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Year : 1997  |  Volume : 63  |  Issue : 6  |  Page : 347-353

Enhanced Toxicity Potential of a Regimen on Addition of Doxorubicin in Combination Chemo-therapy

Correspondence Address:
A M Vimala

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Source of Support: None, Conflict of Interest: None

PMID: 20944376

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A comparative study of cutaneous toxicities of two different commonly used combination chemotherapeutic regimens was conducted on 16 patients of non-Hodgkin's lymphoma. The common drugs in the two regimens were cyclophosphamide, vincristine and prednisone. One of the regimens which was administered to 10 patients, included doxorubicin as an additional drug. This combination is preferred in high grade malignancy. However, the addition of doxorubicin resulted in enhanced severity and multiplicity of cutaneous manifestations. If it is possible to choose between two or more regimens for a given malignancy, the risk-benefit ratio can be weighed to choose the appropriate and least toxic drugs.

Keywords: Doxorubicin, Lymphoma, Cutaneous toxicity

How to cite this article:
Vimala A M. Enhanced Toxicity Potential of a Regimen on Addition of Doxorubicin in Combination Chemo-therapy. Indian J Dermatol Venereol Leprol 1997;63:347-53

How to cite this URL:
Vimala A M. Enhanced Toxicity Potential of a Regimen on Addition of Doxorubicin in Combination Chemo-therapy. Indian J Dermatol Venereol Leprol [serial online] 1997 [cited 2021 Jan 20];63:347-53. Available from:

Cancer chemotherapeutic agents kill or impair susceptible tumour cells by block­ing a drug sensitive biochemical or meta­bolic pathway. Safe use of chemotherapeu­tic drugs requires an appropriate route and schedule of administration. Determination of the drugs, their combinations, safe dos­age range, an awareness of the side effects that are likely to result and knowledge of drug interactions would minimize the tox­icity and maximize favourable response. Each of these factors should be considered in developing a protocol for chemo­therapy.

The principles that are followed in the se­lection of drugs in effective combinations are : (a) only drugs known to be partially effective, when used alone, are selected for use in the combination. The drugs should be preferably those that produce some frac­tion of complete remission. (b) The drug should be selected on the basis of toxicity that does not overlap with the toxicity of other drugs to be used in combination. Such selection leads to a wider range of side effects. For example metabolite for­mation [1] (c) Drug combinations should be given at constant intervals. The treatment free interval between cycles should be the shortest possible time necessary for recov­ery of the most sensitive normal target tis­sue, usually the bone marrow. [2] Based on the results of investigations by numerous workers from different parts of the world, recommendations on specific drug combinations, schedules and routes of administration have been given. [3],[4] Doxorubicin (Adriamycin) is an anthracycline antibiotic with an almost identical structure to daunorubicin. These compounds have a planar anthraquinone nucleus attached to an amino sugar. They have a wide range of antibacterial and anti tumour activities. Doxorubicin is used to treat solid tumours, such as carcinoma of the breast, lung, thyroid and ovary, and soft tissue sarcomas. This study was con­ducted to compare the cutaneous toxicities of two different commonly used combi­nation chemotherapeutic. regimens recom­mended by Burkert H and Herdrich K (1992) [3], for non-Hodgkin's lymphoma.

  Materials and Methods Top

The study was conducted at the Depart­ment of Dermatology and Department of Radiation and Oncology, Kasturba Medi­cal College, Mangalore during the period 1995 to 1997. Sixteen patients were se­lected for the study. All of them were con­firmed cases of non-Hodgkin's lymphoma. Ten of them were administered the drug combination comprising of cyclophospha­mide, doxorubicin, vincristine and prednisone (CHOP). The remaining 6 pa­tients were administered the drug combi­nation comprising of cyclophosphamide, vincristine and prednisone (COP). The two drug combinations were administered in the following dosages:

CHOP : Cyclophosphamide 750 mg/m 2 i.v. day 1, Vincristine 1.4 mg/m 2 (max. dose 2 mg) day 1, Doxorubicin 50 mg/m 2 i.v. day 1, Prednisone 150mg p.o., days 1-5, to be repeated every 2 or 3 weeks.

COP: Cyclophosphamide 650 mg/m 2 I.V. day 1, Vincristine 1.4 Mg/M2 i.v. day 1, Prednisone 40 mg/m 2 p.o. days 1-5, to be repeated every 3 or 4 weeks.

None of the patients were receiving radio­therapy while on chemotherapy. The pa­tients studied were not receiving any other medication which could have caused simi­lar cutaneous manifestations as observed in the present study.

