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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Results Of Randomized Trials Comparing Hepatic Arterial Infusion With Systemic Chemotherapy In Patients With

Early phase II trials employing HAI FUDR given mainly by an external pump have reported encouraging response rates of 29 to 83 (27-31). This sets the stage for prospective, randomized phase III comparison between HAI therapy and systemic chemotherapy or best supportive care. Seven randomized studies were reported between 1987 and 1994 (Table 1) (32-38). One major conclusion that one can draw from these studies is that HAI therapy has resulted in higher tumor response rates than systemic chemotherapy. Since most individual trials are small and therefore not adequately powered to detect a small difference in overall survival (OS), two meta-analyses have been performed in order to determine whether HAI therapy confers a survival benefit over systemic chemotherapy (Table 1) (39,40). The Meta-analysis Group in Cancer included individual patient data from six of seven randomized studies (39). The Northern California Oncology Group (NCOG) trial (34) (representing 143 patients) was excluded...

Prognosis After Chemotherapy

In a prognostic factor analysis of chemotherapy results in germ cell tumors, the International Germ Cell Cancer Collaborative Group (IGCCCG) reviewed 637 patients treated for advanced seminoma. The 3-year survival rate was 82 .9 However, the majority of patients were in a good prognostic subgroup, with metastasis confined to either lymph nodes or lung fields, and in this group, the 5-year survival rate was 86 . Those with nonpulmonary visceral metastases had a 5-year survival rate of 72 . In an analysis of a subset of 236 of these patients treated with cisplatin-based chemotherapy at 1 of 10 European oncology units, a very-good-prognosis group was identified this group comprised patients who had not had previous radiotherapy and who either had abdominal node metastases with any level of serum lactate dehydrogenase (LDH) or were stage C patients without nonpulmonary visceral metastases and whose serum LDH was less than twice the upper limit of normal. These patients had a 94 3-year...

Cell Molecular Biology Breast Cancer

Bi-directional Regulation of Human Progesterone Receptors and the Mitogen Activated Protein Kinase Pathway in Breast Cancer Cell Models Abnormal Properties of Mutants in the Hinge Region of ErV Implications in Breast Cancer Microarray Analysis of Estrogen-Induced Protection Against Breast Cancer

Neoadjuvant Chemotherapy Approaches

In addition to BCNU and PCV (as outlined above), numerous other chemotherapy drugs, alone and in combination, have been used for neoadjuvant treatment of high-grade astrocytomas (see Tables 24.1 and 24.2) 20-24 . Dropcho and colleagues attempted neoadjuvant intra-arterial (IA see Chapter 17) cisplatin (75 mg m2 every 4 weeks) in a series of 22 assessable patients with newly diagnosed high-grade astrocytomas (GBM 13, AA 9) 72 . There were five patients (23 per cent) with partial responses (PR) and five patients (23 per cent) with minor responses (MR) after IA therapy. The time to progression (TTP) ranged from 22 to 115 weeks, with a median of 39.8 weeks overall and 56.3 weeks in responders. Although hematologic, renal, and otic toxicity were mild, there were several patients with significant neurological toxicity. Other investigators have used high-dose intravenous cyclophosphamide (2 g m2 day for 2 doses every 28 days) as neoadjuvant treatment for 14 patients with newly diagnosed GBM...

Chemotherapy for Primary Central Nervous System Lymphoma

ABSTRACT Methotrexate-based chemotherapy has significantly improved the treatment of primary CNS lymphoma. At the present time, several effective single-agent and multiagent methotrexate-based regimens have been reported as well as attempts to enhance delivery using blood-brain barrier disruption, maintenance chemotherapy, and myeloab-lative regimens requiring stem cell support. As no one approach is clearly superior to the others, the relative risks and benefits as well as newer agents and approaches to therapy will be discussed.

Chemotherapy Of Children And Adolescents

The application of chemotherapy to medulloblas-toma patients in this age range is an extensive topic several excellent review articles have been published 3,4,14-16,19,20,46,47 . Several important randomized, multicenter, clinical trials have been conducted by CCG, POG, and other groups in newly diagnosed patients to determine the efficacy of chemotherapy after craniospinal RT (see Tables 29.1 and 29.2). In 1990, the CCG-942 trial was reported, in which 179 newly diagnosed patients were randomized to receive either RT alone (3500-4000 cGy to craniospinal axis, 5000 to 5500 cGy to posterior fossa) or RT plus adjuvant chemotherapy (CCNU 100 mg m2 vincristine 1.5 mg m2, during RT and with each cycle prednisone 40 mg m2 in 6-week cycles for 1 year) 48 . The 5-year survival rate was 65 per cent in both groups. Chemotherapy was not beneficial for patients with low-risk disease. However, in patients with high-risk disease (i.e., large residual tumors after resection, brainstem infiltration,...

Chemotherapy With Bone Marrow Transplantation

In an attempt to improve dose intensity, several investigators have used myeloablative, high-dose chemotherapy followed by bone marrow transplant or rescue (BMT) 3,40,48,74-80 . Preliminary results suggest that durable responses can be achieved in a sub-group of selected patients with high risk or recurrent disease. Chemotherapeutic agents appropriate for high-dose protocols require bone marrow suppression as the dose-limiting toxicity. The most commonly used drugs are busulfan, thiotepa, cyclo-phosphamide, etoposide, melphalan, and carboplatin. The previously mentioned study by Dupuis-Girod used this approach with a regimen of busulfan and thiotepa in infants and young children 40 . They noted 6 CR, 6 PR, and 3 SD in 15 evaluable patients with progressive disease. The event-free survival at 31 months follow-up was 50 per cent. A similar study of young patients with recurrent brain tumors by Gururangan and co-workers included five with medulloblastoma 77 . High-dose chemotherapy...

Breast Cancer Risk Modifiers

The incomplete penetrance associated with mutations in BRCA1 and BRCA2 suggests that environmental or genetic risk-modifying factors may exist that affect the phenotype of BRCA1 and BRCA2 mutation carriers. Initial estimates from clinic-based data indicated that around 80 of carriers of mutations in BRCA1 and BRCA2 from multiple-case families would develop breast cancer (1,2), whereas a later pooled analysis from population-based studies has suggested that for the great majority of mutation carriers, their average lifetime risk is closer to 45 to 66 (3). This pooled-analysis of BRCA1 and BRCA2 carriers also showed that in BRCA1 mutation carriers, the breast cancer penetrance for relatives ascertained through a breast cancer case was significantly higher than for those ascertained through an ovarian cancer case, and even higher if the index case was diagnosed before the age of 35 (3). Conversely, the ovarian cancer risk was higher in families ascertained through an ovarian cancer index...

Tumor Suppressor Activity of E1A in Breast Cancer Experimental Models

The initial link between E1A and tumor suppression in breast cancer was based on the observations that E1A could suppress the transformation phenotype of the neu-transformed NIH mouse 3T3 cells (10-12) by transcriptionally repressing the promoter of rat neu oncogene (9). HER-2 is amplified and overexpressed in approximately 30 human breast cancer patients with poor prognosis (29-31). Because the neu gene is a murine counterpart of the human HER-2 proto-oncogene, it was hypothesized that E1A could also repress HER-2 expression in human breast cancer. Indeed, both HER-2 protein and mRNA levels were reduced in HER-2-overexpressing breast cancer cell lines infected with an E1A-expressing adenovirus (Ad.E1A(+)) but not a mutant adenovirus (Ad.E1A(-)) in which E1A is deleted (13). To test whether the E1A-mediated HER-2 repression affects the cell growth in cell model systems, both the high-HER-2 (e.g., MDA-MB-361 and SKBR3) and the low-HER-2-expressing (e.g., MDA-MB-435 and MDA-MB-231)...

Chemotherapy for Brain Metastases

ABSTRACT Metastatic brain tumors (MBT) are the most common complication of systemic cancer and affect 20-40 per cent of all adult cancer patients. Whole-brain radiotherapy and surgical resection of accessible, solitary lesions have been the mainstay of treatment. Recently, chemotherapy has become a more viable treatment option for MBT. Many different drugs and administrative approaches have been shown to be clinically active. Traditional chemotherapy, given before or during irradiation, can be effective with agents, such as cyclophosphamide, cisplatin, and etoposide. Non-traditional approaches, such as temozolomide and intra-arterial administration of carboplatin, have demonstrated activity against recurrent metastatic disease. In early clinical trials of interstitial chemotherapy, biodegradable polymers have shown some clinical efficacy and have been well tolerated. Molecular approaches are also under investigation in response to new information regarding the metastatic phenotype....

Interstitial Chemotherapy

Interstitial chemotherapy involves the placement of a drug or drugs directly into the brain tumor or resection cavity of the brain parenchyma 89 . With this approach, the tumor and surrounding brain are exposed to high concentrations of drug, which is not limited by the BBB. In addition, there is minimal exposure of the drug to the systemic circulation and organs. Interstitial chemotherapy delivery systems were originally developed for application to malignant gliomas, due to their high local recurrence rate and limited potential for systemic metastases 89-92 . Brem and colleagues were able to devise a biodegradable polymer wafer, ''loaded'' via anhydride bonds to BCNU (3.85 per cent 7.7 mg). After placement of the wafers into the tumor resection cavity, water in the Recent research by Ewend and co-workers has investigated the use of chemotherapy-loaded wafers as a treatment method for MBT 93-95 . In a mouse model, 20 per cent BCNU-loaded wafers were implanted after surgical resection...

Highdose Chemotherapy And Autologous Stem Cell Rescue In Pediatric Gliomas

The dismal prognosis for patients with high-grade gliomas and diffuse intrinsic brainstem gliomas has led to the investigation of high-dose chemotherapy followed by autologous stem cell rescue. The rationale for this treatment is multi-factorial. Primarily, conventional treatments have failed to produce adequate survival results. Radiation therapy alone has not provided adequate outcomes, and the addition of standard-dose chemotherapy to radiation has not significantly improved survival 37 . The failure of chemotherapy to improve survival is likely due to the restrictions of the BBB as well as to intrinsic drug resistance of these tumors 38,39 . The theoretical advantage to high-dose chemotherapy is the ability to overcome these barriers. High-dose chemotherapy with autologous stem cell rescue was first tried in adult patient with Dismal prognosis for pediatric patients with high-risk gliomas, including glioblastoma multiforme and diffuse intrinsic brainstem glioma, has prompted the...

