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! Continue reading...

Chemo Secrets From a Breast Cancer Survivor Overview

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This book served its purpose to the maximum level. I am glad that I purchased it. If you are interested in this field, this is a must have.

Radiation Induced Chemotherapy Resistance

Most of the available data clearly underline that the combination of radiation with cytotoxic drugs increases the level of cell kill however, it has to be mentioned that few data are available showing that radiation may also negatively influence the efficacy of chemotherapy. In most cases, radiation was shown to trigger an up-regulation of the two important MDR-associated proteins, p-glycopro-tein and multidrug resistance protein 1 (Hill et al. 2000 Nielsen et al. 2001 Henness et al. 2002). It is unclear how relevant this phenomenon is in reality since also the opposite phenomenon, i.e., down-regulation of MDR proteins, has clearly been observed (Ryu et al. 2004) thus, there seems to be a cell-type-specific influence of radiation on the expression and

Combination Chemotherapy

A variety of combination schedules using different drugs and dosage regimes is now available and accepted as superior to single drug therapies. Many cancers are already disseminated at the time of clinical diagnosis, and so combination chemotherapy may be commenced concurrently with local treatment (e.g., surgery, radiotherapy) to maximize patient benefits. Early diagnosis is always advantageous because micrometastases associated with the primary tumor are often very sensitive to combination chemotherapy since they have a good blood supply that facilitates drug access. They are also less likely than older tumors to develop drug resistance.

Classification of the drugs used for chemotherapy

The agents used in cancer chemotherapy are divided into four groups. Since cancer during pregnancy is fortunately rare, and antineoplastic therapy is usually conducted as combination chemotherapy following established standard protocols, it is difficult to determine the teratogenic potential of individual cytostatic drugs in the human. Apparently, antimetabolites possess the strongest teratogenic potential after transrctinoic acids such as tretinoin (see Chapter 2.17).

Integration of Radiation Therapy and Systemic Therapy for Breast Cancer

17.1.1 lntegration of Chemotherapy Hormonal Therapy Biological Therapy with Surgery and Radiation in the Management of Breast Cancer 252 17.1.2 Non-invasive Breast Cancer Ductal Carcinoma in Situ 252 17.2 Early-Stage Breast Cancer 253 17.2.1 Sequencing of Radiation Therapy and Chemotherapy after Breast-Conservation Therapy 255 17.2.2 Sequencing of Radiation Therapy and Chemotherapy in Patients Treated with Mastectomy 258 17.2.4 Sequencing of Chemotherapy and Hormonal Therapy 259 17.3 Locally Advanced Breast Cancer 260 17.3.1 Neoadjuvant Chemotherapy 260

Integration of Chemotherapy Hormonal Therapy Biological Therapy with Surgery and Radiation in the Management of Breast

The majority of breast cancer patients are currently treated with a combination of surgery, radiation, and systemic therapy. This is because all these approaches have proven to be valuable for patients with non-invasive disease, patients with early stage disease, and patients with locally-advanced breast cancer. How to best integrate surgery, radiation, and systemic treatments has become a highly relevant clinical question, and one that affects hundred of thousands of patients each year therefore, it has become very important for breast cancer patients to be managed by a multidisciplinary team, with participation of the surgeons, radiation oncologists, medical oncologists, pathologists, and diagnostic radiologists. Multidisciplinary management allows for better coordination of each treatment modality, which may increase the efficacy of the combined treatment, while minimizing its toxicity. This chapter focuses on discussing the role of radiation therapy and systemic therapy in the...

Noninvasive Breast Cancer Ductal Carcinoma in Situ

In addition to radiation therapy, adjuvant tamox-ifen has been found to reduce breast recurrence risk. The NSABP B-24 trial randomized 1804 patients with DCIS to either tamoxifen (20 mg daily for 5 years) or no tamoxifen after lumpectomy and radiation therapy (FisHer et al. 2001). The use of tamoxifen led to a significant reduction in the 7-year rates of all breast cancer events, including ipsilateral and contralateral breast recurrences. The NSABP B-35 trial is currently comparing anastrozole, an aromatase inhibitor, against tamoxifen as adjuvant treatment after lumpectomy and radiation therapy for patients with DCIS.

Sequencing of Radiation Therapy and Chemotherapy in Patients Treated with Mastectomy

There are very few data available concerning the sequencing of chemotherapy and radiation for women treated with mastectomy. In the Danish 82b trial, radiation therapy was sequenced very early in the adjuvant treatment course (OveRGAARD et al. 1997). Since then, there have been several other trials which have shown that the radiation may be delayed safely while the patients are receiving chemotherapy. In the CALGB 9344 trial, there was no decrease in the locoregional recurrence rate in patients treated with mastectomy followed by AC+T in comparison with patients treated with mastectomy followed by AC alone (3.5 vs 4.3 Sartor et al. 2005). CAkiR et al. (2003) reported a retrospective review of 176 patients with stage-II and stage-III disease who underwent mastectomy treated by radiation therapy followed by chemotherapy with six cycles of either CMF or CAF (n 40), six cycles of chemotherapy followed by radiation therapy (n 54), or three cycles of chemotherapy given before and then after...

Advanced Breast Cancer

Tamoxifen is used in postmenopausal women with estrogen-receptor-positive tumors, patients with long disease-free intervals following treatment for early breast cancer, and those with disease limited to bone or soft tissues. However, aromatase inhibitors, such as letrozole or anastrozole, may be more efficacious and are regarded as the preferred treatment in postmenopausal women. Ovarian ablation or a gonadorelin analog should be considered in premenopausal women. Progestogens such as medrox-yprogesterone acetate continue to be used in advanced breast cancer in postmeno-pausal women. They are as effective as tamoxifen but are not as well tolerated. However, they are less effective than the aromatase inhibitors. Cytotoxic chemotherapy is preferred for advanced estrogen-receptor-negative tumors and for aggressive disease, particularly where metastases involve visceral sites (e.g., the liver) or where the disease-free interval following treatment for early breast cancer is short.

Locally Advanced Breast Cancer

Locally advanced breast cancer (stage-III disease) requires multimodality treatment. Many of the same principles regarding the integration of systemic treatment and radiation for patients with advanced disease are similar to those discussed for patients with early stage breast cancer however, patients who present with locally advanced breast cancers are at higher risk for both locoregional and distant disease recurrence and require multidisciplinary care for optimal disease management. Some patients presenting with advanced primary and nodal disease have unresectable disease. In the 1980s investigators began exploring a sequencing approach that used chemotherapy prior to surgery for such patients. These early studies demonstrated that anthracycline containing chemotherapy regimens could achieve a partial or complete clinical response in over 80 of treated patients. This permitted many patients with initially unresectable disease to become operative candidates. With this success, the...

Role of neurotransmitters involved in chemotherapyinduced emesis

Several well-established neurotransmitters (acetylcholine, dopamine, histamine and serotonin) are known to act via their specific receptors to induce emesis. Indeed, selective activation of serotonergic 5-HT3-, dopaminergic D2- or muscarinic Mj receptors in both CTZ and NTS (and also histamine Hx receptors in the NTS), can induce vomiting. More recently, it has been suggested that the neuropeptide, substance P, also plays an important role in the emetic reflex (Bountra et al., 1996). Several classes of drugs, acting as antagonists of the cited receptors, alleviate the symptoms of nausea or vomiting. However, none of these antagonists is completely effective in all cases of vomiting. Thus, the choice of an antiemetic agent depends upon the etiology of nausea and emesis. Chemotherapy-induced nausea and vomiting are commonly classified as anticipatory, acute or delayed. Anticipatory nausea and vomiting (ANV) are learned responses to chemotherapy that develop in up to 25 of patients....

Adjuvant and Neoadjuvant Chemotherapy in Non Metastatic Urothelial Bladder Cancer Meta Analyses

On the basis of the high frequency of micrometa-static spread at diagnosis, chemotherapy has been used as adjuvant or neoadjuvant (preoperative) treatment of muscle-invasive urothelial cancers in combination with radical surgery. The results of the prospective randomized studies have recently been investigated in three meta-analyses (Ghersi et al. 1995 Advanced Bladder Cancer Meta-Analysis Cooperation 2005a, 2005b). The results demonstrate that adjuvant chemotherapy after surgery has no impact on survival, neoadjuvant chemotherapy prior to radical surgery has a modest, but significant, impact on mortality and increases the 5-year overall survival by absolute 5 . Chemotherapy concurrent with radiotherapy has been investigated in only one small study and the results with respect to overall survival rates were not significant however, the relative reduction of mortality (hazard ratio) was more pronounced in this study as compared with studies which used chemotherapy together with...

Neoadjuvant Chemotherapy

There are few data on neoadjuvant chemotherapy prior to radiotherapy. An RTOG phase-II study tested two courses of MVAC prior to radiotherapy plus cisplatin (Tester et al. 1996). The response rate was 62 and identical to the response of earlier trials with identical radiation-cisplatin regimens without additional MVAC, suggesting that upfront MVAC does not improve response or bladder preservation. There is, therefore, currently no indication for upfront chemotherapy prior to radiotherapy.

