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! Read more...

Chemo Secrets From a Breast Cancer Survivor Summary

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Author: Nalie Augustin
Official Website: nalie.ca
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Induction Chemotherapy

A disappointing fact concerning the treatment of younger adults with AML is that the agents used for induction therapy now are much the same as three decades ago. Three days of an anthracycline (generally, daunorubicin or idarubicin) in conjunction with 7 days of continuous infusional cytarabine (100-200 mg m2 per day)17 remains the standard approach. It has been the practice in the Cancer and Leukemia Group B (CALGB) and other cooperative groups to perform a bone marrow examination approximately 2 weeks after the start of induction chemotherapy.1 If a sufficient degree of myeloblast reduction is not achieved, then 2 days of the same anthracycline and 5 days of cytarabine are administered as a reinduction cycle. Occasionally, serial bone marrows are necessary to clarify whether or not a reinduction cycle should be administered. Approximately 30 of younger adults with AML will require a second course (so-called 2 + 5 reinduction).1 Although not certain, the requirement for such a...

Finding the Breast Cancer Genes

Breast cancer is the most frequently diagnosed cancer worldwide, and is heavily publicized as the leading cause of cancer death for women in Britain and the second leading cause of cancer death for women in the United States.7 The news media, medical charities, and public health organizations in each country quote that a British woman has a 1-in-12 chance of developing invasive breast cancer during her lifetime, and that an American woman has a 1-in-8 chance. Although governments and medical charities (including the Imperial Cancer Research Fund and Cancer Research Campaign in Britain and the National Cancer Institute and American Cancer Society) have spent a considerable amount of money to look for a cause and to develop prevention and treatment strategies for the disease, neither an unequivocal cause nor a completely effective prevention, detection, or treatment strategy has yet been found. Mastectomy, which involves breast removal, not only has severe physiological and...

Subversion of Innate Immunity Receptors Stimulation of Toll Like Receptors on Lung Carcinoma Cells Modulates Cell

Some patients with lung cancer are treated by neo-adjuvant polychemotherapy, consisting in platinum salts and often gemcitabine or navelbine. Both A549 and SK-MES cells stimulated by Loxoribin or Poly U were found to be resistant to chemotherapy-induced cell death. It is therefore tempting to postulate that tumoral cells which express TLR7 or TLR8 at high levels could be stimulated upon viral induced inflammation and become resistant to chemotherapy (Cherfils-Vicini et al. 2010). We are currently analyzing a cohort of lung cancer patients having received neo-adjuvant chemotherapy before surgical resection in order to assess whether high TLR7 or TLR8 expressors are less susceptible to chemotherapy than low expressors. If it were so, it would provide a novel mechanism by which tumor cells gain growth and spreading advantages, i.e., resistance to apoptosis, to chemotherapy, expression of chemokine receptors, loss of Fibronectin 1, etc. It also calls some warning on the use of TLR7...

Maintenance Chemotherapy

Survival for adult ALL patients following matched sibling allo SCT in first remission is approximately 50 (range, 20-80 ).73 The International Bone Marrow Transplant Registry (IBMTR) compared 251 patients who received intensive postremission chemotherapy with 484 patients who received matched sibling allo SCT.74 Although 9-year DFS rates were similar 32 for chemotherapy and 34 for allo SCT a higher recurrence rate of 66 was observed for chemotherapy patients versus 30 for those receiving allo SCT, with treatment-related mortality being the main cause of failure in patients who received allo SCT. Allo SCT and autologous stem cell transplantation (auto SCT) in first remission were compared in a large French multicenter trial (LALA 87).75 Based on an intent-to-treat analysis, survival at 10 years was 46 for those receiving allo SCT compared to 31 for those receiving consolidation chemotherapy alone (p 0.04). The value of allo SCT was even more apparent after patients were classified into...

Chemotherapy as a Cancer Therapy

Chemotherapy is more scientifically based than either radiotherapy or cancer surgery. In the five years between 1999 and 2004, over 75 000 peer-reviewed articles have appeared in Medline (PubMed) on the topic of cancer chemotherapy. An additional tens of thousands of abstracts have been presented at the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research annual meetings. Out of this vast amount of research, over 115 new approvals have been made by the US Food and Drug Administration (FDA) for drugs used in the treatment of cancer patients (see http www.fda.gov cder cancer druglistframe.htm). All of these are based on clinical trials of some sort. But what is the nature and quality of these trials Has the current generation of anticancer drugs been proved to improve the overall survival of cancer patients of adults are rarely demonstrated in rigorous trials with chemotherapy. Surveys have shown that the two outcomes that cancer patients seek...

Chemotherapy Strategies

Variations on traditional induction therapy, usually including vincristine, prednisone, and an anthracycline intensified with cyclophosphamide and or L-asparaginase, are frequently used in the salvage setting. A second CR can occasionally be achieved in the subset of patients who had a long first remission or who developed recurrent disease after completing maintenance chemotherapy.10 Even one of the most favorable reports, however, achieved a CR in only 44 of the patients.11 Furthermore, the median survival for these patients was only 8 months, and 3-year survival was only 10 .

Chemotherapy For Acceleratedand Blastphase

Prior to the development of imatinib, the outlook for patients entering the advanced phases of CML was dismal. Chemotherapy was the mainstay for these patients, and the choice of chemotherapeutic agents generally followed the treatment plans for acute myeloid and lymphoblastic leukemia patients with accelerated or myeloid blast phase received cytarabine anthracycline-based regimens, while patients with lymphoid transformation received standard vincristine prednisone-based protocols. Although imatinib may now be considered the treatment of choice for patients with CML entering the accelerated or blast phase, most patients in the future will have already received imatinib as part of treatment for chronic-phase disease, and thus chemotherapy must still be considered as an important part of therapy. What has changed, however, is that patients entering advanced phases will have been treated with imatinib, and whether this changes the efficacy of chemotherapy is yet to be determined....

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....

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...

Breast Cancer Activists

The Washington-based National Breast Cancer Coalition and the San Francisco-based Breast Cancer Action (by the mid 1990s the most influential advocacy groups involved in breast cancer politics at the national level) cautioned against the widespread availability of the new technology. They worried that the risk information generated by BRCA testing would provide ambiguous results, because of the risk, rather than certainty, of future disease incidence and the paucity of medical management options available. Therefore, both suggested that testing be offered in a highly regulated manner and only in conjunction with extensive clinical care. In fact, the Representatives of these patient advocacy groups began to express such opinions almost as soon as the BRCA gene discoveries were announced. In a front-page New York Times article announcing the BRCA gene discovery, Nancy Evans, president of BCA, noted It's a very mixed blessing to have this knowledge . . . it's the first step in a long...

Clients Journey through the Breast Cancer Activists System

After the genes were analyzed, the client returned to the clinic on an ongoing basis for post-test counseling and long-term follow-up.10 Both groups were careful, however, to note that both counseling and laboratory services should remain confidential unless the client decided otherwise. BCA urged that the array and number of unresolved issues related to genetic testing for susceptibility to breast cancer make compelling the need for written informed consent prior to such testing or to the release of the results of such testing to third parties.11 This confidentiality of genetic-test results was already standard practice at genetics clinics in the United States, who had responded to concerns that genomic information in the medical record could fall into the hands of insurers or employers and cause discrimination.

Chemotherapy Plus Active Immunotherapy

Some recent clinical studies provide yet another somewhat surprising perspective on how active immunotherapy might synergize with chemotherapy. With the caveat associated with retrospective analysis, 25 patients with glio-blastoma multiforme were vaccinated with DCs loaded with autologous tumor HLA-eluted peptides or tumor lysate (78). Thirteen of these patients went on to receive subsequent chemotherapy. An additional 13 nonvaccinated patients analyzed in this study also received chemotherapy. Of the vaccine plus chemotherapy-treated patients, 42 were two-year survivors while only 8 of patients treated with chemotherapy alone or vaccine alone survived this long. It is hypothesized that infiltrating CD8+ T cells may upregulate markers on the tumor (e.g., Fas), which render cells more susceptible to chemotherapeutic drugs that kill targets via induction of apoptosis. In another study, a striking response rate of 62 among 21 extensive-stage small cell lung cancer patients treated with...

Combination Chemotherapy Regimens vs Radiation Alone

An early trial sponsored by the National Cancer Institute of Canada failed to establish a significant difference in locoregional control and overall survival when evaluating 212 patients with larnygeal or hypopharyngeal squamous cell carcinoma (SCCA) treated with 50 Gy in 20 fractions over 28 d or split-course radiotherapy of 25 Gy in 10 fractions over 14 d, followed by a 28-d rest and then 25 Gy in 10 fractions over 14 d beginning on d 43 with mitomycin C (10 mg m2 on d 1 and 43) in combination with continuous infusion 5-FU (1000 mg m2 d on d 1-4 and 43-46) (48). Nevertheless, this study suggested that the addition of chemotherapy may overcome the decreased activity of split-course radiotherapy. Adelstein et al. have recently reported preliminary results of a randomized phase III trial in 295 patients with unresectable stage III or IV HNC comparing three treatment arms arm A of standard fractionated therapy (2 Gy d) arm B was the same regimen of radiotherapy with three cycles of...

