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| ID | Type | Description | Link |
|---|---|---|---|
| TMH project No. 377 | Other Identifier | Tata Memorial Hospital |
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Slow accrual implies that clinical questions being questioned have lost its significance.
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Randomized Controlled Trial of Neoadjuvant Progesterone and Vitamin D3 in women with Large Operable Breast Cancer and Locally Advanced Breast Cancer - A Feasibility Study
Primary Progesterone Timing of surgery during the menstrual cycle and its impact on survival in premenopausal women with operable breast cancer has been extensively researched and reinvestigated by Badwe et al in the randomized clinical trial of 'Primary Progesterone Therapy for Operable Breast Cancer' at Tata Memorial Hospital. The underlying assumption was that the presence of unopposed estrogen (in follicular phase) at the time surgery may be deleterious for survival and that circulating progesterone might counteract this deleterious effect.
Vitamin D3 The most prominent physiological role of hormonally active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol), is regulation of calcium and phosphorous homeostasis and bone metabolism via an intracellular receptor (VDR) which is a member of steroid thyroid hormone super-family of receptors. The VDR receptors are also found in other tissues like breast and prostate.
Vitamin D compounds have also been implicated in promotion of apoptosis in breast cancer cells and evidence suggests that 1,25(OH)2D3 and its synthetic analogues may potentiate responsiveness of breast cancer cells to conventional cytotoxic agents.
Objectives
Inclusion Criteria:
Exclusion Criteria:
Methodology / Treatment plan
The study drugs (Injectable Progesterone and Vitamin D3) will be tested in the neoadjuvant setting prior to administration of each chemotherapy cycle, in a 2x2 factorial design as below:
Neoadjuvant D3 will be administered as Inj. Arachitol 300,000 IU/ml intramuscular, before each chemotherapy cycle.
Neoadjuvant Progesterone used will be administered as single IM depot injection 500mg 5 days prior to each CT cycle and surgery date.
Primary Objectives Disease-free survival
Secondary Objectives Improvements in overall survival Tumor response
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| No additional treatment | No Intervention | No Injection Vit D3 or Injection Progesterone prior to chemotherapy cycle | |
| Inj. Proluton | Active Comparator | Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. |
|
| Inj. Arachitol | Active Comparator | Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. |
|
| Inj. Proluton and Inj. Arachitol | Active Comparator | Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM and Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cholecalciferol | Drug | Inj Arachitol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Disease-free survival | Disease-free survival | 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Improvements in overall survival, Tumor response | Overall Survival | 5 years |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rajendra A Badwe, MS (Surgery) | Tata Memorial Hospital, Ernest Borges Road, Parel, Mumbai 400 012 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tata Memorial Hospital | Mumbai | Maharashtra | 400012 | India |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 2571865 | Background | Hrushesky WJ, Bluming AZ, Gruber SA, Sothern RB. Menstrual influence on surgical cure of breast cancer. Lancet. 1989 Oct 21;2(8669):949-52. doi: 10.1016/s0140-6736(89)90956-2. | |
| 1674070 | Background | Badwe RA, Gregory WM, Chaudary MA, Richards MA, Bentley AE, Rubens RD, Fentiman IS. Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet. 1991 May 25;337(8752):1261-4. doi: 10.1016/0140-6736(91)92927-t. |
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|
| Inj. Progesterone | Drug | Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. |
|
|
| 9820181 | Background | Heer K, Kumar H, Speirs V, Greenman J, Drew PJ, Fox JN, Carleton PJ, Monson JR, Kerin MJ. Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery? Br J Cancer. 1998 Nov;78(9):1203-7. doi: 10.1038/bjc.1998.655. |