A comprehensive clinical history, general physical examination, systemic examina­tion and detailed dermatological examina­tion were carried out in all the patients. Relevant investigations were done for each of the patients and the details noted. Der­matological examination was done both prior to and during the chemotherapy. The investigations comprised of tests required for detection and confirmation of the malignancy and for monitoring the patient's condition during chemotherapy. The manifestations studied were those af­fecting the skin, mucous membrane, hair and nails. The pigmentary changes of skin, mucous membrane and nails were graded as : (i) Mild - light grey, light brown (ii) Moderate - dark grey, dark brown (iii) se­vere - black

In case of scalp alopecia the grading was, (i) Mild - no appreciable loss of hair clini­cally, history of significant loss of hair, (ii) Moderate - clinically appreciable loss of hair (less than 50 percent of scalp involve­ment), (iii) Severe - More than 50 percent scalp involvement. The loss of body hair was also recorded.

Follow up studies were carried out on the patients when they reported for successive treatment cycles for administration of the drugs on an inpatient / out patient basis.

  Results Top

The cutaneous manifestations observed in the two groups of patients under CHOP and COP regimens are presented in [Table 1]. CHOP regimen, which was administered to 10 patients was associated with 100 per­cent morbidity this regimen was found to be associated with occurrence of alopecia, glossitis, mucositis, pigmentation of skin and nail, phlebitis, pruritus, exaggerated response to insect bites, oral candidiasis and Muehrcke lines (transverse white lines . on the nails). The administration of CHOP regimen was associated with the darken­ing of palmar creases and hyperpigmenta­tion of palms and soles. Seven of the pa­tients on CHOP regimen manifested nail pigmentation. The CHOP regimen was also associated with varying degrees of se­verity of alopecia.

COP regimen was administered to 6 pa­tients, only 2 of them developed cutane­ous manifestations in the form of alopecia, pruritus, glossitis and Muehrcke lines. COP regimen caused only mild or moder­ate alopecia. No skin or oral pigmenta­tion was observed in patients on COP regimen. One of the patients in COP regimen manifested with Muehrcke lines.

  Discussion Top

The present study was an effort to compare the cutaneous manifestations resulting from the administration of two commonly used combination chemotherapeutic drugs, in which the drugs common to both the regimens were cyclophosphamide, vincristine and prednisone. Among the two, the CHOP regimen contained doxorubicin as an additional drug.

The side effects resulting from the above 2 regimens reveal that the introduction of doxorubicin enhances the toxicity potential of the regimen. This is further confirmed from the observation that all the 10 patients who were on CHOP regimen had cutaneous manifestations, while only 2 out of the 6 patients on COP regimen developed side effects immediately after the first treatment cycle. The remaining 2 patients on CHOP regimen manifested after the second treatment cycle. The observation in our study are, in general in conformity with those of earlier workers on the administration of doxorubicin in cancer chemotherapy. Many workers have reported that the administration of the doxorubicin caused dark pigmentation of nails including pigmented nail bands. [5],[6],[7],[8]

Pigmentation of the tongue and buccal mucosa, localized pigmentation of the palms, soles and axillae as well as pigmen­tation along palmar or digital creases have been reported with the use of doxorubi­cin. [5] Abnormalities of nail including acute paronychia, reversible onycholysis, [9] and onychodystrophy have been seen with the use of doxorubicin. [1] Mucositis has been reported as a side effect of doxorubicin. It has been implicated in the production of a peculiar localized urticarial reaction occurring over infused veins. [5],[11] White lines on the finger nails induced by combina­tion chemotherapy which included doxo­rubicin was reported by Shetty. [12] Trans­verse striate leukonychia, a manifestation of nail matrix injury resulting in a distur­bance of nail plate keratinization has been reported as a result of combination che­motherapy which included doxorubicin. The leukonychia is believed to result from the formation of air pockets or the reten­tion of nuclei within the nail plate. [8],[13],[14] Extravasation of doxorubicin into skin and soft, tissue causes necrosis and ulceration which may become chronic. [15] Cutaneous manifestations distant from the site of in­jection such as alopecia, urticaria, angioneurotic edema, hyperpigmentation, stomatitis and skin reaction at the site of infiltration have been reported, following the use of this anti tumour agent, [15],[16],[17],[18] Squa­mous syringometaplasia has also been ob­served. [15] Radiation recall has been reported in association with administration of doxorubicin [19]. Local necrosis following extravasation is seen following doxorubi­cin administration [5],[15].