Induction chemotherapy and organ preservation

The rationale of induction or neoadjuvant chemotherapy is to decrease the locoregional tumor burden, decrease the need for surgery, promote organ preservation, and fundamentally increase the quality of life. A potential secondary role of induction chemotherapy is to treat micrometastatic disease and in turn prevent the appearance of distant disease. The use of induction chemotherapy has an essential role in laryngeal and hypopharyngeal cancers where primary treatment modalities initially included total laryngectomy with neck dissection followed by radiation therapy. Hence, patients would possibly suffer from loss of voice, develop swallowing dysfunction, and numerous changes in their daily Review of the literature demonstrates little justification for the use of induction (neoadjuvant) chemotherapy outside of a clinical trial, unless in the setting of laryngeal or hypopharyngeal carcinoma. Five well-controlled studies have evaluated induction chemotherapy with the traditional agents,...

Special considerations for chemotherapy in cNS tumors

Drugs that penetrate the BBB have the capacity to produce neurotoxicity as a dose-limiting side effect, which may compound other treatment-related neurotoxicities (e.g., methotrexate and RT). The use of chemotherapy, especially in high doses, in patients with CNS tumors carries additional hazards linked primarily to the infectious risks of ventricular- or lumbar-peritoneal shunts, central venous lines, and frequent episodes of fever, which cause difficulties in discriminating between shunt infections and febrile neutropenia. A recent publication analyzing tolerance of chemotherapy in patients with medulloblastoma showed that patients age 10-20 years were more likely to suffer toxicity and require modifications in treatment than individuals 5-10 years of age 102 . These data suggest that adolescent and young adult patients would benefit from a modification of the aggressive chemotherapy regimens often utilized in children.

Postoperative chemotherapy or chemoradiation

Three prior Lung Cancer Study Group (LCSG) studies have suggested postoperative cisplatin-based chemotherapy may have an impact on survival of NSCLC patients with pathologically documented stage II III disease. Although a treatment effect has been detected for nonsquamous cancer, and is suggested for squamous cancer, the treatment effect has been of marginal significance (35). Other studies have shown a modest improvement in disease-free survival with the use of chemotherapy after surgery, but little impact on overall survival (36,37). A frequent problem with postoperative chemotherapy has been the inability to deliver all the planned amount of drug in patients recovering from lung resection. Drug delivery rates of around 50 are often the rule.

Induction Chemotherapy and Radiation Therapy

It became evident in the 1980s that cisplatin-based chemotherapy improved the survival of patients with advanced NSCLC compared to supportive care (59,60). The higher response rates for stage III compared to stage IV disease, suggested there could be a theoretic advantage to pretreat stage III patients with ChT before RT. Smaller tumors with better oxygenation would potentially be more radioresponsive. Using ChT before radiation would allow assessment of chemoresponsiveness and gage the likelihood of controlling occult micrometastases. Phase II studies of induction (neoadjuvant) ChT followed by standard RT (60-63 Gy 6-7 wk) reported up to 80 response rates, 16 mo median survivals, and 30 2-yr survivals (61). Based on these observations, a series of phase III trials followed comparing RT with and without induction ChT, usually targeting good performance patients (KPS > 70 and weight loss < 5 ).

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...

Established singleagent oral chemotherapy

In patients who have CMML with a significant myelo-proliferative component, high WBC count, or organomegaly, treatment with single-agent chemotherapy has been the standard of care. Oral agents such as busulfan, 6-mercaptopurine, hydroxyurea, and oral etoposide have been used empirically with some success, but a prospective randomized study conclusively determined the superiority of hydroxyurea over etopo-side in terms of overall survival in patients with mostly advanced proliferative disease (i.e., splenomegaly, mild thrombocytopenia, and increased bone marrow blasts) 24 months for hydroxyurea versus 9 months for etoposide.10 This is the only prospective randomized study to date that has compared two treatment regimens in patients with CMML. Although neither regimen induced complete remission (CR) or affected the natural history of the disease, the results supported the idea of using hydroxyurea plus supportive care as the standard-of-care arm in any future randomized trials. No...

Intensive chemotherapy using combination regimens

The first patients with CMML who were treated with combination chemotherapy used to manage acute myel-ogenous leukemia (AML) were probably those whose initial diagnosis was AML that was later reclassified as MDS or CMML. In later trials in patients with AML, patients with CMML were occasionally included, along with RAEB and RAEBt, as all three categories were considered high-risk MDS. More often than not, little information was given on the clinical and hematologic status of CMML patients, and in such prospective studies, selection bias toward treating younger patients with advanced disease was likely. With few exceptions, treatment regimens consisted of cytarabine (given at standard dosages for 5-7 days) plus anthracycline or anthracene-dione antibiotics (daunorubicin, mitoxantrone, or idaru-bicin). A review of six such studies conducted between 1980 and 1995 identified only 35 patients with CMML, 11 (31 95 confidence interval 15.9-47.0 ) of whom achieved a CR.18 Duration of...

Combining Chemotherapy with Radiation Therapy

Several theoretical advantages exist for combining chemotherapy and radiation therapy for the treatment of limited stage SCLC 1. Radiation can control the bulky disease earlier with chemotherapy eradicating the micrometastatic disease outside of the radiation field. 3. The combination can overcome the early emergence of chemoresistant cells since chemotherapy and radiation have independent mechanisms of action (42). The theory is that the earlier the combination is administered the better the chance for the resistance to be overcome. Unfortunately, cross-resistance can occur (9,43,44). Several randomized studies have demonstrated that the combination of chemotherapy and radiation therapy improves overall survival compared to chemotherapy alone (Table 1 and 1A).

Combination chemotherapy

In individual cases, complete responses to combination chemotherapy that included cytarabine have been reported. Although limited information is available, it appears that responses are lower than in CMML and that this approach should be saved for cases evolving into AML. Complete responses may be obtained in a minority of patients with such secondary AML or blast phase of aCML and, as in similar cases of AML secondary to MDS and CMML, the responses are short, and long-term disease-free survival is rarely obtained. Intensive chemotherapy may be considered as a cytoreductive approach before allo-geneic SCT.

Hydroxyurea and other singleagent chemotherapy

Other cytotoxic agents have occasionally been used empirically, mostly for patients with proliferative HES and evidence of end-organ damage. Case reports of successful treatment include use of cyclophosphamide in HES with recurrent eosinophilic colitis,92 vin-cristine,78 93 94 and, in hydroxyurea-resistant HES, cyto-sine arabinoside (100 mg m2 given subcutaneously or intravenously) daily for 5 days plus prednisone 100 mg orally, daily, for 5 days, every month (M. Beran, unpublished observations, 2003). Ameliorated clinical symptoms and suppressed eosinophilia were reported with each of the above treatments. The effect of chemotherapy on the natural course of the disease remains unknown.

Timing and Sequence of Chemotherapy and Radiation

The optimal timing and sequence of combining chemotherapy and radiation therapy is unknown for the treatment of limited-stage small-cell lung cancer. Radiation can be combined with chemotherapy sequentially, alternating, or concurrently. When combined concurrently, radiation can be started early in the treatment or later during the treatment schedule. Sequential combinations complete chemotherapy first and then follow it with radiation therapy. The advantages of this schedule are decreased toxicity and increased ability to deliver full doses of chemotherapy. The disadvantage is that there is an increased chance of developing therapy-resistant tumors (36). Three randomized phase III studies have been performed evaluating sequential chemo -therapy followed by radiation therapy vs chemotherapy alone in patients with LD-SCLC (Table 3). The chemotherapy used in these studies was noncisplatin-based. One study performed by Carlson et al. randomized patients who responded to chemotherapy to...

Standard chemotherapy

When treatment is indicated, no particular chemotherapy regimen has clearly prolonged the survival of patients with advanced-stage follicular NHL compared with another. Extensive experience with single alkylating agents alone or combined with vincristine and prednisone e.g., cyclophosphamide, vincristine, and prednisone (CVP) , or CVP with adriamycin cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP) failed to demonstrate a major difference in outcome.17 20 Thus, until recently, a single alkylating agent or CVP was the standard. The use of CHOP is often reserved for patients for whom there is a concern of histologic conversion, or at the time of such conversion. Single-agent fludarabine is an active agent in previously treated and untreated patients,21-26 and fludarabine-based combinations with cyclophosphamide or mitoxantrone demonstrated high response rates in phase II trials.27 28 The regimen of fludarabine plus mitoxantrone has been...

Preoperative Chemotherapy Alone

The addition of neoadjuvant chemotherapy to surgical resection is another approach in attempting to ameliorate the sometimes disappointing results of surgery alone. Because the majority of patients present with locally advanced disease (T3 or T4 and or lymph node involvement), surgery alone will be curative in only a minority of cases. Moreover, esophageal cancer is a disease where distant dissemination occurs early, and preoperative chemotherapy may help to eradicate micrometastatic disease, which is not visible on routine staging evaluation. In vivo testing of chemotherapeutic agents may help identify those patients who may benefit from additional postoperative chemotherapy. Studies comparing neoadjuvant chemotherapy to surgery alone are summarized in Table 4 (2428). These studies confirm that neoadjuvant chemotherapy is feasible and does not Randomized Trials of Preoperative Chemotherapy vs Surgery Alone Randomized Trials of Preoperative Chemotherapy vs Surgery Alone

Intensified Neoadjuvant Chemotherapy Followed by Intensified Chemoradiotherapy

A phase II Intergroup study (INT0122, ECOG PE289, RTOG 9012) increased the intensity of both chemotherapy and radiation. The neoadjuvant chemotherapy consisted of three courses of cisplatin and 5-FU followed by concurrent chemoradiation consisting of two additional courses of cisplatin and 5-FU and radiation, 6480 cGy 36 fractions. For the 38 eligible patients, there was a 47 complete response, 8 partial response, and 3 stable disease. The site of first failure was local regional in 39 and distant in 24 . Median survival was 20 mo, 3-yr survival 30 and actuarial 5-yr survival 20 . There were six deaths of which four (9 ) were treatment-related. The authors concluded that this intensive neoadjuvant chemotherapy followed by chemoradiotherapy was not significantly better over conventional chemoradiation (47). The higher doses of radiation, however, were felt to be well tolerated, and therefore formed the basis of the Phase III intergroup study (INT 0123 RT0G 94-05) comparing concurrent...