Extent Of Postchemotherapy Surgery

Modified Rplnd

Early in his very large experience, Donohue24 found residual tumor in the para-aortic and right and left suprahilar nodes in patients with a right-sided primary tumor and in the right and left suprahilar, right iliac, and interiliac nodes in patients with left-sided primaries (15 cases). Therefore, due to an obvious risk for the presence of residual tumor in lymph node groups located outside the boundaries of a limited template dissection, a modified retroperitoneal lym-phadenectomy was considered an unacceptable compromise for patients with advanced-stage disease after chemotherapy. On the other hand, a significant number of intra- and postoperative complications have been reported in patients undergoing extended postchemotherapy RPLND.17-19,25 Therefore, several investigators have tried to identify the optimal extent of limited postchemotherapy RPLND. Hendry and colleagues26 evaluated the outcome of the excision of para-aortic tumor masses alone (lumpectomy) in 231 patients after...

Chemotherapy Of Pineal Parenchymal Tumors

The use of chemotherapy for the treatment of pineal region neoplasms has been applied mainly to CNS germ cell tumors, which is extensively reviewed in Chapter 33. The experience with pineal parenchymal tumors is more limited and mainly consists of small institutional series of patients 8,9, 15,37 . In the majority of cases, chemotherapy has been applied to patients with recurrent or progressive pineoblastoma, with less frequent application to those with recurrent pineocytoma. Objective responses have been limited, using a variety of chemotherapy agents including vincristine, lomustine, cisplatin, etoposide, carboplatin, cyclophosphamide, actinomycin D, and methotrexate. Thus far, no single Initial experience with chemotherapy of pineal parenchymal tumors was gained in pediatric patients. Friedman and colleagues reported a small series of young children with poor-prognosis medulloblas-toma (N 14) and pineoblastoma (N 2) that were treated with intravenous melphalan (45 mg m2 every 4...

Chemotherapy of Ependymoma

ABSTRACT Ependymomas are rare neoplasms of the central nervous system (CNS) seen most commonly in children. The most effective treatment modality is surgical resection, and it is widely held that gross total removal of these tumors confers a better prognosis. Radiation therapy (RT) is commonly used to treat residual, recurrent, or progressive disease. The experience with chemotherapy has been a long and frustrating one, both up front and at relapse. Certainly, significant radiographic and clinical responses have been observed with a number of agents, particularly with the platinum compounds, but these successes have been uncommon and unpredictable, have rarely produced prolonged disease-free or overall survival, and have almost never been associated with cure. Alone or in combination, in conventional doses or in the high doses used with bone marrow stem cell rescue, chemotherapy has been a great disappointment in the management of this tumor. One can only hope with the advent of newer...

Prognostication After Chemotherapy

Much experience has been gained in predicting outcomes of patients who complete chemotherapy and in regard to adjunctive therapies following chemotherapy. In particular, post-chemotherapy surgical findings have been analyzed in efforts to identify those who are at high risk for additional events. Foster and colleagues recently reported the role of retroperitoneal lymph node dissection (RPLND) in patients with persistently elevated markers after the completion of standard chemotherapy for disseminated disease. Of those patients with persistently elevated markers and residual radiographic abnormalities, all were able to undergo complete resection. Approximately one-third of the patients were disease free with either surgery alone or surgery plus post-surgery chemotherapy, with a minimum follow-up of 24 months.18 Patients who have an incomplete radiographic response to chemotherapy but a normalization of elevated serum biomarkers frequently undergo post-chemotherapy resection of residual...

Synthetic Nucleotide Analogs Are Used In Chemotherapy

Synthetic analogs of purines, pyrimidines, nucleosides, and nucleotides altered in either the heterocyclic ring or the sugar moiety have numerous applications in clinical medicine. Their toxic effects reflect either inhibition of enzymes essential for nucleic acid synthesis or their incorporation into nucleic acids with resulting disruption of base-pairing. Oncologists employ 5-fluoro- or 5-iodouracil, 3-deoxyuridine, 6-thioguanine and 6-mer-captopurine, 5- or 6-azauridine, 5- or 6-azacytidine, and 8-azaguanine (Figure 33-12), which are incorporated into DNA prior to cell division. The purine analog allopurinol, used in treatment of hyperuricemia and gout, inhibits purine biosynthesis and xanthine oxidase activity. Cytarabine is used in chemotherapy of cancer. Finally, azathioprine, which is catabolized to 6-mercap-topurine, is employed during organ transplantation to suppress immunologic rejection.

Interstitial Chemotherapy and Polymer Drug Delivery

ABSTRACT Malignancies of the central nervous system represent a formidable challenge and prognosis of patients remains dismal. Physiological barriers impede efficacious delivery of tumoricidal concentrations of anti-neoplastic agents to the CNS without incurring undesirable systemic toxicities. The development of local delivery devices for controlled administration of chemotherapeutics provides a new mechanism to effectively treat brain tumors while bypassing many of the harmful toxicities. In this chapter, we describe the rationale and history of the development and use of these polymers to deliver interstitial chemotherapy, and review new investigations of different drug-polymer combinations. Finally, we will briefly describe new local drug delivery systems.

Hypothetical Correlation Of Proliferation Of The Breast Cancer Cell And Sult Activity

FIGURE 8.6 Effects of the progestin R-5020 (promegestone) on the SULT activity and the mRNA expression of SULT1A3 in the hormone-dependent T-47D human breast cancer cell line. Relative expression of the mRNA (using RT-PCR amplification) and the estrogen sulfation activity (in pmol mg protein h) in T-47D cells nontreated (control) and treated with R-5020 at the concentration of 5 x 10 or 5 x 1 0-7mol L. The control value is assigned 100 . The data represent the mean S.E.M. of two to three experiments. Quoted from Chetrite G, Le Nestour E, Pasqualini JR, J Steroid Biochem Molec Biol 66 295-302, 1998. With permission. FIGURE 8.6 Effects of the progestin R-5020 (promegestone) on the SULT activity and the mRNA expression of SULT1A3 in the hormone-dependent T-47D human breast cancer cell line. Relative expression of the mRNA (using RT-PCR amplification) and the estrogen sulfation activity (in pmol mg protein h) in T-47D cells nontreated (control) and treated with R-5020 at the concentration...

Adjuvant Chemotherapy

The use of one or two courses of adjuvant carbo-platin for patients with stage I seminoma has been reported by a number of investigators over the past decade (see Chapter 19).61243-45 Oliver and colleagues, who treated stage I seminoma with one to two courses of adjuvant carboplatin chemotherapy, pioneered this approach. Dieckmann and colleagues, with a median follow-up of 48 months, reported no relapses among 32 patients treated with two courses of carboplatin and reported 8 relapses in 93 patients given only one course. Steiner and colleagues reported their institutional experience over 10 years using two courses of car-boplatin in 99 patients.45 With a median follow-up of 60 months, 2 patients (1.85) developed recurrence both relapses occurred within the first year and were successfully salvaged with cisplatin-based regimens. Reiter and colleagues reported on their 12-year experience with 107 patients treated with two courses of carboplatin. No recurrences or deaths from seminoma...

Contribution Of Known Genes To Familial Breast Cancer

An important question is the extent to which the known susceptibility genes can explain the familial aggregation of breast cancer. The simplest assessment of this is the proportion of the familial risk to first-degree relatives of cases that is explicable by each gene. We might term this the familial attributable fraction of each gene. These estimates can then be added over genes, on the assumption that the genes interact either additively or combined on a log scale, if the genes interact multiplicatively. Unlike the population-attributable fraction, the contribution of known genes to the familial risk cannot exceed 100 , so that it provides an assessment of how much genetic variation remains to be explained and is a much more useful concept. Note, however, that this does not reflect the In the case of BRCA1 and BRCA2, the familial attributable fraction can be estimated using data from population-based studies that have performed mutation screening, based on the proportion of cases...

Hormone Receptor Status Of Breast Cancers

Breast cancer is diagnosed at a level of about 100,000-120,000 new cases per year in the United States, and 40,000 die each year from this most common cause of cancer in women. For some time breast cancers have been classified on the basis of receptor measurements from biopsy specimens. Thus, in general, these cancers fall into three categories estrogen receptor (ER) positive and progesterone receptor (PR) positive ER positive and PR negative and ER negative and PR negative. These measurements show that in those cancers with normal levels of ER and PR the cells should be responsive to the growth-stimulating effects of estrogen. Furthermore, the positive expression of PR indicates that the ER is functional in that PR is a pheno-typic product of ER action. Such tumors are more amenable to treatment and therapy with antiestrogens and other maneuvers. The progression of tumor status from hormone dependent to hormone independent (ER-, PR-) is a bad sign, and a hormone-independent tumor is...

Adjuvant Chemotherapy Approaches

Many different chemotherapy drugs have been used in the adjuvant setting for high-grade astro-cytomas, including the nitrosoureas, as outlined above. The vast majority of these drugs have either been ineffective or unable to demonstrate a clinical advantage (i.e., prolonged survival or TTP) over standard intravenous BCNU 20-24 . This conclusion has been further corroborated by a recent randomized phase III trial of irradiation plus adjuvant PCV versus radiation therapy alone for patients with high-grade astrocytoma (see Tables 24.1 and 24.2) 84 . A total of 674 patients were treated, including 449 with GBM and 113 with AA. The median overall survival for the radiation-PCV and radiation alone groups were 10 and 9.5 months, respectively (hazard ratio 0.95 p 0.50, log-rank test). The addition of PCV did not add a survival benefit and no difference could be detected in the efficacy of chemotherapy between the AA and GBM patients. However, a retrospective analysis of adjuvant chemotherapy...

