Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

Undergoing chemotherapy can be one of the most terrifying things that you go through in your life. One of the most frightening things about chemotherapy is the lack of real information that most people have about it, and the unknown makes it so much more frightening as a result. This eBook, written by a young cancer survivor gives you the real story about what chemo is all about. The most valuable information you can get about chemotherapy is from someone that has already experienced it. This PDF eBook allows you to download and read it as soon as your order it. You can begin your journey of reassurance as soon as you want! Because that's what this is about: chemo does not have to be a terrifying unknown! Other people have gone through it before, and want to help you through it as well! This eBook is the guide through chemo that many people wish they could have had, and now you can have it yourself! More here...

Chemo Secrets From a Breast Cancer Survivor Overview


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Palliative Chemotherapy

CHEMOTHERAPY TRIALS SINGLE AGENTS AND COMBINATION THERAPY Chemotherapy as the sole modality of treatment for head and neck cancer has been limited to almost exclusively recurrent or persistent disease after failure of primary locoregional therapy. In this setting, the goal of treatment is limited to palliation, as no improvement has been demonstrated for either disease-specific or overall survival.1,4-10 Treating recurrent or metastatic head and neck cancer is much different than treating a naive tumor. Previous therapy usually diminishes the effectiveness of chemotherapy by 30 to 50 .11 Theories to explain this include more hypoxic cells, decreased blood flow to the tumor, and chemical resistance.1,5,11,12 The difference in effectiveness can easily be seen when comparing the complete and partial responses achieved with induction (neoadjuvant) chemotherapy (30 to 92 )12-17 to the response rate of palliative treatment for recurrences (10 to 40 ).4-10,13 This section discusses...

Therapeutic Chemotherapy

Radiotherapy has proved effective in head and neck cancer. Its mechanism of cell killing is postulated to be mediated by the direct interaction of superoxide radicals with cellular enzymes and DNA, indicating that adequate oxygen content of the tumor is necessary for efficacy of this treatment.35 In addition, radiotherapy has been found to be most effective during the G2 and M stages of the cell cycle. Adding chemotherapy to radiation has several theoretical benefits. Chemotherapy can prevent the repair of sublethal damage inflicted by ionizing radiation. Certain drugs act as sensitizers (e.g., 5-FU) and improve the effect of radiation on tumors. Some drugs are particularly toxic to hypoxic cells (mitomycin C) and thus can target a population that is radioresistant. Both cause apoptosis, probably by different mechanisms, so each potentiates the other.12 Chemotherapy often causes growth arrest of cells at a certain part of the cell cycle, allowing them to be more sensitive to...

Adjuvant Chemotherapy

The idea behind adjuvant treatment is to eliminate any micro-metastatic disease left behind after locoregional treatment. One benefit of administering chemotherapy after surgery or radiation, or both, is that the tumor is addressed with definitive therapy first, unlike neoadjuvant therapy, where it is delayed. Also, as no chemotherapy is given preoperatively, there is no decrease in the patient's nutritional, immunologic, hematologic, or general health status. The disadvantages are that the vascularity has been interrupted, so theoretically less of the drug will get to the residual cancer. Also, these patients have already been disabled by the initial treatment and are unlikely to be compliant with a further decrease in their performance status. Two trials have shown a significant improvement in survival rates for those who underwent adjuvant therapy.49'68 Unfortunately, these patients also had concomitant chemo- and radiotherapy, so no definite conclusion can be made. Of the many...

Intraarterial Chemotherapy

An exciting prospect in the delivery of chemotherapy is the intra-arterial route. The advantages include directly perfusing the tumor with the drug, thereby not losing efficacy to the firstpass effect. Also, when cisplatin is used, sodium thiosulfate can be given systemically to neutralize the cisplatin by covalently binding to it once it has passed out of the tumor vascular bed. This should allow decreased side effects, including mucositis and nephrotoxicity. The additional risks revolve around the arterial puncture and possible vascular and cerebrovascular events. The main argument against intra-arterial chemotherapy is the increase in complication rates without a significant benefit in survival rates. With the addition of the neutralizing agent, the severe grade 3 and 4 mucositis has decreased, as well as

Chemotherapy for Recurrent or Metastatic Disease

Chemotherapy was initially used for palliation of advanced, unresectable tumors, and systemic disease. Numerous agents have been found to have activity in this setting, including methotrexate, bleomycin, 5-fluorouracil (5-FU), cisplatin, and carboplatin, with response rates ranging from 10 to 35 . Most of these responses are partial, and few are lasting, with median duration of only 4 to 6 months.3,4 Methotrexate has been used most extensively and despite numerous phase II trials, no other single agent has demonstrated a clear superiority over this drug. One trial has reported an improved response and survival benefit using cisplatin, but the numbers treated and the improvement in overall survival (approximately 2 months) were small.5 Newer agents being investigated include the topoisomerase inhibitor, topotecan, and the pyrimidine antimetabolite, gemcitabine. Trials to date have reported modest response rates. Some encouraging results have been seen with the tax-anes, paclitaxel and...

Chemotherapy for Advanced Resectable Disease

Although the success of chemotherapy in unresectable disease has been modest, encouraging results have been achieved in the setting of locally advanced primary disease. Although the primary goal of cancer therapy remains cure or prolonged survival, an important secondary goal of the use of chemotherapy is the reduction of the morbidity of treatment. In the head and neck, this takes the form of preservation of the organs of speech and swallowing. Three general approaches have been used, alone or in combination induction therapy, adjuvant therapy, or chemotherapy concomitant with primary radiation.

Induction Chemotherapy

Induction chemotherapy is given before definitive local therapy in an attempt to downstage local disease and make it more amenable to local therapy, to improve both local recurrence rates, and to treat microscopic systemic disease. This approach is attractive in that the drug is delivered to the tumor bed before it has been interfered with by surgery or radiotherapy and is delivered before the cells have had the chance to develop resistance to therapy. Preliminary studies from single institutions using this approach reported response rates as high as 90 with cisplatin-based regimens, with 40 complete response (CR) rates. Two-thirds of these had a pathologic CR. When followed with definitive radiotherapy, it was found that the response to induction chemotherapy was predictive of the subsequent response to radiation, and ultimately with survival. Several randomized controlled trials of chemotherapy given before surgery14-18 and before radiation19'20 have been reported. The first of...

Option 1 Randomize patients between the three chemotherapy options initially and carry out the second randomization at

This option follows the clinical course of events most closely, and ensures that only those patients to whom the question is relevant are randomized. The 'stop or continue' question was relevant to all the chemotherapy regimens, and any difference in survival in the two arms was not expected to differ across the chemotherapy arms (i.e. no interaction between chemotherapy regimen and duration was anticipated). Thus there appear no obstacles to the planned analysis of survival time (measured from the date of the second randomization) according to stop or continue. In fact this is generally true of the last randomization in any trial involving multiple randomizations. The potential problems are generally limited to the interpretation of the earlier randomizations. Here, entry to the second randomization would depend upon response to the initial chemotherapy regimen. As response rates associated with the different regimens might well vary, the proportion of patients in each chemotherapy...

Twenty First Century View of Tamoxifen as a Treatment for Breast Cancer

The impact of the clinical introduction of tamoxifen on healthcare can be assessed through the work of the Early Breast Cancer Trialists Collaborative Group (EBCTCG) that meets in Oxford, UK every 5 years. The international group has met since 1984 to evaluate the impact of therapies on the treatment of breast cancer. The method is to integrate the positive and negative findings of all the world's randomized prospective clinical trials to reach a consensus on the merits of a treatment approach. Reports on the value of long-term adjuvant tamoxifen therapy in the treatment of node-positive and node-negative estrogen receptor-positive breast cancer can be documented through the EBCTCG publications.138-140 Overall, the reports document the enhanced survival and disease-free survival conferred by tamoxifen. The recent report by the EBCTG141 analyzes the results from 145 000 women in 194 trials of chemotherapy or hormonal therapy begun before 1995. The treatment of estrogen...

Tamoxifen and Breast Cancer Prevention

Adjuvant tamoxifen could prevent contralateral breast cancer in women,201 provided a rationale for Powles to start a toxicology study at the Royal Marsden Hospital, London, UK to test whether tamoxifen would be acceptable to prevent breast cancer in high-risk women. This vanguard study opened for recruitment in 19 8 6202 and was to provide important toxicological and compliance data for subsequent trialists. In the decade following the Powles initiative, several studies were started to answer the question ''Does tamoxifen have worth in the prevention of breast cancer in select high-risk women '' Eventually four studies were available to evaluate the veracity of the question - the Royal Marsden study, the NSABP NCI study, the Italian study, and the International Breast Intervention Study (IBIS). The results have been adequately summarized by Cuzick and coworkers203 but the NSABP Study will be presented in detail because it was the only prospective study to achieve its recruitment goal....

Breast Cancer Adjuvant Therapy

Chemotherapy is traditionally initiated six weeks postoperatively. This allows the tissue time to heal prior to the immunosuppression associated with chemotherapy. Chemotherapy was historically reserved for patients with a poor prognosis. This included patients with greater than 4 positive nodes, primary tumors greater than 4 cm, a grade III tumor, or any tumor with lymphatic or vascular invasion. All of these imply systemic spread of tumor. Neoadjuvant chemotherapy is used in women who desire breast conservation but have large primary tumors. Preoperative chemotherapy has been shown to decrease the size of the primary tumor and, also, the incidence of positive nodes with no change in systemic recurrence.1 Chemotherapy can be divided into cytotoxic, hormonal, and molecular. Cyto-toxic chemotherapy is the classic chemotherapy and includes four main drugs. The classic therapy is CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Adriamycin (doxorubicin) is sometimes added or...