The relative toxicities of various chemo­therapeutic drugs, individually or in com­bination, must be taken into account when choosing treatment regimens for a given malignancy. The risk-benefit ratio can be weighed to choose the appropriate and least toxic drugs. If the physician is alerted to impending complications, the morbid­ity of the disease can be reduced consider­ably. This can ensure a better quality of life for patients in the limited span of life available to them.

  Acknowledgement Top

The authors are grateful to Dr. Dinesh M and Dr Sanat Kumar Hegde of the Department of Radia­tion and Oncology, Kasturba Medical College, Attavar, Mangalore for the valuable help extended by them during the study.

  References Top

1.Grever MR, Chabner BA, Cancer drug dis­covery and development. In : Devita VT, Hellman S and Rosenberg SA, editors, Prin­ciples and Practices of Oncology. Philadel­phia : JB Lippincott Co, 1993; 328-340.  Back to cited text no. 1    
2.Devita VT Jr. Principles of chemotherapy. In : Devita VT, Hellman S and Rosenberg SA, editors. Principles and Practices of Oncology. Philadelphia: JB Lippincott Co. 1993; 276­324.  Back to cited text no. 2    
3.Burkert H, Herdrich K. In : Selected sched­ules of therapy for malignant tumours. Asta Medica Oncol 1992; 1-69.  Back to cited text no. 3    
4.Chabner BA. Anti-cancer drugs. In : Devita VT, Hellman S and Rosenberg SA, editors. Principles and Practices of Oncology. Phila­delphia : JB Lippincott Co. 193; 325-417.  Back to cited text no. 4    
5.Hood AF. Cutaneous side effects of cancer chemotherapy. Med Clin N Am 1986; 70:187­209.  Back to cited text no. 5  [PUBMED]  
6.Prussick R, Knowles S, Shear NH. Cutane­ous drug reactions. Curr Probl Dermatol 1994; May-June : 87-122.  Back to cited text no. 6    
7.James WD, Odom RB. Chemotherapy-in­duced transverse white lines in the fingernails. Arch Dermatol 1983; 119: 334-335.  Back to cited text no. 7  [PUBMED]  
8.Bianchi L. Iraci S, Tomassoli M, et al. Coex­istence of apparent transverse leukonychia (Muehrcke's lines type) and longitudinal melanonychia after 5-Fluorouracil / adriamycin/ cyclophosphamide chemo­therapy. Dermatol 1992; 185: 216-217.  Back to cited text no. 8    
9.Curran EF. Onycholysis in doxorubicin­treated patients. Arch Dermatol 1990; 126: 1244.  Back to cited text no. 9    
10.Singh M, Kaur S. Chemotherapy - induced multiple Beau's lines. Int J Dermatol 1986; 25: 590-591.  Back to cited text no. 10  [PUBMED]  
11.Weis RB, Bruno S. Hypersensitivity reactions to cancer chemotherapeutic agents. Ann Int Med 1981; 94: 66-74.  Back to cited text no. 11    
12.Shetty MR. White lines in the fingernails in­duced by combination chemotherapy. Br Med J 1988; 297: 1635.  Back to cited text no. 12    
13.Unamuno P, Fernandez-Lopez E, Santos C. Leukonychia due to cytostatic agents. Clin Exp Dermatol 1992; 17: 273-274.  Back to cited text no. 13    
14.Hogan PA, Krafchik BR, Boxall L. Transverse striate leukonychia associated with cancer chemotherapy. Ped Dermatol 1991; 8: 67-68.  Back to cited text no. 14    
15.Bhawan J, Petry J, Rybak ME, Histopathologic changes induced in skin by extravasation of doxorubicin (adriamycin). J Cutan pathol 1989; 16: 158-163.  Back to cited text no. 15    
16.Pillans PI, Woods DJ. Drug-associated alopecia. Int J Dermatol 1995; 34: 149-158.  Back to cited text no. 16    
17.Scuderi N. Onesti MG. Antitumour agents; . Extravasation, management and surgical treatment. Ann Plast Surg 1994; 32: 39-44.  Back to cited text no. 17    
18.Kumar L, Kochupillai V. Doxorubicin-in­duced hyperpigmentation. New Zealand Med J. 1990; 11: 165.  Back to cited text no. 18    
19.Stelzer KJ, Griffin TW, Koh W. Radiation recall skin toxicity with bleomycin in a pa­tient with Kaposi's sarcoma related to ac­quired immune deficiency syndrome. Cancer 1993; 71: 1322-1325.  Back to cited text no. 19    


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