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One of the side chains usually contains a hydroxyl moiety erectile dysfunction gnc purchase tadacip online pills, which allows high affinity for calcium and bone mineral erectile dysfunction doctor in patna discount tadacip 20 mg with visa. The structural variation in the other side chain produces differences in the antiresorptive properties and toxicities (12) xatral impotence tadacip 20 mg online. Within the family of bisphosphonates erectile dysfunction drugs pictures purchase tadacip online from canada, there are more similarities in pharmacologic effects than differences, although side effect profiles, rates of oral absorption, and potency do differ. Although differences in their molecular mechanism of action exist, all therapeutic bisphosphonates have a final inhibitory effect on osteoclast function. Bisphosphonates have a powerful affinity for bone; 40% to 70% of an intravenous administration binds rapidly to the bone surface, preferentially at sites of increased bone formation or resorption with the remainder excreted in the urine. However, the half-life in bone is very long with biological effects of the most potent agents such as zoledronic acid still evident years after administration of a single dose (14). Once deposited on the bone surface, bisphosphonates are ingested by osteoclasts engaged in bone resorption. These agents interfere with bone resorption by producing a direct toxic apoptotic effect on osteoclasts, and by inhibiting their differentiation and maturation. Bisphosphonates fall into two classes, based on whether this second side chain is nitrogen-containing or not. Firstgeneration bisphosphonates, such as clodronate and etidronate, do not contain nitrogen. These agents substitute into the production of adenosine triphosphate, which then becomes a toxic adenosine triphosphate analogue that poisons the osteoclast (12). Nitrogen-containing bisphosphonates, such as pamidronate, alendronate, risedronate, ibandronate, and zoledronic acid, interfere with cell signaling and block the prenylation of small signaling proteins that are essential for osteoclast function and survival (12). Several bisphosphonates are available worldwide for various conditions, with variable antiresorptive potency and route of administration (Table 47-1). The clinical impact of the differences in relative potency between bisphosphonates is not well documented, because only a few direct clinical trial comparisons have been conducted. Although all bisphosphonates can theoretically be administered either orally or intravenously, the oral bioavailability of any bisphosphonate is extremely limited and so for some only intravenous formulations have been developed. The dose and frequency of administration varies depending on the clinical indication, with doses used to treat bone metastases being about 10-fold higher than those used to treat osteoporosis. For example, the zoledronic acid dose approved for treating bone metastases is 4 mg intravenously every 3 to 4 weeks. When used in the treatment of osteoporosis, it is approved as a 5-mg dose once yearly. Ibandronate, available in both oral and intravenous forms, is given 50 mg orally daily or 6 mg intravenously monthly for bone metastases, compared with 150 mg orally monthly or 3 mg intravenously every 3 months for osteoporosis. In the United States, ibandronate is approved only for the osteoporosis indication. Doses of bisphosphonates under investigation in the adjuvant breast cancer setting for prevention of metastases have ranged from full bone metastasis treatment doses to somewhat lower doses or less frequent administrations more similar to the osteoporosis treatment schedules. In vitro studies have demonstrated that bisphosphonates can inhibit critical steps in development of metastases in the bone, including adhesion and invasion (15). Animal tumor model systems have shown that bisphosphonates can inhibit development of bone metastases, reduce tumor burden in the bones, and improve survival in nude mice injected with human breast cancer cells (5,16,17). Although most animal models suggest that the primary antitumor effect of bisphosphonates is manifested in the bone, some data indicate also an effect of bisphosphonates on extraskeletal metastases. Additionally, nitrogen-containing bisphosphonates can directly induce tumor cell apoptosis, inhibit tumor cell proliferation, and synergistically with cytotoxic chemotherapy agents commonly used in breast cancer treatment (5,16,21). The high doses of bisphosphonates that have been used in many laboratory studies suggesting direct anticancer activities are incompatible with the clinical doses and schedules approved for the treatment of cancer patients. Whether a direct antitumor effect of bisphosphonates plays a clinically significant role in the treatment or prevention of cancer in humans remains unproved. Although bone-targeted treatments have had a profound effect on skeletal morbidity and quality of life in advanced breast cancer, clear improvements in survival of advanced cancer patients have not been seen. The studies may have been underpowered to detect survival advantages or, more likely, reflect the futility of modifying the bone microenvironment to influence the large burden of disease present with overt metastases. However, in the adjuvant setting, where the disease burden is microscopic and potentially more receptive to cellular changes in the bone marrow, the anticancer effects of bone-targeted treatments seen in the preclinical models are more likely to be mirrored in patients. Clodronate is approved for the treatment of metastatic bone disease in many parts of the world (except the United States) while the development of oral pamidronate was abandoned due to poor absorption and gastrointestinal toxicity at the high doses required for effects on bone metabolism. A larger, randomized, placebo-controlled, multinational trial was conducted in which 1,079 patients with early-stage breast cancer were randomized to receive either clodronate (1,600 mg/day) or placebo for 2 years in addition to standard systemic therapy (26). Patients were assessed for bone metastases at 2 and 5 years, and as clinically indicated. Follow-up showed a continued separation of the survival curves between years 5 and 10 (26). This study showed no reduction in bone metastases in the clodronate treated arm, and, at least at the time of the initial report, a worrisome increase in visceral metastases and a reduction in overall survival at 5 years for patients receiving clodronate. This small study also had some imbalances in important prognostic factors that may explain the apparent adverse effects with clodronate. Nevertheless, this study had a disproportionate effect on the perception of adjuvant clodronate as an adjuvant treatment and regulatory approval based on the other two positive studies was not achieved.