Omission of Chemotherapy

It is currently not clear whether chemotherapy can be omitted in selected patients with good prognostic features. Retrospective data from Boston and from the University of Erlangen suggest that patients with a complete TUR prior to radiotherapy have a very good prognosis with a more than 80-90 chance of definitive local control and survival. The results of TUR and radiotherapy are superior to TUR alone. A comparison of data from TUR plus radiation with the best series in the literature which has used TUR alone (Herr 1987) is listed in Table 19.11. The net effect of additional chemotherapy in this favorable subgroup of patients who undergo adjuvant radiotherapy is probably small therefore, it is currently unclear whether the results of radiation alone can be further improved by the addition of chemotherapy in patients with a complete TUR. Nevertheless, we recommend the use of chemotherapy due to insufficient data.

Incorporating Molecularly Targeted Agents with Radiation Chemotherapy in Gynecological Malignancies

We are now in an era of rationally designed molecu-larly targeted therapy against cancer. Targeted agents are increasingly used, either as single agents or in combination with chemotherapy and radiation. The choice of agents and combinations is dependent on understanding the biology of the cancer and availability of anticancer agents. There is also increasing understanding of the biological effects of radiation on intracellular molecular pathways that will lead to the development of logical synergistic combinations with targeted agents (Prise et al. 2005). To a large extent, current developments in cancer treatment have been to identify biologically active agents, define activity as a single agent, and then empirically combine these with active chemotherapeutic agents or radiation. The burden of identifying improved activity and balancing this with acceptable toxicity is therefore critically dependent on trial design. Generally, initial trials to assess toxicity and efficacy are...

Clinical Studies of Radiochemotherapy in the Elderly

Clinical studies of radio-chemotherapy in the elderly are rare. Since the effects of radio-chemotherapy on the elderly are not very well known, study protocols often include lower radiation doses and or less toxic chemotherapy protocols in this population than in younger patients (Jeremic et al. 1999a Allal et al. 1999). Kodama et al. (2005) carried out a phase-I trial in 15 elderly (> 70 years) or medically unfit patients with head and neck cancer that were treated with combined radio-chemotherapy. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function. In previously untreated patients radiation therapy was applied to a total dose of 60-66 Gy to the primary tumour and 66-70 Gy to involved cervical lymph nodes in 2-Gy fractions. Patients who had received radiation therapy to the neck before (n 5) were treated to doses of at least 39.4 Gy to the primary lesion in 1.8-Gy fractions with the cumulative dose of both...

Antiemetic effect in cancer chemotherapy

Cannabinoids can prevent the nausea and vomiting induced by cancer chemotherapy (Dewey, 1986). Both clinical and animal studies indicate that certain cannab-inoids have therapeutic potential as antiemetic agents. Vomiting is the expulsion of contents of the gut, largely by forces generated by the respiratory muscles (Levitt, 1986). Cannabinoids can affect cerebral function, above the level of the vomiting reflex (Steele, 1980). Therefore, cannabinoids may suppress vomiting through descending inhibitory connections to the lower brain stem centers (Levitt, 1986). However, other possible mechanisms have been investigated (Levitt, 1986) and no agreement about the mode of action has been reached.

Sequencing of Chemotherapy and Hormonal Therapy

Many patients with estrogen receptor-positive breast cancer are treated with both adjuvant chemotherapy and hormonal therapy. The optimal sequencing of chemotherapy and hormonal therapy was recently investigated in a phase-III trial run by the Southwest Oncology Group (SWOG 8814), which randomized patients with pathological stage-I to stage-IIIA breast cancer to concurrent chemotherapy with CAF (cyclophosphamide, doxorubicin, 5-fluroura-cil) chemotherapy with tamoxifen or chemotherapy followed by tamoxifen or tamoxifen alone (Albain et al. 2004). After 10 years of follow-up, there was an improvement in disease-free survival (60 vs 53 vs 48 , respectively p 0.002) and overall survival (68 vs 62 vs 60 , respectively p 0.04) with the sequential treatment compared with the concurrent treatment and tamoxifen only arms. Based on the findings of this trial, most oncologists recommend that hormonal therapy be started after the end of chemotherapy rather than given concurrently.

Sequencing of Radiation Therapy and Chemotherapy after Breast Conservation Therapy

With the increased use of adjuvant chemotherapy in early-stage disease, there has been significant interest in the sequencing of radiation therapy and chemotherapy after breast-conserving surgery. During the 1990s there was significant debate over this issue. One of the first retrospective studies to report on sequencing of radiation and chemotherapy showed that a delay in radiation treatments in order to give chemotherapy may increase the risk of breast recurrence. In this retrospective review of 295 patients treated at the Joint Center for Radiation Therapy (JCRT) by Recht et al. (1991), the 5-year breast recurrence was 4 in patients receiving radiation therapy first, 8 in patients receiving radiation therapy given between chemotherapy courses, 6 in patients receiving concurrent radiation therapy and chemotherapy, and 41 in patients receiving all of their chemotherapy first. Although the results of this study suggested that radiation therapy should be given first, many worried that...

Late Toxicity After Radiochemotherapy

Organ preservation with TUR and radiochemotherapy is as effective as radical surgery for muscle-infiltrating tumors. Moreover, radiotherapy offers a curative chance in patients unsuitable for major surgery. Organ-preserving protocols should presently always include a trimodality approach with transurethral surgery, radiotherapy, and chemotherapy (Fig. 19.2).

Early Stage Breast Cancer

Most of the patients diagnosed with breast cancer either present with stage-I or stage-II disease and are usually treated with a combination of surgery, radiation, and systemic therapy. Typically, patients who present with relatively small primary tumors (i.e., < 3 cm) undergo surgery as their initial treatment. For such patients, surgery can consist of either BCT or a modified radical mastectomy (MRM). Several large randomized trials have conclusively demonstrated that the outcome associated with both of these treatment modalities is equivalent. One example of these trials is the NSABP B-06 trial, which was reported in 2002 with 20 years of follow-up (Fisher et al. 2002). The results of this trial showed that patients treated with BCT achieved equivalent disease-free survival, distant disease-free survival, and overall survival rates as patients treated with MRM. This trial also examined the value of radiation therapy after lumpectomy for patients treated with BCT. In this study,...

Natural Products in Cancer Chemoprevention and Chemotherapy

Abstract Medicinal plants are an important source of diverse chemical compounds that have been used for the past several centuries in the treatment of cancer. About 25 of drugs in the modern pharmacopoeia are derived from plants, including several anticancer drugs currently in clinical use such as vincristine, vinblastine, pacli-taxel, podophyllotoxin, camptothecin and combretastatin. These natural products, their derivatives and analogues based on these drugs constitute an arsenal against various types of neoplasms. The traditional use of plants provides a lead for cancer chemopreventive molecules. The development of new derivatives from bioactive compounds of food origin has been a viable way to reduce toxicity and increase their effectiveness against cancer. The combined efforts of botanists, pharmacologists, chemists and biologists are required to discover new effective drugs to fight cancer. An evaluation of the mode of action of these bioactive molecules will be helpful in...

Concurrent Radiochemotherapy

The combination of chemotherapy and radiotherapy has yielded significantly higher local remission rates of far advanced tumors than radiation alone. The histologically proven complete remission (CR) rates of advanced, transurethrally unresectable tumors lie in the range of 40-50 with radiotherapy alone if standard radiation doses in the range of about 60 Gy are administered. The addition of two to three courses of cisplatin increased the pathological CR rate to 60-70 . The data suggest that the addition of (mainly cisplatin-based) chemotherapy improves local CR rates irrespective of radiation dose. One randomized trial from Canada has compared radiation alone vs radiation plus cisplatin as preoperative treatment prior to cystectomy or as definitive treatment (Table 19.7). The results of this small study with 100 patients confirm that cisplatin improves local control but has no effect on distant metastases (Coppin et al. 1996). The significant improvement in local control was, in this...

Acute Toxicity of Concurrent Radiochemotherapy

Most of the patients treated with a curative radiation regimen experience some mild treatment toxicity, especially bladder and bowel toxicity. Mild to moderate acute radiation cystitis with dysuria and urinary frequency (grades 1 and 2) is present in about half of the patients, but few patients require specific medication (Zietman et al. 1993). The symptoms usually resolve within 2-4 weeks after completion of radiotherapy. In our own experience, patients with a history of multiple TURs or multiple courses of intravesical chemo- or immunotherapy prior to radiotherapy are predisposed to develop some kind of acute radiation cystitis. Acute bowel toxicity is present in < 10-15 of patients. If concurrent chemotherapy is administered, mild to moderate hematological toxic-ity is frequent. Severe leukopenia requiring supportive use of growth factors or thrombocytopenia are rarely observed. The toxicity data of the largest single center prospective study are listed in Table 19.8.

Chemotherapy

Since cancer cells divide more rapidly than normal cells, traditional chemotherapy involves treating patients with cytotoxic compounds designed to kill growing cells. The general approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cell. These medications target various phases of the cell cycle (Fig. 1), resulting in one of the following effects damaging cellular DNA, inhibiting DNA synthesis, or stopping mitosis (splitting of the original cell into two new cells). The majority of drugs currently on the market are not specific, which leads to the many common side effects associated with cancer chemotherapy. Because the common approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cells, adverse reactions typically involve organs and tissues that have a rapid turnover of cells such as blood cells forming in the bone marrow and cells in the digestive tract, reproductive system, and hair follicles.

