempt ifosfamide, which again leads to differential
either to increase the anticancer activity or to pharmacological and toxicological properties of
ifosfamide and cyclophosphamide. Overall
minimise the toxicity. It is often difficult for a busy
metabolism is essentially the same for both
general practitioner to keep up with this new
cyclophosphamide and ifosfamide. Serum half lives
knowledge. Therefore the aim of this review article
in the p phase are similar for both drugs and in the
is to highlight some of the new anticancer drugs
range of 4 to 6 hours3.
which are currently available or will be available
shortly in Hong Kong. The therapeutic index of ifosfamide in respect to
acute toxicity and leukotoxicity is higher than that of
A. Alkalating Agents cyclophosphamide4. Clinical response data suggest
a possible lack of complete cross-resistance between
The traditional alkalating agents such as
ifosfamide and cyclophosphamide5. Urotoxicity was
cyclophosphamide has been used widely and found
dose limiting until the uroprotective agent mesna
to be effective in many tumours (Table 1). Its new
was introduced. The incidence of cystitis after
cyclophosphamide ranges from O - 50%, the average
Hodgkin disease being 7 %. Cystitis is more common with ifosfamide
Non-Hodgkin Iymphoma and for microhaematuria ranges from 20% to 40%
Multiple myeloma and for macrohaematuria from 20% to 30%.
Retinoblastoma The cystitis is mainly due to renally excreted
Mycosis fungoides hydroxy metabolites and acrolein. This is largely
Leukaemia preventable by the administration of mesna (2
Carcinoma of testis mercapto-ethane sulfonate). In the blood the reactive
Breast cancer mesna is oxidized rapidly to the chemically stable
Small cell lung cancer inert disulfide and is excreted rapidly via the
kidneys. In the bladder a large proportion of the
disulfide is again reduced to the reactive mesna
Table 1: Tumours Responsive to
which then interacts with urotoxic oxozaphosphorine
Cyclophosphamide metabolites. By administering mesna the incidence
of haematuria can be reduced to about 2%.
derivative, ifosfamide, has been shown to be more
effective, less marrow suppressive and has a wider In our department, we are currently using
spectrum of activity1. Its major drawback is ifosfamide (1-1.5 gm/m2) for treatment of relapsed
haemorrhagic cystitis. It is shown to be due to non-Hodgkin lymphoma and soft tissue sarcoma.
irritation by its metabolites. This is largely With mesna rescue and adequate hydration, there is
preventable by adequate hydration and regular so far no incidence of haemorrhagic cystitis.
Vol. 10 No. 11 November 1988
B. Antibiotics Group hepatocellular carcinoma, soft tissue sarcoma and
ovarian carcinoma. The maximum cumulative dose
Adriamycin is one of the earliest compound
is kept under 750 mg/m2 and we have not yet
derived from an antibiotic group of chemotherapy
encountered any cardiac toxicity.
known as anthracycline. It is highly effective in
many human tumours (Table 2) and is currently a Mitoxantrone is a hydroxyquinone bound to an
aliphatic side groups with amino functionalities and
Breast cancer is structurally related to doxorubicin but lack an
Bladder cancer aminosugar moiety9. The drug inhibits both RNA
Thyroid cancer and DNA synthesis. In vitro evidence suggests that
Small cell lung cancer mitoxantrone binds to nucleic acid by intercalation,
Ovarian cancer like doxorubicin ' . Data from phase I study
Acute leukaemia showed that the drug can be given by slow infusion
Sarcoma or in dose of 12 mg/m once every 21 days . It has
Neuroblastoma a wide spectrum of anticancer activity particularly in
Hodgkin disease breast cancer, leukaemia and lymphoma. The
Non-Hodgkin lymphoma Southeastern Oncology group study showed that
Ewing sarcoma 16 out of 766 patients (2%) had untoward cardiac
events including 8 patients with ejection fration of less
than 50% and 5 with arrhythmias. Most patients had
Table 2: Tumours Responsive to Adriamycin
no prior doxorubicin. Total mitoxantrone dose
first line anti-cancer drug in many chemoresponsive ranged from 25 to 110 mg/m in the patients with
tumours 'such as ovarian cancer, breast cancer and reduced ejection fractions. It suggests that with
lymphoma. However its long term usage is limited cumulative mitoxantrone doses of less than 100
by its cardiotoxicity which is dose dependant and is mg/m , the incidence of cardiac toxicity is low, less
cumulative. One of its new analogues than 3%.
