Cancer Treatment

Tamoxifen for breast pain

Tamoxifen can be used off-label to treat breast pain (mastalgia), because it reduces estrogen levels that cause breast swelling.In one study, tamoxifen relieved pain in more than two-thirds of women who had a history of severe breast pain. Experts disagree about the use of tamoxifen for breast pain, because it has important side effects and risks.

One double blind randomized comparatiove study(RCT)  compared tamoxifen 20 mg daily versus placebo. It found that significantly more women experienced pain relief (measured by visual analogue scale over 3 months) with tamoxifen compared with placebo (> 50% reduction in mean pain score: 22/31 [71%] with tamoxifen v 11/29 [38%] with placebo; P < 0.025). The second RCT (93 women) compared tamoxifen, danazol, and placebo. It found that significantly more women taking tamoxifen achieved a good outcome (> 50% reduction in mean pain score) at the end of treatment, 6 months later, and 12 months later, compared with placebo (> 50% reduction in pain score after 6 months of treatment: 23/32 [72%] with tamoxifen v 11/29 [38%] with placebo; P = 0.035). The third RCT (88 women, aged 22–44 years) found that 8 months of tamoxifen increased the proportion of women who achieved complete recovery (outcome not clearly defined) compared with placebo (40/44 [90%] with tamoxifen v 0/44 [0%] with placebo; P value not reported).

In conclusion, Tamoxifen is not licensed for mastalgia in the UK or USA. There is a consensus to limit its use to no more than 6 months at a time under expert supervision, and with appropriate non-hormonal contraception, because of the high incidence of adverse effects.

Fentiman IS (2004). Management of breast pain. In JR Harris et al., eds., Diseases of the Breast, 3rd ed., pp. 57–62. Philadelphia: Lippincott Williams and Wilkins.

Kontostolis E, Stefanidis K, Navrozoglou I, et al. Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol 1997;11:393–397. 

Fentiman IS, Caleffi M, Brame K, et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1:287–288. 

Grio R, Cellura A, Geranio R, et al. Clinical efficacy of tamoxifen in the treatment of premenstrual mastodynia. Minerva Ginecol 1998;50:101–103.   GEMB Group. Tamoxifen therapy for cyclical mastalgia: dose randomised trial. Breast 1997;5:212–213.

Adjuvant biphosphonates for breast cancer

Biphopshonates are approved for treatmetn of osteoporosis and to prevent skeltal related events (fractures) in certain cancer patients with bone or other metastases. , clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer and are being studied for adjuvant therapy. In addition to the ABCSG-012 trial, which is still in progress, the parallel-design Zometa®/Femara® Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the U.S. and Europe, respectively) are investigating the benefit of immediate and delayed treatment with zoledronic acid (4 mg every 6 months) in postmenopausal women receiving adjuvant therapy with letrozole (2.5 mg/day) for early-stage hormone-receptor-positive breast cancer. Those trials will also enroll women in whom menopause has been induced by chemotherapy. The poposed trial is ongoing. Based on the results from early clinical trials, bisphosphonates appear to be effective for the prevention of fractures. Current consensus guidelines from the American Society of Clinical Oncology recommend the use of i.v. or oral bisphosphonate therapy in patients who develop T scores below -2.5 standard deviations from normal (osteoporosis) during adjuvant therapy for breast cancer
NCT00127205, is a study of Zoledronate, Clodronate, or Ibandronate in Treating Women Who Have Undergone Surgery for Stage I, Stage II, or Stage III Breast Cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer.

SWOG-S0307. a randomized phase III trial is studying zoledronate to see how well it works compared to clodronate or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.It is an investigational study.

Reid IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–661

Gnant M, Hausmaninger H, Samonigg H et al. Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (± zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: results of a randomized multicenter trial. Presented at the 25th Annual San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX.

Saarto T, Blomqvist C, Valimaki M et al. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 1997;75:602–605

Allan Lipton Toward New Horizons: The Future of Bisphosphonate Therapy The Oncologist, Vol. 9, Suppl 4, 38–47, September 2004
 

Testing the family members for BRCA

Ly Summary:It often makes sense to test teh family member with the cancer first but many insurers object.

The common approach among those suspected of BRCA testing is to test a family member who is already diagnosed with breat or ovarian cancer. If a particular mutation si identified, a search for that mutation is indicated and sequencing of common variants or the entire gene is not necessary. A negattive test decreases the possibility that a family member carries BRCA. It will not completely obviate the need for BRCA testing if there si high suspiction of it in a family member but makes it less likely and necessary.