Of Familial Breast Cancer Genetic Consultations

Butow and Lobb (2004) conducted a major study, examining in detail the process and content of genetic counselling in initial consultations with women from high-risk breast cancer families. Over 158 consultations of women unaffected and affected with breast cancer, conducted in 10 familial breast cancer clinics throughout Australia, were audiotaped and transcribed. A detailed coding system was developed to cover all facts thought to be important to be elicited from or conveyed to the consultant, and all behaviours thought to facilitate active involvement and expression of emotional concerns. This analysis evidenced that the average genetic counselling session was 61 min comparable to that of European clinics (Hopwood et al. 2003a) , that patients spoke on average one-third of the session and consultants demonstrated consistently good practice in providing detailed information on essential aspects related to familial breast cancer. The authors noted that, although the woman's agenda was...

Raloxifene and Breast Cancer Prevention

The rationale for the use of SERMs, including raloxifene, as breast cancer preventives is based on a strategic hypothesis formulated when SERM action was first recognized in the late 1980s. The evidence to support the use of raloxifene in this paradigm stems from observations made in the laboratory91,96 and the clinic165 along with close monitoring of ongoing osteoporosis placebo-controlled trials. Previous studies have shown that raloxifene inhibits the growth of dimethylbenzanthracene-induced rat mammary carcinoma94 but it prevents mammary cancer by reducing the incidence of N-nitrosomethylurea-induced tumors91'92 if given after the carcinogen but before the appearance of palpable tumors. However, as would be anticipated with a drug that has a short biological half-life, raloxifene is not superior to tamoxifen at equivalent doses.91 Studies have shown that raloxifene, when administered orally, is rapidly absorbed from the gastrointestinal tract and undergoes extensive phase II...

E Paclitaxel intravenously 175 mg m2 on days 1 and 8 of 21 day cycle reported in control arm of phase III breast cancer

An additional hurdle for all chemotherapies is adapting the preclinical dosing regimen to the clinic. Efficacy doses for oncology drugs are determined in rodents (usually mice), and maximum tolerated doses are determined in mice, rats, dogs, or other species as warranted by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the drug in discovery phase. Again, due to differences in metabolism between species, the predictive ability of these models is limited. For example, preclinical evaluation of gemcitabine found it to have antitumor activity in several tumor xenografts, including breast (MX-1), colon (CX-1, HC-1, and GC3), NSCLC (Calu-6, LX-1, and NCI-H460), and pancreas (HS766T, PaCa-2, and PANC-1).30 The dosing regimens in these mouse models required 80-160 mg kg 1 of gemcitabine administered intraperitoneally every third day for 4 cycles. In contrast, the optimal dosing in humans for gemcitabine as a single agent in phase III trials for...

Risk Factors for Breast Cancer

A history of breast cancer Exposure to ionizing radiation Familial Risk Factors for Breast Cancer More than 50 of women in family have breast cancer Breast cancer present in more than I generation Multiple occurrences of breast cancer (> 3) in close relatives History of bilateral breast cancer B. Nulliparity and increased age at first pregnancy are associated with an increased risk for breast cancer. Nulliparity alone accounts for 16 of new cases of breast cancer each year. The relative risk for breast cancer increases with advancing age. C. Race is an independent risk factor. While white women are at an increased risk for breast cancer, African American women with breast cancer have higher fatality rates and a later stage at diagnosis. D. A family history of breast cancer, especially in first-degree relatives, increases the risk. E. A history of breast cancer increases a woman's risk for subsequent breast cancers. If the woman has no family history of breast cancer, then the...

Aggressive Systemic Therapies High Dose Mono Chemotherapy

High dose mono-chemotherapy implies an intravenous systemic application of a cytotoxic drug candidates for this type of therapy are methotrexate (63) and liposomal doxorubicin (64). Due to the beneficial side-effect profile, we today recommend only liposomal doxor-ubicin as a mono-chemotherapy for cutaneous lymphoma. It can be given in a dosage of 20mg m2 body surface every two or four weeks.

High Dose Poly Chemotherapy

Poly-chemotherapy is applied for all types of nonHodgkin lymphomas and thus for cutaneous lymphomas. Until now, there is no evidence that this toxic approach has any beneficial impact on survival. Therefore, it should not be routinely used (65). Depending on the drugs used, there are different possibilities to block cell proliferation. The chemotherapy most commonly used is the CHOP therapy. It contains cyclophosphamide, vincristine (oncovin) and adriamycin combined with prednisone. Cyclophosphamide is an alkylating agent requiring metabolism by the liver. Vincris-tine binds to the protein tubulin resulting in an arrest of cells in metaphase with subsequent lysis. Doxorubicin (adriamycin) belongs to the group of anthracyclines, antitumor antibiotics. Depending on the subtypes of lymphoma, remissions which are usually shortly lasting can be expected in approximately 50-70 of the cases (66). There is no proven impact on survival (65,67). The immunosuppressive effects of...


Clinical cancer chemotherapy uses low-molecular-mass agents to destroy rapidly dividing cells (see 7.02 Principles of Chemotherapy and Pharmacology). This strategy was initially dominated by genotoxic drugs that target the integrity of the cell's genetic material. Currently, more than 100 chemotherapeutic drugs are used either alone or in combination regimes. The mechanism of action of these anticancer drugs is very broad and expands from the initial DNA interactive agents, which interfere with the growth of cancer cells by reacting with DNA to block its replication, to the most recent targeted therapeutic drugs, which block components of deregulated signal transduction pathways. (Other types of chemotherapy medications include antimetabolites (see 7.03 Antimetabolites), antitumor antibiotics, mitotic inhibitors, hormonal therapies, nitrosoureas.) Cancer chemotherapy offers a unique advantage over the other treatment modalities it can treat the entire body, even the cells that may...

Breast Cancer

Incidence roughly 1 in 10 women will develop breast cancer in their lifetime. Risk factors for breast cancer 1. History of breast cancer (biggest risk factor) 3. Age (breast cancer is rare before age 30 the incidence increases with age). Greatest risk in women > 75 years old, Signs and symptoms that suggest a mass is breast cancer until proved otherwise fixation of breast mass to the chest wall or overlying skin, satellite nodules or ulcers on the skin, lymphedema peau d'orange, matted or fixed axillary lymph nodes, inflammatory skirt changes (red, hot skin with enlargement of the breast due to inflammatory cancer), prolonged unilateral scaling erosion of the nipple with or without discharge (may be Paget's disease of the nipple), microcalcifications on mammography, and any new breast mass in a postmenopausal woman. 1. In women under 30, breast cancer is extremely rare. With a discrete breast mass in this age group, think of fibroadenoma and observe the patient over a few menstrual...

Risk Factors and Genetics

Breast cancer risk factors are related to prolonged exposure to estrogen. This is seen in women with early menarche and late menopause, older high estrogen dose oral contraceptives, and nulliparity. The highest risk involves a personal history of breast cancer or lobular carcinoma in situ. Family history in a premenopausal first degree relative is also an important risk factor. Familial breast cancer has been associated with certain genes. The two main genes are BRCA I and BRCA II.1 BRCA I is found on chromosome 17 and is also associated with an increased risk of colon, ovarian, and prostate cancer. BRCA I is thought to function as a tumor suppressor gene in DNA repair. BRCA II, located on chromosome 13, is associated with male breast cancer. BRCA II is also thought to function as a tumor suppressor gene. Both of the above genes are inherited in an autosomal dominant pattern with incomplete penetrance. Prophylactic bilateral mastectomy has been shown to decrease breast cancer in women...

Treatment of menopausal symptoms with estrogen

Data from the WHI and the HERS trials has determined that continuous estrogen-progestin therapy increases the risk of breast cancer, coronary heart disease, stroke, and venous thromboembolism over an average follow-up of 5.2 years. As a result, the primary indication for estrogen therapy is for control of menopausal symptoms, such as hot flashes. 2. Estrogen therapy remains the gold standard for relief of menopausal symptoms, and is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous venous thromboembolic event or stroke, or those at high risk for these complications. Estrogen therapy should be used for shortest duration possible (eg, 6 months to 5 years).

Surgical Management

Findings of unresectable hepatic disease are confirmed by biopsy of liver lesions. If the patient has confirmed hepatic metastases, exploration and resection are not indicated and the patient is managed with antisecretory therapy. If the patient suffers complications of disease due to lack of efficacy of antisecretory medication than total gastrectomy may be considered. Objective response to chemotherapy is < 50 and has not been shown to improve survival. Hormonal therapy with octreotide has been reported to improve symptoms, decrease hypergastrinemia, and reduce hyper-chlorhydria in patients with metastatic gastrinoma.

Adjuvant therapy following primary surgery in earlystage carcinoma

Patients with histologically documented extracervical disease (pelvic nodal involvement, positive margins, or parametrial extension) are treated with concurrent pelvic radiation therapy and cisplatin-based chemotherapy. The use of combined adjuvant chemotherapy and radiation therapy in these high-risk patients following primary surgery significantly improves relapse-free survival and overall survival rates when compared with radiation therapy alone.