Chemotherapy In Combination With Wbxrt

Chemotherapy in combination with WBXRT, or combined modality therapy, has been used to treat PCNSL for over two decades. Initially, chemotherapy regimens used to treat systemic NHL were employed. Systemic administration of CHOP or CHOD (with dexametha-sone), either before or after WBXRT, has been studied in two phase II and one randomized phase III trial.26 38 39 In the phase II, trials the reported median survivals of 10 and 13 months were no better than historical controls using WBXRT alone, and were associated with high toxicity and a 15 mortality. The randomized trial of WBXRT followed by CHOP or no further treatment showed no difference in failure-free or OS between the two arms, although the study was terminated early due to poor accrual. These data demonstrate that there is no role for CHOP-type therapy in the treatment of PCNSL. The BBB is a unique obstacle to the successful treatment of brain tumors because high-molecular-weight or polar compounds cannot cross an intact BBB....

Systemic Chemotherapy

Systemic chemotherapy should be restricted to patients with advanced stage disease or with multiple relapsed and refractory plaques and tumors. Established treatment options include single-agent or multiagent chemotherapy such as steroids, methotrexate, chloram-bucil, vincristine, doxorubicin, cyclophosphamide, etoposide, and alkylators. Combination chemotherapy with CHOP or CHOP-like therapies has been shown to achieve higher response rates of approximately 70-80 .39 Eighty-one patients (46 primary CBCL and 35 CTCL) were treated with COP or CHOP regimens. The overall response rate was 40 in CTCL patients, with a CR in 23 of patients. The median response duration was 5.7 months and median survival was 19 months. A phase II trial with the etoposide, vin-cristine, doxorubicin, cyclophosphamide, and oral prednisone (EPOCH) regimen in 15 patients with refractory CTCL resulted in an overall response rate of 80 .40 Twenty-seven percent of patients achieved a CR, and 53 of patients achieved...

Conventional Chemotherapy

Treatment of the non-ALCL T-cell lymphomas with conventional chemotherapy designed for B-cell lymphomas has had only limited success. Common anthracycline-containing regimens result in low response rates and short durations of remission, and the vast majority of patients develop resistant disease. For example, Armitage et al. evaluated 134 cases of PTCL diagnosed at three centers from 1973 to 1986 80 patients had been treated with intensive regimens such as CHOP cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone with or without bleomycin, CAP-BOP (cyclophos-phamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone), COMLA (cyclophosphamide, vincristine, methotrexate, and cytosine arabinoside), and MACOP-B (methotrexate, doxorubicin, cyclophos-phamide, vincristine, prednisone, and bleomycin).21 While the median survival was 17 months and the 4-year survival was 28 for all 134 patients, for the 80 patients who received intensive...

Highdose Chemotherapystem Cell Transplant

Several groups have examined the impact of high-dose chemotherapy on T-cell lymphomas. Investigators at MD Anderson Cancer Center performed a retrospective analysis of 36 patients with relapsed or refractory PTCL who received high-dose chemotherapy and autologous (29 patients) or allogeneic (7 patients) hematopoietic transplantation.88 The 3-year overall survival rate was 36 , and progression-free survival (PFS) rate was 28 . The 3-year probabilities of survival for the autologous and allogeneic groups were 39 and 29 , respectively, while the PFS rates at 3 years were 32 and 14 , respectively. The pretransplant serum LDH level was the most important prognostic factor for both overall survival and PFS results. Furthermore, patients with an IPI score of < 1 had better overall survival, but not PFS rates, than those with greater IPI scores. At a median follow-up of 43 months, 13 patients (36 ) were still alive with no evidence of disease. These data were comparable to published studies...

Combined modality of locally advanced breast cancer

Historically, locally advanced breast cancer (LABC) was defined as disease deemed inoperable on the basis of physical tumor characteristics associated with surgical failure to consistently achieve resection with negative margins edema, skin fixation, ulceration, and chest wall involvement. These characteristics, which comprise T4 disease in the current American Joint Cancer Commission (AJCC) classification system, were identified by Haagensen and Stout at a time when radical mastectomy was the recognized treatment for breast cancer. As clinical practice evolved in the 1970s and 1980s to include the option of lumpectomy or segmental excision plus radiotherapy, many physicians came to consider tumors greater than 5 cm (AJCC T3) to be locally advanced because their size usually precludes breast-conserving surgery. Thus the term LABC now describes a more heterogeneous group of patients with AJCC Stages IIB, IIIA, and IIIB. While all of these patients may be said to have LABC, they have a...

Locally advanced breast cancer sequential therapies

Three prospective randomized trials reported in the 1980s compared local therapy alone to local therapy followed by systemic therapy. Two of the studies included patients with T3b or T4 disease local therapy was radiation therapy (RT) only. It is noteworthy that, although in one of these two studies the addition of systemic therapy improved disease-free survival compared to RT alone, in neither study did the addition of systemic therapy show a significant survival benefit compared to RT (1,2). The failure of systemic therapy to improve overall survival in these studies may be related to the fact that the use of conventional dose RT without surgery was inadequate to ensure local control, a determinant of outcome in LABC. The third randomized study investigating adjuvant systemic therapy in LABC enrolled patients with somewhat earlier stage, operable disease T3, N0-2. All patients underwent a modified radical mastectomy followed by one of three treatment arms RT alone, chemotherapy...

Neoadjuvant Chemotherapy

The large experience with neoadjuvant chemotherapy (also called induction, primary, or preoperative chemotherapy) in patients with LABC allows us to derive the following conclusions Objective response rates are significantly higher than those observed when the same chemotherapy is given to patients with overt metastatic disease. Neoadjuvant chemotherapy has become a standard of care for LABC based on multiple nonrandomized trials demonstrating excellent clinical response rates and improved survival compared to historic controls. Standard anthracycline-based chemotherapy induces responses in 60-90 of patients, as shown in Table 1. However, in spite of high response rates, induction chemotherapy only rarely eradicates the primary tumor in the breast and axilla with most patients found to have significant residual disease at surgery.

Locally advanced breast cancer concurrent chemoradiation

Encouraged by the promising results achieved in other tumor types (4-6), in the early 1990s we hypothesized that locally advanced breast cancer could also be treated by primary concurrent chemoradiation (chemo-RT). Moreover, LABC could be a clinical setting to conduct interesting translational research. A series of observations justified this position 1. Because of the accessibility of large breast cancers it is relatively easy to obtain tissue for molecular studies (7).

Combined modality treatment in inflammatory breast cancer

Inflammatory carcinoma of the breast (IBC) is a unique syndrome characterized by extensive erythema of the breast, dermal lymphatic invasion, and an aggressive clinical course. There is a high likelihood of distant metastatic deposits, even though routine staging procedures are often negative at presentation. The multimodality therapy of inflammatory breast carcinoma thus emphasizes early aggressive systemic therapy. As is the case with noninflammatory LABC, the response to primary chemotherapy provides prognostic information. For example, investigators at M.D. Anderson reported a 10-yr DFS of 48 , 28 , and 10 for those with a CR, PR, and less than PR, respectively, in patients with inflammatory breast cancer treated with anthracyline-based therapy followed by surgery and or radiation (37). Maloisel et al. reported response to primary chemotherapy to be the most significant prognostic factor determining DFS (38). Selected series are shown in Table 3. It should be noted that much of...

Highdose Chemotherapy In First Or Partial Remission

The LNH87-2 trial by the GELA (Groupe d'Etude des Lymphomes de Adulte) group was a phase III trial that enrolled 916 patients with intermediate- and highgrade lymphoma in first CR with one or more unfavorable prognostic factors who received induction treatment using the LHN84 protocol.24 Only those patients who achieved a CR (61 , n 541) were randomized to receive sequential chemotherapy or proceed to autologous stem cell transplantation. Initial analysis revealed no difference in DFS and OS between the two consolidative treatment arms. However, a subset analysis of the higher risk population who had two or three risk factors favored the autologous stem cell

Alkylating Agent Based Combination Chemotherapy

Large Randomized Studies of Alkylating Agent-Based Combination Chemotherapy Large Randomized Studies of Alkylating Agent-Based Combination Chemotherapy Alkylating agent-based combination chemotherapy, particularly with the inclusion of an anthracycline, appear to be more toxic and does not offer a significant advantage in previously untreated patients with CLL compared with single-agent chlorambucil. Among patients with CLL who have relapsed or are refractory to therapy with chlorambucil, combination chemotherapy produces responses in about one-third. Keating et al. (19) obtained responses (complete and partial) in 26 of previously treated patients with the multiagent regimen POACH (cyclophosphamide, Adriamycin, cytosine-arabi-noside, vincristine, and prednisone) the median survival was 15 mo. Similarly, the M-2 protocol produced responses in 35 of previously treated patients, with a median survival of 15 mo (17). Thus, responses are attainable with alkylating agent-based combination...

Adjuvant chemotherapy

For patients whose tumor invades through the mus-cularis propria or into other organs or has either lymph node or distant metastases (T3-4, N1-2, M0-1 Stage III-IV) adjuvant chemotherapy is necessary. For patients with stage III disease, 6 months of 5-FU and leucovo-rin (LV) has been standard treatment. Recently, combinations of 5-FU LV with either irinotecan (FOL-FIRI) or oxaliplatin (FOLFOX) have demonstrated improvements in response and survival. In addition, erbitux (cetuximab), a humanized monoclonal antibody against the epidermal growth factor receptor, and avastin (bevacizumab), a monoclonal antibody against the vascular endothelial growth factor have both recently been approved by the Food and Drug Administration for patients with advanced CRC.

