Becky you are right about the article being re prevention rather than treatment. I had not appreciated that -sorry - but.....
But are they not part of the same string in a sense.
From memory the figures I have seen for tamoxifen v RT and boost are not that high benifit 1/2 % per annum see below.
As I recall I spent ages trying to find stats for Tamoxifen v RT and boost and without much success.
The situation with chemo is different but how much of that is down to chemical ablation in chemo."Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen." E.g. how were women chosen to receive tamoxifen ?- was their treatment influenced by whether they had of had no gone through meonpause QOL issues etc?. IF there was an imbalance in the number in both groups who acheived menopause would that have skewed the results.
My comment on who is included and not included in meta trials holds, and was based on comments posted by those in the medicial industry. The assumption was made on one meta-trial that on the non treatment arm any breast cancer recurrence = a death from BC which is a pretty large jump as re-treatment locally is possible.
I also failed to find stats on long term survival bentifs for tamoxifen over RT and boost.
Tamoxifen with chemo produces the best results but is the amenoreha due to chemical ablation sufficently seperated as a factor.
So many questions particularly for those premenopausal women who have to make QOL decisions.
And that in essence is my moan - how can patients make these decisions without better and clearer stats - if they are available please where??
If anybody can answer theses questions and shoot me down please do. I just seek answers and will be please to post a bright red smiley for raising unnecessary concerns.
Here is most of my tamoxifen collection of odds and ends so they are all in one place in case of help to anybody.
RB
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93.
* Colleoni M,
* Gelber S,
* Goldhirsch A,
* Aebi S,
* Castiglione-Gertsch M,
* Price KN,
* Coates AS,
* Gelber RD;
* International Breast Cancer Study Group.
Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
marco.colleoni@ieo.it
PURPOSE: The value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer has not been adequately assessed. PATIENTS AND METHODS: Between 1993 and 1999, International Breast Cancer Study Group Trial 13-93 enrolled 1,246 assessable premenopausal women with axillary node-positive, operable breast cancer. All patients received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for four courses followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil for three courses), which was followed by either tamoxifen (20 mg daily) for 5 years or no further treatment. The primary end point was disease-free survival (DFS). Tumors were classified as estrogen receptor (ER) -positive (n = 735, 59%) if immunohistochemical (IHC) or ligand-binding assays (LBA) were clearly positive. The ER-negative group included all other tumors (n = 511, 41%). A subset of the ER-negative group was defined as ER absent (n = 108, 9%) if IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. The median follow-up time was 7 years. RESULTS: Tamoxifen improved DFS in the ER-positive cohort (hazard ratio [HR] for tamoxifen v no tamoxifen = 0.59; 95% CI, 0.46 to 0.75; P < .0001) but not in the ER-negative cohort (HR = 1.02; 95% CI, 0.77 to 1.35; P = .89). Tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen in an unplanned exploratory analysis (HR = 2.10; 95% CI, 1.03 to 4.29; P = .04). Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen. CONCLUSION: Tamoxifen after adjuvant chemotherapy significantly improved treatment outcome in premenopausal patients with endocrine-responsive disease, but its use as adjuvant therapy for patients with ER-negative tumors is not recommended.
PMID: 16505417 [PubMed - indexed for MEDLINE]
NSABP B-21, 2002 (1989-98) - Node negative <1 cm tumors - randomized to tamoxifen alone, RT alone, or tamoxifen + RT
o 1009 women. Lumpectomy + AND. ER/PR status not required but was available for 70%
o PMID 12377957 — "Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less." Fisher B et al. J Clin Oncol. 2002 Oct 15;20(20):4141-9.
At 8 years, ipsilateral breast recurrence in 16.5% (TAM), 9.3% (XRT), 2.8% (T/RT). (That is, about 0.5% / year for T/RT). No difference in DM. Contralateral breast cancers in 5.4% (XRT without TAM) vs 2.2% (TAM +/- RT). XRT alone group had fewer IBTR than the TAM group for both ER+ and ER-. In ER+ tumors, adding TAM to RT resulted in a N.S. lower rate of IBTR. Adding RT to TAM resulted in a lower IBTR rate for both ER+ and ER-.