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Bone is the most common site of disseminated disease erectile dysfunction treatment exercises discount 20mg tadacip with visa, and represents approximately 40% of first recurrences erectile dysfunction drugs uk safe 20 mg tadacip. The most commonly involved bones are the spine erectile dysfunction caused by spinal stenosis order genuine tadacip online, ribs erectile dysfunction drugs medications quality tadacip 20mg, pelvis, skull, femur, and humerus. Other common sites for metastatic disease include lung, liver, lymph nodes, and soft tissue. The site of first metastasis from breast cancer is influenced by estrogen receptor status (Table 67-1). Estrogen receptor-positive breast cancer is more likely to spread to bone, while receptor-negative breast cancer is more likely to spread to viscera and soft tissues and is associated with a higher rate of early recurrence (Table 67-1) (22,23). Even in those patients undergoing routine surveillance during follow-up, most recurrent disease is symptomatic at time of diagnosis (24,25). Infiltrating lobular breast cancer has a propensity for recurrences in intra-abdominal and retroperitoneal sites including stomach, intestine, peritoneum, and ureter (often bilateral) (26). Currently available treatment of recurrent or metastatic breast cancer is rarely curative, even when the recurrence is limited (2). Further, the amount of tumor burden in asymptomatic or minimally symptomatic patients does not predict disease response to systemic treatment, ability to palliate symptoms, or overall survival. Thus, there is no advantage to diagnosing asymptomatic, early, subclinical disease. At the time of analysis, 2,140 patients had experienced a relapse, 93 had a second non-breast primary tumor, and 111 had died without relapse during 10-years median follow-up. In this analysis, only alkaline phosphatase was abnormal in at least 20% of patients with recurrent disease, and was abnormal in 32% of patients with bone metastasis and 71% of patients with liver metastasis. Aspartate aminotransferase and -glutamyl transferase were elevated in 62% and 75% of patients with liver metastasis. Bilirubin, calcium, and creatinine were of no value in detecting recurrent disease. Thus, while alkaline phosphatase was the most reliable of the blood tests, it was of low sensitivity for bone or liver disease. In another study of 1,371 patients with node positive breast cancer, serial alkaline phosphatase determinations were found to have low sensitivity and specificity for bone recurrence (28). Thus, monitoring of routine blood tests as a part of breast cancer surveillance is not recommended. In a study of 1,601 women with node positive breast cancer, 1,441 had a baseline and repeat bone scan at one year of follow-up (28). This study documented the inability of the one year bone scan to predict for the eventual development of bone recurrence. With a median of 4 years of follow-up, those women with a normal one year bone scan had a 6. There is, thus, no evidence supporting the use of routine surveillance for bone recurrences in women with a history of early stage breast cancer. Elevations in these antigens are common in patients with newly diagnosed breast cancer, and their levels are prognostic in some studies. Prospective and retrospective studies using these markers in breast cancer surveillance following primary treatment demonstrate that recurrences of breast cancer may be detected with low to modest sensitivity approximately 5 to 6 months prior to the detection of metastatic or recurrent disease by other methods (29). However, false positive elevations in these markers are common with associated risk of incorrectly diagnosing recurrence of disease, and no advantage in overall survival or quality of life has been demonstrated with the use of these markers. Liver Specific Monitoring Prospective study of intensive surveillance including liver ultrasonography and liver function tests versus minimal testing have found no difference in the cumulative rate of detection of breast cancer hepatic metastasis during any time interval up to 5 years (24). No prospective studies testing the value of computed tomography of the liver as surveillance have been reported. Existing data from other surveillance studies predict that computed tomography surveillance would be neither efficacious nor cost effective. Thus, there is no evidence supporting the performance of liver specific monitoring in the surveillance of women with a history of early stage breast cancer. Lung Specific Monitoring Most patients with pulmonary recurrences of breast cancer present with symptoms referable to the chest. Studies addressing the use of routine