| 1863022 | Background | Senie RT, Rosen PP, Rhodes P, Lesser ML. Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival. Ann Intern Med. 1991 Sep 1;115(5):337-42. doi: 10.7326/0003-4819-115-5-337. |
| 9831485 | Background | Mathiasen IS, Colston KW, Binderup L. EB 1089, a novel vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells. J Steroid Biochem Mol Biol. 1993 Sep;46(3):365-71. doi: 10.1016/0960-0760(93)90226-m. |
| 15585794 | Background | Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1721S-4S. doi: 10.1093/ajcn/80.6.1721S. |
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| 11179738 | Background | Narvaez CJ, Zinser G, Welsh J. Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. Steroids. 2001 Mar-May;66(3-5):301-8. doi: 10.1016/s0039-128x(00)00202-6. |
| 8903423 | Background | James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol. 1996 Jul;58(4):395-401. doi: 10.1016/0960-0760(96)00048-9. |
| 7923220 | Background | Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ, Dorssers LC, Birkenhager JC, van Leeuwen JP. Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res. 1994 Nov 1;54(21):5711-7. |
| 10521924 | Background | Sundaram S, Gewirtz DA. The vitamin D3 analog EB 1089 enhances the response of human breast tumor cells to radiation. Radiat Res. 1999 Nov;152(5):479-86. |
| 11391859 | Background | Chaudhry M, Sundaram S, Gennings C, Carter H, Gewirtz DA. The vitamin D3 analog, ILX-23-7553, enhances the response to adriamycin and irradiation in MCF-7 breast tumor cells. Cancer Chemother Pharmacol. 2001 May;47(5):429-36. doi: 10.1007/s002800000251. |
| 12796405 | Background | Sundaram S, Sea A, Feldman S, Strawbridge R, Hoopes PJ, Demidenko E, Binderup L, Gewirtz DA. The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice. Clin Cancer Res. 2003 Jun;9(6):2350-6. |
| 15816543 | Background | Zinser GM, Tribble E, Valrance M, Urben CM, Knutson JC, Mazess RB, Strugnell SA, Welsh J. 1,24(S)-dihydroxyvitamin D2, an endogenous vitamin D2 metabolite, inhibits growth of breast cancer cells and tumors. Anticancer Res. 2005 Jan-Feb;25(1A):235-41. |
| 12496746 | Background | Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ, Egorin MJ, Johnson CS, Trump DL. Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther. 2002 Dec;72(6):648-59. doi: 10.1067/mcp.2002.129305. |
| 10232622 | Background | Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. doi: 10.1093/ajcn/69.5.842. |
| 10570431 | Background | Cooper LS, Gillett CE, Patel NK, Barnes DM, Fentiman IS. Survival of premenopausal breast carcinoma patients in relation to menstrual cycle timing of surgery and estrogen receptor/progesterone receptor status of the primary tumor. Cancer. 1999 Nov 15;86(10):2053-8. doi: 10.1002/(sici)1097-0142(19991115)86:103.0.co;2-h. |
| 9652769 | Background | Cooper LS, Gillett CE, Smith P, Fentiman IS, Barnes DM. Cell proliferation measured by MIB1 and timing of surgery for breast cancer. Br J Cancer. 1998 May;77(9):1502-7. doi: 10.1038/bjc.1998.247. |
| 9643688 | Background | Saad Z, Bramwell VH, Wilson SM, O'Malley FP, Jeacock J, Chambers AF. Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases. Lancet. 1998 Apr 18;351(9110):1170-3. doi: 10.1016/S0140-6736(97)07498-9. |
| 9390034 | Background | Ferrieres G, Cuny M, Simony-Lafontaine J, Jacquemier J, Rouleau C, Guilleux F, Grenier J, Rouanet P, Pujol H, Jeanteur P, Escot C. Variation of bcl-2 expression in breast ducts and lobules in relation to plasma progesterone levels: overexpression and absence of variation in fibroadenomas. J Pathol. 1997 Oct;183(2):204-11. doi: 10.1002/(SICI)1096-9896(199710)183:23.0.CO;2-M. |
| 12469156 | Background | Yang Q, Sakurai T, Yoshimura G, Suzuma T, Umemura T, Nakamura M, Nakamura Y, Mori I, Kakudo K. Prognostic value of Bcl-2 in invasive breast cancer receiving chemotherapy and endocrine therapy. Oncol Rep. 2003 Jan-Feb;10(1):121-5. |
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| ID | Term |
|---|---|
| D002762 | Cholecalciferol |
| ID | Term |
|---|---|
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013261 | Sterols |
| D014807 | Vitamin D |
| D012632 | Secosteroids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |
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