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial.
* Houghton J,
* George WD,
* Cuzick J,
* Duggan C,
* Fentiman IS,
* Spittle M;
* UK Coordinating Committee on Cancer Research;
* Ductal Carcinoma in situ Working Party;
* DCIS trialists in the UK, Australia, and New Zealand.
Clinical Trials Group, Department of Surgery, Royal Free and University College Medical School, Charles Bell House, London W1W 7EJ, UK.
j.houghton@ctg.ucl.ac.uk <j.houghton@ctg.ucl.ac.uk>
BACKGROUND: As a consequence of mammographic breast screening programmes, ductal carcinoma in situ is diagnosed with increasing frequency. Mastectomy for localised ductal carcinoma in situ is thought to be an over-treatment by many physicians, but there is much controversy as to whether complete local excision alone is sufficient. We aimed to assess the effectiveness of adjuvant radiotherapy and tamoxifen. METHODS: We used a 2x2 factorial design in a randomised controlled trial. Between May, 1990, and August, 1998, 1701 patients recruited from screening programmes were randomised to both treatments in combination or singly, or to none, or to either one (eg, radiotherapy) with an elective decision to give or to withhold the other (ie, in this case tamoxifen). Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology. Patients have been followed up at least once a year. Median follow-up was 52.6 (range 2.4-118.3) months. Our primary endpoint was the incidence of ipsilateral invasive disease. FINDINGS: Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall ductal carcinoma in situ was decreased (hazard ratio 0.68 [0.49-0.96]; p=0.03). Radiotherapy reduced the incidence of ipsilateral invasive disease (0.45 [0.24-0.85]; p=0.01) and ipsilateral ductal carcinoma in situ (0.36 [0.19-0.66]; p=0.0004), but there was no effect on the occurrence of contralateral disease. There was no evidence of interaction between radiotherapy and tamoxifen. INTERPRETATION: Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women.
PMID: 12867108 [PubMed - indexed for MEDLINE]
http://www.breastcancer.org/research...ry_013105.html
Background and importance of the study: Compared to lumpectomy alone, lumpectomy followed by radiation has been shown to greatly reduce the risk of cancer coming back in the same breast—by about two thirds, or 66%. Hormonal therapy can reduce the risk of recurrence by about 30% to 50%. But doctors have long questioned whether all women need both radiation and hormonal therapy. In particular, they are trying to figure out whether some women with early-stage breast cancer might not need radiation—for example, women with:
Other Articles in this Edition
• small tumors (less than two centimeters, or about an inch) and
• negative lymph nodes (no cancer cells found in the nodes).
http://professional.cancerconsultant....aspx?id=32736
The current French trial randomly allocated 338 women 65 years of age or older with node-positive breast cancer to receive adjuvant tamoxifin alone or tamoxifen plus an epirubicin-based adjuvant chemotherapy regimen. Approximately 50% of the patients were over the age of 70 years and 60% had 1-3 positive lymph nodes. The 6-year relapse rate was 31% for the tamoxifen alone group and 27% for the chemotherapy group. Local relapses occurred in 6.8% of tamoxifen-alone patients, compared to 2.2% in the chemotherapy group. Overall 6-year survival was 75.8% for the tamoxifen alone group and 75.4% for the chemotherapy group. The authors reported no episodes of heart failure prior to recurrence, but reported 8 cases of decrease in LVEF. These authors stated that more studies are needed to determine which patients might benefit from adjuvant chemotherapy.
http://professional.cancerconsultant....aspx?id=31354
NSABP Presents Long-Term Follow-up of Node-Negative, Estrogen Receptor-Positive Breast Cancer Patients
The long-term follow-up of two randomized clinical trials of women with localized breast cancer performed by the National Surgical Adjuvant Breast and Bowel Projects (NSABP) was published in the September 4, 2004 issue of the Lancet.1
The first trial (B-14) showed that all ages of women with node-negative, estrogen receptor-positive breast cancer benefited from 5 years of adjuvant tamoxifen. The second trial (B-20) showed that adding chemotherapy to tamoxifen improved disease-free survival and overall survival in younger, but not older, patients with node-negative, estrogen receptor-positive breast cancer.