The 216aHydroxylated Estrogen Breast Cancer Risk Hypothesis

On the basis of the studies described above, which showed that increased formation of 16a-hydroxylated metabolites relative to 2-hydroxy-lated estrogen metabolites may be associated with an elevated risk of breast cancer, it was hypothesized that a low urinary 2-hydroxyestrone to 16a-hydroxyestrone ratio should be inversely associated with breast cancer risk.144 Development of a competitive-type enzyme immunoas-say (EIA) method for quantifying these metabolites in urine145 allowed the hypothesis to be tested rapidly and relatively inexpensively in a large number of samples. This assay was used in the study by Kabat and associates,144 who measured the metabolites in spot urine from breast cancer cases (n 42) and controls (n 64), including both premenopausal and postmenopausal women. Although the 2-hydroxyestrone to 16a-hydroxyestrone ratio was not associated with breast cancer overall, the ratio in the post-menopausal group was significantly lower in the cases (n 23) compared to the...

Combination Chemotherapy

There are relatively few prospective randomized trials of different chemotherapy regimens for advanced seminoma. When interpreting reports of uncontrolled trials, it should be remembered that over the last two decades there have been considerable changes in staging classifications, in the use of radiotherapy for metastatic seminoma, and in the definition of response. The modern era of successful chemotherapy for seminoma was heralded by the introduction of cisplatin. As early as 1974, there was a reported case of a complete response of stage C seminoma to cisplatin despite relapse after previous treatment with radiotherapy and with actinomycin D.12 At the same time, at the M. D. Anderson Hospital, less aggressive chemotherapy that also appeared to be effective had been evaluated. This treatment was based on sequential weekly pulse cisplatin combined (in most patients) with cyclophosphamide. The report on 52 patients included 8 patients treated only with cisplatin 85 of patients...

Hepatic Arterial Infusion Chemotherapy as Second Line Treatment

Leonard et al. have recently reviewed the response rates and survival data from trials evaluating second-line chemotherapy after irinotecan or oxaliplatin failure. The response rates were generally less than 20 and median survival is around 10 months (85). For example, Tournigand et al. reported response rates of 15 with FOLFOX6 and 4 with FOLFIRI, respectively (86). As described above, HAI therapy when combined with newer cytotoxic agents has demonstrated encouraging second-line activity (up to 90 ) even in patients who had progressed on modern chemotherapy (Table 4). Dose-finding trials combining HAI with newer chemotherapeutic drugs have now been completed, and randomized trials of HAI plus systemic chemotherapy versus the most active systemic chemotherapy alone should allow determination of the best second-line approach.

Sulfotransferase Expression And Its Control In Breast Cancer

Using reverse transcriptase-polymerase chain reaction amplification, the expression of SULT1A3 mRNA was detected in the hormone-dependent MCF-7 and T47-D, as well as in hormone-independent MDA-MB-231 and MDA-468, human breast cancer cells. An interesting correlation of the relative SULT activity and the SULT1A3 mRNA expression was found in various breast cancer cells studied (Chetrite et al., 1998 Figure 8.5).

Bone Marrow Stimulation During Chemotherapy

Haemopoiesis was studied in 88 patients with lung cancer during combination treatment with chemotherapy and a 5. balcalensls extract. Administration of the plant preparation was associated with haemopoiesis stimulation, intensification of bone marrow erythrocytopoiesis and granulocytopoiesis, and increased numbers of circulating precursors of erythroid and granulomonocytic colony-forming units (Goldberg et al 1997).

Chemotherapy Of Meningiomas

The role of adjuvant chemotherapy in meningioma patients remains unclear and continues to evolve 1,2,43,44,55 . It has mainly been applied to inoperable patients, especially in the setting of progression or recurrence after some form of radiotherapy. Numerous approaches have been taken, including traditional cytotoxic drugs, molecular agents, immunomodulators, and hormone manipulating drugs. Although none of these drugs have been particularly effective, some have been able to demonstrate modest activity in sub-groups of patients. Several investigators have reported the results of cytotoxic and immune modulating chemotherapy approaches in meningioma patients 1,2,43,44,55 . Initial reviews of treatment responses in older sets of patients did not suggest any benefit from chemotherapy 56 . In a review of 25 patients with malignant meningioma treated at MD Anderson from 1944 through 1992, Younis and associates noted 10 that had received cytotoxic chemotherapy. The regimens consisted of...

Molecular Chemotherapy With rAAV

Although a majority of both preclinical and clinical gene therapy studies using molecular chemotherapy approaches have been conducted with recombinant adenoviral Consideration of molecular chemotherapy strategies for selective killing of tumor cells suggests that long-term expression of transgenes is not an imminent requirement hence, AAV-based vectors are less preferred over adenoviral vectors. Further, the efficacy of adenoviral infection in different tumor cells has been reported to be significantly higher than many other available gene therapy vectors. However, it has recently been reported that the efficiency of rAAV transduction of primary tumor material, derived from malignant melanoma and ovarian carcinoma, is significantly higher ( 90 ) than that seen in established tumor cells of the same derivation in culture (86). This observation suggests that it is possible to utilize rAAV in direct targeting of tumor cells for an effective killing by approaches such as molecular...

Strategies Incorporating Hormonal Therapy and Cytotoxic Chemotherapy

The benefit of cytotoxic chemotherapy for patients with hormone-refractory prostate cancer is now firmly established.171,172 Several attempts have been made to determine whether response to and duration of clinical remission from hormonal therapy can be improved by the early addition of cytotoxic chemotherapy. Generally, with the notable exception of a combination of estramustine with selected cy-totoxic drugs (see below, Estramustine in Combination with Cytotoxic Drugs), these attempts have met with limited success. The Southwest Oncology Group studied the combination of endocrine therapy (estrogens or or-chiectomy) with doxorubicin and cyclophos-phamide randomized against endocrine therapy alone with addition of the same chemotherapy regimen at progression.173 This trial accrued between September 1982 and October 1986. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63 ) compared to those on endocrine therapy alone (48 ), but this was not...

QOL in Long Term Survivors of Breast Cancer

In total, 16 studies met our search criteria for breast cancer, all published after 1998. The studies are described in Table 1 and include our study,32 which will be discussed in greater detail following the general review. Quality of life was a primary outcome in all studies. Of the 16, five studies compared the QOL between breast cancer survivors and healthy or normal controls.4,41-44 Two of five also compared QOL outcomes between survivors who have experienced a cancer recurrence to those who have not.4,43 Three of the 16 studies compared QOL between breast cancer survivors receiving different types of treatment.2,45,46 Two of the 16 investigated the QOL between breast cancer survivors diagnosed at different ages47,48 another two studies compared QOL at time of diagnosis and follow-up32,49 and two more examined the impact of treatment on QOL.50,51 One study looked specifically at the role of ethnicity in QOL outcomes,52 while the final study examined the...

Tyrercuzick International Breast Cancer Intervention Study

This is the most recently developed of the breast cancer risk assessment models (32). It was developed using published data regarding BRCA1 and BRCA2 mutation carrier frequencies from a study of mother-daughter pairs (33) and penetrance estimates from the Breast Cancer Linkage Consortium (34) rather than one specific dataset. There are two parts to the model's calculations a genetic part and a personal risk factors part. Like the BRCAPRO model, International Breast Cancer Intervention Study (IBIS) uses Bayesian calculations as a basis for the genetic part of the model. The Bayesian variables used are BRCA1 mutation, BRCA2 mutation, and other genetic risk factor, an as yet unknown low-penetrance gene that is assumed to follow an autosomal-dominant inheritance pattern. Like BOADICEA, IBIS can incorporate exact family relationships and is not restricted to a certain number of first- and second-degree relatives in order to make its assessment. It is also capable of dealing with bilateral...

Modifiers Of Penetrance And Breast Cancer Genes Other Than Brca

Several studies have noted an increased penetrance for BRCA1 2 in more recent birth cohorts. The NYBCS (9) confirmed Narod's earlier observation of a significant increase in breast cancer risk by the age of 50 years in birth cohorts after 1940 (67 after 1940, 24 before 1940) (39). Ovarian cancer risk did not differ by birth cohort. This increase in incidence for BRCA1 2 mutation carriers parallels an increase in breast cancer in the general U.S. population over that period (37). Antoniou et al. (61) analyzed the results of 22 studies in which cases were unselected for family history. The RR for breast cancer among BRCA1 2 mutation carriers in the post-1960 birth cohorts was two to three times the RR in the preceding four decades. A study of Austrian BRCA1 mutation-positive women found that those from birth cohorts after 1958 had a significantly higher incidence of breast cancer by 40 years of age than those from earlier birth cohorts 46 versus 27 , respectively (89). Finally,...

Toxicity Of Ia Chemotherapy

The most common toxicity of patients receiving IA chemotherapy is ipsilateral periorbital erythralgia and visual loss, which in many cases can be dose-limiting 4-7,85,86 . Ophthalmological examination of affected patients suggests a toxic retinal vasculitis, with retinal arteriolar narrowing, hemorrhages, nerve fiber layer infarctions, and arterial phase leaks 31 . An anterior ischemic optic neuropathy may also occur in some patients 58 . The incidence of visual loss among the cases cited in this review was approximately 10-12 per cent for patients receiving a nitrosurea-based regimen and 5-8 per cent for those receiving a cisplatin-based regimen. Intra-arterial PCNU and HeCNU appear to have a higher incidence of visual loss than carmustine. Overall, the potential for visual loss appears to be greater for patients receiving IA carmustine and other nitrosoureas than for patients receiving cisplatin, carboplatin, or methotrexate. Visual loss is less likely when patients Hearing loss is...

Combination Ia Chemotherapy Of Recurrent Gliomas

IA chemotherapy approaches utilizing multiple IA agents or the combination of an IA agent with an oral or intravenous drug have also been extensively reported in the literature (see Table 17.4). The majority of regimens have focused on the use of IA carmustine in combination with other drugs. The initial experience was reported by West and colleagues, when they utilized a regimen of IA carmustine (100 mg m2) plus PCV for nine patients with recurrent malignant gliomas 46 . The objective response rate was 22 per cent, with a median survival of 20 weeks. Neurotoxicity was similar to that reported above for IA carmustine. Another report combined IA carmustine (100-125 mg m2), IA cisplatin (60 mg m2), and IA teniposide (VM-26 150-175 mg m2) in a series of 19 patients 68 . The response rate was 68 per cent, with another 6 per cent stabilizing while on treatment. However, the overall median TTP was only 15 weeks. The regimen was limited by retinal toxicity (19 per cent), hearing loss (5 per...