Purine Analog Based Combination Chemotherapy

Rituximab has shown greater activity when it was investigated in chemotherapy-naive patients. Rituximab at 375 mg m2 weekly for 4 wk produced partial responses in 8 of 14 (57 ) patients with CLL who had not received prior treatment (74). Thomas et al. (75) reported an overall response rate of 83 and a complete response rate of17 in patients with early-stage CLL treated with 8 wk of standard dose rituximab. Despite rituximab's modest single-agent activity in CLL, the combination of this antibody with chemotherapy appears to be a promising strategy. A combination of fludarabine, cyclophosphamide, and rituximab is being studied in patients with CLL. Fludarabine is given at a dose of 25 mg m2 and cyclophosphamide at a dose of 250 mg m2 for three consecutive days rituximab is given on the first day of each cycle. The rituximab dose is 375 mg m2 in the first cycle and 500 mg m2 in the subsequent cycles. Patients receive up to six cycles of treatment. The results of this ongoing study were...

Monoclonal Antibody And Endocrine Therapy For Breast Cancer And Tumor Immunity

Therapeutic monoclonal antibodies that are specific for the tumor cell are promising for combination immunotherapy because they provide a strategy for passively restoring the antigen-specific humoral immune response in the context of activating the cellular immune response with cancer vaccines. Trastuzumab is a humanized monoclonal antibody specific for HER2 neu 2 , a protooncogene overexpressed by up to 25 of human breast cancers 40,41 . HER2 neu-overexpressing tumors are more aggressive, relapse earlier, and are associated with a higher mortality than the majority of breast cancers. Trastuzumab is now in widespread use for the treatment of breast cancer at every stage except ductal carcinoma in situ. This antibody has the capability of potentiating tumor immunity in several ways 2. Like standard-dose chemotherapy, trastuzumab induces significant tumor cell apoptosis in human breast tumors even after only one dose 43 . Bevacizumab is a humanized monoclonal antibody specific for the...

Breast cancer During Pregnancy

Between 0.02 and 0.1 of all pregnancies are complicated by cancer 73 . A high index of suspicion is required to diagnose breast cancer during pregnancy due to the anatomic and physiologic changes occurring in the breast during this period, and studies have found an average delay of 5 months between first symptoms and the diagnosis 74 . Pregnant women have a 2.5fold higher risk of presenting with metastatic disease Table 18.2 Features associated with a high risk of breast cancer Women diagnosed with breast cancer under 40 years of age Women with bilateral breast cancer Male relative with breast cancer Demonstrated germ-line mutation in a high-risk breast cancer-associated gene and a decreased chance of stage I disease, and delay in diagnosis may contribute to the more advanced stage of presentation in such women 75 . The pathology of pregnancy-associated breast cancer is almost identical to that occurring in non-pregnant women but with a higher incidence of ER-negative tumors, probably...

Rsk Reduction in Women with Inherited Predisposition to Breast cancer

The management of young women at an increased risk of developing breast cancer at a young age requires consideration. These include women who have germline mutations in BRCA1, BRCA2, p53 (Li Fraumeni syndrome), or PTEN (Cowden's syndrome). Factors that define women at potentially high risk of developing breast cancer are summarized in Table 18.2. For example, clinical disease may develop in about 50 by age 50 years and 80 by age 70 years in women with a mutated BRCA1 gene. Tp53 gene on chromosome 17 83 . Affected patients have a 50 risk of developing cancer by age 35 years and a 90 lifetime risk. The syndrome is characterized by pediatric bone or soft tissue sarcoma, early-onset breast cancer, and other cancers including those affecting the brain, lung, and adrenals, and leukemia. Cowden's syndrome is caused by a mutation in the PTEN gene on chromosome 10 84 . Affected patients have multiple hamartomas and an increased risk of developing breast or thyroid carcinoma at a young age. It...

Organochlorine Compounds Polycyclic Aromatic Hydrocarbons and Breast Cancer

Environmental exposure to organochlorine compounds such as polychlorinated biphenyls (PCBs), 2,2'-bis (p-chlorophenyl)-1, 1, 1-tri-chloroethane (DDT) and its metabolite DDE, and organochloro pesticides has been suggested as a risk factor for breast cancer. The basis for this claim is that some of these are carcinogenic in animals, have estrogenic activity, and are inducers of cytochrome P-450 enzymes that metabolize drugs, hormones, and various xeno-biotics. Some epidemiological studies have suggested an association between this class of compounds and breast cancer risk, but these studies have been contradictory and inconclusive (reviewed in Reference 172). Because of a purported clustering of breast cancer on Long Island, New York, and a fair amount of political pressure, a 30 million Long Island breast cancer study project was launched to examine the relationship between exposure to environmental agents and breast cancer incidence. The study was carried out under the auspices of the...

Sensitization To Chemotherapy Of Glioma Cells After Dc Therapy

From the TRP-2 transfected cell line (TRP-2-U373). After immunoselection by TRP-2-specific CTL clone, CTL-resistant tumor cells (IS-TRP-2-373) developed significant increased sensitivity to carboplatin and temozolomide compared to W-U373 (59). In a phase I DC vaccination clinical trial by Liu and colleagues, TRP-2-specific cytotoxic T-cell activity was detected in patients' PBMC after active immunotherapy against unselected glioma antigens using tumor lysate-loaded DCs (60). Tumor-cell specimens were taken from postvaccination resections from two patients who developed CTL to TRP-2. Compared to autologous cell lines derived from prevaccination resections in two patients who demonstrated CTL response to TRP-2, these specimens demonstrated significantly lower TRP-2 expression (Fig. 3) and higher drug sensitivity to carboplatin and temozolomide (Fig. 4). Thus, targeting TRP-2 may provide a new strategy in improving chemotherapy sensitivity. However, not all forms of drug resistance in...

Malignant Glioma Responsiveness To Chemotherapy Postdc Vaccination

The processes that can explain a reason why tumor recurs despite CTL induction by DC vaccination are immunoselection and immunoediting. These processes allow tumor cells to escape from CTLs by antigen loss (65,66). The potential synergies between immunotherapy and other therapies must therefore be investigated due to the clinical inconsistency of cancer vaccines and the effects of immunoselection on tumor evolution (67-69). Cedars-Sinai Medical Center (68) and Brigham and Women's Hospital have conducted clinical trials to examine the synergy of vaccines with chemotherapy treatment (70). A retrospective analysis of clinical outcomes (survival and progression times) in 25 vaccinated (13 with and 12 without subsequent chemotherapy) and 13 non-vaccinated de novo GBM patients receiving chemotherapy was performed. Patients who received post-vaccine chemotherapy demonstrated longer survival times and significantly longer times to tumor recurrence after chemotherapy relative to their own...

Radiation therapy versus radiation therapy plus chemotherapy

Clinical trials of limited stage HL have more recently focused on the use of radiation therapy versus combined radiation therapy and chemotherapy. Decades ago, the specific chemotherapy regimen usually employed was MOPP. Given that MOPP has been replaced in the treatment of HL by ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), these pioneering studies are of only moderate relevance to today's practice. As a general statement, these studies included both pathologically staged and clinically staged patients, and generally compared subtotal lym-phoid radiation therapy or total lymphoid radiation therapy versus MOPP (or a variant of MOPP) combined with limited or extended field radiation therapy. Table 73.2 shows a summary of these studies. Two studies found an advantage (FFR) in combined modality therapy (CMT), whereas the others did not. There was no difference in OS in any study. Other findings of studies of this era are important. Multiple sites of disease were associated...

Chemotherapy Regimens Mopp and MOPP derivatives

The dosage, schedule, and frequency of MOPP chemotherapy are described in Table 73.6. Patients receive four drugs over a 2-week interval followed by a 2-week recovery period. A total of 4 weeks constitutes one cycle of treatment. Most patients receive six cycles. Historically, the dose of vincristine used in MOPP frequently exceeded the currently recognized dosage limit of 2 mg. Two updated mature studies with 1045 and 14 years46 follow-up, respectively, showed that 66 of patients have remained disease-free more than 10 years from the end of treatment. Forty-eight percent of advanced HL patients have survived between 9 and 21 years (median, 14 years) from the end of treatment. Nineteen percent of the complete remission cases have died of intercurrent illnesses, free of HL.45'46 Table 73.6 Main chemotherapy regimens used in advanced HL Table 73.6 Main chemotherapy regimens used in advanced HL

Abortion or Miscarriage and Breast Cancer

Some reports have suggested that incomplete pregnancies, terminated either by induced abortion or miscarriage, increases the risk of breast cancer (reviewed in Reference 184). A number of other studies have not shown an increased risk of breast cancer in women who have undergone induced abortions.184 A well-controlled study of the effects of induced abortion and miscarriage on breast cancer incidence, involving age-, parity-, and race-matched cases and controls, showed that neither induced abortion nor miscarriage increased breast cancer risk.184 This claim appears to be more of an issue of politics and religious beliefs than science.

