Ivvitaminc.us

Case Report
The Use of Antioxidants with First-Line Chemotherapy
in Two Cases of Ovarian Cancer
Jeanne A. Drisko, MD, Julia Chapman, MD, and Verda J. Hunter, MD
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology (J.C., V.J.H.) and the Program in IntegrativeMedicine (J.A.D.), School of Medicine, University of Kansas Medical Center, Kansas City, Kansas Key words: ovarian cancer, chemotherapy, antioxidants, vitamin A, vitamin E, vitamin C, carotenoids
Objective: Because of poor overall survival in advanced ovarian malignancies, patients often turn to
alternative therapies despite controversy surrounding their use. Currently, the majority of cancer patients combine some form of complementary and alternative medicine with conventional therapies. Of these therapies, antioxidants, added to chemotherapy, are a frequent choice.
Methods: For this preliminary report, two patients with advanced epithelial ovarian cancer were studied.
One patient had Stage IIIC papillary serous adenocarcinoma, and the other had Stage IIIC mixed papillary serous and seromucinous adenocarcinoma. Both patients were optimally cytoreduced prior to first-line carboplatinum/ paclitaxel chemotherapy. Patient 2 had a delay in initiation of chemotherapy secondary to co-morbid conditions and had evidence for progression of disease prior to institution of therapy. Patient 1 began oral high-dose antioxidant therapy during her first month of therapy. This consisted of oral vitamin C, vitamin E, beta-carotene, coenzyme Q-10 and a multivitamin/mineral complex. In addition to the oral antioxidant therapy, patient 1 added parenteral ascorbic acid at a total dose of 60 grams given twice weekly at the end of her chemotherapy and prior to consolidation paclitaxel chemotherapy. Patient 2 added oral antioxidants just prior to beginning chemother- apy, including vitamin C, beta-carotene, vitamin E, coenzyme Q-10 and a multivitamin/mineral complex. Patient 2 received six cycles of paclitaxel/carboplatinum chemotherapy and refused consolidation chemotherapy despite radiographic evidence of persistent disease. Instead, she elected to add intravenous ascorbic acid at 60 grams twice weekly. Both patients gave written consent for the use of their records in this report.
Results: Patient 1 had normalization of her CA-125 after the first cycle of chemotherapy and has remained
normal, almost 31⁄2 years after diagnosis. CT scans of the abdomen and pelvis remain without evidence of recurrence. Patient 2 had normalization of her CA-125 after the first cycle of chemotherapy. After her first round of chemotherapy, the patient was noted to have residual disease in the pelvis. She declined further chemotherapy and added intravenous ascorbic acid. There is no evidence for recurrent disease by physical examination, and her CA-125 has remained normal three years after diagnosis.
Conclusion: Antioxidants, when added adjunctively, to first-line chemotherapy, may improve the efficacy
of chemotherapy and may prove to be safe. A review of four common antioxidants follows. Because of the positive results found in these two patients, a randomized controlled trial is now underway at the University of Kansas Medical Center evaluating safety and efficacy of antioxidants when added to chemotherapy in newly INTRODUCTION
year, with approximately 14,800 women dying of this disease per year [2]. Unfortunately, women with advanced stage dis- Ovarian cancer remains one of the most lethal of all gyne- ease have dismal five-year survival rates, despite the develop- cologic malignancies, accounting for more deaths than cervical ment of new chemotherapeutic treatments.
and uterine cancer combined [1]. In the last decade, an esti- Despite attempts to improve survival rates in patients with mated 26,700 new cases of ovarian cancer were diagnosed per malignancies, living with the diagnosis of cancer is an ongoing Address reprint requests to: Jeanne A. Drisko, MD, University of Kansas Medical Center, Program in Integrative Medicine, 3901 Rainbow Blvd., Kansas City, Kansas66160. E-mail: jdrisko@kumc.edu.