Screening Guidelines

Mammography alone is 75 sensitive, and, when combined with CBE, the screening sensitivity for detecting breast cancer increases to 88 . Screening guidelines from the US Preventive Services Task Force suggest mammography alone or with CBE every 1 to 2 years for women aged 50 to 69 years. Recent evidence suggests a benefit from annual mammography with or without CBE for women aged 40 to 49 years.

Intradermal Radiocolloid Injection

Giuliano AE, Kirgan DM, Guenther JM et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994 220 391-401. 2. Krag DN, Weaver DL, Alex JC et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993 2 335-340. 3. Albertini JJ, Lyman GH, Cox C et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer see comments . JAMA 1996 276 1818-22. 4. Veronesi U, Paganelli G, Galimberti V et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997 7. Giuliano AE, Kirgan DM, Guenther JM et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994 220 391-8 discussion 398-401. 8. Giuliano AE, Dale PS, Turner RR et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995 222 394-9 discussion 399-401. 9. Giuliano AE, Jones RC, Brennan M et al. Sentinel...


Advice about mammography for a young woman with a family history if breast cancer. BMJ 2001 1040-1042. 3. Smith DN, Christian R, Meyer JE. Large-core needle biopsy of nonpalpable breast cancers. Arch Surg 1997 132 256-259. 5. Rich PM, Michell MJ, Humphreys S et al. Stereotactic 14 G core biopsy of nonpalpable breast cancer What is the relationship between the number of core samples taken and the sensitivity for detection of malignancy Clin Rad 1999 54 384-389.


It is believed that breast cancer progresses from atypia, to ductal carcinoma in situ (DCIS), then to invasive cancer. Infiltrating ductal carcinoma is the most common breast cancer. This is observed as a stellate lesion or architectural distortion on mammogram. In contrast, invasive lobular carcinoma is often not seen on mammogram and can lead to a delay in diagnosis. Any palpable lesion should be fully evaluated. Inflammatory breast cancer presents as an inflamed, hard breast with diagnosis made after not responding to antibiotics. A biopsy will show invasion of dermal lymphatics. Plugging of these lymphatics cause the characteristic edema and peau d'orange seen in inflammatory cancer. This patient usually presents with metastatic disease and is labeled as a T3b lesion. Treatment of inflammatory cancer involves preoperative chemotherapy, for this has been shown to provide the best survival. If the patient survives chemotherapy, mastectomy follows and the radiation to the chest wall...


Breast cancer staging Table 9.1. Breast cancer staging Table 9.2. Breast cancer regional node status Table 9.3. Breast cancer metastasis Table 9.4. Breast cancer survival at 5 years 1. Hill ADK, Doyle JM, McDermott EW et al. Hereditary breast cancer. Br J Surg 1997 84 1334-1339. 2. Meijers-Heijboer H, van Geel B, van Putten WLJ et al. Breast cancer after prophylactic bilateral mastectomy with a BRCA I or BRCA II mutation. NEJM 2001 345(3) 159-164.

Surgical Options

The two main surgical options for invasive breast cancer in females are In 1995 this was unequivocally proven equal to mastectomy in disease-free survival and overall survival, if followed with radiation for tumors less than 4 cm. Patients with DCIS were found to have an 8 ipsilateral recurrence rate with BCT and irradiation compared to 18 for BCT alone. Radiation after lumpectomy decreases local recurrence but does not improve overall survival. Breast conservation therapy is not indicated in T3 or T4 N2 MX lesions or lesions that are multifocal or multicentric. Certain other situations require mastectomy including collagen vascular disease, pregnancy, or a previously irradiated breast. Determination of nodal status should follow lumpectomy to determine the need for adjuvant chemotherapy. Positive axillary nodes increase the risk of metastatic recurrence but have no increased risk of local recurrence (Table 9.5). Sentinel node biopsy can determine the status of the axillary nodal...

Adjuvant Therapy

Use of chemotherapy combined with radiotherapy preoperatively (neoadjuvant therapy) has been shown to improve overall survival when compared to surgery alone. There are currently several randomized controlled studies underway to evaluate this further. The protocol includes 5-fluorouracin and cisplatinin with 4500 cGy radiotherapy over 3 weeks. There is a 3-6 week recovery period during which time WBC is followed with repeat CT scanning. The patient is restaged and surgery performed if possible. In the study conducted at the University of Michigan, 91 were resectable with a 24 month median survival compared to 14 month with surgery alone.1 One significant randomized controlled study in 1996 showed a survival advantage in patients with adenocarcinoma treated with neoadjuvant therapy.3

Risk factors

Family history is highly significant in a first-degree relative (ie, mother, sister, daughter), especially if the cancer has been diagnosed premenopausally. Women who have premenopausal first-degree relatives with breast cancer have a three- to fourfold increased risk of breast cancer. Having several second-degree relatives with breast cancer may further increase the risk of breast cancer. Most women with breast cancer have no identifiable risk factors. B. Approximately 8 percent of all cases of breast cancer are hereditary. About one-half of these cases are attributed to mutations in the BRCA1 and BRCA2 genes. Hereditary breast cancer commonly occurs in premenopausal women. Screening tests are available that detect BRCA mutations.


A mass that is suspicious for breast cancer is usually solitary, discrete and hard. In some instances, it is fixed to the skin or the muscle. A suspicious mass is usually unilateral and nontender. Sometimes, an area of thickening may represent cancer. Breast cancer is rarely bilateral. The nipples should be expressed for discharge. Screening for Breast Cancer in Women


A past history of breast cancer or breast biopsy and a history of risk factors for breast cancer (eg, age, family history of breast cancer, age of menarche, age at first pregnancy, age of menopause, alcohol use, and hormonal replacement therapy). Risk Factors for Developing Breast Cancer Risk Factors for Developing Breast Cancer breast cancer

Triple diagnosis

Triple diagnosis refers to the concurrent use of physical examination, mammography, and FNAB for diagnosing palpable breast lumps. Very few breast cancers are missed using triple diagnosis. Only 0.7 percent of women had breast cancer when all three tests suggested benign lesions, while 99.4 percent of women in whom all three tests were positive have breast cancer.


Although 90 percent or more of palpable breast masses in women in their 20s to early 50s are benign, excluding breast cancer is a crucial step in the evaluation. Mammography is recommended for any woman age 35 years or older who has a breast mass. D. Breast pain. Women who present with breast pain as their only symptom often undergo mammography. Only 0.4 percent of women with breast pain have breast cancer. The vast majority of women have normal findings (87 percent) benign abnormalities are noted in 9 percent. E. Ductal lavage. The cytologic detection of cellular atypia can identify women with a higher risk of developing breast cancer.

Surgical Treatment

Local excision of the tumor mass (lumpectomy) followed by lymph node staging and subsequent adjuvant hormone therapy, chemotherapy, or radiation therapy is an accepted treatment. Long-term studies have found that recurrence rates are similar when lumpectomy was compared with radiation therapy and mastectomy. One study showed no recurrence if 1-cm margins were obtained followed by the use of radiation therapy. C. Radiation Therapy. External beam radiation therapy has proven effective in preventing recurrence of breast cancer and for palliation of pain. The risk of relapse after radiation therapy ranges from 4 to 10 . Lumpectomy can now be performed followed by implantation of high-dose brachytherapy catheters. D. Anti-Hormonal Therapy. Hormonal therapy is indicated for those tumors that test positive for hormone receptors. Tamoxifen has both estro-genic and anti-estrogenic effects. In women who are older than 50 years with breast cancers that test positive for hormone receptors,...


Treatment for Stage IIIA remains controversial however induction therapy has had up to 30 of patients resectable. The remaining stages are managed primarily with radiation and chemotherapy. Stage I carcinoma of the lung can expect 3- and 5-year survival rates of approximately 85 and 70 , respectively. The most favorable group of patients with Stage I disease, those with T 1N 0 disease, experience 5-year survival rates of 80 to 85 . Neither chemotherapy nor radiation therapy is recommended after complete resection of Stage I lung cancer.

Wilms Tumor

An embryonal neoplasm of the kidney which usually presents in children between the ages of 1 and 5 years as a mass of the upper abdomen or flank. It may be associated with such anomalies as aniridia, Beckwith-Wiedemann syndrome, urinary tract defects, hemihypertrophy, and chromosomal deletion. Its workup includes CT of the abdomen and chest and ultrasound which are important to rule out involvement of the renal vein or IVC. Surgical treatment is the primary mode of therapy and involves clamping the renal vein first to prevent venous embolization of tumor cells. Lymph nodes are sampled at the time of resection to assist with staging, which will determine if chemotherapy or radiation therapy will be needed. Patients with disease limited to the kidney which is completely excised, and treated with chemotherapy.

Liver Masses

Most liver tumors in children are malignant, with hepatoblastoma being the most common. Hepatocellular carcinoma is the next most common and has a poorer prognosis. The most common presenting complaint is that of weight loss and an abdominal mass. Workup includes plain x-rays as well as ultrasound and contrasted CT scan. Treatment is by surgical excision when possible. Cure rates for hepatoblastoma treated by resection with chemotherapy are much greater than those for hepatocellular carcinoma.

Molecular Cancer Epidemiology

Remarkable progress in our understanding of the molecular pathogenesis of cancer has been made and is beginning to have positive impact across the whole field of oncology from prevention through screening and diagnosis to the development of molecularly targeted therapies. Major advances in molecular (or genetic) markers have been made which have a great impact on health risk assessment. For example, rather than treating all cases of breast cancer as the same disease, an epidemiologist can use tumor markers to identify potentially more heterogeneous subsets.