Most often, the first person that is tested in a family for BRCA-1 and BRCA-2 mutations is one who developed breast or ovarian cancer since this determines if the cancer in the family is associated with a BRCA mutation. If a mutation is found, it becomes a simple matter to test other blood relatives for the same mutation. If a mutation is not found in the family member who has or had cancer, the test is not informative and would not provide helpful information to other family members. If no family members with cancer are living or available for testing, testing options are generally considered on a case-by-case basis for each family.
There are no guidelines that recommend this approach and no studies. In addition, the benefit is to the family member and coverage for that is the family mebmer's responsibility and that of her plan.

U.S. Preventive Services Task Force (USPSTF). Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005 Sep 6;143(5):355-61.

http://www.cdc.gov/genomics/training/perspectives/factshts/breastcancer.htm#Ref11

Herceptin and tamoxifen for male breast cancer

Male breast cancer is rare. Less than 1% of all breast carcinomas occur in men.The pathology is similar to that of female breast cancer, and infiltrating ductal cancer is the most common tumor type.Intraductal cancer has been described as well. Inflammatory carcinoma and Paget disease of the nipple have also been seen in men, but lobular carcinoma in situ has not. Lymph node involvement and the hematogenous pattern of spread are similar to those found in female breast cancer. The TNM staging system for male breast cancer is identical to the staging system for female breast cancer.

Male breast cancer is usually treated the same as female brest cancer. Because it is rare, the assumption that male breast cancer should be treated the same as female breast cancer, has never been scientifically studies. Male breast cancer responds well to hormonal treatments.Hormonal therapy, chemotherapy, or a combination of both have been used with some success. Initially, hormonal therapy is recommended.

Tamoxifen with Herceptin may be synergistic and research in this area is continuing.Most of teh work is preclincial at this time but severa; pahse II studies ahve been eprformed and pahse III trials are initiated. Taken together the evidence suggests that targeted non-chemotherapeutic combinations of trastuzumab with hormonal therapy, which are currently being studied in large-scale clinical trials, represent active cancer therapy, allowing the individualisation of treatment based on tumour characteristics but remain experimental, especially for male breast cancer at this time.

Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in men. Ann Intern Med 137 (8): 678-87, 2002.

Giordano SH: A review of the diagnosis and management of male breast cancer. Oncologist 10 (7): 471-9, 2005

Athanassios Argiris, Chun-Xia Wang, Steve G. Whalen and Michael P. DiGiovanna
Synergistic Interactions between Tamoxifen and Trastuzumab (Herceptin) Clinical Cancer Research Vol. 10, 1409-1420, February 2004

A. Vazquez-Martin, R. Colomer, S. Ropero, J. Abel Menendez, A. Argiris, C.-X. Wang, D. C. Koay, and M. P. DiGiovanna
Growth and Molecular Interactions between Tamoxifen and Trastuzumab
Clin. Cancer Res., May 1, 2005; 11(9): 3597 - 3597.

A. Jones Combining trastuzumab (Herceptin®) with hormonal therapy in breast cancer: what can be expected and why? Annals of Oncology 14:1697-1704, 2003

Cytochrome P450 in cancer chemotherapy

The majority of human P450-dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced metabolism. The latter situation is due to stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes. An updated list of variant CYP alleles is present at the Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/). Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. Dosage requirements for several commonly used drugs that have a narrow therapeutic range can differ more than 20-fold dependent on the genotype or the enzyme expression status.

Unfortunately, clinical use is in its infancy. Until simpler and more rapid tests become commercially available, phenotyping may remain largely a research tool, or one with applicability limited to special populations likely to have significantly abnormal  activity, particularly those patients who are suspected to have liver disease, declining hepatic function, or who may be receiving inducers or inhibitors of CYP3A4.

E. D. Kharasch, K. E. Thummel, and P. B. Watkins
CYP3A Probes Can Quantitatively Predict the In Vivo Kinetics of Other CYP3A Substrates and Can Accurately Assess CYP3A Induction and Inhibition
Mol. Interv., June 1, 2005; 5(3): 151 - 153.

Noboru Yamamoto, Tomohide Tamura, Haruyasu Murakami, Tatsu Shimoyama, Hiroshi Nokihara, Yutaka Ueda, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Tetsuro Kodama, Mikiko Shimizu, Kazuto Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous CortisolRandomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol JCO 2005 23: 1061-1069 

Male Brest Cancer

Tamoxifen is standard of care for male breast cancer. Hormonal therapy, chemotherapy, or a combination of both have been used with some success. Initially, hormonal therapy is recommended.

Hormonal modalities include:

Orchiectomy.
Luteinizing hormone-releasing hormone agonist with or without total androgen blockage (antiandrogen).
Tamoxifen for estrogen receptor–positive patients.
Progesterone.
Aromatase inhibitors.
Hormonal therapies may be used sequentially. Standard chemotherapy combinations of CMF and CAF are recommended after failure of hormonal therapy. Responses are generally similar to those seen in women with breast cancer. Use of Herceptin was played up in the media in high profile cases but is not well supported by credible literature.
Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in men. Ann Intern Med 137 (8): 678-87, 2002.