Journal of the American College of Nutrition, Vol. 22, No. 2, 118-123 (2003)Published by the American College of Nutrition and difficult experience. Because of the pervasive feeling of sadness, fear, anxiety, anger, and the potential for mortality, patients often turn to complementary and alternative therapies [3,4]. It is reported that the use of complementary and alterna- tive medicine is increasing among cancer patients [5- 8].
A survey of breast cancer patients determined that the interest in megavitamin and herbal therapies was 47.4% and 37.1% respectively, and their use was 25% and 14% respec- tively [5]. This was compared to the use of megavitamin and herbal therapies in the general population at 2% and 3%. This same study found that 80% of these patients never attempted to abandon conventional therapy, but continued to use their con- ventional treatments along with the alternative therapies. In fact, the only patients who reported that they might abandon their conventional therapy (1%) were those with the gravest Other reports place the prevalence of use of complementary and alternative medicine by cancer patients in an estimated range of 7% to 64% [6 - 8]. At the present time, many cancer patients combine some forms of complementary and alternative therapy with their conventional therapies [7- 8]. A recent sur- vey of patients in a comprehensive cancer center placed the use of vitamin and minerals at 62.6%; of these patients, 76.6% combined the use of vitamins and minerals with conventional chemotherapy [8]. The majority of these patients are adding megavitamin and mineral therapies without the knowledge of Patients use complementary and alternative therapies for a variety of reasons [6,7]. Patients use these therapies to improve quality of life (77%), improve immune function (71%), prolong life (62%) or relieve symptoms (44%) related to their disease [6]. Only 37.5% of the survey patients expected complemen- tary and alternative therapies to cure their disease. Whatever the reasons, alternative therapy use is on the rise and this includes megavitamin and mineral cocktails during chemother- Megavitamin and mineral cocktails include antioxidants such as the commonly consumed antioxidants vitamin E (mixed tocopherols and tocotrienols), vitamin C, ␤-carotene (natural mixed carotenoids) and vitamin A. Controversy exists about the use of antioxidants with chemotherapy, but increasing evidence suggests a benefit when antioxidants are added to chemotherapy [9 -16]. We are reporting two cases of advanced ovarian cancer where antioxidants were added adjunctively to chemotherapy without adversely effecting outcome or survival.
Both patients gave verbal and written consent for the use of JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Postoperatively, the patient was felt to be GOG (Gyneco- logic Oncology Group) performance status 2. In the months A 55 year-old female was evaluated for increasing abdom- following surgery, the patient was admitted to the Intensive inal girth. On examination, she was found to have a large pelvic Care Unit (ICU) on two separate occasions and placed on mass, which extended into the abdominal cavity. This was ventilatory support secondary to a respiratory arrest and su- confirmed on CT scan. Her baseline CA-125 was 999.
praventricular tachycardia. After she was discharged from the She underwent surgical exploration and was found to have ICU, she was started on oral megace (80mg/BID) and tamox- disseminated disease involving the diaphragm, small and large ifen (20mg/day). The patient had evidence for progression of bowel, peritoneum, mesentery and omentum with extension to disease with ascites and an elevated CA-125 to 127.
the spleen. The patient was optimally cytoreduced. Final stag- Three months after her primary cytoreductive surgery the ing and pathology was consistent with a Stage IIIC papillary patient began front-line chemotherapy, consisting of carboplati- num (AUC 6) and paclitaxel (135mg/m2) for six cycles (Table Postoperatively, the patient received standard carboplatin 2). Prior to beginning chemotherapy, the patient began oral (AUC 6) and paclitaxel (175 mg/m2) chemotherapy for a total daily antioxidants, consisting of oral ascorbic acid (3,000mg/ of six cycles (Table 1). Her CA-125 fell to Ͻ35 after the day), vitamin E (1,200 IU/day) and beta-carotene (25mg/day) completion of her first cycle of chemotherapy. Her CT scan and vitamin A (5,000 IU/day). The CA-125 normalized after was negative for measurable disease. Consolidation paclitaxel the first cycle of carboplatin/paclitaxel chemotherapy.