Breast Cancer

The management of patients with breast cancer involves surgery, radiotherapy, drug therapy, or a combination of these treatments. Originally, the most common cytotoxic chemotherapy regimen for both adjuvant use and metastatic disease was a combination of cyclophosphamide, methotrexate, and fluorouracil. However, anthracy-cline-containing regimens are now increasingly used and are regarded as standard therapy unless contraindicated (e.g., in cardiac disease). In metastatic disease, the chemotherapy regimen chosen reflects whether the patient has previously received adjuvant treatment and also the presence of any comorbidity. For patients who have not previously received chemotherapy, either cyclophosphamide, methotrexate, and fluorouracil or an anthracycline-containing regimen is the standard initial therapy for metastatic breast disease. However, patients with anthracycline-refractory or resistant disease should now be considered for treatment with a taxane either alone or in...

Early Breast Cancer

All women with early breast cancer should be considered for adjuvant therapy following surgical removal of the tumor because adjuvant therapy can help eradicate the micrometastases that cause relapse. The choice of adjuvant treatment is determined by the risk of recurrence, the estrogen-receptor status of the primary tumor, and menopausal status. Tamoxifen, an estrogen-receptor antagonist, is presently the preferred choice of adjuvant hormonal treatment for all women with estrogen-receptor-positive breast cancer. It is supplemented in selected cases by cytotoxic chemotherapy. Premenopausal women may also benefit from treatment with a gonadorelin analog or ovarian ablation. Treatment with tamoxifen delays the growth of metastases and increases survival. If tolerated, treatment should be continued for 5 years. Tamoxifen also lowers the risk of tumor formation in the other breast. Anastrozole is also licensed for the adjuvant treatment of estrogen-receptor-positive early breast cancer in...

Cancer chemotherapy

In a review it was suggested that thiamine when given to patients with cancer may interfere with chemotherapy in that thiamine may promote nucleic acid ribose synthesis and tumor cell proliferation via the transketolase pathway. The authors suggest that an oversupply of thiamine may actually do harm and may be responsible for the failure of therapeutic attempts to terminate cancer cell proliferation (14). Thiamine is directly involved in ribose synthesis in pancreatic adenocarcinoma cells through transketolase-catalysed non-oxidative pentose phosphate reactions. In addition, the chemically modified co-factor oxythiamine inhibited tumor cell proliferation in vitro and in vivo by 40 and 91 in two distinct tumor models (14). According to a review of thiamine supplementation in patients with cancer this raises serious suspicions that routine thiamine administration may not be warranted and could possibly be harmful (15). Thiamine deficiency in cancer patients is most often observed during...

Very Brief Retrospective

The advancement of medicine and chemistry complemented and were complemented by pharmacology during the eighteenth and nineteenth centuries. The modern age of pharmacology might be marked by the research of Paul Ehrlich (1854-1915), the Father of Chemotherapy. Winner of the 1908 Nobel Prize in Medicine and Physiology for his pioneering work in immunology, Ehrlich developed the concept of drugs which were tissue and cell specific - his magic bullets. Although no magic bullets existed in Ehrlich's day, the concept guides drug research to this day.

Pharmaceutical interest

Cytotoxic properties Cananga odorata (Lamk.) Hook. f. & Thoms. contains a cytotoxic oxoaporphine alkaloid known sas liriodenine, which inhibits the enzymatic activity of topoi-somerase II in vitro and in vivo (Woo S etal., 1997). The inhibition of topoisomerase II, a key enzyme of the DNA replication, causes a quickcleavageof the DNA backbone and thereby cellulardeath. Topoisomerase II inhibitors are of critical chemotherapeutic importance and the family Annonaceae, which abound with liriodenine-like alkaloids, may appear as a potential reserve of chemotherapeutic agents. Examples of therapeutic topoisomerase II inhibitors are the relatively newly introduced oral antibacterial broad-spectrum antibiotic fluoroquinolones. An example of fluoroquinolone is ciprofloxacine, generally regarded as the most significant development in the field of antibacterial chemotherapy. The fruits contain some alkaloids, and sesquiterpenes which have cytotoxic properties (Hsieh TJ etal., 2001).

Other Parenteral Routes of Drug Administration

Venous access ports are totally implanted ports with a self-sealing septum that is attached to a catheter leading to a large vessel, usually the vena cava. These devices are most commonly used for chemotherapy or other long-term therapy and require surgical insertion and removal. Drugs are administered through injections made into the portal through the skin. These drugs are administered by the primary care provider or a registered nurse.

Spermatogenesis and Fertility adapted from Creasy 1997

The possible genomic alterations are listed in Table 1.1.1 Alterations of the genome of the postmeiotic, haploid cells may be transported to the zygotes. In human sperm, transient increased chromosomal abnormalities were observed by FISH within the first months after chemotherapy with antineoplastic drugs. The knowledge of the mechanisms underlying the alterations is limited, since only few compounds have been tested sufficiently. It is also unknown which drugs produce transient, and which produce possibly permanent, alterations of maturing germ cells.

Placebocontrolled studies

In a small randomized, double-blind, placebo-controlled study, liposomal amphotericin (2 mg kg three times weekly) was investigated as prophylaxis against fungal infections in 161 patients undergoing chemotherapy or bone marrow transplantation for hematological malignancies (61). There were no statistically significant differences between the two study arms in the incidences of the most frequently reported adverse events or in changes in renal and hepatic laboratory parameters. Despite a sizable rate of suspected or documented fungal infections in the placebo arm, prophylactic therapy with liposomal amphotericin did not lead to a significant reduction in fungal infections or the requirement for systemic anti-fungal therapy.

Organs and Systems Cardiovascular

Lymphomas, soft tissue and osteogenic sarcomas, pediatric malignancies, and adult solid tumors (particularly lung and breast cancers) treatment refractory advanced breast cancer, acute leukemias Breast cancer In a randomized study of adjuvant chemotherapy comparing bolus against continuous intravenous infusion of doxor-ubicin 60 mg m2, cardiotoxicity, defined as a 10 or greater reduction in left ventricular ejection fraction, occurred in 61 of patients on a bolus median dose equal to 420 mg m2 compared with 42 on the continuous infusion schedule with a median dose of 540 mg m2 the rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm (10). Hypokinetic heart wall motion abnormalities and early signs of chronic cardiomyopathy have been identified as a significant toxic effect of mitoxantrone in patients who received cumulative doses of 32-174 mg (31). Electrocardiographic T wave inversion and cardiac complications...

Biological Response Modifying Agents

Many so-called biological response modifiers (BRMs), or biologicals, are either in use or development. These include agents as diverse as antibodies, antibody-drug conjugates, interferons, interleukins, enzymes, vaccines, and other types of immune stimulants (see Chapter 8). For example, several tumor types, including some types of breast cancer, have been found to produce specific tumor antigens on their cell surfaces, and this has led to the development of monoclonal antibodies specific for these tumors (e.g., Herceptin see Chapter 5 and Chapter 7 ). Tumor-specific antibodies can also be used to selectively deliver a cytotoxic agent (e.g., Mylotarg ) or a radionuclide (see Chapter 7) to the tumor site. An antibody-enzyme conjugate designed to release an active form of a cytotoxic agent from a nontoxic prodrug selectively at the tumor site (i.e., antibody-directed enzyme prodrug therapy ADEPT see Chapter 7) is presently being evaluated in clinical trials. Finally, research is ongoing...

Infertility Following Cancer Treatments

Both chemotherapy and radiotherapy treatments can cause sterility in males and females of childbearing age. This is a particular problem with DNA-interactive agents such as cisplatin, which damage the genome of germ line cells in the testes and ovaries. One solution to this problem in young male patients is sperm storage prior to treatment. A similar solution for women was not realized until 2004, when Belgian researchers showed that it was possible to remove and store ovarian tissue from a patient prior to both radiotherapy and chemotherapy. After seven years of storage, the ovarian tissue was grafted back on to the patient's ovaries and she was able to conceive normally. It is anticipated that this procedure will become more widely available in the future.

Medical Marijuana A Brief History

Not since prohibition began in 1937 has there been such a large body of knowledge. Millions now know that medical marijuana provides safe, effective relief for a wide array of ailments, from chronic pain and migraines to glaucoma, epilepsy, multiple sclerosis and the debilitating effects of chemotherapy and AIDS.

Posaconazole Prophylaxis

Posaconazole is also an attractive agent for use as prophylaxis in patients at high risk for invasive fungal infections due to its potent activity against Aspergillus species and availability as an oral formulation. Prospective clinical trials have demonstrated that posaconazole is effective in preventing invasive fungal infections and reducing fungal related mortality in high-risk patients. In a randomized multicenter study posaconazole prophylaxsis was compared to fluconazole or itraconazole in patients with neutropenia secondary to chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome (41). Significantly fewer invasive fungal infections were observed in patients randomized to posaconazole (5 ) compared to those who received fluconazole or itraconazole (11 P 0.003) within 100 days following randomization. This difference was primarily due to a lower incidence of invasive aspergillosis in the posaconazole group (1 vs. 7 , respectively P < 0.001 Fig. 2B). A second...