screening chest radiographs have demonstrated very low rates of metastases detection in the asymptomatic patient. In a study of 241 patients with node positive breast cancer who underwent serial chest radiography the first two years following diagnosis, 3. In a prospective randomized trial of intensive versus spontaneous surveillance, the utility of chest radiographs was specifically assessed (37). Neither disease free nor overall survival was improved with the routine performance of chest radiographs. Thus, the use of chest radiography in the surveillance of women with early stage breast cancer is discouraged. Bone Specific Monitoring Bone pain is a common symptom of bone metastasis from breast cancer. However, many patients with bone pain do not have recurrent cancer, and up to 32% of patients with bone metastasis do not have pain (33,34). Radionuclide bone scanning is, in general, a sensitive and moderately specific imaging modality for breast cancer metastatic to bone. At the time of the analysis, 779 patients had experienced a recurrence, and 163 of these were in bone only.

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Internal mammary lymph node recurrence: rare but characteristic metastasis site in breast cancer impotence at 17 purchase 20mg tadacip with visa. Thoracoscopic approach in the treatment of breast cancer relapse in the internal mammary lymph node erectile dysfunction doctors in kansas city generic 20mg tadacip mastercard. Review of local soft tissue recurrence of breast cancer irradiated with and without actinomycin-D erectile dysfunction treatment operation buy 20mg tadacip. A trial of human alpha interferon as an adjuvant agent in breast cancer after loco-regional recurrence impotence lower back pain buy generic tadacip 20 mg on-line. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03-05 study. Prognostic value of genomic analysis after neoadjuvant chemotherapy for breast cancer. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. Regression of skin recurrences of breast carcinomas treated with intralesional injections of natural interferons alpha and gamma. Partial breast irradiation for locally recurrent breast cancer within a second breast conserving treatment: alternative to mastectomy An evaluation of photodynamic therapy in the management of cutaneous metastases of breast cancer. Systemic drug treatments such as chemotherapy, endocrine therapy, biological targeted therapy, and supportive therapies, including bisphosphonates for bone disease, are the mainstay of care. The clinical decision as to which is the most appropriate treatment option is based on a number of patient- and disease-related factors (Table 70-1). Excellent clinical responses can be achieved with simple well-tolerated endocrine therapy such as the antiestrogen tamoxifen, albeit maximal response and tumor shrinkage may take between 6 and 9 months to occur. However, sites of visceral metastases such as the liver may also respond well to endocrine therapy provided appropriate selection of patients is undertaken. They may lack any symptoms from their advanced disease and show good overall performance status. Therefore, appropriate selection of patients who are suitable for initial endocrine therapy is therefore crucially important in order to maximize the benefits from such treatments, in particular as long-term disease control for up to 18 months with minimal side effects is not uncommon. In this chapter the evidence for each of the current endocrine therapy options that are available for advanced disease in both post- and premenopausal women are reviewed in more detail, together with the emerging strategies that might be used in the future to further enhance their effectiveness. In particular, recent results from several key clinical trials of endocrine therapy (including those in combination with various targeted signaling inhibitors) will be discussed, along with the implications for the optimal sequence of endocrine therapies in advanced breast cancer. However, one of the key factors that determine whether endocrine therapy will be an effective option for metastatic disease relates to prior exposure to adjuvant endocrine therapy and to the level of hormone receptor expression. These issues will be addressed first, before reviewing the clinical data that are available with each of the various current endocrine treatments in first- and secondline settings and the future strategies that might be used to circumvent/prevent endocrine resistance. Initial sensitivity to adjuvant therapy in early breast cancer can be an important predictor for the likelihood of response to further endocrine therapy in the metastatic setting. Alternatively, some patients may relapse