(175 mg/m2) was given for an additional 6/12 intended cycles.
After the completion of her first course of chemotherapy, Prior to the first cycle of chemotherapy, the patient elected to the patient was found to have disease in the pelvis. An MRI start daily oral antioxidants, which included vitamin E (1,200 identified a heterogeneous 8 cm mass in the pelvis and a new IU), coenzyme Q10 (300 mg), vitamin C (9,000 mg), beta- 2 cm ϫ 2 cm retroperitoneal mass felt to be metastases. The carotene (mixed carotenoids, 25 mg), and vitamin A (10,000 patient declined consolidation chemotherapy, instead opting for IU). At the completion of the first course of chemotherapy, but continuation of oral antioxidants and initiation of parenteral prior to initiation of consolidation chemotherapy, the patient ascorbic acid infusions. After normal G6PD status was con- began parenteral ascorbic acid. To prevent the possibility of firmed, ascorbic acid infusions were begun at 15 grams and hemolysis, G6PD status was assessed prior to intravenous increased to 60 grams per infusion. The dose was adjusted by ascorbic acid and found to be normal.
a pre- and post-ascorbic acid infusion to maintain plasma levels The ascorbic acid infusions were begun at 15 grams and at above 200mg/dL. The patient had daily 60-gram ascorbic increased to 60 grams per infusion given twice weekly. The acid infusions for one week and then began twice weekly 60-gram dose was tailored to the pre- and post-infusion ascor- infusions, which continues to date 36 months post-diagnosis.
bate level, which maintained plasma ascorbate levels above 200 Although further diagnostic imaging was declined, physical mg/dL. At this plasma level, ascorbic acid is reported to pro- examination has remained normal. Her most recent CA-125 is mote neoplastic cell cytotoxicity [9 -10].
5, and she is over three years out from diagnosis.
The 60-gram ascorbic acid infusions were given two times per week during the six cycles of consolidation chemotherapy,after which the patient continued the 60-gram ascorbic acidinfusions once per week. This dose and schedule was continued for one year, after which the patient chose to reduce thefrequency of the infusions to every 10 to 14 days.
In the first patient, CA-125 levels fell to a normal range The patient is currently over 40 months from initial diag- after surgery and remain normal to date. Positron emission nosis and remains on ascorbic acid infusions. She has had sev- tomography and CAT scans remain without evidence of eral CT scans, as well as a PET scan, all of which remain nega- tive for disease. Her CA-125 remains normal at a value of 8.8.
Patient 2 had a co-morbid condition that prevented her from receiving first line chemotherapy until three months after di- agnosis. Prior to institution of chemotherapy, patient 2 had A 60-year-old, gravida 0 para 0, post-menopausal woman evidence for progression of disease with ascites and an elevated presented with increasing abdominal girth. Ascites and a CA-125 at 108 and 127 onto separate evaluations. The CA-125 13ϫ8ϫ9.6 cm complex pelvic mass were identified on ultra- normalized after the first cycle of carboplatin/paclitaxel che- sound. Her initial CA-125 was 81. At laparotomy, the patient motherapy. After completion of the six cycles of chemotherapy was found to have a large exophytic mass filling the pelvis and as noted above, the patient was found to have disease in the attached to the omentum. She was optimally cytoreduced.
pelvis. The patient declined further consolidation chemother- Pathology was consistent with a mixed papillary serous and apy, but instead elected to continue with oral antioxidants and seromucinous adenocarcinoma of the ovary, FIGO (Interna- parenteral ascorbic acid infusions. CA-125 levels remain nor- tional Federation of Gynecology and Obstetrics) stage IIIC.
mal to date over three years after diagnosis.
Both patients were monitored for toxicity, and neither pa- tient had grade three or four toxicity that limited completion of six cycles of front-line chemotherapy. Both patients had mild, self-limited nausea. Patient 1 noted the onset of numbness and tingling of both hands and feet during the first course of chemotherapy, but prior to the institution of parenteral ascorbic acid. Patient 1 also complained of the onset of fatigue, in- creased shortness of breath and peripheral edema during the first course of chemotherapy, but prior to the introduction of intravenous ascorbic acid. Subsequent evaluation by an echo- cardiography identified tricuspid and aortic valve regurgitation.