Giordano SH: A review of the diagnosis and management of male breast cancer. Oncologist 10 (7): 471-9, 2005.

Intrapleural chemotherapy

Intrapleural chemotherapy is given through large or small chest catheters that may be connected to an implantable port. These catheters can be used to give drugs as well as to drain fluid that often accumulates in the pleural or peritoneal cavity when cancer has spread to these areas. Malignant pleural effusion (MPE) is a common and life-threatening problem in patients with advanced malignancies. In most cases, MPE is controlled by tube drainage combined with pleurodesis and the intrapleural instillation of various sclerosing or chemotherapeutic agents. Most reports on intrapleural chemotherapy are dated and consist of case reports and case series. There are no propective studies and it is not known how it performs aganst pleurodysis or systemic chemotherapy alone.

Erasmus, Jeremy J. MD; Patz, Edward F. Jr MD Treatment of malignant pleural effusions. Current Opinion in Pulmonary Medicine. 5(4):250, July 1999.

Tan, A. Sedrakyan, J. Browne, S. Swift, and T. Treasure
The evidence on the effectiveness of management for malignant pleural effusion: a systematic review.
Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 829 - 838.

Weekly adjuvant Taxol after AC

The evidence for weekly paclitaxel comes from ECOG 1199 trial, a randomized trial of doxorubicin and cyclophosphamide (AC) chemotherapy followed by 1 of 4 taxane-based treatments -- paclitaxel given either weekly or every 3 weeks, or docetaxel given either weekly or every 3 weeks.

Consistent with previous reports, the updated data showed that most of these regimens could be delivered effectively; only weekly docetaxel was associated with < 80% dose delivery. The side-effect profiles of the various treatments differed in ways predictable from extensive use of these regimens in breast cancer. For example, every-3-weeks docetaxel produced the highest rates of neutropenia and febrile neutropenia, whereas weekly paclitaxel had the highest rate of neuropathy.

The primary study end point was a comparison of paclitaxel vs docetaxel and a comparison of weekly vs every-3-weeks therapy, based on the 2 x 2 randomization scheme. The primary end points were all negative -- that is, there was no overall difference between the taxanes or the schedules in the aggregate.

However, analysis of each of the 4 treatment arms does suggest emerging winners and losers. In particular, weekly paclitaxel and every-3-weeks docetaxel had the lowest rates of disease recurrence, whereas weekly paclitaxel had the highest 5-year overall survival and was the only treatment with statistically significant improvement in overall survival compared with every-3-weeks paclitaxel.

This is now one of several trials that has shown that the every-3-weeks schedule of AC followed by paclitaxel (P) (AC → P) is an inferior treatment program. In CALGB 9741, every-2-weeks AC → P was shown to be superior to an every-3-weeks regimen.

1. Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in operable breast cancer: results of Intergroup Trial E1199. Proc Am Soc Clin Oncol. 2007;25:6s. Abstract 516.
2. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439. Abstract
3. Loesch DM, Greco F, O'Shaughnessy J, et al. A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer. Proc Am Soc Clin Oncol. 2007;25:7s. Abstract 517.
4. Verill MW, Lee J, Cameron DA, et al. Anglo-Celtic IV: first results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC). Proc Am Soc Clin Oncol. 2007;25:33s. Abstract LBA1005.

Ca-125 for breast cancer

CA-125 is an important part of the workup for suspicious adnexal massess and for for following treated ovarian cancer. It is not a common marker in clinical use for breast cancer and  not much is known about it. In one recent study, thirty-three patients had increasing or continuously high concentrations of CA 125. Thirty (91%) of these had involvement of the pleura, either as pleural metastasis or metastasis in surrounding tissue i.e. bone structures in the thorax cavity or lung parenchyma. MUC1 and CEA were elevated in 27 (82%) and 24 (73%) of the 33 patients, respectively. Increased concentrations of these two markers did not relate to the site of metastasis. However, the three tumor markers complemented each other in detecting early metastases. Increased CA 125 was associated with metastasis in or near the pleura, and in stage IV breast cancer it was related to poor prognosis. Another study suggested that it can be elevated with any cancer that involves pleural surface, just like ovarian cancer involves peritoneal surface. As such, Ca-125 can be potentially misleading if used as marker for breast cancer.

Samuel S et al, .Validation of Referral Guidelines for Women With Pelvic Masses
Obstetrics & Gynecology 2005;105:35-41

Amy C. Dearking et al, How Relevant Are ACOG and SGO Guidelines for Referral of Adnexal Mass?Obstetrics & Gynecology 2007;110:841-848

Lars F. Noruma et al, Elevated CA 125 in Breast Cancer - A Sign of Advanced Disease Tumor Biology Vol. 22, No. 4, 2001   

D. Shitrit, B. Zingerman, A. B.-G. Shitrit, D. Shlomi, and M. R. Kramer
Diagnostic Value of CYFRA 21-1, CEA, CA 19-9, CA 15-3, and CA 125 Assays in Pleural Effusions: Analysis of 116 Cases and Review of the Literature
Oncologist, August 1, 2005; 10(7): 501 - 507.