4'epidoxorubicin has been developed to overcome
part of this problem. Therefore, mitoxantrone is an interesting new
4'epidoxorubicin differs from doxorubicin for the anticancer agent that is effective against breast
epimersation of the OH group in position 4 of the cancer, lymphoma and acute leukaemia. It has a low
aminosugar moiety and acts by binding to DNA and incidence of serious toxicities. These features make
inhibits nucleic acid synthesis. It is mainly excreted it a promising agent in the treatment of cancer.
through urine with a plasma clearance of 0.9-1.4 We have found that mitoxantrone is useful in the
1/min6. The single active dose is between 60-90 induction therapy of acute myeloid leukaemia.
mg/m2 given 3 weekly. However, the bone marrow toxicity is marked with a
Clinical trials had shown that up to 500 mg/m2 prolonged period of marrow hypoplasia. We have
the incidence of congestive heart failure is nil for also tried mitoxantrone in the resistant case of breast
4'epidoxorubicin and 1.7% for adriamycin, while in carcinoma and nasopharyngeal carcinoma. However
the range of 500-1000 mg/m2 it remains nil for the number of cases are too small to make any
4'epidoxorubicin and rises to 22% for adriamycin. comment about its usefulness.
Also significant is the difference between minimal Bleomycin has a wide spectrum of activity (Table
cumulative dose to induce congestive heart failure 3). It can be given intramuscularly or intravenously.
being respectively about 1000 mg/m2 for Extra precaution is required for patients with
4'epidoxorubicin and 500 mg/m2 for adriamycin7, 8. pulmonary disturbances or renal disturbances. In
We have been using 4-epidoxorubicin singly or in combination with radiotherapy bleomycin can
combination in the treatment of breast carcinoma, aggravate the pneumonia - like symptoms and signs.
New Anticancer Drugs
nasopharyngeal carcinoma, testicular tumours and
Cancer of the skin ovarian carcinoma.
Cancer of the head and neck
Cancer of the oesophagus D. Vinca Alkaloid
Cancer of the uterine cervix Vincristine is the first of its kind shown to be
Cancer of the testis effective in certain tumours such as acute
lymphoblastic leukaemia, lymphoma and breast
cancer. It acts by inhibiting the spindle activity
Table 3: Tumour Responsive to Bleomycin
during the mitotic phase. Its new derivative
Bleomycin is also highly effective in the treatment vinblastine has been developed mainly to overcome
of malignant pleural effusion by intrapleural the neurotoxicity induced by this drug.
installation14, 15. Its toxicity in lung can largely be
Vindesine is a chemically derived structural
prevented by limiting its maximum cumulative dose
analogue of vinblastine in an attempt to alter or
of not exceeding 180 mg.
enlarge the spectrum of tumour response, and
Its new derivative peplomycin has a more potent increase the therapeutic index. Activity against most
antitumour activity, a broader antitumour spectrum of the solid tumour was comparable for the two
and a lesser toxicity than bleomycin16"9. However, drugs. Contrary to vincristine, vindesine induced
the maximum cumulative dose should not exceed paraesthesia appears more rapidly reversible after
200 mg. The antitumour effect of peplomycin occurs discontinuing the drug. Other mainifestation of drug
early20, permitting the reduction of the tumour mass toxicity are less frequent. •
at about 3 weeks.
1. 4th European Conference on Clinical Oncology and Cancer Nursing.
Ifosfamide Abstracts Nov., 1987.
This is probably one of the most active anti-cancer 2. Brock N., Pohl J., Stekar J. Studies on the Urotoxicity of
drug available in the market. Its clinical application Oxazaphosphorine Cytostatics and its Prevention. Eur. J. Cancer 17:
is largely restricted by renal and neurological 3. Wagner T., Heydrick D., Jork T. Comparative Study on Human
toxicity. Its new derivative carboplatin (JM8) has Pharmacokinetics of Activated Ifosphamide and Cyclophosphamide
by a Modified Fluorometric Test. J. Cancer Res. Clin. Oncol. 100:
been shown to be less nephrotoxic due to the rapid 95-104, 1981.
4. Marcy R., Semont H., Prost R. Comparative Leucotoxic Effects of
clearance of the drugs in the first few hours after the Two Isomeric Anticancer Agents Cyclophosphamide and
administration. Ifosfamide ICRS Med. Sci. 5: 427, 1977.
5. Goldin A. Ifosfamide in Experimental System. Semi Oncol. 9 Suppl.
I: 14-23, 1982.
