Doxorubicin

 Risk Factor: DM
 Class: ANTINEOPLASTICS

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Doxorubicin is an antineoplastic agent used for the treatment of various types of cancer. The drug is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits (1).

Several reports have described the use of doxorubicin in pregnancy, including three during the 1st trimester (2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 and 18). One of the fetuses exposed during the 1st trimester to doxorubicin, cyclophosphamide, and unshielded radiation was born with an imperforate anus and rectovaginal fistula (15). At about 3 months of age, the infant was small with a head circumference of 46 cm (<5th percentile) but was doing well after two corrective surgeries (15). A 1983 report described the use of doxorubicin and other antineoplastic agents in two pregnancies, one of which ended in fetal death 36 hours after treatment had begun (18). Other than maceration, no other fetal abnormalities were observed. The investigators could not determine the exact cause of the outcome but concluded that the chemotherapy was probably not responsible. The only other complication observed in exposed infants was transient polycythemia and hyperbilirubinemia in one subject. Infants who have been evaluated have shown normal growth and development.

A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (18). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two spontaneous abortions (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (18). Doxorubicin (D), in combination with cyclophosphamide (C), fluorouracil (F), or vincristine [V]), was administered to four of the women at a mean dose of 68.7 mg/m2 (range 50100 mg/m2). The outcomes were four surviving liveborn infants (two exposed to DCF and one each to DF and DV in the 2nd or 3rd trimesters).

Three studies have investigated the placental passage of doxorubicin (2,19,20). In one, the drug was not detected in the amniotic fluid at 20 weeks of gestation, which suggested that the drug was not transferred in measurable amounts to the fetus (2). Placental transfer was demonstrated in a 17-week-old aborted fetus, however, using high-performance liquid chromatography (HPLC) (20). High concentrations were found in fetal liver, kidney, and lung. The drug was not detected in amniotic fluid (<1.66 ng/mL), brain, intestine, or gastrocnemius muscle. A third study examined the placental passage of doxorubicin in two pregnancies, one resulting in the birth of a healthy infant at 34 weeks' gestation and one ending with a stillborn fetus at 31 weeks' gestation (19). Using HPLC, doxorubicin was demonstrated in the first case, 48 hours after a 45 mg/m2 dose (total cumulative dose, 214 mg/m2), on both sides of the placenta and in the umbilical cord but not in cord blood plasma. In the stillborn, doxorubicin was not detected in any fetal tissue, 36 hours after a single dose of 45 mg/m2. However, a substance was detected in all fetal tissues analyzed that the investigators concluded may have represented an unknown doxorubicin metabolite.

Long-term studies of growth and mental development of offspring exposed to doxorubicin and other antineoplastic agents in the 2nd trimester, the period of neuroblast multiplication, have not been conducted (21).

Doxorubicin may cause reversible testicular dysfunction (22,23). Similarly, normal pregnancies have occurred in women treated before conception with doxorubicin (24). In 436 long-term survivors treated with chemotherapy for gestational trophoblastic tumors between 1958-1978, 33 (8%) received doxorubicin as part of their treatment regimens (24). Of the 33 women, five (15%) had at least one live birth (data given in parentheses refer to mean/maximum doxorubicin dose in milligrams) (100/100), two (6%) had no live births (150/200), one (3%) failed to conceive (100/100), and 25 (76%) did not try to conceive (140/400). Additional details, including congenital anomalies observed, are described in the monograph for methotrexate (see Methotrexate).

The long-term effects of combination chemotherapy on menstrual and reproductive function have been described in a 1988 report (25). Only one of the 40 women treated for malignant ovarian germ cell tumors received doxorubicin. The results of this study are discussed in the monograph for cyclophosphamide (see Cyclophosphamide).

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents, including doxorubicin, are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

Breast Feeding Summary

Doxorubicin is excreted into human milk. A 31-year-old woman, 7 months postpartum, was given doxorubicin (70 mg/m2), infused over 15 minutes, for the treatment of ovarian cancer (26). Both doxorubicin and the metabolite, doxorubicinol, were detected in the plasma and the milk. Peak concentrations of the two substances in the plasma occurred at the first sampling time (0.5 hour) and were 805 and 82 ng/mL, respectively. In the milk, the peak concentrations occurred at 24 hours with levels of 128 and 111 ng/mL, respectively. The area under concentration time curves (AUC) of the parent compound and metabolite in the plasma were 8.3 and 1.7 mol/L hours, respectively, while the AUC in the milk were 9.9 and 16.5 mol/L hours, respectively. The highest milk:plasma ratio, 4.43, was measured at 24 hours. Although milk concentrations often exceeded those in the plasma, the total amount of active drug available in the milk was only 0.24 g/mL (26).