The Clinical Features of Uncomplicated Malaria

A non-immune individual is infected with about 100 sporozoites on average, of which one or two will be able to invade hepatocytes post-hepatic infection will become symptomatic in almost all cases. Left untreated, parasites multiply in red blood cells at a rate of about a 10-fold increase every 2 days, leading to a high parasitaemia within a few days and associated clinical complications such as anaemia, metabolic derangements (acidosis and hypoglycaemia) and severe organ impairment (renal or cerebral malaria or pulmonary oedema). The complications may lead to death, which may occur within a week after the onset of disease. However, death will not occur within a day or two after the start of disease. Therefore, the initiation of prompt and effective chemotherapy is the cornerstone of therapeutic intervention.

Susceptibility Factors

Oncology patients treated with intensive chemotherapy are usually immunosuppressed and in one study the overall incidence of reactions to blood transfusion was 0.3 of all transfused units, which is significantly lower than expected (136). Febrile non-hemolytic reactions and allergic urticarial reactions were the most frequent, and the number of delayed hemolytic post-transfusion reactions was much lower than in non-oncology patients. This probably reflects a relative inability of oncology patients to produce allo-antibodies against blood group antigens.

Pi3k And Cell Migration

And the formation of lamellipodia at the front edge of the cell. Recent studies in the neutrophilic cell line HL60 have shown recruitment of a fluorescently tagged PKB-PH domain to the edge of the cell exposed to the highest concentration of chemoattractant. This has led to the suggestion that PI3-K and the localization of Ptdlns (3,4,5)P3 act as a molecular compass, guiding the direction of neutrophils toward the source of chemoattractant (85). The role of PI3-K activation in the movement of nonleukocyte cell types has also been established for example, the migration of breast cancer cells in response to EGF stimulation (86). A comprehensive analysis of chemokine receptor expression in breast tumor cell lines has revealed an upregulation of the chemokine receptors CXCR4 and CCR7 (87). Stimulation by stromal cell-derived factor (SDF)-1, the ligand for CXCR4, leads to PI3-K activation in a variety of cell types. Considerable efforts have been made to identify the PI3-K isoforms...

General Information

In a phase II study, 17 patients with progressive indolent non-Hodgkin's lymphoma, previously treated with chemotherapy, received bryostatin 1 (5). Phlebitis was initially due to the 60 ethanol formulation used for administration, and the subsequent use of another formulation (60 polyethylene glycol, 30 ethanol, 10 Tween 80) reduced the incidence. In one patient, bryostatin 1 was withdrawn because of grade 2 thrombo-cytopenia. The dose-limiting adverse effect was myalgia, which occurred in eight patients.

Inhibition Of Pi3k Signaling In Tumor Cells

Resulted in a dose-dependent inhibition of tumor growth (96). In addition, a suboptimal dose of LY294002 produced further inhibition of tumor growth when combined with a suboptimal dose of the nucleoside analog, gemcitabine. Similar synergistic effects of chemotherapeutic agents and LY294002 have been observed in vitro with nonsmall-cell lung carcinoma and breast cancer cell lines (97,98). More recently, LY294002 was shown to have minimal anti-tumor effect in mice bearing bladder tumor cell xenografts. However, in combination with radiation therapy, LY294002 treatment resulted in a significant and syner-gistic reduction in clonogenicity and growth delay (99).

Rationale For Pulmonary Delivery Of Anticancer Agents

As with other respiratory diseases treated locally through the use of inhalation aerosols, there are numerous pharmacokinetic and pharmacodynamic arguments favoring this delivery route in cancer therapy. In general, chemotherapy is characterized by a dose dependent response (cell apoptosis) coupled to a high degree of non-specificity, so that despite the introduction of several newer generations of chemotherapy agents, toxicity remains the principle limitation for effective anti-tumor response. Accordingly, the rationale for pulmonary delivery of these agents primarily focuses on the ability to increase regional targeting and the associated benefits arising from this pharmacokinetic advantage. These additional potential benefits are briefly described here, and are specific to the nature of the tumor microenvironment to which inhalation aerosols are targeted.

Increasing Tumor Penetration

There now exists significant evidence that cells distant from blood vessels are resistant to conventional chemotherapy and though this observation may be attributed to several mechanisms, the most straightforward explanation, and indeed one well supported by recent studies, is that cells distant from blood vessels are, due to limited drug access, exposed to insubstantial levels of therapeutic agents (7). Clearly, current methods of drug administration (e.g. i.v.) are poorly suited to overcome these barriers to tumor penetration. In marked contrast to these aforementioned treatments, direct aerosol delivery of chemotherapy to the tumor vicinity possesses the potential to significantly increase the concentration gradient for enhanced drug penetration, resulting in enhanced effectiveness and improved outcomes.

Preventing Accelerated Tumor Cell Repopulation

Administration of both radiotherapy and chemotherapy is performed in multiple doses, which are interrupted to allow for the recovery of normal tissues, such as the bone marrow and the GI tract, between treatments. Unfortunately, this interval between treatments presents surviving cancer cells an opportunity to proliferate, a process of repopulation that severely undermines the benefits of the therapy (9). There is significant evidence that not only does the repopulation of tumor cells limit the effectiveness of therapy, but that tumor-cell repopulation actually accelerates during the course of the treatment (9,27-30). While pulsatile delivery is necessary using standard chemotherapy regimens due to the non-specificity of cytotoxic agents, recent efforts have been directed toward delivering therapies with reduced intervals between doses. An example is the accelerated fractionation of radiotherapy, which seeks to minimize the overall treatment time, thereby providing decreased...

Case Study Aerosol Delivery Of Camptothecin Analogues

9-NC, like many other chemotherapy agents, is water insoluble. Preclinical investigations of aerosol formulations therefore required the development of a dispersed liquid system to facilitate aerosol generation. Liposomal formulations of 9-NC were developed and studied in animal models (53). Dilauroylphosphatidylcholine (DLPC) liposome systems had been well characterized in terms of synthesis and safety in animal models (110,111). Rats exposed to 1 h of continuous aerosol for 28 consecutive days exhibited no effect of the phospholipid (112). Phase I II studies in humans with DLPC aerosol have also demonstrated its safety and tolerability (113). Liposomes were prepared using DMSO to dissolve the lipophilic drug before addition to the phospholipids dissolved in butanol. The mixtures are snap frozen and then lyophilized. Reconstitution of the liposomes was a simple procedure, involving addition of water for injection and after which, aerosol formation by nebulization was readily...

Potential Effects Of Airway Obstruction And Concurrent Lung Disease

The presence of airway obstruction and tumors in the airway lumen will lead to increased turbulence and higher resistance to flow. This is generally known to result in the removal of more particles (specifically smaller particles) from the inhaled aerosol. Accordingly, for pulmonary delivery of chemotherapy aerosols, the particle size distributions and breathing parameters will need to be specifically engineered and controlled for these conditions. In fact, breathing parameters may be identified in which tumor targeting is maximized. Recently Kleinstreuer and Zhang modeled the effects of tumor in-growth into the airway lumen and the effects of different airflow conditions expected in lung cancer patients (129). They found that particle deposition near tumors could be modulated using particle size and breathing parameters such that deposition fractions of 30-90 could be achieved (Fig. 4). Most particles land on the front surface of the tumor and some deposit on the tubular wall....

AEA VR1 and Cell Proliferation and Apoptosis

By activating native vanilloid receptors, AEA may also induce tumor cell apoptosis (Maccarrone et al., 2000) or cause inhibition of tumor cell proliferation (Fowler et al., 2001). In the former case the effect was completely blocked by capsazepine, thus suggesting that AEA was exclusively acting via vanilloid receptors. Accordingly, AEA binding distinctly displaced by capsaicin but not by SR141716A was detected in membranes from human neuroblastoma cells, whose apoptosis was induced by AEA. Interestingly, when tumor cells also express cannabinoid receptors, as in the case of C6 glioma cells, the apoptotic effect of AEA was smaller and was increased by SR141716A, thus pointing to a possible protective action of cannabinoid receptors against apoptosis (Maccarrone et al., 2000). This possibility would be in contrast with previous investigations carried out with the same cell line (Sanchez et al., 2001). In a more recent investigation with C6 cells, again somewhat different results were...

Estrogens And Their Involvement In Carcinogenesis

The link between ovarian function and breast cancer has been known for more than a century, and endocrine therapy can be considered as the oldest, safest, and best-established systemic treatment for breast cancer. Many breast and endome-trial tumors are estrogen-dependent, and for this reason their treatment is based on the modulation of these hormones. This can be achieved directly by

Developmental Aspects Of Cannabinoids The cannabinoid system in development

These latter data are compatible with the observation in mice that motor depression in an open field and hypoalgesia in response to administration of anandamide or A9-THC are not fully developed until adulthood (Fride and Mechoulam, 1996a). Interestingly, A8-THC at relatively high doses (18mg m2) prevented vomiting caused by anti-cancer chemotherapy in young children, without producing undesirable cannabimimetic CNS effects (Abrahamov et al., 1995). At such doses one would normally expect very significant cannabimimetic effects, as seen in adults. A tentative explanation based on the data from animals studies (Fride and Mechoulam, 1996a), was offered on one hand, in the developing organism, the cannabinoid receptor system is not fully developed (hence the lack of cannabimi-metic effects). On the other hand, the antiemetic effects are not transmitted through the cannabinoid receptors. The existence of nonspecific effects caused by cannabinoids has been shown previously (Felder et al.,...