Residual Masses And Postchemotherapy Radiation

Especially with cases of large-volume seminoma, it is common to find a residual mass on scanning the patient after a course of chemotherapy. However, approximately 90 of these masses do not contain residual malignancies and appear to be fibrotic remnants (Figure 20-3).30,31 Attempted resection can be hazardous because of extensive dense scar tissue involving the great vessels and retroperitoneal tissues. The analysis from the Memorial Sloan-Ketter-ing Cancer Center suggested that there was a higher risk of residual malignancy if the residual mass was 3 cm in diameter.32 This suggestion has led, at some centers, to a policy of particularly close surveillance or adjuvant radiotherapy for this subset of patients.33 However, other investigators have not found that recurrence was more likely when the residual mass was 3 cm in diameter.34 Furthermore, retrospective data from 302 patients treated in 10 European centers with chemotherapy for metastatic seminoma indicated that 174 of those...

Systemic Chemotherapy

Systemic chemotherapy is not used routinely for advanced HCC. There are factors related to the tumors. HCC is relatively chemoresistant, partly due to the presence of drug-resistant genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins and mutations in p53. There are also factors related to the patients. Patients often do not tolerate chemotherapy well because of the underlying liver dysfunction and liver cirrhosis. Several chemotherapy agents, including doxorubicin, epirubicin, 5-fluorouracil and leucovorin, gemcitabine, thalidomide, and capecitabine, have been studied in the treatment of advanced HCC either as single agents (41-46) or in combination (47-49). The response rates vary from 20 to 50 , but no improvement in overall survival has been reported. A number of small uncontrolled studies report an overall response to doxorubicin monotherapy to be less than 20 . The only controlled trial involving 104 patients showed a modest improvement in median...

Prospective Dose Intensity Trials for Breast Cancer

Tannock et al. (7) evaluated the dose-intensity concept in a prospective setting for patients with metastatic breast cancer. Patients were randomly assigned to receive two dose levels of CMF chemotherapy every 3 wk standard (cyclophosphamide 600 At the M.D. Anderson Cancer Center, Hortobagyi and colleagues (8) evaluated the impact of higher dose anthracycline therapy in metastatic breast cancer. Patients were randomly assigned to receive either standard 5-fluorouracil (F), doxorubicin (A), and cyclophosphamide (C) or 260 higher FAC. The median response durations and overall survival rates were not significantly different. Furthermore, hematologic, infection-related, and gastrointestinal complications were increased in the high-dose FAC group (8). The studies by Tannock et al. (7) and Hortobagyi et al. (8) seemed to indicate that a threshold dose existed for the treatment of breast cancer, but a large confirmatory trial was needed.

Treatment Of Chemotherapyinduced Febrile Neutropenia

The treatment of patients with chemotherapy-induced FN is multifactorial and includes not only antibiotic and CSF therapy but also supportive measures. Observational vigilance is an important aspect in the care of patients with chemotherapy-induced neutropenia there is no substitute for frequent observation and examination, particularly of the oropharynx, chest, and abdominal and perirectal areas. Frequent blood cell counts, blood cultures, and culture and examination of exudates and other bodily fluids in patients with fever remain the mainstay of good medical care. In addition to good skin care and oral hygiene, every effort should be made to maintain good functional status through nutritional support and exercise. Patients with cancer should be encouraged to decrease or eliminate smoking and maintain their immunization status, including influenza immunizations. Education of the patient and family, as observers of health status, is also important, particularly to recognize the...

Biological Basis For Tamoxifen As A Breast Cancer Preventive

Tamoxifen was selected for testing as a preventive based on (1) animal studies that demonstrated it could prevent carcinogenesis,49-52,103 (2) extensive clinical experience that showed few serious side effects, and (3) a beneficial profile of estrogen-like action in maintaining bone density and reducing circulating cholesterol. Ta-moxifen was already known to reduce the incidence of contralateral breast cancer47 and to have a favorable toxicity profile, making the drug the primary agent to test in high-risk women. Sporadic reports19,104 and placebo-controlled randomized trials20,105 demonstrated that ta-moxifen can increase bone density in the lumbar spine, forearm, and neck of the femur by 1 -2 . Although the increases are modest compared to the results obtained with estrogen or biphosphonates (5 increase in bone density), tamoxifen produced a marginal decrease in hip and wrist fractures as a secondary end point in the breast cancer prevention trial.106 Tamoxifen reduces circulating...

Expression in Breast Cancer

Situation analogous to the regulation of promoter II by FSH in the ovary. Indeed, it appears that in breast cancer cell lines an additional CRE, located within promoter 1.3 ( 66 59), contributes to cAMP-induced transcription from promoters II and I.3.59 This CRE-like sequence overlaps a binding site for the zinc-finger tran-scriptional factor Snail (SnaH), which was identified by yeast one-hybrid screen using the CRE as a probe.60 SnaH acts as a repressor of promoter 1.3 activity and was expressed at higher levels in normal breast epithelial cell and stro-mal fibroblast cell lines than in breast cancer cell lines.60 Thus, downregulation of SnaH in stro-mal cells adjacent to malignant breast epithelial cells might contribute to induction of aromatase through promoter I.3. Figure 8.5 Proposed regulation of aromatase gene expression in breast adipose tissue from cancer-free individuals and from those with breast cancer. In the former case, expression is stimulated primarily by class I...

Evidence For Inherited Predisposition To Breast Cancer

Familial Breast Cancer

Mutations in BRCA1 or BRCA2 account for the majority of families with multiple cases of either breast cancer alone or breast and ovarian Figure 7.1 Familial breast cancer. Individuals were diagnosed with primary breast cancer at the ages shown. A familial pattern such as this is strongly suggestive of autosomal dominant predisposition by a single predisposing gene. These cases proved to be due to mutation in BRCA1. Figure 7.1 Familial breast cancer. Individuals were diagnosed with primary breast cancer at the ages shown. A familial pattern such as this is strongly suggestive of autosomal dominant predisposition by a single predisposing gene. These cases proved to be due to mutation in BRCA1. cancer. It is perhaps surprising that they account for only a small part of the excess familial clustering of these cancers in the population as a whole. The overall extent of familial clustering can be measured by ascertaining a large series of breast cancer cases from the population and...

Prevention Of Breast Cancer With Tamoxifen

In 1986, Cuzick et al.156 outlined a prevention trial with tamoxifen in women at high risk of breast cancer. The previous year, Cuzick and Baum157 documented a marginally significant reduction in the risk of a second primary cancer in the contralateral breast of breast cancer patients after 2 years of tamoxifen. This initial observation was confirmed in larger randomized clinical trials. Fornander et al.158 recruited 1846 postmenopausal patients for the Stockholm Adjuvant Tamoxifen Trial and randomized them to a trial of adjuvant tamoxifen or nothing for early breast cancers. In the tamoxifen patients, new primary breast cancers occurred less often (RR 0.55). Similar results were obtained by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14.159 These results led to the obvious interest in tamoxifen as a possible preventive for primary disease. Carefully controlled clinical chemoprevention trials continue to establish the activity and toxicity of specific agents and...

Further Chemotherapy For Radically Resected Residual Cancer

The presence of viable cancer cells in completely resected residual masses carries the worst prognosis when compared with the presence of mature teratoma or necrosis alone (see also Chapter 16).26,33 Since the study by Einhorn and colleagues,37 which reported a dismal outcome for all 18 patients with residual cancer at postchemotherapy surgery who received no further therapy, many investigators have opted for the routine use of postoperative adjuvant chemotherapy. 2,5,9,11,12,24,26,33 No compelling evidence has existed to confirm whether adjuvant chemotherapy for consolidation is justified in this setting. Thus, my colleagues and I recently challenged this approach as we found no difference in the 5-year survival in a retrospective study of 49 evaluable patients who were treated (24 patients) or not treated (25 patients) with adjuvant chemotherapy following complete resection of residual cancer after first-line (30 patients) or salvage (19 patients) chemotherapy.38,39 An international...

Management of Nonseminomatous Testicular Cancer Chemotherapy for Poor Risk Patients Standard Dose Therapy

And actinomycin D, cyclophosphamide, and etopo-side (ACE) was devised in 1977.4 The concept behind this essentially alternating schedule of chemotherapy was to alternate the POMB schedule, which was less myelosuppressive than the ACE schedule, and to increase the dose intensity by having a schedule of every two weeks rather than the more commonly used schedule of every three weeks of chemotherapy. Although the POMB ACE schedule contains seven drugs, the total cumulative dose of each individual drug is less than that in schedules such as PVB and such as bleomycin, etoposide, and cisplatin (BEP)5 because the component schedules essentially alternate. The experience of the past 25 years of treating these patients is that durable remissions are maximized if the chemotherapy contains a minimum of 300 mg m2 of cisplatin and that the proportion of remissions probably increases with the total dose of etoposide administered.*

Commonly Used Chemotherapy Regimens For Metastatic Germ Cell Tumor

We try for normalization of the main two serum tumor markers hCG and AFP and continue alternating POMB and ACE until the patient has been in tumor marker remission for approximately 4 weeks (Figure 14-1). In common with other centers, as confidence in the stability of the complete remissions obtained with chemotherapy has increased, we have shortened the total duration of treatment. It should be noted that we have modified our current approach to this regimen, shortening the duration of treatment by omitting the second 24-hour infusion of bleomycin. two courses usually are sufficient to reduce the organ failure so that the full POMB ACE schedule can be started as described above. This approach allows chemotherapy to be delivered to patients who would otherwise get major toxicity if they received either BEP in full dose or POMB in full dose. In our last analysis of the patients treated with POMB ACE chemotherapy for metastatic NSGCT between 1977 and 1995,16...