The patient is well controlled on aldactone and lasix.
Neither patient demonstrated hematologic toxicity, includ- ing neutropenia or thrombocytopenia. Neither patient required colony-stimulating factors. There was no evidence for febrile neutropenia or infection. Neither patient demonstrated elevated DISCUSSION
The use of antioxidants during chemotherapy remains a matter of controversy. The prevailing opinion is that antioxi- dants may reduce the effectiveness of chemotherapy by inter- fering with reactive oxidant neoplastic cytotoxicity. In addition, Golde's group at Memorial Sloan-Kettering Cancer Center has implicated vitamin C in tumor growth [17]. However, there is increasing evidence that antioxidants may improve efficacy of chemotherapy and inhibit neoplastic cell growth selectively OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO3 One of the most controversial therapies is the use of high- dose ascorbic acid [9,10,19,21-24,17]. Riordan et al. have shown that vitamin C in doses many times over the RDA is a potent immunomodulator and has been found to be preferen- tially cytotoxic to neoplastic cells [9,10]. Vitamin C enhances the activity of natural killer cells in vivo and also enhances both B and T cell activity [25,26]. At doses in the gram range, it has been demonstrated to increase survival time of patients with Roomi et al. investigated the underlying critical features for toxic activity of ascorbic acid on neoplastic cells [27]. The investigators manipulated the structure of ascorbic in vitro to maximize its cytotoxic effect on tumor cell growth. It was found that the cytotoxic activity was not apparently related to the metabolic or vitamin activity at the cellular level. The cytotoxic activity was a result of direct cell killing by ascorbate.
Benade described a tenfold to hundredfold greater content of catalase, the enzyme that reduces hydrogen peroxide to water and oxygen, in normal cells when compared to tumor cells [28]. Increased intracellular hydrogen peroxide generation by vitamin C coupled with a lack of catalase activity in neo- plastic cells results in preferential cytotoxicity to tumor cells.
Yet, little toxicity has been demonstrated to normal host cells JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION [9,10,19,29]. When vitamin C is given intravenously to main- reactive oxygen species; thus, the concept that antioxidants are tain plasma levels above 200mg/dL, cytotoxicity is induced in contraindicated during most chemotherapy regiments is no tumor cells with negligible toxic effects to the host [9,10]. One longer valid [11-16,36]. In fact, as demonstrated with the potential concern is hemolysis in G6PD deficiency that has reported cases, antioxidants when added adjunctively to che- been reported with high-dose intravenous ascorbic acid and all motherapy may improve the efficacy of chemotherapy and may patients should be pre-screened prior to high dose infusion prove to be safe. Because of the positive results found in the two reported patients, a randomized controlled trial is now Teicher suggests a role for carotenoid supplementation in underway at the University of Kansas Medical Center to further conjunction with cytotoxic therapies in established malignant evaluate safety and efficacy of antioxidants when added to disease [30]. However, other studies have found a negative chemotherapy in newly diagnosed ovarian cancer.
correlation between the use of ␤-carotene and tumor regressionor development [31,32]. These conflicting results are mostlikely related to the use of high-doses of a single antioxidant in REFERENCES
the study design and its negative effect on redox buffering.
When taken alone in high doses, synthetic ␤-carotene sup- 1. Markman M: Ovarian cancer update: Management challenges and presses uptake of other carotenoids and acts as a prooxidant advances. Cleve Clin J Med 61:51-58, 1994.