It has a similar spectrum of activity as its parent 6. Natale N. 4'Epidoxorubicin and Doxorubicin Toxicity and
compound cisplatinum21-24. It compares favourably Pharmacokinetics in Cancer Patients p. 1447. Cancer Chemotherapy
and Immunotherapy ED: Periti P., Am. Soc. Microbiol.,
with cisplatinum in terms of toxicity25, 26. Washington, 1982.
7. Bonfanti V. Toxic and Therapeutic Activity of 4'Epidoxorubicin.
Tumori 68: 105, 1982.
Carboplatin can be administered without high 8. Von Hoff D. Risk Factors for Doxorubicin Induced Congestive Heart
volume hydration and diuretic which are Failure. Ann. Intern. Med 91: 710, 1979.
9. Johnson R., Zee-Cheng R., Lee W. Experimental Antitumour
recommended to reduce the incidence of renal Activity of Annuioanthraquinones. Cancer Treat. Report 63:
impairment during cisplatinum administration. 425-439, 1979.
10. Traganos F., Evanson D. Action of Dihydroxyanthraquinone on Cell
Therefore, hospitalisation is often not required for Cycle Progression and Survival of a Variety of Cultured Mammalian
Cells. Cancer Res. 40: 671-681, 1980.
carboplatin therapy. 11. Lown J., Hanstock C., Bradley R., Scarbe D. Interactions of the
Antitumour Agents Mitoxantrone and Bisantrene with
Carboplatin is a second line drug used in our Deoxyribonucleic Acids Studied by Electron Microscopy. Mol.
Pharmacol. 25: 178-184, 1984.
department. It is reserved for patients having 12. Prentice M., Wimperts J., Robbins G. Sequential Studies on the Role
of Mitoxantrone in the Treatment of Acute Leukaemia. Invest. New
impaired renal function or intolerable nauseation and Drugs 3: 207-212, 1985.
vomiting after cisplatinum therapy. We have found 13. Gams R., Wesler M. Mitoxantrone Cardiotoxicity - Results from
Southeastern Cancer Study Group. Cancer Treat. Symp. 3: 31-33,
it useful in head and neck cancer especially 1984.
Vol. 10 No. 11 November 1988
14. Paladine W., Cunningham T., Sponzo R., Donavan M., Olson K. Tumours of the Head and Neck. Practica Otologica 71: 1517-1527,
Intracavitary Bleomycin in the Management of Malignant Effusion. 1978.
Cancer 38: 1903-1908, 1976. 21. Smith I., Harland S., Robinson B. Carboplatin: A Very Active New
15. Trotter J., Stuart J, McBeth F. The Management of Malignant Cisplatin Analog in the Treatment of Small Cell Lung Cancer.
Effusion with Bleomycin. British J. of Cancer 40: 310, 1979. Cancer Treat. Report 69: 43-46, 1985.
16. Kusakari J. Clinical Experience with Pepleomycin (NK631). 22. Wiltshaw E. Ovarian Trials at the Royal Marsden. Cancer Treat.
Japanese J. of Antibiotics 3: 659-663, 1978. Rev. 12: 67-71, 1985.
17. Sakuta M. Clinical Effects of NK631, New Bleomycin Derivative in 23. Rossof A., Bearden J., Coltman C. Phase H Evaluation of
Advanced Recurrent Carcinoma of Oral and Maxillo Facial Region. Carboplatin in Lung Cancer. Cancer Treat. Report 60: 1979-1980,
Japanese J. of Oral Surgery 24: 849-860, 1978. 1976.
18. Niijima T. Effect of Pepleomycin in Prostatic Cancer. Scand. J. 24. Farastiere A., Natale R., Takasugi B. A Phase I-1I Trial of
Urol. Nephrol. Suppl. 55: 177-179, 1980. Carboplatin and 5FU Combination in Advanced Carcinoma of the
19. Homma H., Niitani H. A Preliminary Report on the Treatment of Head and Neck. J. of Clinical Oncology 5: 190-196, 1987.
Lung Cancer with Pepleomycin. Cancer Treatment Reviews 7: 25. Smith I., Evans B., Gore M. Carboplatin and Etoposide as First Line
183-189, 1980. Combination Therapy for Small Cell Lung Cancer. J. Clin. Oncol. 5:
20. Inuyama Y. Clinical Effects of NK631 in the Treatment of Malignant 185-189, 1987.
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