Standard Dose Salvage Chemotherapy Summary

Approximately 50 of recurrent testicular cancer patients will achieve a disease-free status when VeIP is administered as second-line therapy.72,73 Half of the patients who achieve complete remission on VeIP eventually relapse therefore, approximately 25 of patients with recurrent germ cell tumors can have the expectation of long-term disease-free survival with standard salvage chemotherapy. The substitution of paclitaxel for vinblastine has yielded impressive results in a patient population with favorable prognostic features. However, a direct comparison to VeIP is needed to determine its true worth in this setting.

Postchemotherapy Histology

The histology of a residual mass after initial chemotherapy varies substantially in different series. Steyerberg and colleagues5 reviewed 996 postchemo-therapy resections from 19 studies published between 1983 and 1990. Residual cancer was present in an average of 16 of cases, mature teratoma was in 36 of cases, and fibrotic and or necrotic tissue was in 48 . In resected lung lesions, necrosis was found more often (57 of cases) and teratoma was found less frequently (27 of cases). The same author6 reviewed six studies published between 1986 and 1993 that included a total of 556 patients undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) 13 of patients had residual cancer, 42 had mature teratoma, and 45 had fibrosis-necrosis. Steyerberg and colleagues7 also found a higher frequency of residual necrosis in patients treated with regimens containing etoposide (as I and my colleagues had predicted in 1985).8 Last, but not least, about 50 of patients undergoing...

Combining Hepatic Arterial Infusion Therapy With Contemporary Systemic Chemotherapy

The combination of HAI FUDR with systemic oxaliplatin has also been evaluated in a phase I study where patients were assigned to receive two different oxaliplatin-containing systemic regimens (Table 4) (74). In Group A, patients receive HAI FUDR in combination with escalating doses of systemic oxaliplatin and irinotecan. In group B, patients receive HAI FUDR plus systemic oxaliplatin at 100 mg m2, LV at 400 mg m2, and escalating doses of continuous infusion of 5-FU. Systemic treatment was given every two weeks. Sixty-nine percent of the 36 patients were previously treated with irinotecan. An impressive 90 (Group A) and 89 (Group B) response rates were obtained (74). In Group A, seven of 21 patients were able to undergo liver resection, and two patients had no remaining tumor. The MTD for Group A was oxaliplatin 100 mg m2 and irinotecan 150 mg m2, not dissimilar to the recommended dose of oxaliplatin 85 mg m2 and irinotecan 200 mg m2 when given without HAI therapy. The MTD of 5-FU in...

Twin Studies and Bilateral Breast Cancer

In principle, the familial aggregation of breast cancer may be due either to genetic factors or to lifestyle or environmental factors that are shared among relatives. The latter possibility is unlikely in that no lifestyle risk factors that are sufficiently strong to materially affect familial aggregation of the disease have been identified. More formal evidence that familial aggregation has a genetic basis comes from twin studies. Based on an analysis of population-based twin registers from the Nordic studies, Lichtenstein et al. (23) found that the risk of breast cancer in the monozygotic (MZ) twins of cases was about twice as great as the risk in the dizygotic (DZ) twins. Using a particular multifactorial model, this study estimated that about 27 of the variation in breast cancer risk was genetic. This particular estimate should be viewed cautiously since it does depend on the model used and on how one defines the variation in breast cancer risk, but it does point to a substantial...

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67). Another important low-risk susceptibility gene is CHEK2, another DNA repair gene that acts downstream of ATM. Mutations in this gene were first identified in patients with a family history reminiscent of Li-Fraumeni syndrome, and it was therefore suspected that this was another high-risk...

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1). These results imply that such risk factors can be assumed to multiply the familial risks of breast cancer (an assumption made in the Tyrer et al. and Gail models). It also suggests that such risk factors are largely independent of genotype. Whether this is true for specific susceptibility genes, in particular BRCA1 and BRCA2, is less clear however. Several studies have examined the effects of these risk factors in BRCA1 2 carriers but many of the results are contradictory, perhaps reflecting...

Newer Chemotherapy Agents

The results of the numerous clinical trials of adjuvant therapy for pancreatic cancer leave many questions unanswered with no definitive answer as to the optimal treatment for these patients. In addition, newer chemotherapy agents such as gemcitabine and molecularly targeted agents have emerged, and the possible benefit of their addition to adjuvant therapy has yet to be reported in larger trials. Based on the results of a prospective randomized trial, gemcitabine has become the standard first line agent in patients with advanced pancreatic cancer. Burris and colleagues randomized 160 previously untreated patients with advanced and metastatic pancreatic cancer to receive either gemcitabine or 5-FU. Patients who received gemcitabine had a statistically improved median survival, one-year survival rate, and clinical benefit compared to patients who received 5-FU (19). In radiobiologic models, gemcitabine has also been observed to be a potent radiosensitizer. Although the mechanism of...

Rationale For Hepatic Arterial Infusion Chemotherapy

Until recently, the pyrimidine analog 5-fluorouracil (5-FU) had been the palliative standard for patients with metastatic colorectal cancer. It resulted in response rates of approximately 20 (12). The addition of leucovorin (LV) to 5-FU results in a higher response rate without significant improvement in survival (13). Changing the method of administration of 5-FU from bolus to continuous infusion can modestly improve response rates, without significant impact on survival (12). Thus, the poor response to 5-FU-based system chemotherapy provided the initial impetus for developing alternative approaches to the management of metastatic colorectal cancer. Regional chemotherapy by HAI is based on sound physiological and pharmacological grounds. First, liver metastases that grow beyond 2 to 3 mm are dependent on the hepatic artery for vascularization, whereas normal liver tissues are perfused by the portal vein (14,15). Second, HAI therapy allows delivery of increased local concentration of...

Concurrent Use With Chemotherapy

In 1994, Livingston et al. (43) began a series of studies exploring the concept of dose density, namely, multifractioned doses of chemotherapy given at shorter intervals than standard regimens. To prevent dose-limiting myelosuppression, they began intermittent and then continuous neutrophil support with daily filgrastim. In the first study, vinorelbine 35 mg m2 was given weekly with continuous filgrastim 5 mg kg to 40 patients previously treated with anthracyclines and resistant to paclitaxel. They observed that continuous filgrastim allowed a nearly twofold increase in the delivered dose intensity, from 46 to 73 , compared with similar historical series without filgrastim. The increase in delivered dose intensity was suggested as the basis for the observed 25 objective response rate. Use of continuous filgrastim with an alkylating agent, cyclophosphamide 60 mg m2 d, continously with doxorubicin 24 mg m2 wk was tested preoperatively in 122 patients with locally advanced breast cancer...

Chemotherapy In Practice

From chemotherapy has emerged in terms of disease progression, overall survival, and quality of life. Several randomized trials have revealed chemotherapy to be valuable when compared to best supportive care (BSC) or delayed chemotherapy (4,5). In 2000, the Colorectal Cancer Collaborative Group (6) reported on a meta-analysis examining individual patient data (866 patients) and published summary statistics from 13 randomized controlled trials comparing palliative chemotherapy with supportive care reported between 1983 and 1998 (total patients 1365). They examined survival, disease progression, quality of life, and toxicity. They found that palliative chemotherapy was associated with a 35 reduction in the risk of death (95 Confidence Intervals (CIs) 24-44 ) translating into an absolute survival benefit of 16 at 6 and 12 months, and an improvement in median survival of 3.7 months. Similarly, a systematic review of results of chemotherapy in colorectal cancer was performed by the Swedish...

Postoperative Chemotherapy

The potential advantage of using postoperative therapy is that one can be relatively selective, based on pathological factors, in the patients who receive treatment, and there is no delay in definitive surgical therapy. However, the selection of only fit postoperative patients for clinical studies of postoperative treatment should lead one to be cautious in interpreting the applicability of such treatment to the general population, for example, excluding patients with R1 or R2 resections (microscopic and macroscopic residual disease, respectively) or those with prolonged postoperative complications. This potential bias is not present in trials of pre- or perioperative therapy. Indeed, patients randomized to receive chemotherapy before and after surgery show that less than 50 of the patients are able to receive full doses of chemotherapy following major upper GI surgery (1,15). The results of three Japanese randomized control trials have failed to show a benefit for postoperative...

Dose Intensity in Breast Cancer Preclinical and Retrospective Clinical Data

Preclinical in vivo and in vitro data suggest that increasing the dose of chemotherapy increases tumor cell kill, but with significant myelosuppression (4). Hryniuk and Bush (5), in a literature review of regimens for metastatic breast cancer, calculated the dose of CMF chemotherapy given over a unit of time and concluded that a relationship was apparent with dose intensity and response rate in the setting of metastatic breast cancer. For the adjuvant setting, Hryniuk and Levine (6) evaluated chemotherapy trials for women with stage II breast cancer treated with CMF-like regimens. In this retrospective study, the authors concluded in both univariate and multivariate analyses that dose intensity was a significant predictor of relapse-free survival (6). These initial observations of dose intensity, although suggestive, were retrospective.

Risk Factors for Chemotherapy Induced Febrile Neutropenia

Cytokines reset the thermoregulatory center in the hypothalamus to retain heat and allow the core temperature of the body to increase. Mononuclear phagocytes are the principle producers of the endogenous cytokines that cause fever and are much less affected by chemotherapy than neutrophils. Therefore, fever is reliable as a marker of infection in patients receiving chemotherapy, including neutropenic patients. In a review of the risk of FN among patients with intermediate-grade NHL receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy, Lyman and coworkers (5,6) identified several factors associated with an increased risk of neu-tropenia-related complications. Data for this study came from 577 patients and 224 occurrences of FN in 12 community and academic oncology practices. Age 65 yr (p 0.001), significant cardiovascular or renal disease (p 0.02), baseline hemoglobin concentration 12 g dL (p 0.018), and administration of 80 planned dose intensity (p...

Use in Increasing Chemotherapy Dose Intensity

The guidelines note that there is an apparent steep dose-response curve in preclinical studies but that retrospective analyses of dose-delivered intensity in the clinic suggest that bias may have been introduced. Some of the randomized trials compared lower than standard-dose chemotherapy with standard-dose chemotherapy. In the late 1990s, trials increasing dose intensity above standard levels were not shown to improve survival. The recommendation was that outside the setting of clinical trials, the use of CSFs to increase dose intensity was not justified.