Is Sentinel Node Biopsy a Substitute for Elective Neck Dissection

Another controversy surrounding elective neck dissection concerns the value of sentinel node biopsy. Considering the experience with this technique in patients with melanoma and breast cancer, it is anticipated that gamma probe-directed biopsy of the sentinel node may be useful in the management of the NO neck in patients with squamous cell carcinoma of the head and neck. To that end, a recent study of 5 patients conducted by Koch et al.12 showed that identification and biopsy of the sentinel node are feasible in these patients. However, a number of substantial problems were identified (1) the proximity of the primary tumor obscures the lymphoscintigram, particularly when the tumor is located in the oral cavity (2) intramucosal injection of the radiolabeled material is more difficult than intradermal injections and the isotope often extrudes into the saliva and (3) some sites in the head and neck are inaccessible, and the technique is limited in patients who have been previously...

Conventional Medical Therapy for MS

Since 1993, six medications for MS have been approved by the U.S. Food and Drug Administration (FDA). Four of these are commonly used as initial MS therapies interferon beta-1b (Betaseron), interferon beta-1a once-weekly (Avonex), interferon beta-1a three-times-weekly (Rebif), and glatiramer acetate (Copaxone). Mitoxantrone (Novantrone) is a chemotherapy medication that is typically used for people who do not respond to the other four medications. Another MS medication known as natalizumab (Tysabri) was approved by the FDA in 2006. These drugs decrease the number and severity of relapses, slow the progression of the disease, and decrease the development of new brain lesions. In addition to these medications, several other medications are used to treat MS. Steroids are used for exacerbations. These may be taken orally (prednisone, dexamethasone) or intravenously (methylprednisolone or Solu-Medrol). Some chemotherapy medications other than mitoxantrone, including methotrexate,...

Risk Factors and Cancer

Diet and obesity in adults account for 30 of all cancer deaths in the USA. Diet has been shown to play a significant role in the causation of cancer but little is known about how it plays its role as a carcinogen.15,18 Excessive fat in the diet raises the risk of colorectal and breast cancer and possibly prostate cancer. Adult obesity is associated with endometrial cancer, postmenopausal breast cancer, and cancers of the colon, rectum, and kidney.15,18 Obesity in concert with other risk factors such as low activity level, menopausal status, and predisposition to insulin resistance significantly increase the risk of cancer. While some methods of food preparation and preservation have been shown to increase the risk of various forms of cancers, certain classes of foods appear to contain protective substances against cancer including vegetables, whole grain products (fiber), and citrus fruits.12,15,18,20 Salt intake has been associated with risk of stomach cancer, but no other food...

Primary Nursing Diagnosis

Much of the collaborative management is based on pharmacologic therapy (see below). Supportive management consists of treatment of malignancies with chemotherapy and irradiation, treatment of infections as they develop, and the management of discomfort with analgesia. Surgical management may be needed to excise lesions from Kaposi's sarcoma or to drain abscesses. If the patient becomes short of breath, oxygen is often prescribed to improve gas exchange. Dietary support is important in the treatment of HIV infection and AIDS throughout the progression of the illness.

Catechol Omethyltransferase

COMT is localized to chr22q11 where a microdeletion results in velocardiofacial syndrome (22qDS DiGeorge or Shprintzen syndrome), a genetic subtype of schizophrenia. The COMT gene exists in two versions Met158 and Val158, the former coding for a form of COMT that is less thermostable and thus has lower activity than the Val158. COMT is important for regulating DA but not norepinephrine (NE) levels in the prefrontal cortex.28 Val158Met heterozygotic mice which have high COMT activity and, correspondingly, low prefrontal cortex DA levels show greater tyrosine hydroxylase expression in the midbrain, indicative of increased DA synthetic capability. In human Val158 carriers, neuroimaging studies showed greater midbrain F-DOPA uptake than Met158 carriers, consistent with increased DA biosynthesis. DA levels in prefrontal cortex play a key role in cognitive function and high-activity Val158 is associated with poorer performance and 'inefficient' prefrontal cortex function in some but not all...

Patient information sheets

Providing the right level of information and achieving a balance between avoiding complex scientific language and being patronizing can be difficult. It is important to remember that average reading skills of the public are low, and that participants are not uniform in their skills, experiences or need for information. In the UK, given that the average reading age of the adult population is around nine years, the Plain English Campaign advocates that public information should be written in language that can be understood by a nine year old child. Very few patient information sheets are pitched at this level and indeed such a level would not be appropriate for all individuals. One approach might be to produce a range of participant information material targeted at different types of individual. For example, an MRC EORTC trial of chemotherapy in osteosarcoma has three separate information sheets one for adults and adolescents, one for children and one for parents. Clearly each requires...

Box 22 Example of controversial trial results reported by the press in advance of scientific publication

Results of a trial of complementary treatment offered to women with breast cancer who attended the Bristol Cancer Help Centre 38 published in 1990 were reported in the press three days before the Lancet publication date. The women involved in the trial, who still believed it to be ongoing (they had completed only four of the planned five annual questionnaires that they had been asked to complete), first learned the results from the television news. The news report stated that those of them who had been to the Centre were twice as likely to die and three times as likely to relapse as women who had not been to the centre. This was certainly not the most sensitive way of breaking such news. In fact it later emerged that the study was fundamentally flawed in that those who had chosen to pay to attend the centre in addition to NHS treatments were as a group more ill than the controls. The women involved in the trial challenged the results and complained to the Charities Commission about...

Cancer Screening Diagnosis and Prevention

This is best exemplified for prostate and breast cancers which are diagnosed relatively early. Using biomarker analysis performed on the primary tumor recommendations can be made as to which patients will benefit from no treatment or from localized treatment such as surgery and or radiation or early systemic therapy, which should likely lead to improved therapeutic success rates and quality of life. Several potential prognostic biomarkers have been proposed and are being used for different tumors.58-66 Unfortunately many of the current screening programs to detect early stages of solid tumors are not very efficient, as for example mammographic screening for breast cancer.68 Regular screening is relatively nonspecific and identifying benign lesions requires further investigation and biopsy. Large studies have shown that mammographic screening has only a small effect on overall breast cancer mortality and only in the 50-64 age group.68

Involving the public in designing trials and setting research agendas

To help encourage researchers to involve lay input at all stages of clinical research, a concerted effort to systematically collect and collate evidence of situations where lay input has improved research proposals or defined new proposals would be extremely useful. Encouragingly, a national survey of UK Clinical Trial Coordinating Centres, carried out in 1999 2000, found that most centres had involved or were planning to involve consumers in their work, and less than a quarter had no plans to do so 44 . Almost a third of trials covered by the survey (19 60) had consumer representation on the Trial Steering Committees (though none were involved in data monitoring). Consumer input was mostly at the level of single trials and largely related to preparing information for patients. This type of representation is typical of UK cancer trials, conducted during the 1980s and 1990s. Individual consumer representatives or groups were usually involved in the development of individual protocols,...

Available Treatment Modalities

Anticancer treatment often includes more than one approach, and the treatment modality adopted by the oncologist is largely dependent on the type of tumor and how far it has progressed in the patient. Surgery, chemotherapy, radiotherapy, and photodynamic therapy are among the most common and broadly used treatment strategies available today. These treatment modalities are briefly discussed in this section. Cancer surgery attempts to remove localized, well-defined tumors or precancerous conditions. Additional treatment with chemotherapy or radiotherapy is often required due to the impossibility of removing the tumor completely or of eliminating malignant cells that may linger after surgery or metastasize to other tissues or organs.

Education and raising public awareness of trials

Although open and informed public debate concerning medical research may often accelerate implementation of research findings, the process of rigorous evaluation must not be hijacked by those with vested financial, professional or political interests. An example of such difficulties is illustrated by a controversy regarding breast cancer screening policy for women under fifty in the US. This story which is described in more detail elsewhere 50 and summarized in Box 2.4 highlights some of the difficulties that we are increasingly likely to face as the world of clinical research becomes more open.

Communication Compass

You're lucky, the oncologist tells his patient with breast cancer. Your tumor seems to respond well to the hormone therapy. And we still have a lot more possibilities in the future. Does that mean that I am going to be cured after all the woman asks. After the consultation the doctor sighs How is it possible after all the explanations I have given, that the patient still has not understood that this therapy does not have a curative intent The first axis in the compass is the axis of perspectives. Who is lucky in the above-mentioned example It is the doctor who is lucky, because his therapy is working. From the perspective of the patient, being lucky has a completely different meaning. She does not know the doctor's other patients. For her, being lucky means to be free of cancer. That is how she understands her doctor's statement. Doctor and patient look at the same situation from a completely different perspective.

Placebos and the Placebo Effect

As would be expected, a placebo effect occurs in studies of people with multiple sclerosis (MS). A notable response to placebos has been observed in studies of therapy for MS itself, as well as for MS-related symptoms. In older MS studies, from 1935 to 1950, a variety of ineffective therapies produced 60 to 70 percent improvement. More recently, trials with chemotherapy drugs in MS showed a placebo effect on the rate of MS attacks. In recent research studies using interferon beta-1b (Betaseron), the first U.S. Food and Drug Administration (FDA)-approved immune therapy for MS, the number of MS attacks was determined for people taking Betaseron and for another group taking placebo. The placebo-treated group had a 28 percent decrease in the rate of MS attacks. Similarly, the placebo group showed decreased attack rates of 33 percent in trials using intramuscular interferon beta-1a (Avonex), 13 percent in trials with subcutaneous interferon beta-1a (Rebif), and 43 percent in trials with...