Chemotherapy in advanced disease

Certainly a minimum requirement of the addition of systemic chemotherapy to a local therapy such as radiation is that chemotherapy has significant activity in metastatic disease, even if that therapy is not associated with either curative potential or significant prolongation of survival. Certainly, combination chemotherapy for transitional cell carcinoma is able to achieve this requirement. In the early 1980s, cisplatin and methotrexate were felt to be the most active single agents, and a series of cisplatin and methotrexate-based regimens were developed. The most common of these was the cisplatin + methotrexate + vinblastine (CMV) regimen developed by the Northern California Oncology Group (22), and the same three drugs in combination with doxorubicin (M-VAC), utilized at Memorial Sloan-Kettering Cancer Center (23). The phase II data with M-VAC at Memorial in over 120 patients suggested true clinical synergism with the regimen, with a response rate of 72 , a complete response rate...

Chemotherapy radiotherapy

The inferior results with radiotherapy alone compared to cystectomy in patients with muscle-invasive disease have prompted a large number of trials adding systemic chemotherapy to radiotherapy in an attempt to increase local control and eliminate micro-metastatic disease frequently present at the time of diagnosis of muscle-invasive disease. It is not easy to directly compare surgical series with trials of bladder-sparing approaches. A number of confounding factors can potentially complicate the interpretation of trials of chemoradiotherapy, including the effect of the TURBT on the natural history of this disease, the errors of clinical staging both before and after chemotherapy radiotherapy, and the endpoints utilized to determine efficacy.

Studies of cisplatincontaining chemotherapy in combination with radiation therapy

In contrast, multiagent cisplatin-containing regimens have produced fairly high response rates in women with untreated locally advanced disease. Although complete responses to chemotherapy are uncommon, partial response rates of 60 or more led clinicians to investigate the sequential use of cisplatin-containing regimens and radiation.

Cytotoxic Chemotherapy

Effects of age on the pharmacology of cytotoxic chemotherapy Table 5. Effects of age on the pharmacology of cytotoxic chemotherapy change, but the peak concentration of these agents is increased and the risk of toxicity enhanced as a results of volume of distribution (Vd) alterations. The effects of Vd changes may be ameliorated by correction of anaemia, when this is present. Several studies have shown that anaemia is an independent risk factor for chemotherapy-induced myelodepression 28 , as many agents bind to red blood cells consequently, anaemia is associated with increased concentration of circulating free drug. A decline in the glomerular filtration rate (GFR) is almost universal with aging, and may lead to an increased half-life of cytotoxic compounds, such as carboplatin, methotrexate, and bleomycin, whose parent compounds are excreted through the kidneys, and drugs that give origin to active or toxic metabolites excreted from the kidneys. For example, 80 of the...

Proposed Doses of Micronutrients To Be Used as an Adjunct to Radiation Therapy andor Chemotherapy

The scientific rationale for the proposed micronu-trient protocol has been discussed in detail in recent publications (8, 10). The micronutrient supplement protocol is divided into two categories active treatment phase and maintenance phase. - During the active treatment phase, daily mi-cronutrients are given orally at least 48 hours before radiation therapy or chemotherapy, and continued for the entire treatment period. After the completion of treatment, doses of supplementary antioxidant micronutrients are reduced to half over a four-week period, which is maintained during the maintenance phase (lifetime). The rational for giving micronutri-ents at least 48 hours before standard cancer therapy is that antioxidant-induced damage is initiated in cancer cells but not in normal cells prior to initiation of cancer treatment with standard therapeutic agents. A brand name, Sevak (Premier Micronutrient Corporation, Nashville, Tennessee), which contains the above ingredients, is being sold...

Combination Chemotherapy With Concurrent Thalidomide

Six cycles of therapy, 46 of newly diagnosed patients had either a CR or nCR, a rate comparable to that seen with HDC ASCS.34 It remains to be seen whether the time to disease progression will be as long as that typically expected from HDC ASCS. The regimen is clearly more toxic than DVd alone, requiring prophylactic antibiotics because of high rates of infection, particularly pneumonia, and also daily aspirin because of a high rate of DVTs.109 The latter complication is not wholly unexpected, given the higher rate of throm-botic complications seen with TD.68' 69 Investigators at the University of Arkansas have published their extensive experience using combination chemotherapy with thalidomide in both the up-front and relapsed setting (Table 83.3).110-112 As in the other trials discussed, an increased rate of DVT was observed with these combinations, particularly during concomitant anthracycline and thalidomide administration.111, 112 Based on the results of the two randomized...

Artificial Nutrition as an Adjunctive Therapy in Patients Receiving Chemotherapy or Radiation Therapy

Twenty-seven randomised controlled trials (RCT) assessing the impact of TPN on a total of 1050 patients were reviewed 19 studied TPN in patients receiving chemotherapy, three investigated cancer patients being treated with radiation therapy, and four were on patients undergoing bone marrow transplantation. Results showed that there was no apparent effect of TPN on mortality in the overall series, even if a single RCT in patients undergoing bone marrow transplantation 75 showed an increase of survival in the fed patients. There was, however, a poorer response to chemotherapy in particular (absolute risk difference -7 confidence intervals -12 , -1 ) in TPN patients.

Second Primary neoplasms after Breast cancer

As noted in a review 12 , before the implementation of breast-conserving surgery and localized radiotherapy to treat node-negative breast cancer, the principal method of local control was radical mastectomy and extensive radiotherapy to the chest wall and lymph nodes. Consequently, such women have experienced an excess risk of leukemias and cancers of the contralateral breast and lung, and possibly of esophagus, bone, connective tissue, and thyroid gland 22-26 . The risk of second primary leukemia is associated with radiotherapy (relative risk 1.8), alkylating agents (relative risk 6.5), and both (relative risk 17.4) 23 . The radiation dose to the contralateral breast can amount to several Grays and a review 12 has inferred that women irradiated in young adulthood are probably at increased risk of contralateral breast cancer, based mainly on one study 22 . However, another review 27 suggests no convincing evidence of such an effect. As the dose and effect appear to be less than...

Background results of chemotherapy alone in acute promyelocytic leukemia

Significant coagulopathy, present at diagnosis in 80 of APL cases, is worsened (or triggered in the remaining patients) by the onset of chemotherapy. Intensive platelet support during chemotherapy is crucial in the management of APL coagulopathy and clearly reduces the incidence of hemorrhagic deaths. The optimal postinduction chemotherapy remains controversial in APL. In AML as a whole, it is proved that intensive consolidation chemotherapy generally improves outcome, by comparison to milder consolidation courses followed by prolonged maintenance therapy. However, in APL, two studies have suggested that prolonged maintenance chemotherapy with 6 mercaptopurine and methotrexate can prolong remissions when compared with shorter consolidation regimens (8,9). Age older than 50 yr (9), hyperleukocytosis at diagnosis (5), microgranular APL variant, severe bleeding at diagnosis, and or major thrombocytopenia were associated with a higher risk of early death in newly diagnosed patients with...

Adenoviral p53 Gene Transfer with Chemotherapy in NSCLC

The Phase I studies with Ad-p53 alone demonstrated low toxicity possibly because of the tumor selective nature of action of wild-type p53 as opposed to conventional antitumor agents. Several clinical limitations were also identified with Ad-p53 alone. First, not all patients responded to Ad-p53. Second, perhaps because of the locoregional delivery, antitumor activity in systemic noninjected metastases was not observed. The clinical implications of this observation are that Ad-p53 may require treatment in conjunction with other conventional agents to enhance response. The potential use of Ad-p53 in combination with chemotherapy agents is supported by preclinical studies which demonstrate that the antitumor effects of p53 gene transfer are enhanced by combined treatment with cisplatin, paclitaxel, CPT-11, 5-fluorouracil, and doxorubicin (19-22). Because toxicity with Ad-p53 is low, this may be a reasonable strategy especially if Ad-p53 does not increase chemotherapy related toxicity....

Chemotherapy Regimens

Regimens that often include agents belonging to separate classes of cytotoxic chemotherapy described in this chapter. Doses and scheduling have been determined over many years of experience and through use of evidence-based medicine through trial and error (experiments based on the inherently empirical way), classical cytotoxic agents have been developed (i.e., without direct reference to molecular mechanisms). Many cytotoxic chemotherapeutic agents are given via intravenous infusions. With regard to optimizing efficacy and reducing side effects, scheduling of administration can have significant effects. This aspect of clinical cancer trials is less widely appreciated than the effects of dose. The empirical effects of scheduling make developing combination regimens particularly challenging because complexities can mount exponentially with the addition of novel agents to an established regimen. To optimize ratios of efficacy to adverse effects (therapeutic window), historical...

Breast Cancer Mammography

While mammography is the best screening method for the early detection of breast cancer, missed lesions do occur. Misses of lesions on radiographic images may be due to the presence of quantum mottle, overlapping normal structures, or radiologists' insufficient search patterns and lapses in perception. In addition, variability in mammographic image interpretation among different radiologists has been reported 20, 21 . In screening programs, the detection of an abnormality is a tedious task, since although most cases are normal, each requires a thorough review by the radiologists. Use of output, however, from a computerized analysis of an image may help the radiologist in detection or diagnostic tasks and potentially improve the overall interpretation of medical images and perhaps overall interpretation time. As noted earlier, CAD for the detection (i.e., localization) of regions in an image suspected of possessing the disease has been referred to as CADe in order to emphasize the...

Monitoring Chemotherapy

Dard for monitoring cardiac function in patients receiving chemotherapy. However, this technique is not sensitive enough and measurable changes in LV ejection fraction are usually indicative of an already significant amount of myocardial damage. Several clinical studies have attempted to use the natriuretic peptides to monitor doxorubicin cardiotoxicity. In a study of 30 adult patients who received 8-10 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone to a cumulative doxorubicin dose of 400-500 mg m2 of body surface area for non-Hodgkin's lymphoma, Nousiainen et al. (18) sought to determine the value of serial measurements of the natriuretic peptides for the early detection of doxorubicin-induced cardiomyopathy. LV ejection fraction decreased early in these patients, at a cumulative doxorubicin dose of 200 mg m2 of body surface area. However, ANP, NT-proANP, and BNP levels increased significantly when compared to prechemotherapy values only when the total...