Although the above amounts may be considered negligible, the American Academy of Pediatrics considers doxorubicin to be contraindicated during breast feeding because of concerns for possible immune suppression, carcinogenesis, neutropenia, and unknown effects on growth (27).

References

1. Product information. Adriamycin. Pharmacia & Upjohn, 2000.
2. Roboz J, Gleicher N, Wu K, Kerenyi T, Holland J. Does doxorubicin cross the placenta? Lancet 1979;2:13823.
3. Khursid M, Saleem M. Acute leukaemia in pregnancy. Lancet 1978;2:5345.
4. Newcomb M, Balducci L, Thigpen JT, Morrison FS. Acute leukemia in pregnancy: successful delivery after cytarabine and doxorubicin. JAMA 1978;239:26912.
5. Hassenstein E, Riedel H. Zur teratogenitat von Adriamycin ein fallbericht. Geburtshilfe Frauenheilkd 1978;38:1313.
6. Cervantes F, Rozman C. Adriamycina y embarazo. Sangre (Barc) 1980;25:627.
7. Pizzuto J, Aviles A, Noriega L, Niz J, Morales M, Romero F. Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep 1980;64:67983.
8. Tobias JS, Bloom HJG. Doxorubicin in pregnancy. Lancet 1980;1:776.
9. Garcia V, San Miguel J, Borrasca AL. Doxorubicin in the first trimester of pregnancy. Ann Intern Med 1981;94:547.
10. Garcia V, San Miguel IJ, Borrasca AL. Adriamycin and pregnancy. Sangre (Barc) 1981;26:129.
11. Dara P, Slater LM, Armentrout SA. Successful pregnancy during chemotherapy for acute leukemia. Cancer 1981;47:8456.
12. Lowenthal RM, Funnell CF, Hope DM, Stewart IG, Humphrey DC. Normal infant after combination chemotherapy including teniposide for Burkitt's lymphoma in pregnancy. Med Pediatr Oncol 1982;10:1659.
13. Webb GA. The use of hyperalimentation and chemotherapy in pregnancy: a case report. Am J Obstet Gynecol 1980;137:2636.
14. Gililland J, Weinstein L. The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv 1983;38:613.
15. Murray CL, Reichert JA, Anderson J, Twiggs LB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. A case report. JAMA 1984;252:26078.
16. Haerr RW, Pratt AT. Multiagent chemotherapy for sarcoma diagnosed during pregnancy. Cancer 1985;56:102833.
17. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:43540.
18. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy. Cancer 1999;86:226672.
19. Karp GI, Von Oeyen P, Valone F, Khetarpal VK, Israel M, Mayer RJ, Frigoletto FD, Garnick MB. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep 1983;67:7737.
20. D'Incalci M, Broggini M, Buscaglia M, Pardi G. Transplacental passage of doxorubicin. Lancet 1983;1:75.
21. Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.
22. Lendon M, Palmer MK, Hann IM, Shalet SM, Jones PHM. Testicular histology after combination chemotherapy in childhood for acute lymphoblastic leukaemia. Lancet 1978;2:43941.
23. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:10914.
24. Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 1984;288:1036.
25. Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:2705.
26. Egan PC, Costanza ME, Dodion P, Egorin MJ, Bachur NR. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep 1985;69:13879.
27. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.
    
    

Questions and Answers

Dear Doctor Vincent Rajkumar-Where do you position Pegylated liposomal doxorubicin in your treatment protocol?, Sir as you are aware that there are lot of options in Newly diagnosed MM and Refractory MM for the usage of various drugs,i request you to guide me in the usage of DOXIL in MM.This info i need for my knowledge.

wtf?

Has anyone used Doxorubicin (chemo) on their ferret and with what results?, My ferret is presently undergoing chemo using Doxorubicin for a huge lymphoma tumor (diagnosed thru a biopsy) on his neck. We are injecting it directly into the neck tumor with fantastic results. It has been 2 weeks and the tumor has significantly gotten smaller. He goes in next week for a 2nd session. His only side effect that I can see is he is very tired. I do give him Pet Tinic which seems to help. I will ask the vet next week if there is anything else I can give him for his possible anemia. Any info on anyone who has used this on their ferret would be greatly appreciated. I have had several ferrets with Lymphoma but none who have has such a huge tumor on the side of their neck. He is only going on 4 years old and such a sweetheart thru all this. Thank you.

Then only problem with Doxorubicin is that there is a limit as to how many treatments you can give (5). Once you have given 5 treatments, remission ends.

effect of doxorubicin and viblastine on leukemic cells, What are the effects of doxorubicin and vinblastine on phases of cell cycle such as G0/G1 phase, M phase or G2/M phase for a leukemic patient?