Appendix A State Medical Marijuana Laws

Current Law For glaucoma and cancer chemotherapy and radiology or other procedures. The program has never been operational. Current Law For cancer chemotherapy and radiology, glaucoma, and asthma (marijuana or THC). The program has never been operational. For glaucoma and cancer chemotherapy (marijuana or THC) patients with other diseases must get approval from Patient Qualification Review Board.

Contraindications

The antiemetic and antivertigo drugs are contraindicated in patients with known hypersensitivity to these drugs, those in a coma, or those with severe central nervous system (CNS) depression. In general, these drugs are not recommended during pregnancy, lactation, or for uncomplicated vomiting in young children. Metoclopramide is contraindicated in patients with a seizure disorder, breast cancer, pheochromocytoma, or gastrointestinal obstruction. Prochlorperazine is contraindicated in patients with bone marrow depression, blood dyscrasia, Parkinson's

Clinical Course and Treatment

Most deaths from severe malaria occur within 24 h after admission to hospital (Krishna et al. 1994b Marsh et al. 1995 Waller et al. 1995). Ifhyperlactataemia is present at the time of admission, it usually resolves within a few hours of instituting conservative fluid resuscitation and anti-malarial chemotherapy (Agbenyega et al. 2000, 2003 Krishna et al. 1994a). Whilst blood lactate is an independent predictor of mortality in malaria (Allen et al. 1996 Krishna et al. 1994b Waller et al. 1995), a prolonged hyperlactaemia (> 4 h) that occurs in a small proportion of cases is an even better indicator of a fatal outcome (Krishna et al. 1994a). It follows that interventions that decrease circulating lactate may improve survival by 'buying time' until anti-malarials can exert

Second Generation Effects Fertility

Of 23 men treated with either cyclophosphamide or non-alkylating agent combinations, there was a dose-related disturbance of gonadotrophin secretion in the cyclophosphamide group (60). The chances of maintaining normal gonadal function after combined treatment of Hodgkin's disease are significantly greater among girls than boys at 9-year follow-up (61). Pre- and post-pubescent boys were affected by six cycles of MOPP, whether or not pelvic radiation was administered on the other hand, in girls similarly treated, ovarian function was directly affected by the number of courses of chemotherapy and the ovarian radiation dose (62). In a study of male gonadal function at 9 years follow-up after regimens containing cyclophosphamide, mechlorethamine, vincristine, or procarbazine, there was azoospermia, whereas regimens containing dactinomycin and vinblastine did not have a toxic effect on spermatogenesis (63). Testicular volume and sperm count in 18 patients, 1-3 years after chemotherapy,...

Reproductive system

Gynecomastia is frequent in men with testicular tumors that produce large amounts of human chorionic gona-dotrophin (HCG), and its appearance after completion of chemotherapy may indicate residual or recurrent disease. However, not uncommonly, gynecomastia is a harmless, although troubling, late adverse effect of chemotherapy. In 16 patients who developed gynecomastia

Physical description It is a dioecious rr

Uses In Burma, the seeds of Momordica cochinchinensis (Lour.) Spreng. are eaten to assuage chest pain. In China, the seeds are eaten to treat fluxes, liver diseases, hemorrhoids, breast cancer and malaria, and to heal wounds and ulcers. In Indonesia, the leaves are applied externally to swollen legs. In Laos, Cambodia and Vietnam, the seeds are used to counteract putrefaction of the skin. In the Philippines, the roots are used to produce soap.

L01Antineoplastic Agents and Radiation

Antineoplastic agents used for the treatment of cancers and lymphomas cause spermatogenic dysfunction in the majority of cases. At a cellular level, they also induce chromosomal abnormalities. The aneuploidy rates of sperm chromosomes was found to be enhanced after antineoplastic chemotherapy. The toxic effect was clearly dose related. Radiation aggravated the effect. Malformations in the children fathered, on the other hand, were not more frequent than in controls, but conception should be avoided for at least 90 days after the end of antineoplastic therapy, and an interval of 1 year is favourable.

Tissue Levels of Anandamide Continued

Measurable amounts of anandamide (Schuel etal., 2002). A small amount of anandamide was also found in human milk (Fride et al., 2001). In addition, anandamide was detected in rat plasma collected by decapitation or by cardiac puncture and in the sera from normal donors and patients with endotoxin shock (Wang etal., 2001). Giuffrida, Rodriguez de Fonseca, Nava, et al. (2000) reported that the administration of AM404, an anandamide transport inhibitor, to rats induced the elevation of the plasma anandamide level. On the other hand, Yang et al. (1999) described that the levels of anandamide in the rat brain, spleen, testis, liver, lung, and heart were below the detection limit (< 0.1 pmol mg protein). Anandamide was also detected in several tumor cells. Bisogno et al. (1998) detected appreciable amounts of anandamide in human breast cancer EFM-19 cells and rat pheochromocytoma PC-12 cells. Schmid, P.C., et al. (2002) reported that there is variation in the contents of A...

Long Term Effects Tumorigenicity

Exposure to diethylstilbestrol during pregnancy in 4836 women has been reported to carry a relative risk of 1.27 of breast cancer later in life. However, the authors found no evidence to support the link between diethylstilbestrol exposure and ovarian, endometrial, or other cancers.

Pregnancy Category C

Dronabinol is used to reduce nausea in persons undergoing cancer chemotherapy and to stimulate appetite in AIDS (acquired immunodeficiency syndrome) patients. Alzheimer's patients who received experimental drona-binol showed improved appetites and reduction of behavior associated with the disease. Research indicates that the drug may widen airways, a help to persons suffering from breathing difficulty. Experimental success has also been achieved in treating spasticity, reducing not only that affliction but its associated rigidity and pain. Research has also examined whether dronabinol may work as a cough medicine. Human testing shows that oral dosage of dronabinol's active ingredient THC can help reduce pain. nol). Journal of Psychoactive Drugs 30 (1998) 187-96. Devine, J.W., L.A. Mahr, and C.R. Rieck. Effectiveness of Delta-9-Tetrahydrocannabinol in Chemotherapy-Induced Nausea and Vomiting. Journal of the Iowa Pharmacy Association 54 (1999) 22-24, 47-50. Gonzalez-Rosales, F., and D....

Non Small Cell Lung Cancer

Topo-1 inhibitors have demonstrated activity in NSCLC (Chastagner et al. 2001). Concurrent administration of chemotherapy and radiation therapy in the definitive management of locally advanced NSCLC has been shown to improve outcomes (Clamon et al. 1999). While acute toxici-ties are increased compared with radiation therapy alone, they are tolerable. Irinotecan has been combined with radiation in phase-I and phase-II trials with demonstrated efficacy. Takeda et al. (2001) performed a phase-I II trial of escalated doses of irinotecan with standard radiation of 60 Gy in 30 fractions over 6 weeks. Inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, unresectable disease, non-small cell histology. Irinotecan doses started at 30 mg m2 IV weekly concurrent with radiation to a maximally tolerated dose of 60 mg m2. YamadA et al. (2002) investigated the maximally tolerated dose of irinotecan when combined with carboplatin in the same group of...

An Unfair Rap for Hemp

O'Brien, Jr. appointed by the AG, who dissented from the panel's conclusions, had for years dominated this group, rigidly controlling what research could be performed - and limiting those applications to control of nausea and vomiting that is secondary to cancer chemotherapy.

Ionizing Radiation and Angiogenesis Inhibitors

7.5 Trimodal Treatment with Anti-Angiogenic Agents, Radiotherapy, and Chemotherapy 110 opment and growth of solid tumors were published by FoLKMAn (1971, 1986, 1995). Tumor angiogenesis results from imbalance between pro-angiogenic factors, e.g., vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), and endogenous anti-angiogenic factors such as angiostatin and endostatin (FoLKMAn 1995 O'REiLLY et al. 1996, 1997 EnDRiCH and Vaupel 1998 Ferrara and ALiTALo 1999 Kerbel 2000 CARMELiET and jAiN 2000 Yancopoulos et al. 2000). A large body of experimental data indicate that application of either inhibitors of pro-angiogenic factors or administration of anti-angiogenic factors reduce the formation of new blood vessels. As a result, tumors grow at a slower rate or even decrease their size. However, in most cases no permanent tumor control can be achieved therefore, the combination of anti-angio-genic strategies with cytotoxic...