Scheduling of All TransRetinoic Acid and Chemotherapy in Acute Promyelocytic Leukemia

The original combinations of ATRA and chemotherapy in APL used ATRA alone until CR achievement, followed by chemotherapy. The European group (APL 93 trial) randomized newly diagnosed APL patients with WBC counts < 5000 mm3 between ATRA followed by chemotherapy (ATRA chemother-apy) and ATRA plus chemotherapy (ATRA + chemotherapy, where chemotherapy was started on day 3 of ATRA treatment). The CR rate was similar in the two groups, but relapses at 2 yr were significantly less frequent in the ATRA + chemotherapy group (69). This suggested that the additive or synergistic effect of ATRA and chemotherapy on reducing the incidence of relapse in APL was optimal when the two treatment modalities were administered together. Also of note was that early addition of chemotherapy to ATRA reduced the incidence of ATRA syndrome (see following section).

Role of AraC in Acute Promyelocytic Leukemia Chemotherapy

For treatment with chemotherapy alone, it is unclear whether it is useful to combine AraC to anthracyclines in APL treatment, when chemotherapy is combined to ATRA. Recently, Sanz et al. (29) treated 100 cases of newly diagnosed APL with ATRA and four successive courses of chemotherapy with idarubicin or mitoxantrone alone, followed by maintenance treatment with intermittent ATRA and low-dose continuous chemotherapy. The CR rate was 89 , and the 2-yr EFS was 79 . After the end of chemotherapy, 93 of the patients were polymerase chain reaction (PCR) negative. No mortality and limited morbidity were seen during consolidation chemotherapy, whereas a 5 mortality was observed by the European APL group after consolidation chemotherapy with two daunorubicin-AraC courses (69). Updated results of this study, with longer follow up, did not show a increased incidence of late relapses (30). Estey et al. (31) also obtained favorable results in APL using ATRA followed by idarubicin without AraC in...

Myelosuppressive Chemotherapy

Several methods to mobilize PBSC from an extra vascular location into circulation have been described. Myelosuppressive chemotherapy was the first method described for stem cell mobilization.14 During the recovery phase after myelosuppressive chemotherapy, there was a 14- to 100-fold increase in peripheral blood CFU-GM above the baseline. The extent of this increase is proportional to the severity and duration of the cytopenia. High-dose cyclophosphamide (CY) is the most commonly used regimen since it is active against most tumors. However, there are several disadvantages to chemotherapy mobilization, including the length of time required, toxicity, neutropenic fever and or sepsis, bleeding diathesis, and the unpredictable timing of apheresis. In addition, little or no increase in peripheral blood CFU-GM was observed in some patients who had received extensive prior therapy and patients with marrow involvement with tumor.15 With the introduction of hematopoietic growth factors, it is...

Chemotherapy Plus Growth Factors For Stem Cell Mobilization

Although chemotherapy alone can produce increases in progenitors in PB, multiple phase II studies have shown that the addition of growth factors such as G-CSF and GM-CSF to myelosuppressive chemotherapy enhances mobilization and allows for more progenitors to be collected with fewer apheresis procedures while reducing myelotoxicity. Siena et al.37 reported that after highdose CY, an approximately 30-fold expansion of CFU-GM numbers was observed. This increase was further magnified, to over 100 times control values, when GM-CSF was given to accelerate post-CY hematopoietic recovery. These precursors were both increased in number and enriched in the more immature forms. In addition, there was an increase of the most immature CD34+ CD33- progenitors to multipotent and unipotent colony-forming cells (CD34+ CD33+) in PB. In a randomized cross-over trial reported by Koc et al.,38 high-dose CY plus G-CSF results in mobilization of more progenitors than GM-CSF plus G-CSF when tested in the...

Highdose Therapy For Highrisk Breast Cancer Phase II studies

The use of high-dose therapy with, initially, BM and, later, Peripheral blood progenitor cell(s) (PBPC) rescue was first explored and reported by Peters et al.25 at Duke University and by Gianni et al.26 at Milan. Each reported results that appeared superior to outcomes after conventional-dose chemotherapy using similar patient selection criteria. Specifically, Peters et al. reported a 72 5-year EFS in a prospective phase II trial of high-dose cyclophosphamide cisplatin BCNU in patients with 10 or more positive axillary nodes. These results have stood the scrutiny of time, with 61 EFS rate at 11-year follow-up.27 Gianni et al.26 used a sequential high-dose single-agent regimen in this patient population. At a median follow-up of 4 years, the observed EFS rate was 57 .

Randomized trials in highrisk breast cancer

Rodenhuis et al.28 randomized 885 patients with four or more involved lymph nodes to receive four cycles of conventional-dose chemotherapy followed by one more cycle of conventional-dose chemotherapy or one cycle of HDC. At a median follow-up of 57 months, there was a trend for an EFS advantage in favor of high-dose therapy (65 vs 59 , P 0.09), with no significant OS differences. The EFS of those patients randomized to high-dose therapy who were actually transplanted appeared superior to those in the control arm (P 0.03). Prospectively planned subset analysis showed that highdose therapy improved EFS among patients with 10 or more involved nodes (68 vs 49 , P 0.05). 10 or more positive nodes to receive four conventional-dose chemotherapy cycles followed by one cycle of cyclophosphamide cisplatin BCNU or by one additional cycle of those drugs at intermediate doses with granulocyte colony-stimulating factor support. Twenty-five patients who relapsed on the intermediate-dose arm (15 )...

Conjugation of Chemotherapy Agents

Other cytotoxic drug conjugates, HA-doxorubicin (HA-DOX), and hydroxy-propylmethacrylamide (HPMA) copolymer-DOX containing HA as a side chain (HPMA-HA-DOX), were studied in vitro for their anti-proliferative property against a number of human tumor cell lines. The cytotoxicity of HPMA-HA-DOX bioconjugate was found to be higher than that of the nontargeted HPMA-DOX conjugate against human breast cancer (HBL-100), ovarian cancer (SKOV-3), and colon cancer (HCT-116) cells. Fluorescence confocal microscopy revealed that the targeted HPMA-HA-DOX conjugates were internalized more efficiently by cancer cells and that internalization of the polymer conjugates correlated with their cytotoxicity (59). Both conjugates showed minimal cytotoxicity toward mouse fibroblast NIH 3T3 cells. Finally, MMC conjugated to cross-linked HA hydrogels was shown to reduce postoperative adhesions (58).

Targeting cancer chemotherapy

The investigations to be exemplified in this final case study from academe have been directed toward studying the SAR associated with biological transporter systems with the hope of eventually establishing a database of transportophore relationships that might be generally applicable toward enhancing the selection and or development of efficacy leads from another data set. To provide immediate relevance to this long-term project, it has initially focused upon the P-glycoprotein pump (P-gp)332,333 that is associated, in part,334,335 with the development of multidrug resistance (MDR)336,337 during cancer chemotherapy. P-gp is a 170 kDa transmembrane glycoprotein belonging to the ABC class of transporters that serves as an energy-dependent, unidirectional efflux pump having broad substrate specificity. In humans it is encoded by the MDR gene, MDR1, whose classical phenotype is characterized by a reduced ability to accumulate drugs intracellularly, and thus the deleterious impact of...

Micronutrients Breast Cancer

To reduce the chances of developing breast cancer To reduce the chances of developing breast cancer Higher intakes can sharplyre-duce risk of breast cancer41 Fig. 5.30 Vitamin C intake and risk of breast cancer. In 12 studies of diet and breast cancer, vitamin C intake had the most consistent and significant inverse association with breast cancer risk. The risk was nearly one-third lower with the highest intakes of vitamin C, compared with lower intakes. The mean intake of the lowest quintile was the current recommended dietary allowance for vitamin C. (Adapted from Howe GR, et al. J Natl Cancer Inst. 1990 82 561)

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...

The History Of Cancer Chemotherapy

The term chemotherapy refers to the treatment of cancer or other malignant diseases by using specific drugs that selectively destroy growing cells. Prior to the advent of chemotherapy, two main modalities were used in the treatment of cancer surgery and radiation. Both options, although effective for many types of cancer, are localized forms of therapy. Chemotherapy provided the first systemic form of treatment, using the bloodstream as a means of disseminating drug to both the tumor site as well as areas of metastasis. Additionally, this provided a major breakthrough in the treatment of hematologic malignancies, such as leukemia and lymphoma, which had previously been virtually untreatable with surgery or radiation. The advent of modern chemotherapy originated during World War I, with the observation that soldiers who had been exposed to mustard gas, or sulfur mustard, experienced significant decreases in their white blood cell counts, specifically their lymphocytes. Krumbaar first...

Chemotherapy Regimens and Cancer Care

VADEMECUM Chemotherapy Regimens and Cancer Care LANDES BIOSCIENCE Georgetown, Texas U.S.A. Chemotherapy regimens and cancer care Alan D. Langerak, Luke P. Dreisbach. 1. Antineoplastic agents--Handbooks, manuals, etc. 2. Cancer--Chemo therapy--Handbooks, manuals, etc. I. Dreisbach, Luke P. II. Title. III. Series.