Splenic Hematopoiesis

HSC and lineage-restricted hematopoietic progenitor cells are found in the developing spleen on gestational day 13, at approximately the same time they are found in the fetal liver (Landreth 1993) (Figure 1.2). Although the expansion of hema-tolymphoid cells in the spleen never rivals that found in the developing liver, the spleen maintains this low level of hematopoietic activity well into postnatal life. For this reason, splenic hematopoiesis serves as a reserve of HSC following damage to the bone marrow organ following chemotherapy or radiation in postnatal animals. The persistence of the hematopoietic microenvironment in the spleen is revealed by the seeding of HSC to that organ following hematopoietic transplantation in rodents.

Treatment Options for Major Cancers and Future Directions

According to the most recent statistics, one in three people will be diagnosed with cancer during their lifetime. Increased life expectancy (cancer can be considered a disease of advanced years), environmental factors (e.g., exposure to carcinogens), and social habits (e.g., diet and or smoking) have dramatically increased the risk of cancer in Western populations. Breast, lung, colorectal, and prostate are the four major types of cancer in adults, and they account for over half of all cases diagnosed. The treatments of these major cancers depend upon a variety of factors, but the most common ones involved surgery combined with radiation and or chemotherapy. These treatments are briefly discussed in this section. Table 1 shows representative examples of anticancer agents and their mechanism of action. Depending on the tumor size and the stage of the disease, treatment for breast cancer may involved surgery, radiation therapy, chemotherapy, hormone therapy, or a combination of two or...

FSee 708 Kinase Inhibitors for Cancer

Cyclophosphamide, doxorubicin, and vincristine sulfate (CAV) cyclophosphamide, doxorubicin, and etoposide (CAE) etoposide and cisplatin (EP) and cyclophosphamide, etoposide, and vincristine (CEV). Depending on the extent of the disease, non-small cell lung carcinoma can be removed by surgical resection or treated with radiation therapy in combination with chemotherapy (e.g., gemcitabine hydrochloride together with cisplatin and vinorelbine). In addition to the preceding treatment modalities, photodynamic therapy is use for the care of patients with inoperable lung cancer or with distant metastasis. Surgery is the treatment of choice for colorectal cancer and, depending on the stage of the disease, chemotherapy and radiation are used as adjuvant treatment.76 For example, a cocktail of different agents (fluorouracil, leucovorin, and irinotecan) is used for metastatic colorectal cancer. An important advance in the treatment of colorectal cancer has been reported recently with...

Randomized Neoadjuvant Trials

These reports and others, including the noncontrolled trial from M.D. Anderson, show that induction chemotherapy can be used to retain a functioning larynx without compromising survival.13 A major question raised from these studies is whether the neoadjuvant chemotherapy is really any benefit or is simply a selection marker for those who will respond to radiation. To help answer this question, the Head and Neck Intergroup is conducting a study that will accrue 546 patients divided into three groups (1) induction chemotherapy (similar to the VALCS protocol) followed by radiotherapy for responders, and salvage surgery with postoperative radiation for nonresponders (2) radiotherapy with concomitant chemotherapy (cisplatin alone) and (3) radiotherapy alone.46 The goal of this study is to determine the true benefit of induction chemotherapy over radiotherapy alone for organ preservation, as well as to evaluate the efficacy of concomitant chemo- and radiotherapy. There is still the question...

Concomitant Chemo And Radiotherapy

Is concomitant chemo- and radiotherapy better than radiation alone Early concomitant trials employed single-agent chemotherapy with simultaneous radiotherapy. Agents included methotrexate, hydroxyurea, bleomycin, 5-FU, and cisplatin.48-50 Except for a few trials, one each with methotrexate, bleomycin, and 5-FU, all results showed no significant difference over radiation alone. Recent trials have more often used combination chemotherapy in conjunction with various delivery schedules of radiation.45' 51-56 The subjects are varied, but most trials concentrate on previously untreated patients with or without resectable disease. The locoregional control and survival statistics of the combined-modality arms of these trials are improved from their predecessors (Table 8-3). Of interest are five trials employing cisplatin and 5-FU with different radiation regimens. Using a hyperfractionation scheme with 150 centigray (cGy) twice a day (b.i.d.) with a 2-week scheduled break after the first 10...

Nasopharyngeal Cancer

Nasopharyngeal cancer is a highly radioresponsive tumor. This is especially true for the World Health Organization (WHO) class II and III (nonkeratinizing and undifferentiated squamous cell carcinoma). In the United States, however, 30 to 50 of patients will have WHO class I (keratinized squamous cell carcinoma), which is associated with alcohol and tobacco use and is much less radiosensitive.77 Advanced-stage disease is associated with poor 5-year survival rates, within a range of 10 to 40 when treatment is with radiotherapy alone. For this reason, adding chemotherapy to the treatment protocol has been investigated. Several trials have evaluated the use of neoadjuvant chemotherapy in this disease. In a noncontrolled study from Israel, 27 patients treated with induction cisplatin and 5-FU achieved a 93 response rate (37 CR).78 The 5 -year actuarial survival was 66 . Again, those patients achieving a CR did significantly better, with all patients in this subgroup alive at the end of...

In Vivo Reconstitution Of Immunocompetent Cells

A second complication to understanding the effect of toxic compounds on hema-tolymphoid cells is that they have extensive renewal potential, and acute damage to hematopoietic cells may not be detectable later in life because of the unique ability of these cells to reconstitute losses (Bacigalupo et al. 2000). Numerous studies have demonstrated rapid recovery of immune responsive cells following cytotoxic drug therapy, and the ability of hematopoietic cells to recover following depletion is sufficiently robust to justify clinical utility of bone marrow transplantation (Banfi et al. 2001 Mudry et al. 2000). For that reason, relatively dramatic acute toxicity to either blood cell development or immune cell function may not lead to persistent detection of immunotoxicity. However, underlying damage to stem and progenitor cell populations, not detected by standard assays that enumerate numbers of cells responding to a single antigen, may in fact manifest itself when the hematopoietic system...

Different Classes of Markers

Pharmacogenetic phenomena, as pointed out previously, need not be restricted to the observation of a direct association between allelic sequence variation and phenotype, but may extend to a broad variety of indirect manifestations of underlying, but often (as yet) unrecognized sequence variation. Thus, differential methylation of the promoter region of O6-methylguanine DNA methylase has recently been reported to be associated with differential efficacy of chemotherapy with alkylating agents. If methylation is present, expression of the enzyme that rapidly reverses alkylation and induces drug resistance is inhibited, and therapeutic efficacy is greatly enhanced.21

Intraportal fluorouracil for colorectal cancer

In 1989, the UK Coordinating Committee on Cancer Research identified improving survival of colorectal cancer patients as a national priority, and set up a working group to develop trial proposals. This group conducted a systematic review 14 of published adjuvant chemotherapy trials, and also contacted other trials organisations to find out about ongoing trials and to obtain, where possible, unpublished data. This review identified portal vein infusion of fluorouracil given immediately post-operatively for one week as a highly promising treatment six trials had evaluated this treatment and together they suggested a striking, and highly statistically significant, reduction in the annual odds of death. However, the total number of patients included in the trials was only 1500 (only 300 of whom had died) and a high proportion of randomized patients were excluded from the published analyses which may have biased results in favour of chemotherapy (see Section 9.4.1). The data were therefore...

Recommendations For Dietary Fiber Intake Levels

Deaths would result in the United States if dietary goals for cancer prevention such as increasing DF intake levels are not achieved (27). This could cost as much as 25 billion a year. Based on international correlation statistics, an inverse relationship has been found between fiber and fiber-containing foods and colon cancer risk (28, 29). After examination of all fiber sources, the Life Science Research Office (LSRO) (30) determined that the IDF-rich wheat bran most consistently reduced colon tumor incidence in animal models. Recurrence of precan-cerous polyp lesions in the rectum has also been shown to be lower with wheat bran in humans (31). Both IDF and SDF may reduce breast cancer risk by binding estrogen, a potent promoter, and thus preventing enterohepatic reabsorption and lowering circulating levels (32). Although increased DF intake seems to be beneficial in terms of cancer, there are concerns about impaired mineral availability. Examination of populations that consume much...

Mandibular Reconstruction

Since the late nineteenth century, many reconstructive techniques have been used for mandibular restoration after extirpation of oral cavity malignancies or traumatic injury. The challenge of achieving oromandibular rehabilitation is a formidable task involving soft tissue restoration as well as bone in most cases. Ideally, the aim of the reconstruction is to achieve both a functional and aesthetic restoration, addressing specific functions related to the oral cavity, including salivary continence, aspiration, mastication, deglutition, and speech. Prior exposure to irradiation and chemotherapy may further complicate the success of a restoration.

Animal Models of Acute and Chronic Graft VersusHost Disease

Graft-versus-host disease (GVHD) represents a special situation in transplantation immunology in which immunocompetent donor cells are engrafted into recipients that are incapable of rejecting them due to tolerance (parent offspring, or P F1), immaturity (adult neonate), or radiation- or chemotherapy-induced immune deficiency (donor irradiated host). Donor T cells encountering allogeneic stimulators become activated, secrete cytokines, proliferate, and differentiate into effectors this in vivo immune response is known as the graft-versus-host reaction (GVHR). The systemic effects of this initial donor anti-host reaction comprise a multiorgan syndrome, graft-versus-host disease (GVHD). Murine GVHD experiments have been utilized to model the clinical disorders of acute and chronic GVHD (AGVHD and CGVHD) that occur after allogeneic bone marrow transplantation, and also to study T cell regulation, induction of tolerance, and autoimmune diseases.