Transcription Factors

Curcumin may operate through suppression of various transcription factors, including nuclear factor-kappa B (NF-kB), signal transducer and activator of transcription 3 (STAT3), early growth response protein 1, activator protein 1 (AP-1), peroxisome proliferators-activated receptor gamma (PPAR-y), and P-catenin 13, 14, 19 . These transcription factors play essential roles in various diseases. The constitutively active form of NF-kB has been reported in a wide variety of cancers. NF-kB is required for the expression of genes involved in cell proliferation, cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. Bharti et al. demonstrated that curcumin inhibited IL-6-induced STAT3 phosphorylation and consequent STAT3 nuclear translocation 20 . Activation of PPAR-y inhibits the proliferation of nonadipocytes. Xu et al. demonstrated that curcumin dramatically induced expression of the PPAR-y gene and activated PPAR-y 21 . AP-1, another transcription factor that has been...

State schedules USA Availability Prescription where legal

This quick-acting and long-lasting drug is widely used around the world for legitimate medical purposes. Flunitrazepam is prescribed to treat insomnia and anxiety, to relax muscles, to stop convulsions, and to calm people. In the 1990s it was Western Europe's most commonly prescribed calming and sleep-inducing medicine. The drug is administered to treat alcohol withdrawal syndrome, and experimental use in treating depression has found flu-nitrazepam promising. Some unauthorized use of the drug is believed to be for self-medication of depression and low self-esteem. The drug has specialized usefulness in surgery as a medication given prior to administration of anesthesia, and its tendency to reduce pressure inside the eyeball can avert the rise caused by the anesthetic succinylcholine (important if patients are at risk for glaucoma). In hospice care where doses can be higher and more frequent than normal, flunitrazepam has reduced nausea and vomiting from cancer chemotherapy.

Flt3 Kinase Inhibitors

Therefore, it has to be taken under serious consideration that administration of such a compound to leukemia patients might prevent or delay recovery from chemotherapy- or leukemia-induced cytopenias. On the other hand, combined inhibition of both wild-type c-KIT and FLT3 tyrosine kinase activity of AML blasts, even in the absence of activating FLT3 mutations, could have a beneficial effect and may result in a clinical response. Thus, it will be important to find an optimum treatment regimen without development of prolonged marrow suppression or any other serious adverse effects.

Pregnancy Category X

In women the drug is used to fight breast cancer by interfering with hormones that encourage the disease. Research has found fluoxymesterone effective in reducing a cancer called myeloma and for counteracting anemia caused by myeloma. Mixed results have occurred when using the drug for correcting anemia associated with kidney failure. The substance has been a treatment for osteoporosis, a condition in which bones become susceptible to easy breakage, and for hereditary angioedema an affliction that may involve throat swelling that interferes with breathing. Drug interactions. In female breast cancer patients receiving levothyroxine to boost thyroid gland activity, fluoxymesterone can interact and elevate thyroid activity too much. Experiments have administered fluoxymesterone in combination with other drugs to alter the mood of older persons exhibiting nervousness, irritation, and suspiciousness toward caregivers. One study reported no change another reported substantial change the...

Applications in Malignant Brain Tumors

12.2.4 Postoperative Chemotherapy 168 Chemotherapy with different sequentially or simultaneously administered agents can be used to enhance the effect of local treatment aiming either at additive cell kill or true radiosensitization, to defer intense, potentially toxic local treatment in vulnerable subgroups, or to treat distant tumor sites based on the principle of spatial cooperation. In general, primary brain tumors are not curable by chemotherapy alone however, certain histological groups with better response to chemotherapy as well as radiotherapy have been defined, e.g., medullo-blastoma. The main prerequisites of successful chemotherapy are sensitivity of the tumor cells to the mechanisms of the drug and sufficient drug exposure. The key issues of tumor heterogeneity with primary and acquired resistance as well as pharma-cokinetics, pharmacodynamics, and tumor microenvironment deserve particular attention because of several facts that are specific for CNS tumors. First of all,...

Antimicrobial Drugs II

This chapter will concern itself with antimicrobial agents (as broadly defined earlier) of synthetic origin.1 Unlike the semisynthetic antibiotics, which were obtained from biological sources and then modified by one or more synthetic steps, these compounds are synthetically created. In many cases the prototype compound was discovered by a more or less random screening process (e.g., sulfanilamide, Chapter 2) and then, by first applying empirical and now more scientifically predictive SAR methods, optimized, or at least improved. The ultimate goal, of course, is to design a potential new drug from theoretical biochemical concepts, synthesize it, and find it to have the desired antimicrobial and pharmaceutical properties. When our abilities reach that point, we will have extended Paul Ehrlich's goals of selective chemotherapy to the level he must have envisioned over eight decades ago.

Organs and Systems Gastrointestinal

Nine patients who received hepatic arterial infusion chemotherapy developed gastritis heralded by epigastric pain and tenderness, nausea, vomiting, weakness, and anorexia (1). In 7 patients, 18 gastric ulcers were detected endoscopically. Mucosal damage developed despite prophylactic antiulcer therapy and healed only on withdrawal. In 17 biopsy specimens there were variously inflammatory changes, reactive glandular changes, and cell necrosis, even in patients without ulcers. In addition, there was floxuridine-induced glandular atypia in eight biopsy samples from six patients the crowded glands A patient who received regional intrahepatic chemotherapy from a continuous infusion pump for 31 months developed a gastroduodenal artery-duodenal fistula, and presented with signs and symptoms of upper gastrointestinal bleeding.

Localized Pancreatic Cancer Clinical Studies

When the use of chemoradiation for localized pancreatic cancer is considered, it is important to appreciate several disease characteristics that differ greatly from those of most other malignancies. In patients who cannot undergo curative resection the median survival is usually less than 1 year, with eventual radiographic progression of local and distant disease occurring commonly after chemoradiation or chemotherapy treatment, and very modest improvement in median survival to be expected. Even if the primary tumor is completely resected, disease-specific mortality is typically at least 80 due to the problems of local disease recurrence and distant metastases. Most pancreatic cancer patients have some combination of host-related factors, such as advanced age, poor performance status, and medical comorbidity, or tumor related factors, such as anorexia and exocrine insufficiency, that often make them relatively poor candidates for aggressive therapy. Since outcome is so poor with...

Pharmacogenomics Space

Both FDA and the European Agency for the Evaluation of Medicinal Products (EMEA) are proactive but follow different paths. Whereas FDA provides guidance documents, EMEA conducts meetings with sponsors. The established clinical pharmacogenomics tests for the European countries would include HER2 testing for breast cancer and thiopurine methyltransferase (TPMT) for acute lymphoblastic leukemia. It concluded that many interdependent variables would contribute to clinical applications of pharmacogenomics.

Antisense Oligonucleotides

Antisense oligonucleotides inhibit gene expression by binding in a sequence-specific manner to an RNA target. Modern nucleotide chemistry has enabled the synthesis of chemically modified oligonucleotides that are highly resistant to nuclease degradation. With progress made in chemical modifications, target selection and drug delivery systems, antisense oligonucleotides are emerging as a novel approach to cancer therapy used alone or in combination with conventional treatments such as chemotherapy and radiation therapy (17). Further improvements in antisense chemistry and nanoparticles are promising avenues in antisense therapy of cancer (18).

Enzymes and antibodies exerting antineoplastic effects

Trastuzumab is a monoclonal antibody which blocks the human epidermal growth factor 2 protein and has an estimated half-life of 12 days. Waterstone (2006) reported on an uneventful prcgnancy and the delivery of a healthy girl whose mother conceived 3 days after her second cyclc of trastuzumab. There is one case report of inadvertent exposure of a 28-year-old with breast cancer who was given the drug every 3 weeks until week 20 of her pregnancy. When, in week 23, the pregnancy was noticed, a lack of amniotic fluid prevailed with a healthy female fetus. Gradually, Lhe amount of amniotic fluid recovered. In week 37, a healthy girl was delivered whose kidney function was normal at the age of 6 months and who showed no sign of pulmonary hypoplasia (Watson 2005). There is another report regarding the development of an oligohydramnios after trastuzumab therapy. Fanale (2005) described a case where therapy with trastuzumab and vinorelbine was started after week 27 because of metastatic breast...

General adverse effects

In a retrospective study of the adverse effects of gemcitabine 1000 mg m2 on days 1 and 8 in patients with non-small cell lung cancers, the adverse effects of gemcitabine involved the gastrointestinal system (nausea, vomiting, and diarrhea) and the hemopoietic system (leukopenia, neutropenia, thrombocytopenia, and anemia), but only in the last (8th-11th) cycles (1). There was grade 4 vomiting in three patients, grade 4 thrombocytopenia in two, and grade 3 leukopenia in three. Other adverse effects were mild. None of the patients died during chemotherapy.

Antineoplastic drugs with endocrine effects

The hormone antagonist tamoxifen is used for the treatment of breast cancer. Its effect on the endometrium might indirectly pose a risk to prenatal development. In 37 pregnancies collated by the manufacturer, 19 newborn babies were healthy and 2 children had craniofacial deformities. Two other case reports describe a child with anomalies resembling Goldenhar syndrome (Cullins 1994), and a newborn girl with indifferent genital development (Tewari 1997). An adenoma of the vagina was diagnosed in a girl aged 2 years whose mother had taken tamoxifen until the fourth month of pregnancy. There are also reports of apparently normal pregnancies (Andreadis 2004, Isaacs 2001, Lai 1994). Nine pregnancies following induction of ovulation with tamoxifen resulted in newborn babies that had no malformations (Ruiz-Velasco 1979). There is, however, insufficient data for a discriminative risk evaluation. Andreadis CH. Charalampidou M, Diamantopoulos N et al. Combined chemotherapy and radiotherapy...