Breast Cancer

Kytril 1 mg PO IV 30 minutes before and 12 hours after chemotherapy 2. Dexamethasone 20 mg IV 30 minutes before chemotherapy 1. Kytril 1 mg PO IV 30 minutes before and 12 hours after chemotherapy 2. Dexamethasone 20 mg IV 30 minutes before chemotherapy 1. Kytril 1 mg PO IV 30 minutes before and 12 hours after chemotherapy (for AC) 2. Dexamethasone 20 mg IV 30 minutes before chemotherapy 1. Kytril 1 mg PO IV 30 minutes before and 12 hours after chemotherapy on days 1, 15, 29, 85, 99, and 113 2. Dexamethasone 20 mg IV 30 minutes before chemotherapy on days 1, 15, 29, 85, 99, and 113 3. Dexamethasone 20 mg IV 30 minutes before chemotherapy on days 43, 57, and 71 Dexamethasone 20 mg PO 6 hours and 12 hours prior to chemotherapy on days 43, 57, and 71 4. Cimetidine 300 mg IV 30 minutes before chemotherapy on days 43, 57, and 71 5. Diphenhydramine 25-50 mg IV 30 minutes before chemotherapy on days 43, 57, and 71 6. Compazine 10 mg PO IV 30 minutes before chemotherapy on days 43, 57, and 71...

Chemotherapy

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...

Cancer Chemotherapy

Selective intracellular drug delivery assumes great importance in cancer chemotherapy, because most of the anti-cancer drugs are cytotoxic to normal cells. To achieve selective drug targeting, drug delivery scientists have been exploiting the differences in cell physiology of normal and cancerous cells 30 . Various approaches based on these differences include (i) the use of high-molecular-weight polymer-drug conjugates that preferentially accumulate in solid tumor tissue by enhanced permeability and retention (EPR) effect

Biochemotherapy

The use of bio-chemotherapy has been shown to have response rates of 40-60 in patients with measurable disease 86, 98 . Although the exact regimen varies between studies, bio-chemotherapy generally consists of cisplatin-based chemotherapy in combination with interferon and IL-2. The activity of chemotherapy is augmented by the addition of biologic response modifiers 99 . The response rate, complete response rate, and median time to progression were 48 , 6 , and 4.9 months, respectively, for bio-chemotherapy, as compared to 25 , 2 , and 2.4 months, respectively, for chemotherapy alone. This increase in activity is at the cost of significant increase in toxicity. Atkins et al. reported a randomized phase III study comparing chemotherapy to bio-chemotherapy performed in patients with metastatic disease 100 . Biochemotherapy was associated with higher response rate and higher toxic-ity, but no difference was seen in OS.

Initial Chemotherapy

Include conventional-dose salvage chemotherapy, The choice of the best salvage approach should rely on the evaluation of prognostic factors and clinical characteristics of patients with recurrent or resistant disease. Since 1979, it has been observed that the length of remission after first-line therapy has a significant effect on the success of subsequent salvage treatment thus, failures to chemotherapy can be classified as primary resistant disease complete remission (CR) never achieved , as early relapse (within 12 months since remission), or as late relapse (beyond 12 months since remission). In a recent retrospective analysis of the German Hodgkin's Lymphoma Study Group on 513 patients, no patient with primary progressive disease, treated with conventional-dose chemotherapy survived more than 8 years by contrast, the projected 20-year survival for patients with early or late relapse is 11 and 22 , respectively thus, conventional-dose therapy has virtually no curative potential in...

Diet Breast Cancer

High intakes of saturated fat may increase risk of breast cancer, whereas intake of monoun-saturated fats (such as in olive oil and avocados) reduces the risk.34,35 Higher intakes of dietary fiber (> 25-30 g day) may also help protect against breast cancer.36,37 Regular consumption of vegetables, particularly cabbages, brocolli, and cauliflower, reduces estrogen activity in the body and risk of breast cancer.35 Foods rich in isoflavonoids, such as soy products like tofu and soy milk, are also protective. It is important for women to maintain a normal weight women who are overweight are much more likely to develop breast cancer. Alcohol should be consumed only in moderation. Women who drink more than 2-3 drinks per day increase their chances of developing breast cancer by about 50 .38,39 Heavy, chronic alcohol intake nearly triples the risk.

Chemotherapy Alone

Chemotherapy approaches have included using MTX as a single agent, combining MTX with other drugs that penetrate the BBB, and administering high-dose chemotherapy and stem cell rescue in patients who respond to induction MTX-based regimens. These studies are outlined in Table 58.2 and demonstrate a wide range of OS. The striking difference compared to combined modality treatment appears to be the minimal neurotoxicity. While the majority of studies have focused on using combinations of chemotherapy agents that penetrate the BBB, other investigators developed administration strategies that improve drug delivery to the brain. With the patient under general anesthesia, the femoral artery is catheterized and an osmotic agent, mannitol, can be used to temporarily disrupt the BBB. This is followed by the intravenous and intraarterial infusion of chemotherapy, and is repeated monthly for up to 12 cycles in responding patients.59 One Table 58.2 Results of selected trials of MTX based...

Progesterone Receptors

PR is highly expressed in this compartment 31 . One interpretation for the reduction of mammary gland tumourigenesis in PR-KO mice is that the progenitor cells for alveologenesis, the PR-expressing epithelial cells, are absent in the PR-KO mice. As the majority of mammary gland tumours are of alveolar origin, the absence of these progenitor cells might reduce the number of target cells susceptible to neoplastic transformation. These results strongly support the application of anti-progestins in the therapy of breast cancer because they might inhibit the prolactin-induced mitogenic activity on the luminal-epithelial compartment. Depending on the tissue, progesterone has been classified as a hormone able to induce proliferation or differentiation. However, growth stimulation of the ERa- and PR-positive human breast cancer cell line T47D by progestins is restricted to one cell cycle, and is followed by growth arrest at the G1 S boundary of the second cell cycle 32,33 . Afterwards, the...

Ligand Independent Activation of Steroid Hormone Receptors and Nongenomic Effects of Steroids

Experimental evidence indicates that translocation of the ERa to the membrane in the absence of estrogen is dependent on the caveolin-1 protein. Dependent on the cellular context, the membrane-localised ERa seems to be capable of activating c-Src 62 . In breast cancer cells it has been demonstrated that this can activate kinases, in particular the EGFR tyrosine kinase, imparting cellular growth and survival signals 63 . This demonstrates that membrane-associated ERa might utilise a classic growth factor signalling cascade in breast cancer cells 63 . The anti-estrogen ICI 182,780 inhibits translocation of the ERa to the membrane and the association of the signal transduction complex. Additional non-genomic effects for classic steroid hormone receptors have been reported 64 (Fig. 5). Moreover, the interaction of ligand-bound PR with c-Src activates Ras, Raf and the MAPK-cascade. The GPR30 is expressed ubiquitously and expression in placenta, breast, ovaries, prostate, neural tissue,...

Rationale for the Use of Aromatase Inhibitors in Cancer Treatment

Reticulum of placenta and granulosa cells of ovarian follicles. In three consecutive hydroxylating reactions, estrone and estradiol are synthesised from their precursors androstenedione and testosterone, respectively (Fig. 6). The final hydroxylating step in aromatisation does not require enzymatic action and is not product-sensitive. Aromatase is also present in peripheral tissues, including adipose tissue, liver, muscle, brain and breast cancer tissue. In the peri-menopausal period, the ovaries, as a result ofthe complete loss ofprimor-dial follicles, stop producing estrogens. This leads to a steady decline in ovarian estradiol production although serum estradiol concentrations can vary considerably. In post-menopausal women, approximate plasma estradiol levels are 20 pmol L, and most of the estradiol is formed by peripheral, extra-gonadal conversion of testosterone. As peripheral aromatase activity increases with age, peripheral estrogen production approximately doubles. Estrone is...

Competitive Aromatase Inhibitors

As a common chemical feature, non-steroidal AIs contain a hetero-atom, which binds to the heme iron of cytochrome P450 and is thus involved in the hydroxylation reaction by which estrone and estradiol are synthesised from their obligatory precursors androstenedione and testosterone. Aminog-lutethimide was the first AI to be studied in breast cancer patients and is therefore referred to as a first-generation AI. Due to the unspecific inhibition of other heme iron-containing enzymes, aminogluthetimide had severe side effects. Therefore, research and development was directed towards more specific second-generation (imidazole type fadrozole) and third-generation (triazole type vorozole, anastrozole, letrozole) AIs (Fig. 7). The competitive inhibitor fadrozole is more potent and selective than aminoglutethimide, but

Defining the Users of Technology

As we shall see throughout this book, differences in the architectures of genetic testing for breast cancer in the United States and Britain, in terms of the types of clinical care and laboratory analysis that were used and the way testing systems were organized, had important implications for the identities of the individuals interested in using the technology, for the way risk and disease was defined, and for the organization of genetic medicine. The idea that technologies shape those who use them has been explored by many sociologists of technology. Steve Woolgar, for example, has noted that technologies configure users while Madeline Akrich suggests a more dynamic interaction between users and technologies, arguing that technological objects articulate a script for the identities behavior, interests, skills, and motives of users.54 Like a film script, Akrich notes, technical objects define a framework of action together with the actors and the space in which they are supposed to...