at the end, or shortly after completing adjuvant endocrine therapy, and as such could have developed "acquired" resistance, which may still allow response to alternative endocrine therapies. Alternatively, patients may relapse at a much later time point many years following completion of their adjuvant endocrine therapy (late relapse), and cancer cells in this situation may have retained full endocrine sensitivity. Thus the time point for relapse from diagnosis (disease-free interval) and also from prior adjuvant therapy (treatment-free interval) both might determine the response to further endocrine therapy in the metastatic setting. However, its actions are complex due to partial estrogenic agonist effects that in some tissues. The proportional risk reduction was not significantly affected by age, the use of chemotherapy, nodal status, or expression of PgR, with the absolute benefit relating to absolute risk of recurrence. Increasingly, it has become important to establish whether the receptor status in the tumor changes during progression from early breast cancer to regional or metastatic recurrence, because this itself may be the most important factor in determining the likelihood of response to further endocrine therapy. As such, re-biopsies taken from sites of metastatic disease whenever clinically appropriate and feasible are increasingly recommended in order to plan appropriate systemic further therapy, in particular whether an endocrine approach will be effective option. Tamoxifen was generally well tolerated with a low incidence of serious side effects, including a low but significantly increased incidence of endometrial cancer and thromboembolic events due to its partial estrogenic agonist effects (16). The time-point for relapse from diagnosis (disease-free interval) and also from prior adjuvant therapy (treatment-free interval) both might determine the response to further endocrine therapy in the metastatic setting. Exemestane is a steroidal aromatase inactivator with a half-life of 27 hours. The North American study in 353 women showed that anastrozole significantly prolonged the time to disease progression from 5. Short-term side effects such as hot flashes, vaginal dryness, and headaches were infrequent and similar in both trials in comparison with tamoxifen. Of particular note in this trial, nearly 20% patients had received prior tamoxifen in the adjuvant setting, although it had ceased a median of 3 years prior to development of metastatic disease-in this subgroup, retreatment with tamoxifen had a low response rate of 8% compared with a 32% response rate with letrozole. The improvements in clinical efficacy for letrozole resulted in an early improvement in survival during the first 2 years, although with longer followup this difference was lost (39). The explanation for this may relate to the high number (>50%) of patients who prospectively crossed over to the alternate treatment at the time of progression, because significantly more patients benefited from second-line letrozole after progression on tamoxifen than from second-line tamoxifen after letrozole. Likewise, a European study in 383 patients compared the efficacy and tolerability of the steroidal aromatase inactivator exemestane with tamoxifen as first-line therapy (40). It is not clear that one drug is significantly better than any other when direct comparisons have been made, although letrozole achieved greater aromatase inhibition than anastrozole in a crossover pharmaco-dynamic trial (42). While there are no comparative data for exemestane with anastrozole or letrozole, further clinical responses have been reported for both exemestane and the second-generation steroidal inhibitor formestane in patients relapsing after anastrozole, letrozole, or the other nonsteroidal inhibitors, suggesting some partial non-cross resistance between the two types of inhibitors (44,45).

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The endothelial cells are distributed in a flat monolayer around the vascular spaces without papillary endothelial proliferation erectile dysfunction drugs natural discount tadacip 20 mg without a prescription, and rare mitoses are seen erectile dysfunction from steroids order tadacip 20mg on-line. These tumors consist of prominent epithelial tufting and solid papillary formations with cytologically malignant endothelial cells impotence from steroids buy generic tadacip 20mg line. Areas of necrosis and hemorrhage impotence psychological buy tadacip 20mg amex, so called "blood lakes," are only found in high-grade angiosarcomas. The high-grade tumors have infiltrative borders that feature low-grade vascular channels, which may lead to the erroneous diagnosis of a low-grade