Organs and Systems Liver

Hepatotoxicity, with raised bilirubin and liver enzymes, is common with gemtuzumab (30-50 ) and is mostly reversible. A more severe complication, hepatic veno-occlusive disease, a syndrome consisting of hyperbilirubinemia, painful hepatomegaly, and fluid retention or ascites, is less common and is mostly seen in patients previously undergoing bone marrow transplantation (4-5 ). It occurs most commonly after high-dose chemotherapy and hemopoietic stem cell transplantation. Patients with severe veno-occlusive disease die from progressive multiorgan failure. Close monitoring of patients receiving gem-tuzumab is necessary, even if they have not had previous bone marrow transplantation (2). In 119 patients (92 with acute myeloid leukemia, 25 with advanced myelodysplastic syndrome, and two with chronic myeloid leukemia), who did not receive concomitant stem cell transplantation, 14 developed veno-occlusive disease (3). Five of these 14 patients had not received prior antileukemic therapy,...

Strategies To Enhance Cancer Drug Delivery

Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since chemotherapeutic agents are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge (45). Current cancer drug delivery is no longer limited to traditional methods and dosage forms. It utilizes extensively some state-of-the-art technologies, such as nanotechnology, polymer chemistry, and electronic engineering (46). Our expanding knowledge of the molecular biology of cancer and the pathways involved in malignant transformation of cells have revolutionized cancer treatment with a focus on targeted cancer therapy. New approaches to cancer treatment not only supplement conventional chemotherapy and radiotherapy, but also aim to prevent damage to the normal tissues and overcome drug resistance. Innovative methods of cancer treatment require new concepts of drug...

Drug dosage regimens

In febrile neutropenic episodes after intensive chemotherapy, once-daily gentamicin (7 mg kg day) in combination with azlocillin was more effective than a multiple-daily dosing regimen, but the incidence of toxi-city was low overall and was slightly but not significantly higher in the once-daily group (55).

Sequencing of Radiation and Hormonal Therapy

Another area of clinical controversy surrounding treatment sequencing is whether to administer hormonal therapy concurrently or sequentially with radiation. Historically, sequential treatment was recommended based on preclinical data suggesting that tamoxifen may arrest breast cancer cells in radioresistant cell-cycle phases, which theoretically would decrease the efficacy of radiation treatment (Sutherland et al. 1983). In addition, tamoxifen has been associated with increased levels of circulating TGF-P, which is an important mediator of radiation normal tissue injury (Colletta et al. 1990 Knabbe et al. 1991).

Hypothalamic releasing hormones

Releasing hormones are responsible for regulating the synthesis and secretion of FSH and LH. Many synthetic human GnRH agonists are marketed, including buserelin, gonadorelin, goserelin, leuprore-lirt, nafarelin, and triptorelin. Cetrorelix and ganirelix are inhibitors of GnRH. In women, GnRH agonists have been used to treat estrogen-dependent breast cancer, endometriosis, hirsutism, and polycystic ovarian syndrome, but the widespread use of protocols using GnRH agonists antagonists in assisted reproductive technologies has led to an increasing number of pregnant women being exposed to these types of drugs. Most of the data concerning the safety of the GnRH analogs have not demonstrated serious side effects, such as increase in the incidence of miscarriage, birth defects, or fetal growth restriction, in human pregnancies exposed to GnRH (Tarlatzis 2004,

New Directions Radiation Therapy and Biological Therapy

A recent exciting advance in the treatment of breast cancer has been the finding that trastuzumab, a humanized monoclonal antibody to the extracellular domain of the HER2 protein, when combined with chemotherapy, improves the overall survival of patients with HER2 positive disease. Two large randomized trials regarding the use of trastuzumab as adjuvant treatment in operable breast cancer were recently published. The Intergroup Study (comprising of the NSABP B-31 and the North Central Cancer Treatment Group (NCCTG) study N9831) treated patients with HER2 positive (defined as 3+ on immunohistochemistry or amplified by FISH) breast cancer with either adjuvant chemotherapy with trastuzumab or adjuvant chemotherapy alone (Romond et al. 2005). In the B-31 trial, patients were initially treated with four cycles of AC followed by either 12 weeks of paclitaxel (given either every 3 weeks or weekly) with or without concurrent trastuzumab. The trastuzumab was given weekly for 1 year. In the...

Disparaging disparities

These are pretty impressive facts, which raise the obvious questions are blacks genetically weaker than whites Are they more susceptible to disease because they did not evolve the capacity to fend off infection as well as whites Preposterous - but you'd be surprised what people glean from statistics. The fact is, when immunization programs targeted inner cities in the 1970s to lower the rate of measles, the rates lowered for African Americans. More recently, when breast cancer and heart disease awareness programs were enacted in the US, rates lowered as well, though there are still significant disparities between whites and blacks. The point is that a higher percentage of African Americans reside in poor neighborhoods where access to health education, healthcare and healthy lifestyle choices is far more limited than in the burbs, where more whites tend to live. This is a direct result of segregation policies and racism through the last century that are reverberating in society today....

Oxidation of DNA bases

Attack of hydroxyl radicals to purine or pyrimidine bases produces other DNA damages. The structures of the degradation products arising from this reaction have been established mainly from studies with ionizing radiation,9 but many of them were similarly isolated from patients receiving anthracyclines for the treatment of breast cancer.10

Endogenous Cannabinoids Endocannabinoids

De Petrocellis et al. (1998) reported that anandamide potently and selectively inhibited the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently suppressed the proliferation of MCF-7 and EFM-19 human breast carcinoma cells but did not affect the proliferation of several nonmam-mary tumoral cell lines. The anti-proliferative effect of anandamide was apparently not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. The stable analog of anandamide R-methanandamide and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation. The drug effects were blocked with the CBi antagonist SR141716A, suggesting that anandamide blocked human breast cancer cell proliferation through a CB1 -like receptor-mediated inhibition of endogenous prolactin action at the level of the prolactin receptor. Facci et al. (1995) reported that mast cells, multifunctional bone marrow-derived cells found in...

PH Responsive Carrier Systems

Non-targeted or antibody-targeted pH-sensitive polymer-doxorubicin conjugates were designed to facilitate site-specific chemotherapy. Doxorubicin is attached to the polymer carrier via a simple hydrolytically labile spacer containing either a hydrazone bond or cis-aconitic acid residue (108). In vitro incubation of the conjugates in various buffers demonstrated fast drug release from the polymer at pH 5 (tumor environment) with minimal release at pH 7.4 (physiologic plasma). Thus, doxorubicin conjugates were stable and inactive during transport in the body, but activate inside target cells as a result of regional differences in pH. Cytotoxicity of the conjugate depends on the detailed structure of the polymer and of the spacer between the drug and polymer carrier. In vivo antitumor activity of the pH-sensitive conjugates containing doxor-ubicin was significantly enhanced compared with free drug or conjugate alone (109).

Radiation Therapy and Biological Therapy

As stated previously, there have been two recently published studies the Intergroup (NSABP B-31 NCCTG 9831) and HERA trials which showed improved recurrence-free survival and overall survival (Romond et al. 2005 PiccaRT-GEBHaRT et al. 2005). These studies allowed the inclusion of patients with locally advanced breast cancers however, the percentage of the enrolled patients who had large primary tumors was low. In the NSABP B-31 trial, 16.7 of patients had tumors greater than 4.0 cm, and 42.6 of patients had four or more positive Herceptin has also been used as part of neoad-juvant treatment. Buzdar et al. (2005) reported the results of a trial from MDACC, which randomized 42 patients with HER2 positive breast cancer (T1-T4, N0-N2, M0) treated with four cycles paclitaxel followed by four cycles of FEC (5-fluorouracil, epi-rubicin, cyclophosphamide) to either concurrent trastuzumab (given weekly) or additional therapy as neoadjuvant treatment. Patients either underwent BCT or mastectomy...

Drug Drug Interactions Busulfan

During long-term follow-up of patients treated with busulfan and hydroxycarbamide for essential thrombo-cythemia, seven patients (13 ) taking hydroxycarbamide developed secondary acute leukemia, myelodysplasia, or solid tumors, compared with only one of the control group none of the 20 patients who had never been treated with chemotherapy developed secondary malignancies compared with three of the 77 given hydroxycarbamide only and five of the 15 given busulfan plus hydroxycarba-mide. This suggests that the combination of busulfan plus hydroxycarbamide causes a significantly increased risk of secondary malignancies (13).

Direct Intratumoral Delivery and Convection Enhanced Delivery

In an effort to improve survival from malignant gliomas, investigators have used intratumoral chemotherapy protocols to deliver high doses of tumoricidal agents directly to the brain. Theoretically, these infusions bypass the BBB, minimize systemic drug levels and the side effects of chemotherapy, and achieve prolonged elevations of intracerebral chemo-therapeutic agents relative to those obtainable by systemic administration. Almost all major classes of chemotherapeutic agents have been examined as possible intratumoral therapies via delivery approaches ranging from simple intratumoral injections to implantable computer-driven constant infusion pumps and biodegradable polymer matrices (122).