Box 42 Control arms in advanced ovarian cancer trials

In the late 1990s, several chemotherapy regimens were in use in the treatment of advanced ovarian cancer. In the US, both cisplatin (P) alone and cyclophosphamide + cisplatin (CP) combinations were standard, although evidence from a meta-analysis of trials comparing CP with CAP (cyclophosphamide, doxorubicin, cisplatin) showed a survival benefit to the 3-drug combination 1 . The US Gynaecological Oncology Group (GOG) used CP as the control arm in one trial evaluating a paclitaxel-based combination 2 and P as the control in another 3 . The former trial showed striking benefits to the paclitaxel arm, which were at odds with the results of the European ICON3 trial 4 . ICON3 compared a similar paclitaxel combination with a control group comprising either CAP or single agent carboplatin. This choice followed from the results of the ICON2 trial 5 , which demonstrated the clinical equivalence of adequately dosed carboplatin and CAP. ICON3 did not find a benefit to the paclitaxel combination,...

How to Motivate Sedentary People to Be More Active

A sedentary lifestyle increases the risk of developing many diseases 24-27 , particularly colon cancer and breast cancer. A sedentary lifestyle has become more and more prevalent during the last decade, as shown for example by successive Swiss Health Surveys 28 . In 2002, up to two-third of Swiss people reported that they practiced less physical activity than is minimally recommended 29, 30 (30 minutes per day of moderate intensity physical activity, such as brisk walking, or 3x20 minutes per week of vigorous intensity physical activity, such as jogging or other forms of cardio-respiratory training). It has been estimated that a sedentary lifestyle is annually responsible for 1.4 million disease cases, 2,000 deaths and 1.6 billion Swiss francs of treatment costs 31 .

Nonrandomized treatments

The specific treatments being randomized will rarely be the only treatments which the patient receives, but these 'other' treatments constitute another source of variability which might be controlled or encouraged. They range from ancillary or supportive care such as antibiotics or antiemetics to more fundamental aspects of treatment. For example, in high grade glioma trials comparing the addition of adjuvant chemotherapy to standard treatment, there are possible sources of variability in standard treatment, for example the extent of surgery a patient had, and the radiotherapy schedule they received. Should any of the 'other treatments' be controlled It is useful to consider the extremes. The early, exploratory, trial aiming to limit variability wherever possible, might choose to do so - specifying a prophylactic anti-emetic schedule or a specific radiotherapy dose and fractionation, or even imposing a strategy for supportive care which is identical in both arms of the trial, even if...

Specific Cell Extraction

Generally, the extraction of diseased cells by magnetic particles is based on the chemical difference between healthy and infected cells. Two steps should be considered. The first involves targeting the microspheres to a specific site by applying a magnetic field. Magnetic guidance makes it possible to reach areas that are difficult to access, and its efficacy usually depends on the properties of the carrier, such as particle size and stability in the environment. Secondly, the infected cells are then recognized and immobilized on sensitized particles. Capture yield varies from patient to patient since recognition depends on the properties of tumor cells and their affinity vis-a-vis the antibodies immobilized on the colloidal particles. Hancok 36 , Rembaum 59 and Ugelstad 60 initiated the use of magnetic particles to purify marrow. The method was then extended to other tumors such as the treatment of lymphocytes, leukemia and lung cancer. Using chemotherapy and radiation to cure...

Applications of Omics Technologies in Biomarker Discovery

Biomarkers (as well as potential drug targets in their own right if critically important to the same pathway). Microarray transcript profiling can be applied in preclinical models with the aims of better understanding of the pharmacodynamic effects of drug candidates (or other bioactive agents) and ultimately of identification of biomarkers that can be applied during clinical testing. Several examples of this approach have been described, including the use of tumor xenograft models to probe for gene expression biomarkers modulated by in vivo exposure to an antiangiogenic small-molecule kinase inhibitor31 exposure of bone marrow-derived macrophages to Gram-positive bacteria to identify gene expression change32 animal models for evaluating bladder tissue responses to inflammation-inducing agents33 and treatment of cancer cell lines with chemotherapy drugs and signal transduction inhibitors to probe for biomarkers of combination therapy.34 In one of these studies,31 a transcript whose...

When You Need to Gain Weight

Some men are underweight because of an eating disorder or because of treatment for a chronic disease such as cancer. They need to maintain their weight and add more pounds. For these men, taking in more calories than they burn is the answer. As simple as this may sound, underweight men often have to struggle with this concept. Some of these men experience appetite loss from chemotherapy or radiation therapy taken for cancer. Others struggle with an overwhelming fear of being fat that compels them to restrict their intake of food while burning calories by obsessively exercising. If you are underweight, there are a number of steps you can take to gain additional pounds.

Tumor Necrosis Family Apoptosis and Immune Surveillance

Subclones that express lower levels of Fas when injected into mice lacking FasL. , In patients, mutations in the Fas pathway, identified in NSCLC, significantly correlated with development of lymph node metastases.209 TRAIL knockout mice have also been shown to be more susceptible to development of metastases, while administration of TRAIL, or agonistic antibodies that activate its cognate receptors DR4 and DR5 suppress the formation of metastases.210,211-213 Consistently, mutations of DR4 and DR5 were found to be significantly associated with highly metastatic breast cancers.214 Mutations appear to be relatively rare, however, and other mechanisms, such as deficient DR transport to the cell surface or abrogation of the intracellular apoptosis inducing pathways (described above), may be more common. DAP kinase (DAPK), a serine threonine kinase involved in mediating FasL and TRAIL proapoptotic signals, has been linked to metastases in several studies. Aberrant methylation of DAPK has...

Genetic Considerations

Breast cancer is a feature of several cancer syndromes including Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Bloom syndrome, Werner syndrome, ataxia-telangiectasia, and xeroderma pigmentosum, but these account for less than 1 of all breast cancers. More familiar to most people are the nonsyndromic breast cancer susceptibility genes, which account for 5 to 10 of breast cancer cases. The two most widely known genes are BRCA1 and BRCA2, both tumor suppressor genes. Lifetime risk of becoming affected by breast cancer for mutation carriers has been estimated at between 60 and 88 . Breast cancer is considered a complex (multifactorial) disorder caused by both nongenetic and genetic factors. Several genes have been shown to contribute to susceptibility. These include the tumor suppressor gene CHEK2.

Gender Ethnicracial And Life Span Considerations

Breast cancer is predominantly a disease of women over 40, with incidence rates increasing with age. Annual incidence of breast cancer is less than 60 per 100,000 below age 40 100 per 100,000 by age 50 and nearly 200 per 100,000 at age 70. Only 1 of breast cancer affects men, and it usually occurs when they are over the age of 60. The case of the elderly with breast cancer is essentially the same as with younger patients. While white women have a higher frequency of breast cancer, African Americans are more likely to die from the disease this is attributed to late detection of the cancer and perhaps more aggressive tumors.

Epidemiology of Blood Transfusion

Both the collection rate and red blood cell transfusion rates increased consid- m erably throughout the 1970s and early 1980s, with a peak in 1986. Between 1986 I and 1992, there was a decrease in total collections, although a pattern of a slight increase is evident in the later 1990s. The growth in blood collections during the 1970s and 1980s was related to increased demands for blood, particularly red blood cells, in the support of cardiac surgery and trauma, and platelets in the support of cancer chemotherapy and bone marrow transplantation. The plateau in the mid-1980s was driven by public concern regarding the potential for blood to transmit human immunodeficiency virus (HIV-1), which resulted in a more conservative approach to blood transfusion.

Biomarker Endpoints Applied in Pharmacokinetic Pharmacodynamic Modeling

As the molecular underpinnings behind disease processes and drug mechanisms begin to become better characterized, regulatory agencies are increasingly focusing attention toward biomarkers and their potential role in drug approvals or usage guidelines. As previously mentioned, a subset of biomarkers known as surrogate endpoints have already been established, in select indications, to be predictors of clinical benefit suitable for regulatory approval decision making prior to definitive assessment of clinical outcome per se (e.g., survival). Further, there have been in recent years a few examples of therapeutics which are prescribed on the basis of presence or absence of specific molecular determinants in the disease tissue a prime case in point is the aforementioned trastuzumab, which is prescribed only for breast cancer patients whose tumor cells express the HER2 protein. Additional cases where molecular or pharmacogenomic information (e.g., in polymorphisms in metabolic enzymes) is...

Sequential randomizations within and between trials

In factorial designs, patients are subject to two or more randomizations, but all take place simultaneously. As a consequence, there is no possibility that the outcome of one randomization could influence the decision to take part in another. When designing a trial in which patients may become eligible for further randomizations with respect to some aspect of their treatment, at some time after the initial randomization, some caution is needed, particularly with respect to the impact of subsequent randomizations on the outcome assessments of earlier randomizations. These issues also arise when considering patients for more than one trial. The fundamental question is, is entry into the second trial (or second randomization) more likely amongst patients allocated one arm rather than another If the answer is yes, then one needs to consider the impact of this on the endpoints of the first trial. For example - suppose the first trial randomizes between chemotherapy and no chemotherapy and...