Regional Intraarterial Chemotherapy

In patients with HCC, uncontrolled tumor in the liver is the most significant cause of morbidity and mortality, although extrahepatic metastases are apparent in up to 25 of patients at the time of diagnosis and up to 90 on autopsy. Thus, effective local chemotherapy would have a significant clinical effect. Administration of the drug into the hepatic artery could theoretically increase local drug delivery to the tumor tissue and possibly lower systemic toxicity. An ideal pharmacologic profile would be a high degree of hepatic extraction, high systemic clearance, rapid biotransformation to less toxic metabolites, and a steep dose-response relationship with respect to tumor cell kill.

Neoadjuvant Chemotherapy

Disease that is felt to be inoperable initially may still be rendered potentially operable by the use of the newer chemotherapy agents with their improved rates of response. One of the first reports (38) investigated chronomodulated chemotherapy in unresectable liver metastases. They reported a trial in which 53 of 330 patients initially deemed to have unresectable liver disease (due to location, large size, multinodular lesions, or extrahepatic disease) were downstaged with systemic, chronomodulated chemotherapy using 5-flurorouracil, folinic acid, and oxaliplatin to the point at which operation could be performed. The cumulative three- and five-year survival rates were 54 and 40 . In 15 cases, hepatic recurrence amenable to repeat surgery occurred. A larger series reported by the same group (37) revealed a 13.5 rate of conversion from inoperable to operable with a potential for cure by the use of neoadjuvant therapy. Adam and coworkers treated 701 patients with unresectable...

Technical Aspects Of Hepatic Arterial Infusion Chemotherapy The Totally Implantable Pump

Early experience with regional chemotherapy involves the use of a percutaneously placed catheter attached to an external infusion device. Treatment required hospitalization and was often associated with a high incidence of complications such as catheter dislodgement, bleeding, thrombosis, and infection (19). Another approach is the implanted port which allows repeated access to the arterial system as well as attachment to an external portable pump for ambulatory treatment. However, these ports still had a high failure rate, particularly with regard to hepatic arterial thrombosis (20). The development of a totally implantable arterial-infusion pump in the late 1970s marked the modern era of HAI therapy (21). Slightly larger than a pacemaker, these pumps can provide a constant slow infusion of chemotherapy at infusion volumes of 30 to 50 mL. The constant flow of fluid is driven by the pressure generated from a self-charging system of fluorocarbon liquid present in the sealed chamber of...

Breast Cancer Prognosis In

Many studies have indicated that a p53 somatic mutation is an independent poor prognostic indicator for breast cancer (86), with some data suggesting that the prognosis may be influenced by the nature of the mutation (87). Miller et al. (30) have shown that an expression signature for p53 functional status in breast cancer is more predictive of outcome than p53 sequence analysis, and suggest that p53 may be functionally attenuated in the absence of DNA sequence variants. From those data one might assume that the breast cancer in germ line p53 mutation carriers would also carry a poor prognosis surprisingly little data are available to support that expectation, and the absence of data perhaps speaks loudly. Given that there are no published survival data for breast cancer in p53 mutation carriers, the frequent reports of multiple primary tumors occurring over 10 to 30 years (71) suggest that many of these patients do not succumb to their breast cancer. Unlike BRCA1,2 mutation carriers...

Chemotherapy Of Infants And Very Young Children

Sensitive to the effects of irradiation 12,14,29-31 . More than 60 per cent of surviving brain tumor patients will develop significant cognitive impairment after exposure to cranial RT. In this group of medulloblastoma patients (roughly 20 per cent of all pediatric cases, which also have the poorest prognosis for survival), chemotherapy has a very prominent role, because it is often applied ''up front'' to delay the use of RT until the patient matures beyond 2.5 to 3 years of age (see Tables 29.1 and 29.2) 3-5 . Initial reports by van Eys and colleagues have suggested that MOPP chemotherapy, using nitrogen mustard (6 mg m2), vincristine (1.4 mg m2), procarbazine (100 mg m2), and prednisone (40 mg m2) was effective against pediatric brain tumors, including medulloblastoma in infants 32-34 . They were able to demonstrate durable responses in 30-40 per cent of their infant cohort. In a subsequent report from the same group, follow-up data was available for 12 infants with medulloblastoma...

Granulocyte Colonystimulating Factor And Granulocytemacrophage Colonystimulating Factor For Chemotherapyinduced

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are endogenous glycoproteins that participate in the differentiation and proliferation of granulocytes, monocyte-macrophages, and other cells for hematopoeisis (17). Myelosuppresion is the major toxicity of chemotherapy for solid organ tumors, and prolonged myelosuppression and neutropenia lead to a reduction in chemotherapy dose intensity. Therefore, with the discovery, cloning, and production of recombinant human forms of G-CSF and GM-CSF (rHuG-CSF and Fig. 1. The relationship between absolute neutrophil count (ANC) and neutropenic fever after salvage chemotherapy is shown for patients with metastatic breast carcinoma. When the ANC decreases to a level below the threshold of 500 mL, the incidence of neutropenic fever increases in a linear trend (p 0.01). *, Number of courses with fever number of courses with nadir ANC in the same range. Fig. 1. The relationship between...

Threshold Dose in the Treatment of Breast Cancer

The Cancer and Leukemia Group B (CALGB) did a randomized trial evaluating different doses and dose intensities of adjuvant chemotherapy in patients with node-positive breast cancer 1572 patients were randomized to receive CAF at three dose levels low-dose (5-flurouracil 300 mg mL, doxorubicin 30 mg mL, cyclophosphamide 300 mg mL), moderate dose (5-fluorouracil 400 mg mL, doxorubicin 40 mg mL, cyclophosphamide 400 mg mL), and high dose (5-fluorouracil 600 mg mL, doxorubicin 60 mg mL, cyclophosphamide 600 mg mL). Women treated in the moderate- and high-dose-intensity groups had significantly longer disease-free and overall survival than those in the low-dose group. Survival was not different between the moderate- and high-dose groups (9). This study validated the idea of a threshold dose in the treatment of breast cancer.

Estrogens Aromatase and Risk of Breast Cancer

These observations provide the rationale for the use of endocrine therapy as preventative measures against BC in women with high risk ofthe disease. Four trials using tamoxifen have been published (55-57), as has a fifth trial using raloxifene (58). Although there are differences among studies, a recent metaanalysis of the tamoxifen trials indicated that results were compatible with a 42 reduction in short term incidence of breast cancer with tamoxifen use (59).

Apoptosis Pathways and Chemotherapy

ABSTRACT Tumor cell death is the ultimate goal of chemotherapy. In particular, the induction of apoptosis has been suggested as a strategy for efficient and selective elimination of tumor cells. However, in malignant gliomas, the most common malignant intrinsic brain tumors, there is little evidence that the currently available chemotherapeu-tic drugs mediate their effects via induction of apoptosis, with the possible exception of anaplastic oligodendrogliomas which often show striking tumor regression on neuroimaging. Nevertheless, the induction of apoptosis plays a major conceptual role in the majority of novel experimental approaches to brain tumors.

Genetic models of breast cancer susceptibility

It is likely that the inheritance of most common cancers is polygenic. Breast cancer, like other common cancers, exhibits some degree of familial clustering, with disease being approximately twice as common in first-degree relatives of cases (Amundadottir et al., 2004 Collaborative Group on Hormonal Factors in Breast Cancer, 2001). The higher rate of most cancers in the monozygotic twins of cases than in dizygotic twins or siblings suggests that most of the familial clustering is the result of genetic variation rather than lifestyle or environmental factors (Lichtenstein et al., 2000 Peto and Mack, 2000). Further evidence for the relative importance of genetic factors comes from the observation that more distant relatives of a case (i.e. those beyond the nuclear family) are also at increased risk of disease even though they would be expected to share environmental or lifestyle factors to a lesser degree (Amundadottir et al., 2004). Furthermore, the magnitude of the risks in distant...

Practical Effects Of Aedchemotherapy Interactions

The potential for subtherapeutic chemotherapy dosing in patients on EIAEDs has affected clinical trial design for patients with malignant gliomas, and should also be taken into account in trials for patients with central nervous system metastases as well. Clinical trials for patients with brain tumors must stratify patients by the use or non-use of EIAEDs, and seek separate maximum tolerated doses for any CTA that might be metabolized by the CYP system 49,51,54 . In effect, there has to be a separate Phase I clinical trial in patients on EIAEDs, because the dose determined in Phase II trials done in patients who are not taking such agents is an inadequate estimate of the dose that will produce toxicity or effectiveness in patients on EIAEDs. This leads to a complicated accrual process for clinical trials for brain tumor patients. To find the proper dose in patients on EIAEDs, there must be one arm that dose escalates to find the MTD in patients on EIAEDs. At the same time, another arm...

Penetrance For Breast Cancer In P53 Mutation Carriers

Overall data from the IARC TP53 Database (14) confirm findings of smaller series that breast cancer is the most common cancer in LFS, accounting for about 25 to 30 of all cancers. For p53 mutation carriers the median age of breast cancer onset is 33 years, significantly earlier than for non-p53 LFS at 42.5 years. To date no genotype-phenotype correlation, that is, no association of specific p53 mutations by structural or functional domain, or by mutation type, has been observed for breast cancer overall however, breast cancer median age of onset was significantly younger in those with mutations in the DNA-binding domain (average age 32 years) as compared with missense mutations not in the DNA-binding domain (average age 42 years) age of onset for those with inactivating or likely null mutations was similar to that for mutations in the DNA-binding domain (median age 33 years) (14). This is in contrast to previous findings (57) of a higher incidence and earlier onset of breast cancer in...

Ia Chemotherapy For Primary Cns Lymphoma

Primary CNS lymphoma (PCNSL) has been shown to be a chemosensitive tumor, and can respond well to multi-agent chemotherapy, including methotrexate-based or carboplatin-based IA regimens 5,6,78,79 . In the majority of cases, IA chemotherapy for PCNSL is used in combination with IA mannitol and blood-brain barrier disruption, to further improve delivery of chemotherapy drugs to tumor cells 5,79,80 . Many patients are also treated ''up-front'', before any form of irradiation. The median survival with this approach ranges from 42 to 48 months, with an acceptable level of systemic and neurological toxicity. For an in-depth review of this topic, see Chapter 18.