Between 1982 and 1988, the B-14 trial randomly allocated almost 3,000 women with node-negative, estrogen receptor-positive breast cancer to receive 5 years of tamoxifen or placebo. Table 1 summarizes the major findings of the B-14 trial at 15 years:
Table 1: 15-year Follow-up of B-14 Trial
Disease-Free Survival Overall Survival
Placebo 65% 65%
Tamoxifen 78% 71%
Disease-free survival was improved for all age groups with tamoxifen and survival was improved in all age groups except the 50-59 age group, where the difference was not statistically significant. These authors reported more benefit in women with a higher estrogen receptor population.
Between 1988 and 1993, the B-20 trial randomly allocated over 1,500 women with node-negative, estrogen receptor-positive breast cancer to receive 5 years of tamoxifen or 5 years of tamoxifen plus CMF adjuvant chemotherapy. Table 2 summarizes the major findings of the B-20 trial at 12 years:
Table 2: 12-year Follow-up of B-20 Trial
Disease-Free Survival Overall Survival
Tamoxifen 79% 83%
Tamoxifen plus CMF 89% 87%
They also reported that women aged 49 years or younger benefited the most from chemotherapy, while in women over the age of 60 years, there was no advantage in DFS or OS for the adjuvant chemotherapy group. There was also the suggestion that women with lower concentrations of estrogen receptors benefited more from chemotherapy.
http://professional.cancerconsultant....aspx?id=29143
In this current study, 1701 women with DCIS were randomly allocated to receive surgery alone, surgery plus radiation therapy, surgery plus tamoxifen, or surgery plus radiation therapy and tamoxifen. The median follow-up was 52.6 months. The rates of recurrence of DCIS or invasive cancer were 22% for no adjuvant therapy, 18% for tamoxifen alone, 8% for radiation alone, and 6% for combined radiation and tamoxifen. The overall rate of recurrence of DCIS or invasive cancer for those receiving tamoxifen was 14% compared to 18% for those not receiving tamoxifen. Radiation therapy reduced the ipsilateral combined DCIS and invasive cancer rate from 14% to 6% with essentially no impact on the 2% contralateral recurrence rate. The authors stated that there were too few deaths to use survival as an endpoint in this study. Eight gynecologic tumors occurred in this study and 7 of these had received tamoxifen. These researchers concluded that “Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women.”
Comments: This study confirms that radiation therapy following local surgery prevents recurrence of ipsilateral DCIS. However, this treatment is unlikely to improve survival in this group of women and longer follow-up will be needed to determine if there are harmful effects. The most controversial part of this study was the apparent lack of effect of tamoxifen in preventing local and distant recurrences. This result is at odds with other adjuvant studies in DCIS and invasive breast cancer where the addition of tamoxifen or an aromatase inhibitior has been beneficial. It is likely that in the US, women who have hormone receptor positive DCIS or localized invasive breast cancer will receive tamoxifen or more likely an aromatase inhibitor.
http://www.thelocal.se/article.php?I...&date=20050901
A drug prescribed to more than half of all patients suffering from breast cancer can in some cases actually stimulate tumour growth and increase the likelihood of a relapse, Swedish researchers said on Thursday.
The drug, tamoxifen, has since the 1970s been widely prescribed to fight breast cancer since it has shown to counteract the cancer-promoting effects of estrogen in the breast by binding itself to the estrogen receptor in the cancerous cell, thus impeding tumour growth.
According to new research conducted at the Malmö University Hospital, UMAS, in southern Sweden however, the drug can have the opposite effect on certain types of tumours.
"The result shows that tamoxifen is a very efficient treatment for most patients. But for 15 percent of tumours that contain many copies of the cell-splitting gene cyclin D1 tamoxifen however appears to have the opposite effect," researcher Karin Jirström said in a statement.
The study conducted by Jirström and her colleagues was based on examinations of patients from southern Sweden who had been treated with the drug. It was recently published in the US medical journal Cancer Researcher.