Atypical hyperplasia: preventing development of breast cancer

You have atypical ductal hyperplasia, a condition which raises a risk of cancer but is not in itself cacner. As such, it does not fit the guidelines criteria to approve BRCA testing on the absis of the eprsonal hsitory of breast cacner. In fact, this condition is known to be prophylaxed by the sue of tamoxifen, which is also an option for BRCA carriers. However, other BRCA options, such as prophylactic mastectomy and oophorectomy are not routinely performed for atypical ductal hyperplasia. Performing BRCA testing is not idicated for prevention of this condition.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study report ed a nearly a 57% increase in invasive cancer compared to patients without atypical hyperplasia (10.11 events per 1,000 patients vs 6.44 events per 1,000 patients) with a mean follow-up of 47.7 months.

The most extensive evaluation of chemoprevention agents has been with tamoxifen. Tamoxifen, a selective estrogen receptor modulator (SERM), inhibits the binding of estrogen to estrogen receptors and also acts as an agonist on bone, the uterus, and liver. The data from multiple, randomized studies have supported the use of tamoxifen for prevention of breast cancer in high-risk individuals. The largest of these studies, the Breast Cancer Prevention Trial (NSABP P-1), compared tamoxifen to placebo in over 13,000 women with a Gail model score ≥ 1.66%. The study was halted early due to a 49% reduction of invasive breast cancer. More specifically, tamoxifen reduced the risk of breast cancer in LCIS patients by 56% and in atypical hyperplasia patients by 86%. It is interesting that tamoxifen preferentially decreased the incidence of estrogen receptor (ER)-positive tumors, a common finding of atypical hyperplasia and LCIS.[61,62] In addition, there was a 50% reduction in the incidence of noninvasive cancers in the tamoxifen arm. Adverse outcomes due to tamoxifen, such as increased risk of endometrial cancer and thromboembolic events, were reported (risk ratio of 2.53 for endometrial cancer and 3.01 for pulmonary embolism).

A smaller reduction was noted in the International Breast Cancer Intervention Study (IBIS-I) in which a 32% risk reduction was noted after 50 months in patients with a greater than twofold relative risk of breast cancer. Two additional European studies, the Royal Marsden Hospital study and the Italian study, have failed to demonstrate a statistical benefit toward tamoxifen, but many believe that differences in patient selection, poor compliance, and insufficient power account for the differences. A further meta-analysis of these four trials produced a 38% reduction in the incidence of breast cancer and decreased ER-positive tumors by 48%.

Raloxifene
Raloxifene, a second-generation SERM, is similar to tamoxifen in its effects on breast, bone, and liver. However, raloxifene is not an estrogen agonist on the uterus. The initial study, the Multiple Outcomes of Raloxifene Evaluation (MORE), primarily evaluated osteoporosis with a secondary endpoint of breast cancer incidence. A 76% decrease in breast cancer incidence was noted in the raloxifene group compared to placebo over 4 years. The Continuing Outcomes Relevant to Evista (CORE) trial further evaluated raloxifene after 4 additional years of use, for a total of 8 years. A 66% reduction was noted in the raloxifene arm of the study. The results of these trials led to the NSABP STAR P-2 trial where 5 years of raloxifene was compared head-to-head with 5 years of tamoxifen in high-risk, postmenopausal individuals. Raloxifene could not be administered to premenopausal women secondary to increased incidence of ovarian cyst. In approximately 20,000 randomized patients, there were no statistical differences in invasive breast cancer incidence between the two groups (P=.83). Compared with tamoxifen, the raloxifene arm had fewer in the number of uterine cancers (P=.07), thromboembolic events (P=.01), and cataracts (P=.002). These results support the use of raloxifene as an alternative to tamoxifen. It is important to note that the incidence of noninvasive cancer was lower in the tamoxifen arm although this was not statistically significant (P=.052).

1. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360:817-824.
2. Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101.
3. Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cannncer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998;352:93-97.
4. Bao T, Prowell T, Stearns V. Chemoprevention of Breast cancer: tamoxifen, raloxifene, and beyond. Am J Ther. 2006;13:337-348.
5. Cuzick, J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296-300.
6. Cummings SR, Eckert S, Krueger KA, et al. The effect on raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Mutiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-2197. Erratum in: JAMA. 1999 Dec 8;282(22):2124.
7. Martino S, Cauley JA, Barrett-Conner E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96: 1751-1761.