[15]. Natural mixed carotenoids, in doses up to 20 - 40 mg/day, 2. Parker SL, Tong T, Bolden S, Wingo PA: Cancer statistics. CA were found to be without toxicity and to act synergistically with 3. Williams T, O'Sullivan M, Snodgrass S, Love N: Psychosocial Vitamin E has a very important impact on the phenotype of issues in breast cancer: helping patients get the support they need.
dedifferentiated malignant cells by causing differentiation, most likely indirectly through the effects of adenylate cyclase 4. Cassileth B, Chapman C: Alternative cancer medicine: a ten-year [33]. This has been shown to result in an increase and release update. Cancer Invest 14:396-404, 1996.
of transforming growth-factor ␤, which acts as a growth inhib- 5. VandeCreek L, Rogers E, Lester J: Use of Alternative therapies itory signal for malignant cells [15]. Vitamin E has been shown among breast cancer outpatients compared with the general pop- ulation. Alt Ther Health Disease 5:71-76, 1999.
to decrease the toxicity of chemotherapy without reducing its 6. Ernst E, Cassileth BR: The prevalence of complementary/ alternative medicine in cancer: a systematic review. Cancer 83: The precise mechanism of vitamin A actions on inhibition of cancer growth is unknown; however, it seems to increase 7. Boon H, Stewart M, Kennard MA, Gray R, Sawka C, Brown JB, inhibitory levels of specific signaling pathways in neoplastic McWilliam C, Garvin A, Baron RA, Aaron D, Haines-Kamka T: cells. Examples of vitamin A actions include inhibition of Use of complementary/alternative medicine by breast cancer sur- protein kinase C activity in cancer cells and reduction of vivors in Ontario: prevalence and perceptions. J Clin Oncol 18: expression of c-myc and H-ras oncogenes and other cellular genes in cell culture [11,13,15]. Vitamin A also induces cell 8. Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary differentiation in some tumors of epithelial origin and appears SE: Complementary/Alternative Medicine use in a comprehensive to work synergistically with chemotherapeutic agents [11].
cancer center and the implications for oncology. J Clin Oncol Animal studies also show an inhibition of transplanted tumor 9. Riordan NH, Riordan HD, Meng YL, Jackson JA: Intravenous growth when high doses of vitamin A are administered; this is ascorbate as a tumor cytotoxic chemotherapeutic agent. Med Hy- associated with the absence of toxicity to normal tissues [13,34,35]. In addition, vitamin A combined with the biological 10. Riordan NH, Riordan HD, Casciari JP: Clinical and experimental response modifier interferon ␣2a has been shown to be effec- experiences with intravenous vitamin C. J Orthomol Med 5:201- tive in the treatment of squamous cell carcinoma of the cervix [11]. Although significant benefits are demonstrated when 11. Prasad KN, Cole WC, Kumar B, Prasad KC: Scientific rationale combined with chemotherapy, there is no evidence for the for using high-dose multiple micronutrients as an adjunct to stan- reduction of effectiveness of chemotherapy when vitamin A is dard and experimental cancer therapies. J Am Coll Nutr 20(Suppl): In summary, human, animal and in vitro studies have shown 12. Weijl NI, Cleton FJ, Osanto S: Free radicals and antioxidants in chemotherapy induced toxicity. Cancer Treat Res 23:209-240, that antioxidants inhibit neoplastic cell growth by complex mechanisms. These include increases in neoplastic cell differ- 13. Lamson DW, Brignall MS: Antioxidants in cancer therapy: their entiation, increases in apoptosis, inhibition of protein kinase C actions and interactions with oncologic therapies. Alt Med Rev activity, adenylate cyclase activity and other mechanisms. De- spite the fact that chemotherapy-induced formation of free 14. Schmitt CA, Lowe SW: Apoptosis and therapy. J Pathol 187:127- radicals is well demonstrated, chemotherapy-induced cytotox- icity in general does not seem to depend on formation of 15. Prasad KN, Kumar A, Kochupillai V, Cole WC: High doses of multiple antioxidant vitamins: essential ingredients in improving 26. Vojdani A: In vivo effect of ascorbic acid on enhancement of the efficacy of standard cancer therapy. J Am Coll Nutr 18:13-25, natural killer cell activity. Nutr Res 13:753-764, 1993.