Sean Bydder a, Nigel Spry a, David J Joseph a and Hany Elsaleh a
Sir
The method used by the EBCTCG1 to define cause of death: “all deaths after recurrence were classified as breast cancer deaths”, is potentially flawed. This assumes that no recurrences are salvageable, which may be untrue, especially for the breast conservation trials. Patients who develop a local recurrence within a conserved breast, have a quite different outlook to women who develop metastatic disease as their first relapse. Because radiotherapy reduces the recurrence rate by a third, the proportion of patients in the control groups whose cause of death is misclassified by this assumption is much larger than in the radiotherapy groups. Because the percentage difference in breast cancer deaths was relatively small (18•6% vs 21•3%), this classification procedure alone could account for the difference.
http://www.nci.nih.gov/cancertopics/...e7#Section_261
The meta-analysis showed that the reduction in risk of recurrence was similar in the presence or absence of tamoxifen, irrespective of age (younger than 50 years vs. 50-69 years), though the result did not attain statistical significance in women younger than 50 years at randomization. This finding, however, is most likely due to the relatively small number of younger women in trials of combined chemoendocrine therapy.
http://www.nci.nih.gov/cancertopics/...e7#Section_261
Tamoxifen toxic effects
The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is 2 times to 7 times greater than that observed in untreated women.[91-94] Women taking tamoxifen should have routine follow-up pelvic examinations and should be evaluated further if they experience any abnormal uterine bleeding. Although one retrospective study raised concern that endometrial cancers in women taking tamoxifen (40 mg/day) had a worse outcome and were characterized by higher-grade lesions and a more advanced stage than endometrial cancers in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 mg/day) have not supported this finding.[91,95,96] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer randomized to receive tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range, 3-75 months; median, 24 months), while no cases occurred on the control arm.[97] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[98,99] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.[100]
Tamoxifen is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[79,87,88,101,102] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen.[103] The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen may also be associated with an increased risk of strokes.[102,104,105] In the NSABP Breast Cancer Prevention Trial, this increase was not statistically significant.[104]
Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[106] Physicians should be aware of this toxic effect during the annual pelvic examination that should be performed for all women receiving tamoxifen. The relationship between tamoxifen and ovarian tumors requires further study.[107] Short-term toxic effects of tamoxifen may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation).[108] Clonidine can ameliorate hot flashes in some patients.[109]
Ophthalmologic toxic effects have been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[110-112] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug.
Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[113,114] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than for women taking it for 2 years.[115] In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone.[114] In the NSABP B-14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant.[116] To date, 3 large controlled trials have shown a decrease in heart disease.[114-116]
Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[117-119] In premenopausal women, decreased bone mineral density is a possibility .[120]
http://www.nlm.nih.gov/medlineplus/n...ory_26734.html
Many also worry that the drugs are being overused, and that side effects are being downplayed.
"My impression is that the oncology community has jumped on this category of drugs in lieu of tamoxifen in a huge number of people much too quickly," said Dr. Steven Goldstein, a professor of obstetrics and gynecology at New York University School of Medicine. "When aromatase inhibitors first came out and were tested, it was stage 3 and 4 women. Survival was clearly better than with tamoxifen. Now they're giving it to all these women with stage 1 and stage 0 cancer, who are likely to be cured, and they have no long-term data."
http://www.news-gazette.com/localnew...m?Number=19015
Women with breast cancer tumors are routinely tested for the presence of estrogen receptor protein as an indicator of whether they will respond to commonly used treatments. Tamoxifen and other "anti-estrogen" compounds, which reverse the stimulatory actions of estrogen, and aromatase inhibitors, which curtail production of estrogen, act through the receptor protein.
But only about 60 percent of women whose tumors test positive for the receptor will actually respond to treatment with tamoxifen and its relatives or to aromatase inhibitors.
http://www.jco.org/cgi/content/abstract/9/7/1283
Journal of Clinical Oncology, Vol 9, 1283-1297, Copyright © 1991 by American Society of Clinical Oncology
________________________________________
ARTICLES
Tamoxifen in premenopausal patients with metastatic breast cancer: a review
MC Sunderland and CK Osborne
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7884.
The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (less than 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration.
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