Intrahepatic Chemotherapy

The rationale for administering intrahepatic arterial chemotherapy is that by delivering chemotherapy directly to the target organ, high levels of drug will reach the metastatic lesions. As 5-FU undergoes arterial extraction at first pass the concentrations will be far greater (up to 100 times) than that obtained with intravenous administration. This will be of particular benefit due to the steep dose-response curve seen with cytotoxic drugs. However, the procedure is complex and potentially dangerous, requiring insertion of an intra-arterial catheter. The meta-analysis Group in Cancer carried out a meta-analysis of early trials of intrahe-patic arterial (IHA) chemotherapy, using data from individual patients, reviewing response rates and survival rates (39). Their report revealed that IHA treatment gave improved objective tumor response rates when compared to intravenous therapy (IHA 41 vs. 14 IV or 0.25, 95 CI 0.16-0.40, p 0.0001) but a statistically significant survival advantage...

Radiation And Chemotherapy Risks

Most series of LFS families, as well as case reports, have noted not only the high risk of multiple primary tumors but the frequent occurrence of new cancers in radiation-treated sites (48,53,58,60,71-73). Hisada et al. (71) observed only one of 14 subsequent breast cancers arising in a previously irradiated area however most of the subsequent sarcomas arose in previously irradiated areas, and studies of childhood cancer survivors, especially young soft tissue patients (67,74), have noted a significant excess of female breast cancer, both within and in the absence of radiation therapy. It seems clear that there is an extremely high risk of multiple primary tumors in LFS patients, occurring both spontaneously and in irradiated sites. This is consistent with observations in heterozygous p53 knockout mice in which radiation significantly accelerates tumor development (75). Many authors have suggested that radiation not be used for cancer treatment in p53 mutation carriers if feasible,...

Efficacy of Chemotherapy Regimens

A sizable number of patients with locally advanced anal tumors receiving chemoradio-therapy will still ultimately require salvage APR. In an attempt to improve outcome and reduce toxicity, several investigators have examined the role of cisplatin, a potentially more effective chemotherapy agent and radiosensitizer, as a substitute for MMC. In a retrospective analysis, Hung et al. reported their experience with 92 patients treated with protracted daily infusion of cisplatin (4 mg m2 day) and 5-FU (250 mg m2 day) during radiation therapy (55 Gy in six weeks without a planned break) (31). The five-year survival rate was 85 , and colostomy-free survival was 82 with no patient requiring colostomy for symptom control. Local control was achieved in 83 of patients (T1 T2 90 and T3 T4 72 ). The regimen was well-tolerated with 3 toxicity and one treatment-related death. As all these studies used higher doses of radiation, comparison with MMC-based chemoradiotherapy regimens is made with...

Breast Cancer As A First Or Subsequent Cancer In

Not only is breast cancer the most common cancer observed in LFS, it plays a major role in subsequent cancers. In the Hisada et al. (71) series, 200 LFS patients had at least one cancer, including 104 females and 96 males among 30 patients who developed one or more additional cancers, 19 (63 ) were in females. The 19 females who had multiple primary tumors experienced a total of 46 cancers (original plus subsequent), with breast cancer accounting for 26. Forty-five of the original tumors were female breast, and 10 of those patients developed at least one additional tumor, including eight with an additional breast cancer. Breast cancer also accounted for 5 6 (83 ) of second cancers in those with an initial sarcoma (the other common original tumor). These data overall suggest an extremely high probability of breast cancer in LFS females, most of which occur before age 45, with a remarkably high probability of a second breast cancer. In Hwang et al. (58), the cumulative risk of female...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

Blood Brain Barrier Disruption Chemotherapy

ABSTRACT The goal of chemotherapy administered in conjunction with blood-brain barrier disruption (BBBD) is maximizing drug delivery to the brain, while preserving neurocognitive function and minimizing systemic toxicity. Translational blood-brain barrier (BBB) pre-clinical and clinical studies at Oregon Health & Science University (OHSU) evaluate the toxicity and antitumor efficacy of chemothera-peutics, chemoprotectants, and monoclonal antibodies (mAbs) as well as novel therapeutics and imaging agents. A current program focus is thiol chemo-protection against the hearing and bone marrow toxicity that is caused by platinum chemotherapy. Thiols may permit increased dose intensity of agents administered in conjunction with BBBD. In the clinic, BBBD has shown promising results in chemo-sensitive brain tumors such as primary central nervous system lymphoma (PCNSL) and offers a new strategy for global delivery of chemotherapy to tumors, such as anaplastic oligodendroglioma and central...

Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6 and 3.5 , respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed between 45 and 54 years of age to be just 0.3 and 1.0 , respectively (79). These studies underestimate the true prevalence of mutations because studies use methods that are not fully sensitive. Indeed, the fraction of mutations that are detected by such studies is somewhat uncertain because some variants in BRCA1 and BRCA2 are of uncertain significance and may or may not be associated with risk. Nevertheless, overall fraction of breast cancer patients in outbred populations carrying BRCA1 and BRCA2...

Chemotherapy and Anti Epileptic Drug Interactions

ABSTRACT Patients with primary or metastatic brain tumors are often on medications that alter the pharmacokinetics of chemotherapeutic agents (CTAs). The most common drugs administered to neuro-oncology patients that can affect their chemotherapy are anti-epileptic drugs (AEDs). Oncology patients who require chemotherapy may also be on AEDs for pre-existing epilepsy, neuropathic pain or headaches. These enzyme-inducing anti-epiletic drugs (EIAEDs) induce the production and activity of hepatic enzymes that are responsible for the metabolism of many drugs. The most common mechanism for this effect is induction of the cytochrome p450 (CYP) system. The induction of CYP by EIAEDs can affect the metabolism and effectiveness of CTAs. When patients require chemotherapy, it is important to know, how their concomitant medications affect the pharamacokinetics of the chosen CTA, because significant under or overdosing can occur. It is also important that these interactions be taken into account...

Concomitant Chemotherapy And Irradiation Approaches

A potent radiosensitizing effect, independent activity against tumor cells, non-cell-cycle specific, and amenable to dose-intensive or prolonged administration schedules. The three most common mechanisms for radiosensitization are inhibition of radiation damage repair (e.g., purine and pyrimidine analogs), perturbation of the cell cycle in order to increase the fraction of tumor cells in the G2 M phase (e.g., vinca alkaloids, paclitaxel), and alteration of hypoxic cell populations (e.g., RSR 13). Although numerous compounds have been tested for a radiation sensitizing effect, chemotherapy drugs have been most effective and form the basis for the evolving discipline of chemoradiation 42-45 . Chemoradiation has been applied to high-grade astrocytomas, initially with alkylating agents such as BCNU and methyl-CCNU, and halogenated pyrimidines (e.g., iododeox-yuridine) 45-49 . Other chemotherapy agents that have been used in chemoradiation regimens include cisplatin, fluorouracil,...

PTEN and Cowden Syndrome Prevention Of Breast Cancer In Cs

Some women with CS consider prophylactic mastectomy, especially if breast tissue is dense, making surveillance difficult, or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90 in women at high risk (63), although no studies have specifically addressed this intervention in patients with CS. There is no direct evidence to support the routine use of agents such as tamoxifen or raloxifene in individuals with CS to reduce the risk of developing breast cancer. Physicians should discuss the limitations of the evidence and the risks and benefits of chemoprophylaxis with each individual. In addition, the clinician must discuss the increased risk of endometrial cancer associated with tamoxifen use in this population that is already at increased risk for this malignancy.

Comparisons Of Longterm Effects Of Diagnosis And Treatment By Cancer Site Breast Cancer And Hodgkins Disease

Was expected that type and frequency of the physical dimension of QOL would be explained by type of treatment, age at the time of treatment and time since diagnosis. It was also expected that social and psychological dimensions of QOL would be explained by differences in educational attainment. The sample was composed of 141 individuals (55 male) who participated in two different surveys conducted at Stanford University Medical Center. The initial interviews were conducted in-person while the 12-year follow-up interviews were self-administered both surveys were conducted when the individual came to the clinic for a routine check-up. The second study was a 5-year follow-up of a population-based cohort of 185 women who were younger 50 years of age at diagnosis of breast cancer and were cancer-free 5 years later. The initial survey was in-person, often in the women's home, and the 5-year follow-up was a telephone survey.32 Comparative findings are organized according to Ferrell and...

What Is Hereditary Breast Cancer

It is worth stating at the outset that the term hereditary breast cancer, while in widespread usage, is somewhat problematic. Hereditary implies that the propensity to disease in that individual has been inherited. Thus, the implication is that breast cancer can be dichotomized into those cases where susceptibility is inherited and those where it is not. This concept arose from consideration of cancers with a simpler genetic basis such as retinoblastoma and Wilm's tumor, which can be usefully categorized in this way (2,3). As we shall see, the situation is much more complex for breast cancer. There are many different susceptibility genes for breast cancer, and a substantial fraction (in fact the majority) of breast cancer cases occur in women who are predisposed in some way. It is also worth emphasizing here that there is no known pathologically distinct type of breast cancer that is hereditary (although certain pathological features are more common in BRCA1 carriers), so it is not...

Clinical Pharmacology of Brain Tumor Chemotherapy

ABSTRACT Chemotherapy has become a more common adjunctive treatment for most patients with malignant brain tumors and for selected patients with benign neoplasms. In general, the most effective chemotherapeutic drugs are alkylating agents, such as the nitrosoureas, procarbazine, temozolomide, cisplatin, carboplatin, and cyclophosphamide. Other agents that have been applied to brain tumors include methotrexate, vincristine, etoposide, irinotecan, hydroxyurea, and paclitaxel. Molecular therapeutic strategies are also under development, such as tyrosine kinase inhibitors and angiogenesis inhibitors. Overall, the efficacy of chemotherapy for brain tumors remains modest in the majority of patients. This chapter will review the detailed pharmacology and clinical application of chemotherapy in brain tumor patients.