27. Roomi MW, House D, Eckert-Maksic M, Maksic ZB, Tsao CS: 16. Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp RD, Growth suppression of malignant leukemia cell line in vitro by Coffey RJ: Antioxidants enhance the cytotoxicity of chemothera- ascorbic acid (vitamin C) and its derivatives. Cancer Lett 22:3-99, peutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBP␤. Nat Med 3:1233-1241, 1997.
28. Benade L, Howard T, Burk D: Synergistic killing of Ehrlich ascites 17. Agus DB, Vers JC, Golde DW: Stromal cell oxidation: a mecha- carcinoma cells by ascorbate and 3 amino-1,2,4-triazole. Oncology nism by which tumors obtain vitamin C. Cancer Res 59:4555- 29. Park CH, Amare M, Savin MA, Hoogstraten B: Growth suppres- 18. Prasad KN, Hernandez C, Edwards-Prasad J, Nelson J, Borus T, sion of human leukemic cells in vitro by L-ascorbic acid. Cancer Robinson WA: Modification of the effect of tamoxifen, cisplatin, DTIC and interferon-2b on human melanoma cells in culture by a 30. Teicher BA, Schwartz JL, Holden SA, Ara G, Northey D: In vivo mixture of vitamins. Nutr Cancer 22:233-245, 1994.
modulation of several anticancer agents by ␤-carotene. Cancer 19. Cameron E, Pauling L: Supplemental ascorbate in the supportive Chemother Pharmacol 34:235-241, 1994.
treatment of cancer: prolongation of survival times in terminal 31. Alpha-tocopherol, Beta-carotene Prevention Study Group: The ef- human cancer. Proc Nat Acad Sci 73:3685-3689, 1976.
fects of vitamin E and beta-carotene on the incidence of lung 20. Lupulescu A: Ultrastructure and cell surface studies of cancer cells cancer and other cancers in male smokers. New Engl J Med following vitamin C administration. Exp Toxic Pathol 4:3-9, 1992.
21. Cameron E, Pauling L: The orthomolecular treatment of cancer. 1.
32. Mackerras D, Irwig L, Simpson JM, Weisberg E, Cardona M, The role of ascorbate in host resistance. Chem Biol Interact 9:273- Webster F, Walton L, Ghersi D: Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnor- 22. Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, malities. Br J Cancer 79:1448-1453, 1999.
Rubin J, Frytak S: Failure of high dose vitamin C (ascorbic acid) 33. Prasad KN, Edwards-Prasad J: Vitamin E and cancer prevention: to benefit patients with advanced cancer: a controlled trial. N Engl recent advances and future potentials. J Am Coll Nutr 11:487-500, 23. Murata A, Morishige F, Yamaguchi H: Prolongation of survival 34. Cole WC, Prasad KN: Contrasting effects of vitamins as modula- times of terminal cancer patients by the administration of large tors of apoptosis in cancer cells and normal cells: a review. Nutr doses of ascorbate. In Hanck A (ed): "Vitamin C: New Clinical Applications in Immunology, Lipid Metabolism and Cancer." 35. Seifter E, Returra A, Padawar J, Levenson SM: Vitamin A and ␤-carotene as adjunctive therapy to tumor excision, radiation ther- 24. Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, apy, and chemotherapy. In Prasad KN (ed): "Vitamins, Nutrition, Ames MM: High dose vitamin C versus placebo in the treatment of and Cancer." Basel: Karger, pp 1-19, 1984.
patients with advanced cancer who had had no prior chemotherapy: 36. Prasad KN, Edwards-Prasad J: Expressions of some molecular A randomized double-blind comparison. N Engl J Med 312:137- cancer risks factors and their modification by vitamins. J Am Coll 25. Vojdani A: Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase C. Immunopharm Immunotox Received January 18, 2002; revision accepted August 24, 2002. JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION

Source: http://www.ivvitaminc.us/highdosevitamincarticles/Antioxidants_with_Chemotherapy_in_Ovarian_Cancer.pdf