lesion on a core biopsy. These reagents are useful for distinguishing angiosarcomas from carcinoma and other neoplasms. Postirradiation Angiosarcomas of the Skin the histological features of post-radiation angiosarcomas differ from primary breast angiosarcomas and mainly involve the skin with or without occasional invasion of the subjacent breast parenchyma (24,25). High-grade areas are solid, epithelioid, or spindle cell foci with slit-like spaces with intraluminal or extravasated red blood cells. In addition, regardless of the microscopic pattern, malignant cells in post-radiation angiosarcoma have poorly differentiated nuclei with prominent nucleoli and mitotic activity. Open, anastomosing vascular channels with prominent endothelial nuclei are evident. More cellular than low-grade, with small buds of endothelial cells projecting into the vascular lumen. Solid papillary formations and prominent endothelial tufting containing cytologically malignant cells are evident. Histologically, a focal proliferation of anastomosing vascular channels lined by a single layer of endothelial cells with occasional hyperchromatic nuclei is seen. The vascular spaces are usually empty and are limited to the superficial and mid-dermal areas. However, in this study, the response rate to anthracycline- and gemcitabine-based chemotherapy in the metastatic setting was 48%, suggesting that breast angiosarcoma is potentially a chemosensitive disease (21). Osteogenic Sarcoma of the Breast Extraskeletal osteosarcoma of the breast is an extremely rare tumor, accounting for 12. Primary breast osteosarcomas are considered highly aggressive tumors with early local recurrence and hematogenous spread (most commonly to the lungs). The most common presentation is a circumscribed and movable mass that on mammography may show osseous trabeculae or coarse calcifications. The most common variants observed are fibroblastic, osteoblastic, and osteoclastic. In the osteoblastic osteosarcoma, the osteoid is deposited in a fine, ramifying, lacelike, or coarsely trabecular pattern Treatment of Angiosarcomas of the Breast the optimal surgical treatment of breast angiosarcoma is segmental mastectomy if negative margins can be achieved or total mastectomy if the former is not possible (27,28). Patients with angiosarcomas have a worse prognosis than patients with other types of sarcoma (6). The most important prognostic markers are histologic grade (subtype) and tumor size although histologic grade was not prognostic in one study (9). Of the 3,500 cases of rhabdomyosarcoma registered with the Intergroup Rhabdomyosarcoma Group of the United States between 1972 and 1992, only 7 (0. When the data were restricted to the 423 women aged between 10 and 21 years of age, only 1. Histologically, alveolar rhabdomyosarcoma is composed of small, round cells that make poorly defined aggregates. The differential diagnosis, which includes malignant lymphoma and invasive lobular carcinoma, can be resolved by using immunostains for myoid, epithelial, and lymphoid markers. Cytogenetic studies may show the characteristic translocations t(2;13)(q35;q14) or t(1;13)(p36;q14) (32). The treatment of choice for embryonal rhabdomyosarcomas of the breast is surgical resection with wide tumor-free margins. Treatment of rhabdomyosarcomas is multidisciplinary and may include radiation and chemotherapy in addition to surgery. A five-year survival rate of 43% was reported in patients with breast rhabdomyosarcomas. Malignant cells with round nuclei and prominent nucleoli with lacelike osteoid are seen. Multinucleated osteoclastic giant cells are usually present in areas of bone formation. The relationship between prior breast or chest wall irradiation and breast osteosarcoma is not clear. Like other sarcomas, spread to regional lymph nodes is uncommon with breast osteosarcoma. Of 39 patients with follow-up, locally recurrent (n = 11) or metastatic disease (n = 15) was documented at a mean of 10. Based on the limited data Figure 64-3 Alveolar rhabdomyosarcoma of the breast in a 16-year-old girl. The tumor is composed of a proliferation of small round cells mimicking a lymphoma. They should be described, classified, and treated in a manner similar to sarcomas originating in other sites. Some, such as malignant fibrous histiocytoma and fibrosarcoma, are sequelae of prior postmastectomy irradiation (5,35). These tumors can occur in all age groups but tend to be more frequent in women older than 50. Wide excision or total mastectomy has been performed, with the decision based on the characteristics of the tumor and the patient. The rather high local recurrence rate after wide excision in some studies suggests that total mastectomy might be preferred.