Models Of Breast Cancer Susceptibility

Several models have been developed to derive estimates of risk to women with a family history of breast cancer or to estimate the probability of carrying a mutation in the BRCA1 or BRCA2 gene. These models can be broadly categorized as empirical models and genetic models. Empirical models are based summarily on measures of family history, such as the number of affected relatives and other risk factors. Perhaps the most widely used model of this kind is the Gail model, which incorporates a variety of breast cancer risk factors in addition to the number of affected relatives (31). Such a model is useful in the general population context, for example, in selecting women for prevention trials but is less useful in high-risk families where the nuances of the family history cannot be captured well. Genetic models seek to model the familial aggregation of the disease in terms of the effects of specific genes or other familial risk factors. These models are developed from population-based...

Chemotherapy of High Grade Astrocytomas

ABSTRACT High-grade astrocytomas, including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), are frequently diagnosed tumors that continue to have a poor prognosis and protracted survival. Chemotherapy has recently been demonstrated to provide a survival benefit in patients with AA and GBM, in addition to surgical resection and irradiation, by several meta-analyses. The improvement in survival has been modest and mainly associated with the use of nitrosourea drugs such as BCNU and CCNU, as well as platinum compounds. Recent clinical trial data also suggests that the alkylating agent, temozolomide (TZM), has activity against AA and GBM in the neoadjuvant, adjuvant, and recurrent settings. In addition, TZM has been shown in phase II and III clinical trials to improve survival of patients with GBM in combination with radiation therapy. Further drug discovery and clinical trial testing will be needed to make more substantial improvements in the survival of patients with...

Breast Cancer Risk In Males

Familial clustering of female breast cancer was demonstrated as early as 1926 (81), and epidemiological studies have shown that although both men and women with breast cancer are more likely to have family histories in first-degree relatives than unaffected individuals, men with breast cancer were even more likely to have a first-degree relative with ovarian cancer than affected women (82,83). It is noteworthy that initial linkage studies of BRCA1 did not reveal an association with male breast cancer (14,84). Linkage studies for BRCA2, on the other hand, did contain male breast cancer cases (16). Germline analyses of 50 men affected with breast cancer unselected for family history revealed that 14 of these men carried a BRCA2 mutation (85). Easton et al. (52), in a study of two large kindreds linked to BRCA2, estimated the cumulative risk of breast cancer in male carriers to be 6.3 by the age of 70 years. In an analysis of 164 BRCA2 kindreds, a similar estimate for cumulative risk...

Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk estimates from epidemiological studies are required. Fortunately, many such studies have been conducted. Most are case-control studies that compare the family history of breast cancer in cases with the family history in controls. Other studies are cohort studies of relatives of breast cancer patients. These latter studies include those based on record linkage with national records, notably those done in Sweden, Iceland, and Utah, and they provide estimates that are free from any potential recall bias...

Chemotherapy of Medulloblastoma

ABSTRACT Medulloblastoma is the most common primary brain tumor in children and accounts for 25 per cent of newly diagnosed cases. Recent advances in treatment have extended 5-year survival rates from 3 to over 70 per cent during the past 50 years. These improvements in survival have resulted from a multi-modality approach that includes surgical resection, posterior fossa and craniospinal irradiation (RT), and chemotherapy for selected, high-risk patients. The literature regarding chemotherapy of adult and pediatric patients is reviewed in depth. The most active agents include cisplatin, CCNU, cyclophosphamide, vincristine, and carboplatin. Although patients are living longer with their disease, neuro-cognitive function and quality of life are often impaired after RT to the developing brain. To safely allow reductions in the dose of RT, the specificity and efficacy of chemotherapy must be improved. Recent advances in the molecular genetics of medulloblas-toma transformation (e.g.,...

Intrathecal Chemotherapy

Although the experience from systemic lymphoma and leukemia clearly supports the use of intrathecal chemotherapy to prevent or treat leptomeningeal disease, its role in the treatment of PCNSL remains controversial. Most therapeutic regimens for PCNSL rely on high-dose MTX and high-dose ARA-C, both of which, when administered as a rapid infusion, can achieve tumoricidal CSF levels, thus obviating the need for IT chemotherapy 41,46 . Furthermore, at least two retrospective studies have failed to demonstrate any advantage in terms of disease control or survival for patients treated with intrathecal chemotherapy 41,46,47 .

Marrow Ablative Chemotherapy with Hematopoietic Stem Cell Rescue

ABSTRACT Marrow ablative chemotherapy with hematopoietic stem cell rescue (also referred to as hematopoietic stem cell transplantation) is a therapeutic strategy used to treat children and young adults with brain tumors whose conventional therapy is either too toxic (e.g., radiotherapy in infants) or ineffective (e.g., rhabdoid tumors or progressive malignant tumors). In this strategy, highdose chemotherapy (typically including alkylating agents and or other radiomimetic drugs) is given to patients after initial conventional therapy, including surgery and irradiation, if possible, and conventional-dose chemotherapy. The success of marrow ablative chemotherapy with hematopoietic stem cell rescue depends on several variables, including the histological type of tumor, extent of disease and of surgical resection, and response to prior chemotherapy. In this chapter, we shall review results of marrow ablative chemotherapy with hematopoietic stem cell rescue in brain tumors of differing...

Intra Arterial Chemotherapy

ABSTRACT Intra-arterial (IA) chemotherapy is a form of regional delivery to brain tumors, designed to enhance the intra-tumoral concentrations of a given drug, in comparison to the intravenous route. Drugs that are likely to be benefit from IA delivery have a rapid systemic clearance and include carmustine and other nitrosoureas, cisplatin, carboplatin, etopo-side, and methotrexate. Clinical studies have demonstrated activity of IA chemotherapy approaches for low- and high-grade gliomas, cerebral lymphoma, and brain metastases. However, a survival benefit for IA drug delivery, in comparison to intravenous administration, has not been proven in phase III trials. The technique is limited by the potential for significant vascular and neurological toxicity, including visual loss, stroke, and leukoencephalopathy. More recent studies suggest that toxicity can be reduced by the use of carboplatin- and methotrex-ate-based regimens. Further clinical studies will be needed to determine the...

Preirradiation Or Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy refers to treatment given at diagnosis before other modalities such as radiation. It has several potential advantages. First, neoadjuvant chemotherapy allows early treatment of the infiltrating tumor cells that may be at or beyond the border of the radiation field. Second, neoadjuvant chemotherapy allows true assessment of the efficacy of the chemotherapy. Such information is important at the time of tumor progression in deciding whether treatment with the same regimen might be helpful. Finally, new agents are most effectively screened for activity in this setting (51). If a given agent has no efficacy in newly diagnosed patients, it will not help patients with recurrent tumors, and further testing in these patients can be avoided. The risk of tumor progression during chemotherapy, however, is significant, particularly for patients with GBM. The neoadjuvant trial design for patients with HGG requires very close monitoring. Most such trials appropriately...

Reducing Chemotherapy Sideeffects

Results from a small, open, prospective study of subjects with advanced gastric cancer suggests that intravenous administration of a polysaccharide fraction isolated from E. purpurea may be effective in reducing chemotherapy-induced leucopenia (Melchart et al 2002). Test subjects had advanced gastric cancer and were undergoing palliative chemotherapy with etoposide, leucovorin and 5-fluorouracil. The median number of leukocytes 14-16 days after chemotherapy was 3630 microL (range 1470-5770) in the patients receiving herbal treatment compared with 2370 microL (870-3950) in the patients of the historical control group (P 0.01 5).

Biological Basis For Raloxifene As A Breast Cancer Preventive

Raloxifene, originally named keoxifene or LY156758,170 was discovered in the breast cancer program at the laboratories of Eli Lilly (Indianapolis, IN). The drug has a high binding affinity for the ER,171,172 primarily because it has strategically located phenolic groups (Fig. 12.1). Raloxifene and an analogue, LY117018,59,173-175 are short-acting compounds with poor bioavailability due to rapid phase II metabolism.176 Indeed, a concern in the early clinical trials was an inability to monitor blood levels. Although numerous assays are available to monitor ta-moxifen and its metabolites,177 the structure of raloxifene does not permit the use of similar chemical methods of detection. The analytical technique used to monitor raloxifene has not been published therefore, there has been limited clinical experience for the treatment of breast cancer. The initial study, conducted at the M.D. Anderson Cancer Center in Houston, showed no responses in heavily pretreated patients with stage IV...

Highdose Chemotherapy At First Relapse

High-dose chemotherapy as the first salvage treatment of relapsed germ cell tumors has been less extensively investigated.115 Unlike patients with multiply recurrent germ cell cancer, patients in first relapse can expect a 50 likelihood of complete remission and a 25 chance of long-term freedom from disease with conventional-dose salvage chemotherapy. The goal, therefore, is not the salvage of otherwise doomed patients but improvement in the efficacy of salvage therapy. Demonstrating efficacy in this setting is thus more challenging. The typical approach employed to date has included one or two cycles of conventional-dose chemotherapy followed by one or two courses of high-dose chemotherapy with carboplatin etoposide, with or without an alkylating agent.116119 Less commonly, high-dose therapy has been administered alone, without a prior conventional-dose salvage regimen.120,121 Investigators at Indiana University Table 16-2. PROGNOSTIC SCORING FOR OVERALL SURVIVAL AND FAILURE-FREE...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

Mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not differ between premenopausal and post-menopausal women.129 However, when these enzymatic activities were compared between breast cancer patients (n 33) and matched controls (n 10), 16-hydroxylation was associated with increased risk of breast cancer, whereas the competing 2-hydroxylation pathway was either neutral or associated with decreased risk.135 The investigators suggested that the breast cancer patients had an increased extent of 16a-hydroxylation prior to the onset of the disease, unless the increase was a consequence of the cancer itself. In a subsequent study, using a murine mammary tumor model, Bradlow and associates136 reported a close correlation between the extent of tumor incidence and 16a-hydroxylation, but not 2-hydroxylation, of estra-diol....

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