Doxorubicin:
From American Society for Pharmacology and Experimental Therapeutics. Volume 49, Issue 5, pp. 832-841, 05/01/1996
Our results suggest that anthracycline-induced cytotoxicity is cell cycle dependent and is mediated, at least in part, by disturbance of the regulation of p34cdc2/cyclin B1 complex, thus leading to G2/M phase arrest.

Vinblastine is M phase dependent, as it inhibits microtubule formation, and microtubules are important during mitosis.

is doxorubicin a hydrophobic drug or hydrophilic one?,

Hydrophilic. It has 5 hydroxyl groups, 1 amino group, 3 ether oxygens, and 3 ketonic functions.
http://en.wikipedia.org/wiki/Doxorubicin

can you cite a paper on doxorubicin carcinogenesis?,

No, but have you looked on asco.org or jco.org?

As to the answerer below, yes doxorubicin is carcinogenic. There is like a 1-2% incidence of AML in patients who receive a full course (4 cycles) adriamycin. I mean, if you consider leukemia a cancer (not a solid tumor, obviously)

My son is on the following chemo drugs: Oncovin,Doxorubicin,cytoxan,etoposide,... ifosfamide?, he wanted me to ask if anyone knows, when his hair will start falling out. He's 13 and had his 1st treatment, and is not looking forward to his hair loss, i tell him its only hair and will grow back.

I would expect his hair to start falling out within 2 weeks of the treatment. It probably will start getting thin then all ths sudden, fall out in big chunks. He will most likely lose his eye brows, eye lashes, and facial hair if he has any yet along with his pubic hair and hair on his arms and legs too.
He most likely will develop sun sensitivity and his appetite may diminish greatly. I always tell my pts not to eat their favorite foods while recieving chemo treatments because it will never be there favorite again after they throw it up. Sounds like your sons oncologist is serious here about killing cancer cells. I am curious to know what kind of cancer your son has. This is very aggressive chemotherapy he is recieving.
My prayers are with you and you child.

Streptozocin, 5FU (Fluorouracil), and Doxorubicin (Adriamycin)?, Has anyone been on any or all of these chemotherapy drugs? I would like to know what to expect while taking this combination. I have cancer on my pancreas and this is the combination that the oncologist has prescribed for me to take for 10 cycles (five days in a row, then two weeks off before beginning the next cycle). Thanks for your help:)

I was on Adriamycin for 4 cycles. It caused me to sleep constantly for the first 2-3 days after my first treatment. After that, it wasn't quite so bad. It never did cause me to get sick, but that could also be because the dr. had me on Emend to help with any of the nausea, etc. I didn't really have an upset stomach. It was more of an overly full/bloated feeling and I had no appetite at all for the first few days after a treatment.

Certain smells would make my stomach turn. I found that whatever foods I would eat on treatment day (I went every 2 weeks for the Adriamycin) I would not want to even see again after that. I still cannot stand the thought of orange Gatorade or apples...I had both for lunch the day of my first treatment. LOL

My hair started coming out in big chunks on day 13 after the first treatment. Within 4 days, I was down to just little tufts of hair here and there. I never did go completely bald and though my eyebrows thinned out a bit, if a person did not know me, they could not tell a bit. Looking for the positives of chemo, I told hubby at least I shouldn't have to shave my legs for awhile and wouldn't have to worry about bad hair days. Wouldn't you know, I still had to shave my legs. LOL

Keep in mind that every medicine effects everyone differently. While I was never REALLY sick from the chemo, there was another lady with me that was on the same meds and would be sick for 2 days straight. The day of my 2nd. treatment I went home, put on sweatpants and a t-shirt and sat on the couch waiting to feel bad or sleepy....NOTHING. LOL I wound up going to a high school soccer game that evening! You just don't know til you get in there.
Best of luck to you and if you need someone to talk to, feel free to email me.

If you have Kaposi's Sarcoma and are given DOXIL chemo - is limb amputation still an option?, My mom had a liver transplant 12 years ago. She is now battling KS - started on her leg in a small way but now is whole lower limb. They did radiation which did not help - the lesions are overwhelming and she is unable to walk. She has had one treatment of DOXIL ( liposome doxorubicin) and was told that the next treatment would be in 2-3 weeks. She's at the point of wanting amputation if it will prolong her life. My question: it seems that prescribing DOXIL means the cancer is systemic - would amputation be an option or has the cancer already travelled beyond the leg?

I guess the Doxil really is for systemic treatment. Does mom have a good Oncologist? If there is no indication of mets outside the affected limb, the amputation may be the way to go. Get a couple of opinions.