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The majority of patients enrolled in the extension trial received a combination of chemotherapy and trastuzumab male erectile dysfunction age buy generic tadacip canada, with the remainder receiving either trastuzumab alone or a combination of trastuzumab and palliative radiotherapy or hormonal therapy erectile dysfunction treatment with exercise cheap tadacip 20mg without prescription. The most commonly used chemotherapeutic agents used in the extension trial in combination with trastuzumab were paclitaxel erectile dysfunction over the counter medications order tadacip 20mg amex, vinorelbine erectile dysfunction drugs and high blood pressure buy tadacip 20 mg on line, docetaxel, and fluorouracil, although 8% of patients received concomitant doxorubicin. Although efficacy information from the trial was limited (safety was the primary objective), 14% of patients in group 1 and 11% of patients in group 2 experienced an objective response. These responses were observed both when trastuzumab was combined with chemotherapy and when single agent trastuzumab therapy was employed. The incidence of cardiac toxicity was relatively low, occurring in 9% of patients in group 1 and 2% of patients in group 2 (41). Despite these encouraging results, a separate retrospective review offers contrasting results. Among 132 patients who had progressed on trastuzumab-based therapy at the time of analysis, 21 patients experienced rapid progression and did not receive additional therapy, 40 patients received further trastuzumab-based regimens, and 71 patients received further non-trastuzumab-based regimens. Because this data is complicated by issues related to retrospective methodology, further trials were necessary to clarify the role of trastuzumab therapy beyond the time of initial progression. Patients (n = 78 in each arm) were then randomized to receive either capecitabine (at 2,500 mg/m2 on days 1 to 14 every 3 weeks) alone, or in combination with trastuzumab (at 6 mg/kg every 3 weeks). Continuation of trastuzumab beyond progression was not associated with increased toxicity (44). Although some questions and concerns continue regarding the efficacy of trastuzumab beyond progression, in light of the prospective, randomized data in support of treatment in multiple lines, and the potential for synergy by changing the chemotherapy base, continuation of trastuzumab beyond initial progression is widely practiced. In response to the observations that as many as half of chemotherapy + trastuzumab-treated subjects fail to achieve clinical response, and those that do have modest response duration, a significant body of evidence has been generated in the laboratory focused on mechanisms of trastuzumab resistance. Other purported mechanisms of trastuzumab resistance include limitations in drug distribution secondary to the size of the antibody. Additionally, vascular distribution of trastuzumab was highly irregular, and distribution of trastuzumab did not correlate with vascular density, as one would expect with unhindered trastuzumab transport (50). Interestingly, preclinical studies indicate lapatinib has significant activity even in trastuzumab refractory cell lines (51), leading to clinical investigations of lapatinib-based regimens following trastuzumab in subsequent randomized trials (52). The most commonly observed adverse events were diarrhea and cutaneous rash, the former in a dose-dependent fashion (33). In three of the four responders, inhibition of activated phospho-Akt and phosphor-Erk1/2 was noted, concordant with preclinical studies suggesting these moieties were inhibited by lapatinib. As in the phase I monotherapy study, diarrhea and rash were the most commonly observed toxicities (56). The most common toxicities incurred with this regimen were diarrhea, rash, nausea, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis (58). An interim analysis met pre-specified criteria for early reporting given superiority of the group receiving combination therapy. In contrast to trastuzumab-containing regimens, no symptomatic cardiac events were observed with lapatinib therapy (52). Similar preclinical observations led to the initiation of multiple clinical trials investigating the combination of lapatinib and taxanes. In 192 patients receiving either docetaxel or paclitaxel in combination with lapatinib, the rates of neutropenia and rash were similar to each agent alone, although the frequency of diarrhea was more pronounced. Although the analysis was centered on safety, a preliminary report from one trial assessed suggested a response rate of greater than 70% with the combination of lapatinib and paclitaxel (61). Data from placebo-controlled randomized trials combining lapatinib and paclitaxel have been reported. A total of 579 patients were randomized 1:1 to receive either lapatinib at a dose of 1500 mg daily with paclitaxel at 175 mg/m2 every 3 weeks, or placebo and paclitaxel on the same schedule. This observation served as the rationale for a phase I trial of lapatinib and capecitabine in advanced solid tumors. The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm; however, just 4% of patients in this group reported febrile neutropenia. The incidence of hepatic adverse events was similar in both arms, and there were no fatal adverse events in the lapatinib plus paclitaxel arm (63). Preclinical data focused on the comparisons between trastuzumab and pertuzumab and the synergy between the two agents. Scheuer and colleagues showed that as compared to trastuzumab or pertuzumab monotherapy, there was a synergistic effect of the two agents (71). Several phase I clinical trials testing pertuzumab as monotherapy or in combination with chemotherapy or trastuzumab in patients with metastatic breast cancer were undertaken in patients who were refractory to standard therapies. A second trial conducted by Baselga and colleagues included 66 patients who had prior trastuzumab therapy and had progressed. No clinically significant cardiac events were seen in this trial, in contrast to the Portera study, most likely because the eligibility criteria were more stringent with regards to cardiac dysfunction and study entrance (74). Similarly, treatment with trastuzumab had little effect on apoptosis or survivin concentration. However, the combination of lapatinib and trastuzumab led to markedly enhanced tumor cell apoptosis and downregulation of survivin (64). In a separate series of experiments examining a broad panel of breast cancer cell lines (including cells maintained in trastuzumab-conditioned media), synergy with concomitant trastuzumab and lapatinib treatment was observed in four cell lines (65). This open label trial used a two-stage design, with the initial stage comprised of lapatinib dose escalation to establish the optimally tolerated dose.

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