Option 2 Randomize patients with respect to both questions at the same time

Here all patients who consent to both randomizations are randomized 'up front' to their chemotherapy regimen and its duration, and so the choice of whether or not to be randomized with respect to duration does not depend on their experience of the initial chemotherapy regimen nor its effectiveness. However, since the question of stopping or continuing is relevant only to those who achieve a response or stable disease (and continuation of the same regimen in the face of progressive disease would not be considered appropriate), it is apparent from the start that a number of patients will not follow their allocated treatment. For example, approximately 50 per cent of patients in all the chemotherapy arms were expected to have progressive disease at three months. Therefore, half of those randomized to continue would in fact have progressive disease, and would not continue. Here then, the major effect could be on the stop versus continue randomization - analysis by intent to treat will...

Option 3 Conduct two completely separate trials in different groups of patients

If two independent trials are conducted, cross contamination is eliminated though it maybe necessary to provide guidelines concerning duration of chemotherapy in each of the three arms of the first trial. However, the trials will take longer than if the questions were combined in a single trial and, on a practical note, data collection is increased. The option chosen for CR06 was option 1, having performed sensitivity analyses. These assumed a 10 difference in survival for stop versus continue in those patients whose disease had not progressed at three months, and showed that even for unrealistically extreme differences in the proportion of patients achieving a response (or agreeing to be randomized) at three months across the three chemotherapy arms, the estimated differences in survival between any two of the three chemotherapy arms would be increased or decreased by less than 1 . Some of the calculations are detailed in Box 4.5. Similar orders of effect were found when allowing for...

Deregulated Receptor Tyrosine Kinases

The EGF family of type I receptor tyrosine kinases comprises four structurally related proteins EGFR (erbB-1, HER1) erbB-2 (HER2, Neu), erbB-3 (HER3), and erbB-4 (HER4). The biological activities of these transmembrane proteins are intimately interrelated, and their activation by a broad spectrum of growth factors (e.g., EGF, TGF-a amphiregulin, betacellulin, heparin-binding EGF, and, epiregulin) triggers the initiation of signal transduction pathways that in the main result in cellular proliferation, apoptosis, differentiation, angiogenesis, motility, and invasion. This family of receptors was first implicated in cancer when the avian erythroblastosis tumor virus was found to encode an aberrant form of the human EGFR. Additional studies have supported an important role for this family of RTKs in the development and progression of numerous human tumors. Overexpression of EGFR or coexpression of both receptor and ligand(s) is a frequent event in a large variety of epithelial cancers...

Background and Introduction

In 1896 George Beatson1 demonstrated that removal of the ovaries from premenopausal women could cause the regression of breast cancer. By the turn of the century it was established2 that about one-third of all premenopausal women with advanced breast cancer could benefit from oophorectomy and from that time, a principal strategy for the treatment and prevention of breast cancer has been either to block or to restrict the action of estradiol in its target tissue, the breast. However, the successful clinical development of the antiestrogenic drug tamoxifen did not initially focus on the therapy for breast cancer but evolved to this application by drawing upon expertise in several unrelated disciplines. Most of the early interest in antiestrogens was focused on reproductive endocrinology but it was clear from the beginning of clinical studies that the effects of the drugs on cholesterol biosynthesis would play a pivotal role in assessing safety considerations for long-term therapy....

The Discovery of ICI46474

Although the discovery of ICI46,474 (tamoxifen) (Figure 4), the antiestrogenic, pure trans isomer of a substituted triphenylethylene, was made by Harper, Richardson, and Walpole45-47 as part of the Fertility Control Program at ICI Pharmaceuticals (now AstraZeneca), Cheshire, UK, the study of cancer therapies was Walpole's long-term interest.48 In the late 1940s Walpole was a member of staff at ICI's Dyestuffs Division Biological Laboratory in Wilmslow, Cheshire. This establishment was the fledgling predecessor of the Pharmaceuticals Division Research Laboratories built in 1956-57 at Alderley Park near Macclesfield, Cheshire. Walpole was asked to establish animal models for the bioassay of potential alkylating agents49-54 to evaluate compounds as bladder carcinogens55 and to assess the potential health hazards for workers in the dyestuffs industry.56 Walpole made the important discovery that tris-ethyleneimino-S-triazine (M9500) was an active anticancer agent in the Walker rat...

Studies Published by Scientists at ICI Pharmaceuticals Division

The work of others, testing compounds from competing pharmaceutical companies, established the activity and potential value of antiestrogens for the induction of ovulation in subfertile women.12,13,24,26,78-80 Cancer therapy was a remote possibility as the treatment strategy at the time for advanced (metastatic) breast cancer was either endocrine ablation or additive high-dose hormonal therapy.81 Although additive hormonal therapy was cheap, only one in three patients responded and the average response duration was 1 year. Nevertheless, a few unsuccessful attempts to test antiestrogens had occurred (Table 1). Table 1 Preliminary clinical trials of antiestrogens for the treatment of metastatic breast cancer Table 1 Preliminary clinical trials of antiestrogens for the treatment of metastatic breast cancer The compound ICI46,474 was discovered in the screening process for antifertility agents in the rat. Many of the laboratory studies with ICI46,474 focused on the application of an...

Evaluation of Therapy in Advanced Head and Neck Cancer

If survival cannot be used as an endpoint, the morbidity associated with these approaches needs to be compared. Radical surgery is certainly associated with significant functional deficits, as is radical radiation with or without chemotherapy. Comparing the deficits after the different approaches would be useful, but this can be quite difficult given the myriad of surgical and reconstructive procedures available and the different organ preservation approaches used.

Conversation between the Laboratory and the Clinic

In 1973, Nolvadex was approved by the UK Committee on the Safety of Medicines for the treatment of breast cancer. Nolvadex subsequently became available in more than 110 countries as first-line endocrine therapy for the treatment of breast cancer. The early remarkable clinical success of tamoxifen encouraged a closer examination of its pharmacology with a view to further development and wider applications. Originally, 4-hydroxytamoxifen was believed to be the major metabolite of tamoxifen in patients but Adam at ICI Pharmaceuticals Division demonstrated that N-desmethyltamoxifen was the principal metabolite found in patients.97 There was usually a blood-level ratio of 2 1 for N-desmethyltamoxifen to tamoxifen in patients maintained on tamoxifen therapy, since N-desmethyltamoxifen had twice the plasma half-life of tamoxifen (14 days vs. 7 days). Recent studies demonstrate that a new metabolite 4-hydroxy-N-desmethyltamoxifen could play a role in breast cancer therapy of select...

The Discovery of Posaconazole

Medicinal Chemistry Health And Healthy

Posaconazole15 (21) is a novel triazole that has broad-spectrum antifungal activity against Aspergillus spp., Cryptococcus spp., Histoplasma spp., and a variety of other pathogens. In the clinic, posaconazole has been found to be well tolerated, with common side effects being gastrointestinal in origin. Life-threatening opportunistic fungal infections occur in AIDS patients, and also in patients undergoing chemotherapy for cancer, or those who have undergone organ transplants. The older antifungals do not work well with these patients, and the use of amphotericin B, a broad-spectrum antifungal, is limited in its use by its inherent toxicity. Posaconazole has been demonstrated in extensive clinical trials to be a potent orally active antifungal agent that works very well in the above-mentioned patient population. In recent years, considerable progress has been made in cancer chemotherapy, with the discovery of paclitaxel,

Sectio N 314.166 Of

The concept of randomization was first introduced in clinical research in the early 1930s for a study of sanocrysin in the treatment of patients with pulmonary tuberculosis (Amberson et al., 1931). However, the principle of randomization was not implemented in clinical trials until mid-1940s by the British Medical Research Council under the influence of Sir Austin Bradford Hill (1948). Since then there have been tremendous debates over the use of randomization in clinical research (e.g., see Feinstein, 1977, 1989). The primary concern is that it is not ethical for the patient not to know which treatment he or she receives, especially when one of the treatments is a placebo. However, it was not realized that before a clinical trial is conducted, no one can be 100 sure that the active treatment is indeed effective and safe for the indicated disease compared to the placebo. For many drug products it is not uncommon that the active treatment has inferior efficacy and safety than the...

Selective Estrogen Receptor Modulation

In the 1960s and 1970s, antiestrogenicity was correlated with antitumor activity. However, the finding that nonsteroidal antiestrogens expressed increased estrogenic properties, i.e., vaginal cornification and increased uterine weight in the mouse, raised questions about the reasons for the species specificity. One obvious possibility was species-specific metabolism, i.e., the mouse converts antiestrogens to estrogens via novel metabolic pathways. However, no species-specific metabolic routes to known estrogens were identified but knowledge of the mouse model created a new dimension for study that ultimately led to the recognition of the target site-specific actions of antiestrogens. This concept was subsequently referred to as selective estrogen receptor modulation (SERM) to describe the target site-specific effects of raloxifene (see 8.09 Raloxifene), an antiestrogen originally targeted for an application in breast cancer but now used, paradoxically, as a preventive for...

Mast Cell Disease Urticaria Pigmentosa

Urticaria Pigmentosa

Chemotherapy including interferon alfa if bone marrow involvement topical steroids close clinical follow-up in patients with adult-onset disease Treatment options vary with the extent of disease. Cutaneous lesions can be watched or treated with topical steroids or even surgical excision of limited lesions. More extensive disease requires topical steroids, antihistamines, chemotherapy, interferon, and ultraviolet light therapy. None of these options are entirely effective.