Pharmacology of 17 HSD Inhibitors

HSDs in homogenised cells is reversible, their activity in intact cells is mainly uni-directional. Based on these findings, each member of the 17 -HSDs family has now been classified as either reductive or oxidative. The effects of 17 -HSD inhibition on tumor cell proliferation has been evaluated only in the human breast cancer cell lines MCF-7 and T47D. Compounds from the class of pure steroidal anti-estrogens (ICI 164,384) inhibit the conversion from E1 to E2 by 53 . However, the high IC50 values which range between 0.5-5 M preclude the use of these compounds in vivo 101 . Clinical and pre-clinical observations demonstrated that progestins can interfere with 17 -HSD expression and activity. Inhibiton of both, oxidative and reductive activities have been reported 102 . Whether 17 -HSD inhibition alone is sufficient to suppress the growth of breast cancer or whether a combination with an aro-matase inhibitor might provide additional clinical benefit still remain open questions.

Rationale for the Use of Steroid Sulfatase Inhibitors in Cancer Treatment

The biologically inactive estrone sulfate (E1S) and dehydro-epiandrosterone-sulfate (DHEAS) are the most abundant circulating estrogenic precursors in the plasma of post-menopausal women 103 . Desulfation of inactive steroid-3-O-sulfates by estrone-sulfatase (STS) plays a key role in the regulation of levels of receptor-active estrogenic steroids (estradiol and androstenediol) in breast cancer cells (Fig. 9). There is strong evidence suggesting that estrone sulfatase (STS) and DHEA-sulfatase are the same enzyme 103 . Although the affinity of androstenediol for the ER is much lower than that of estradiol, the plasma concentration of androstenediol is 100-fold higher than that of estradiol and it is presumed that the amount of circulating an-drostenediol is sufficient to stimulate hormone-dependent breast cancer cells. In addition, the activity of the STS and the tissue concentration of estrone sulfate were found to be higher in tumour than in normal breast tissue 104 . This led to the...

Chemistry of Steroid Sulfatase Inhibitors

Coumarine 4-methylcoumarin-7-0-sulfamate derivative, COUMATE, with an IC50 of 380 nM. SAR analyses led to a simplified pharmacophore (Fig. 9) with the sulfamate group attached to a carbon backbone as the most important group within potential non-steroidal inhibitors of STS 110 . Potent sulfamoyloxy-substituted stilbenes with anti-estrogenic activity were synthe-sised and evaluated as inhibitors of STS by Walter et al. 111 . These compounds inhibited the STS with IC50 values in the submicromolar range. The data disclosed in the recent publications have confirmed STS as an attractive target for a range of potential indications, primarily for the therapy of estrogen-dependent breast cancer. Now, the new STS inhibitors await validation of their therapeutic potential in clinical trials.

Pharmacology of Steroid Sulfatase Inhibitors

The available information on the pharmacology of STS inhibitors is restricted to a few in vitro and in vivo models. From all steroidal compounds, the irreversible inhibitor EMATE was found to be the most potent STS inhibitor with an IC50 of 65 pM 107 . However, it has been proposed that the sulfamate moiety of EMATE irreversibly binds to the active site and releases the steroidal backbone estrone. This means that EMATE, although a potent inhibitor of STS, counteracts its own effect by releasing estrone. The most potent derivative from a series of sulfamoyloxy-substituted stilbenes inhibited the growth of MCF-7 breast cancer cells with an IC50 value of 13 nM 111 . Recently Shields-Botella et al. 112 reported novel, orally active STS inhibitors. Several compounds were synthesised and explored for the treatment of estrogen-dependent breast cancer. The compounds TX 1299, TX 1492 and TX 1506 proved to be inhibitors of STS in the choriocarcinoma cell line JEG-3 at an IC50 of 5-70 nM and in...

Structure of the Book

Not only were both the laboratory and clinical aspects of the BRCA-testing systems built differently according to national context and each developer's objectives, but each provider also clearly defined its appropriate use. One provider in the United States, for example, offered BRCA testing as a commercial product that provided genomic information using state-of-the-art techniques. Here, the user of the testing service was a consumer who had the right, even the obligation, to demand access to DNA analysis as long as she could pay for it. The national testing system in Britain, by contrast, used an integrated clinical and laboratory service to identify, counsel, and manage individuals at low, moderate, and high risk for breast cancer. Individuals who used this system were simultaneously citizens and patients, with the right of equal access to health care but forced to heed the triage recommendations of her physician. In chapter 4, I argue that the way BRCA testing was integrated into...

Rationale for the Use of Antiestrogens in Cancer Treatment

The effects observed after surgical oophorectomy and the discovery of steroid hormones and the steroid hormone receptors led to the concept that inhibition of steroid hormone receptor function by antagonists should prevent tumour growth. While the first anti-estrogen, tamoxifen, was found accidentally, a deeper understanding of the estrogen receptor as a transcription factor enabled more rational, SAR-based drug discovery. The introduction of the anti-estrogen tamoxifen has changed the treatment of all stages of breast cancer. It is still the method of choice not only for the treatment of advanced disease in pre- and post-menopausal women but also for prevention in women at high risk for developing breast cancer 141 . Tamoxifen has some interesting side effects that render this compound so unique that the term selective estrogen receptor modulator (SERM) was coined for this class of compounds. Although tamoxifen is an anti-estrogen, the drug is a partial estrogen receptor agonist with...

Chemistry of Antiestrogens

Non-steroidal analogues of the potent 7a-substituted steroidal anti-estrogens were synthesised with the goal of identifying orally active, pure anti-estrogens 152 . The benzopyrene derivatives aclobifene (EM-652) and its prodrug EM-800 are active anti-estrogens in human breast cancer cells in vitro as well as in nude mice in vivo 153 . Although EM-652 and EM-800 have frequently been proposed as pure anti-estrogens, partial estrogenicity was observed in some experiments (Hoffmann, unpublished results). GW5638 is a SERM with a rather conventional triphenylethylene structure that was identified in a screen for compounds that are mechanistically distinct from tamoxifen and raloxifene. In contrast to tamoxifen, the dimethylamino-ethyoxy group is replaced by an acrylate side chain. This structural modification should result in beneficial estrogenic properties, but unlike tamoxifen, it is a more potent antagonist in breast cancer cells and has no uterotrophic behaviour 154,155 . Bazedoxifene...

Pharmacology of Antiestrogens

From a clinical perspective, tamoxifen is still the first and only SERM worth mentioning from the first- and second-generation compounds. The pharmacology of tamoxifen has been reviewed extensively 142 . The NSABP-11 adjuvant trial and the Breast Cancer Prevention Trial (BCPT-1) are some of the milestones in the history of tamoxifen 141 . genic, which results in a different side-effect profile. While lipid levels were similar, the proliferative effects on the endometrium were reduced and the osteoporosis protection was less effective under toremifene treatment 160 . Although droloxifene was more potent in pre-clinical assays, it was significantly less active than tamoxifen in a randomised phase III trial in advanced breast cancer 161 . Levormeloxifene and idoxifene were noted to increase uterine prolapse and incontinence during phase III trials and therefore the trials were terminated prematurely 162 . Raloxifene was successfully approved for osteoporosis prevention after initial...

Rationale for the Use of Progesterone Receptor Antagonists in Cancer Treatment

It is well known that progesterone in physiological concentrations - beside estradiol - may be required for the proliferation of mammary carcinomas 174 . Therefore, it is expected that progesterone receptor (PR) antagonists (PRAs) will be able to block the growth of those mammary carcinomas that express a functional PR, and that PR antagonists might be promising new tools for breast cancer therapy 175 . Although these compounds require a functional PR in order to block tumour growth, there is strong experimental evidence that PR antagonist-mediated tumour growth inhibition is not solely based on progesterone antagonism. The ability of these compounds to induce tumour cell differentiation that leads to apoptosis is a unique ability compared to all other endocrine therapies 176 . mechanism, PR antagonists bind to the PR and modulate PR-dependent gene transcription. In addition, it has been demonstrated that the biological response to a PR antagonist involves more factors and that this...

Pharmacology of Progesterone Receptor Antagonists

PR antagonists such as onapristone, ZK112993, ZK136798 and ZK230211, which are highly selective for the progesterone receptor and possess a reduced anti-glucocorticoid activity compared to mifepristone, exerted a strong anti-tumour activity in a panel of hormone-dependent mammary tumour models 187-189 . Observations from these pre-clinical experiments in different model systems led to the conclusion that the strong anti-tumour activity of these pure PR antagonists in breast cancer does not only depend on the classic anti-hormonal mechanism. For the first time Michna et al. (1992) described that the morphological pattern in experimental breast tumours after treatment with PR antagonists differs totally from that after treatment with tamoxifen, high doses of estrogen, or ovariectomy 190 . By using light and electron microscopy they found that the anti-tumour action of PR antagonists is accompanied by the initiation of differentiation by induction of active secretory glandular formations...

Rationale for the Use of Antiandrogens in Cancer Treatment

These compounds are pure anti-estrogens and in addition they destabilise the receptor protein and lead to a complete disruption of steroid receptor-mediated growth stimulation. Complete blockade of all AR functions by AR destabilising anti-androgens could represent an important therapeutic option for prostate cancer treatment.

Pharmacology of Antiandrogens

Combined androgen blockade, first proposed by Labrie, is under investigation in a number of randomised studies. For example, in a recent study the combination of flutamide or nilutamide with a GnRH agonist has been evaluated. Although the combination seems to improve time to progression (TTP) and overall survival (OS), final data have not yet been published 212 . Whereas the EORTC trial reported significant advantages of a combination of goserelin plus flutamide 213 , this combination failed in other studies 214 . A meta-analysis showed a 5 increase of the 5-year survival under combination therapy 215 . A final consensus for endocrine treatment options for prostate cancer, comparable to the St. Gallen consensus for breast cancer, still has to be established. In some clinical trials, finasteride, an inhibitor of the 5a-reductase type 2, has been added to the combined androgen blockade (goserelin and flutamide) 216 .

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