Reversal of Multidrug Resistance

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for Pgp and other ABC transporters have been studied as an approach to improve therapeutic outcomes in cancer patients. There have been a number of clinical studies conducted to determine whether modulation of Pgp activity improves the efficacy of cancer chemotherapy (135). Studies have shown that Pgp modulators such as verapamil and cyclosporin indeed reverse resistance in a small number of patients, but significant side effects are observed with these therapeutically active medications. Additionally, it is likely that the principal effect of these modulators may be through altered pharmacokinetics and not MDR reversal in cancer cells (136).

Clinical trials with levonantradol

Levonantradol is another synthetic cannabinoid. It was synthesized by Pfizer researchers, and belongs to the nonclassical cannabinoids group. Levonantradol is a tricyclic analog of A9-THC where the oxygen in its pyran ring is replaced by a nitrogen atom. Levonantradol is one of the four stereoisomers of nantradol. Levonantradol possesses analgesic (Johnson and Melvin, 1986), cannabimimetic (Levitt, 1986 Compton et al., 1991) and antiemetic action (Table 13.3 Johnson and Melvin, 1986) in both animals and humans. This compound is stereoselective in its cannabinoid effects and is 30 times more potent than A9-THC (Little et al., 1988). Currently, it is not clinically available as an antiemetic. Table 13.3 summarizes the clinical antiemetic efficacy potential of levonantradol from 10 clinical trials. In these studies, levonantradol (0.5-2mg) was administered either intramuscularly or orally. In nearly all studies, the initial dose of levonantradol was administered 1-2 h prior to...

Pregnancy Category D

This antianxiety drug is also known for its sedative properties and is used to promote sleep and to fight convulsions. The substance is given to treat status epilepticus, a dangerous condition in which people have one epileptic seizure after another, back-to-back. It can reduce and sometimes even eliminate vomiting from cancer chemotherapy. Lorazepam has been used to treat LSD and methamphetamine overdose and has been a standard medicine to help alcoholics through the alcohol withdrawal syndrome. Recreational sedative users report euphoria from lorazepam. When given experimentally in combination with other drugs, it has helped reduce depression. In contrast, experimentation using motion picture excerpts to evoke particular emotions found that lorazepam may reduce happy feelings and increase unhappy ones. One study found that lorazepam worked as well as alprazolam for treating panic attacks, and a case report tells of success in treating mania. Lorazepam has been used to cure...

Randomized Trials of Postoperative Concurrent RCT

Historically, the combination of postoperative radiotherapy and 5-FU-based chemotherapy has been shown in several randomized trials to reduce local recurrence rates and to improve overall survival compared with (conventional) surgery alone or surgery plus postoperative radiotherapy (Table 18.1). In the early GITSG 7175 trial, the best local control was achieved with combined RCT (local relapse rate of 11 vs 20 with RT alone), whereas no impact on local control was noted with chemotherapy as single adjuvant treatment (local relapse rate of 27 vs 24 with surgery alone Gastrointestinal Tumor Study Group 1985). Although rates of distant metastases were slightly lower in the two arms that contained chemotherapy, no single arm had a significant impact on distant failure thus, the survival advantage achieved with combined RCT appeared to relate primarily to the marked reduction in local relapse rates. These result were later confirmed by a trial conducted by the Norwegian Adjuvant Rectal...

Possible role of other neurotransmitter systems in the antiemetic properties of cannabinoids

Although the cholinergic neurotransmitter system per se is not directly involved in chemotherapy-induced vomiting (see section 2.1), dopaminergic and serotonergic mechanisms do appear to be important downstream in cannabinoids' antiemetic actions. Indeed, in the feline, nabilone dose-dependently prevents emesis produced by the dopamine D2 receptor agonist apomorphine (London et al., 1979). In a similar manner, A9-THC prevents vomiting produced by dopamine D2 D3 receptor agonists such as apomorphine, quinpirole, quinelorane and 7-OH DPAT in the least shrew (Darmani, unpublished observations). In this context, the least shrew seems to be an excellent dopamine animal model of emesis since the cited selective and nonselective dopamine D2 receptor agonists can potently induce emesis in this species, whereas D2 antagonists prevent the induced behavior (Darmani et al., 1999). As discussed earlier, clinical findings further underscore the role of blockade of the dopaminergic system in the...

Summary And Conclusions

At least six naturally occurring and synthetic cannabinoids have been investigated for their antiemetic properties in man. However, only A9-THC, nabilone and levonantradol have been studied extensively in more than 40 clinical trials involving over 1529 patients who had completed these studies. Although a large number of these trials differ in their study design and suffer from methodological inadequacies, it is generally clear that cannabinoids possess significant antiemetic properties in cancer patients receiving chemotherapeutics. Though cannabinoids appear to be a more efficacious class of antiemetics than dopamine D2 receptor antagonists for the prevention of chemotherapy-induced vomiting, the efficacy of tested cannab-inoids to date seems not to be as high as the more potent antiemetics such as the selective 5-HT3 receptor antagonists. However, one interesting advantage of can-nabinoids is that many of the patients who are protected from the acute phase of emesis, also respond...

Randomized Trials to Optimize the Sequence Preoperative RCT

Until recently, the only randomized trial that directly compared preoperative to postoperative radiation therapy (both without chemotherapy) in rectal cancer has been the Uppsala trial, which was carried out between 1980 and 1985 in Sweden (Frykholm et al. 1993). In the preoperative arm, patients received intensive short-course radiation (five fractions of 5.1 Gy to a total dose of 25.5 Gy in 1 week), postoperatively conventional radiation therapy (2 Gy to a total of 60 Gy with a 2-week split after 40 Gy) was applied. Preoperative radiation significantly decreased local failure rate (13 vs 22 p 0.02), however, there was no significant difference in 5-year survival rates (42 vs 38 ). Prospective randomized trials comparing the efficacy of preoperative with standard postoperative RCT in UICC stage-II and stage-III rectal cancer were initiated both in the United States through the Radiation Therapy Oncology Group (RTOG 94-01) and the NSABP (R-03) as well as in Germany (Protocol CAO ARO...

Conclusions from Trials with 5FUBased RCT

In summary, if the available data on post- and preoperative RCT with 5-FU-based chemotherapy for rectal cancer are considered, the following conclusions can be drawn 1. There is evidently a higher local effectiveness of concurrent radiation and 5-FU as compared with surgery alone or adjuvant radiotherapy or chemotherapy alone. In the postoperative setting, this is manifested by a higher probability of the combined approach to eradicate subclinical disease left behind after potentially curative surgery and, consequentially, by improved long-term local control rates (GITSG 7175, NCCTG 794751, Norway trial, NSABP R-02). In the preoperative setting, increased tumor downsizing and downstaging, increased pathological complete regression, and improved local control rates are seen with concurrent radiation and 5-FU (EORTC 22921 FFCD 9203 Frykholm et al. 2001 Bujko et al. 2004). 4. The impact of 5-FU-chemotherapy and the various ways of its administration and modulation on the control of...

Cannabis in the international prohibition regime

However, the international control system is increasingly inclined to disregard the scientific advice it receives from the WHO. Perhaps the most dramatic instance of this is the turning back by the CND in 2007 of a recommendation for a rescheduling of dronabinol (A-9 tetrahydrocannabinol, THC), the principal psychoactive constituent of cannabis, under the 1971 Convention on Psychoactive Substances. Dronabinol is prescribed particularly in the USA under the brand name Marinol as an appetite stimulant, primarily for AIDS and chemotherapy patients. While the plant cannabis and its natural products are included in the 1961 Convention among the substances which are considered the most dangerous and without any therapeutic usefulness (Schedules I & IV) , dronabinol was listed under Schedule I of the 1971 Convention (the most restrictive schedule) at the time of that Convention's adoption. The 1989 WHO Expert Committee on Drug Dependence recommended that dronabinol be transferred to...

Critical Thinking Exercises

Burton is receiving methyltestosterone (Oreton Methyl) for treatment of metastatic breast cancer. The drug has caused changes in her appearance, namely deepening of her voice, some male pattern baldness, and facial hair. Analyze the situation and decide what suggestions you could give this patient who has a limited income and may be unable to afford extensive cosmetic and wardrobe changes.

Observational studies

In 63 patients with stage III and stage IV squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx, with no distant metastases, randomized to either adjuvant oral chemotherapy with futraful, uracil, and levamisole (n 29) or no treatment (n 34), oral chemotherapy showed a trend of better control of distant tumor recurrence (4). However, there was no statistically significant improvement in overall long-term survival. Of the 29 patients who received adjuvant oral chemotherapy, 17 finished the 1-year course without withdrawing. In nine patients futraful, uracil, and levamisole was withdrawn because of local, regional, or distant metastases. Three patients withdrew after 4 months because of vomiting and mucositis. One developed a mild gastric upset and completed the course. There were no major hematological or nephrotoxic adverse effects. In two patients with thymoma associated with myasthenia gravis, who both had recurrent oral candidiasis after thy-mectomy,...

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