Current Chemoprevention

Based on a thorough review of all the available data, the FDA approved tamoxifen for the reduction of breast cancer incidence in high-risk pre- and postmenopausal women in 1998. However, the report that tamoxifen caused a small but significant increase in uterine sarcoma209 resulted in an industry request for a black box inclusion for tamoxifen from the FDA. Additionally, the IBIS-1 study noted an unacceptable increase in deaths from tamoxifen treated patients who inadvertently had surgery during the study acceptability of tamoxifen as a chemopreventive.210 This led to the development of IBIS-2 using an aromatase inhibitor to prevent breast cancer. Aromatase inhibitors have fewer side effects than tamoxifen and it is known that during adjuvant treatment, they reduce the incidence of contralateral breast cancer even more than tamoxifen.211-213 Another approach is the evaluation of the SERM raloxifene as a preventive for breast cancer in high-risk postmenopausal women. The Study of...

Tamoxifens Legacy A Menu of Medicines

Tamoxifen became the most investigated anticancer agent over the 40 years of its development. The success of the drug as an adjuvant therapy has been quantified 400 000 women with breast cancer are alive because of long-term tamoxifen treatment. Most importantly, the development of tamoxifen demonstrated that there was an advantage for patients by targeting the estrogen receptor specifically. This in turn encouraged the pharmaceutical industry to invest in research to discover both safer and more effective drugs. This is best illustrated by comparing treatment options for advanced breast cancer in 1970, i.e., before tamoxifen (Figure 7) with the therapeutic options for all stages of breast cancer in 2005 (Figure 8). Figure 7 The endocrine options in the early 1970s for the patient with metastatic breast cancer. Surgery to remove endocrine organs (ablative surgery) which secreted estrogenic hormones or their precursors. In the case of postmenopausal patients, additive high-dose...

Altered Biodistribution of Radiopharmaceutical

Significant dehydration, ascites, anasarca, and renal and or hepatic failure cause increased soft-tissue uptake, resulting in a low bone-to-background ratio and degraded scan images. Unlabeled 99mTc-pertechnetate and oxidation of 99mTc-labeled phosphate complex may also increase the background activity, with undesirable tracer accumulation in the thyroid and liver as well as disturbance of alimentary tract excretion (see Chap. 5). On the other hand, the systemic administration of adjuvant chemo-therapeutic agents, steroids, or iron is known to suppress bone uptake of tracer (Hladik et al. 1982). It is of interest that adjuvant chemotherapy may occasionally cause healing bone malignancies to flare up with increased tracer uptake so that they appear unresponsive to the treatment (Gillespie et al. 1975 see Chap. 17).

Bone Marrow Medullary Stroma Cells

Bone Marrow Osteoblasts Blood Film

Fig. 20 Bone marrow stroma. a Spindle-shaped fibroblasts form the structural framework of the bone marrow (shown here aplastic hematopoiesis after therapy for multiple myeloma). b A macrophage has phagocytosed residual nuclear material (here after chemotherapy for acute leukemia). c Bone marrow osteoblasts are rarely found in the cytological assessment. The features that distinguish osteoblasts from plasma cells are their more loosely structured nuclei and the cloudy, busy basophilic cytoplasm. d Osteoclasts are multinucleated giant cells with wide, spreading cytoplasm. Fig. 20 Bone marrow stroma. a Spindle-shaped fibroblasts form the structural framework of the bone marrow (shown here aplastic hematopoiesis after therapy for multiple myeloma). b A macrophage has phagocytosed residual nuclear material (here after chemotherapy for acute leukemia). c Bone marrow osteoblasts are rarely found in the cytological assessment. The features that distinguish osteoblasts from plasma cells are...

Identification and Structural Characterization of Human Collagenase3

These considerations, led us to speculate that samples of human tumor specimens were an appropriate starting material to identify putative novel members of the MMP family potentially involved in the spread of cancer. To test this idea, we designed a PCR-based homology cloning strategy, using RNA isolated from breast carcinomas and degenerate oligonucleotides encoding structural motifs conserved in MMPs. When we initiated this work, a total of nine human MMPs had been isolated and characterized at the amino acid sequence level (interstitial collagenase, neutrophil collagenase, gelatinases A and B, stromelysins-1, -2, -3, matrilysin, and macrophage metalloelastase).3,4 A comparison of their amino acid sequences revealed two sequences conserved in all of them, the activation locus (PRCGVPD) and the Zn-binding site (VAAHEXGH). After synthesizing two degenerate oligonucleotides encoding these conserved motifs and performing RT-PCR of total RNA isolated from a mammary carcinoma, a band of...

Analysis of Cytotoxic Agents in Xenograft Models

Retrospective evaluation of activity of established cytotoxic agents in clinical trials versus preclinical models shows that, in general, activity in xenograft models is predictive of some level of clinical response. Several reports have detailed good correlations between xenograft response and clinical response for rhabdomyosarcoma, colon cancer, lung cancer (particularly small-cell lung cancer), breast cancer, and myeloma.26'52'53 Table 1 shows a partial compilation of data generated in our department examining the activity of numerous standard cytotoxic agents as well as selected novel targeted agents in a variety of xenograft and syngeneic flank tumor models. Both early treatment (ET) and staged tumor (ST) trials are included and it can be seen that in some cases the magnitude of response is quite similar in the two cases (e.g., paclitaxel in the A549 model), while in others there are significant differences in response (e.g., paclitaxel in breast cancer).

Raloxifene and Lipids

To address the question of whether raloxifene reduces the risk of CHD, a total of 10 101 women (at increased risk of CHD) have been recruited to receive placebo or raloxifene in the RUTH trial, with cardiovascular disease as a primary endpoint.177 The RUTH trial (Figure 9) is designed to determine whether raloxifene (60mgday 1), compared with placebo, reduces the risk of coronary events and invasive breast cancer in postmenopausal women at risk for a major coronary event. Figure 9 Study design of the Raloxifene for Use in The Heart (RUTH) trial. The RUTH trial is a double-blind, placebo-controlled, randomized clinical trial designed to evaluate whether 60 mg day-1 of oral raloxifene compared with placebo reduces the risk of coronary events. Between June 1998 and August 2000,11 767 women signed an informed consent agreement to participate in RUTH at 187 sites in 26 countries. After excluding 1411 women who did not meet inclusion criteria and 255 women who met more than one exclusion...

Drug Resistance and its Clinical Circumvention

Drug resistance is the most significant reason for treatment failure in cancer and there are several underlying causes for this phenomenon. Perhaps the most well-defined and researched factor is the presence of ABC transporters, including P-glycoprotein (P-gp), the product of the MDR1 gene the MRP or ABCC transporter subfamily ABCG2, a mitox-antrone transporter (also known as the breast cancer resistance protein (BCRP) the ABC transporter in placenta (ABCP) and mitoxantrone-resistance gene (MXR) (Table 2).

In Vivo and In Situ Methods

Although there is a general relation between BBB permeability and lipophilicity (Figure 4), such plots show a number of outliers. Those considerably above the line generally prove to be substrates for uptake carriers at the BBB, while many below the line prove to be substrates for efflux transporters, such as P-gp. This was most strikingly demonstrated in P-gp knockout mice (initially mdrla, later double-knockout mdr1a 1b - -), when log BB increased up to 90-fold for certain compounds, identifying them as P-gp substrates.32 A high proportion of established CNS-active drugs are proving to be substrates for P-gp33 yet these are efficacious drugs there are indications that if passive BBB permeability, and potency on the target site, are high enough, these factors can outweigh the effect of P-gp-mediated efflux at the BBB. Nevertheless, transport by P-gp needs to be taken into account in designing and optimizing new CNS drugs, since it will affect the free drug concentration in brain ISF...

Comparing means an example

Suppose we wish to design a study in which the aim is to compare glomerular filtration rate (GFR) in two groups of ovarian cancer patients, one receiving carboplatin-based chemotherapy and one receiving cisplatin-based therapy. The GFR follows an approximate Normal distribution, and so it would be appropriate to summarize the GFR by the group means, and to compare the groups using a two-sample t-test (see also Section 9.3.3). Assume the GFR in the carboplatin group is 100ml min one year after start of chemotherapy. We wish to determine the sample size needed to detect a decrease in GFR of 10 ml min in the cisplatin group at the same time point. From equation 5.2, we need not only an estimate of the difference in GFR, but also an estimate of the standard deviation in each group (here assumed to be the same). This can be taken from previous data or, as an approximate rule, one can divide the range of possible values of a Normally distributed variable by four to get an estimate of the...

Other Selective Estrogen Receptor Modulators

Current interest in new SERM molecules has built on the experience of the prototypes with the goal of enhancing bioavailability and selectivity and decreasing side effects (i.e., breast cancer, uterine cancer, and blood clots). All compounds under study have predominantly antiestrogenic effects in the rodent uterus with virtually no estrogen agonist properties. In order to improve upon the raloxifene pharmacophore, some groups have reported on the effect of modifying the benzothiophene nucleus. Particularly noteworthy were two discoveries made by the chemists at Eli Lilly which improved upon raloxifene.77 One change involved the introduction of a methyl ether on either the 5-OH or the 4'OH position, which resulted in compounds with increased potency in a cholesterol reduction assay in ovariectomized rats.178'179 The other change involved the replacement of the carbonyl 'hinge' with other atoms or groups, including N, CH2, S, and O. The change to the oxygen atom resulted in a compound...

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