Early Breast Cancer Ebook

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!

Chemo Secrets From a Breast Cancer Survivor Summary


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Adjuvant chemotherapy

There is well-documented evidence that the administration of chemotherapy (two or more agents) will improve survival (overall and disease free), albeit in a small group of women. These effects are greatest in women who are younger than 50 years of age and particularly in patients who have lymph node involvement by tumour. Initially, combination chemotherapy comprising cyclo-phosphamide, methotrexate and 5-fluorouracil (CMF) was given at monthly intervals for 6 months and this was shown to be beneficial in reducing disease recurrence and increasing overall survival. In recent years, the Early Breast Cancer Trialists Collaborative group has carried out an overview to examine all the studies. The key points to emerge from this overview are that (c) A doxorubicin-containing regimen also reduces the risk of death when compared with combination chemotherapy regimens which do not contain an anthracycline such as doxorubicin. Whilst there are different combination chemotherapy regimens in...

Ipsi and contralateral breast cancer recurrences

Lumpectomy followed by radiation therapy, i.e. the conservative management of breast cancer, has been accepted as a standard of care for the majority of women with early breast cancer. Long-term follow-up data have consistently shown a risk of ipsilateral breast tumour recurrence (IBTR) of 0.5-2 per year (Recht et al., 1988 Fourquet et al., 1989 Kurtz et al., 1989 Fisher et al., 1991 Veronesi et al., 1995), but breast cancer survival was not significantly affected by IBTR when compared with patients undergoing a radical mastectomy (Haffty et al., 1991a Fisher et al., 1995 Jacobson et al., 1995 Veronesi et al., 1995 Winchester et al., 1997). Early age of onset is associated with an increased risk of IBTR (Schnitt et al., 1984 Haffty et al., 1991b de la Rochefordiere et al., 1993), but an association was not consistently found when the patient reported a positive family history of breast cancer (Chabner et al., 1998 Harrold et al., 1998). Young age at primary breast cancer diagnosis, a...

Chemotherapy and immunochemotherapy


There have been extensive studies on the chemotherapy of pathogenic mammalian trypanosomes (e.g. Peregrine, 1990) however, little is known about the effectiveness of drugs on Cryptobia. Trypanosoma and Cryptobia are related but many trypanocidal drugs (e.g. suramin, berenil and antrycide) have no detectable in vitro effects on C. salmositica (P.T.K. Woo, unpublished). Although a combination of antibiotics (penicillin, streptomycin and amphotericin B) affects the in vitro viability of C. salmositica in cultures, it does not seem to affect try-panosomes. However, the antibiotic combination does not have a therapeutic effect in rainbow trout with cryptobiosis (Thomas and Woo, 1991). Similar results were obtained when cultures of newly isolated C. salmositica were exposed to a similar combination of antibiotics. Amphotericin B is the main cryptobiocidal factor in the antibiotic combination (Chapman, 1994). In general, chemotherapy is selective toxicity. Woo (1995) suggested that...

From the Normal Breast to Cancer the Concept of Breast Cancer Stem Cell

It is now well established that breast cancer originates from the TDLU, but it is not clear which are the cells targeted by tumorigenesis (6-10). A recent interesting hypothesis based on experimental evidence from tumor subpopulation transplantation and animal models suggests that mammary tumors may derive from adult breast stem cells (2, 11). The involvement of stem cells in carcinogenesis was suggested more than 30 years ago (10, 1214), but only recently the tools of stem cell biology were applied to the study of carcinogenesis (14). Adult stem cells are defined by their ability for self-renewal and differentiation into cell lineages present in the specific tissue. Self-renewal ensures propagation of the stem cell compartment, which sustains morphogenesis, tissue repair and maintenance, whereas differentiation generates the specialized cells that constitute each organ (7, 15-17) (Figure 1A). The adult mammary gland requires stem cells or stem cells like activity to fulfill the...

Complications of chemotherapy

A number of complications can arise while an animal is receiving chemotherapy. Many of the intravenous injectable agents are either irritant or vesicant if perivascular injection occurs and prompt action should be taken (see below). Immediate hypersensitivity reactions can happen with some drugs. Cytotoxic drugs are not specific to tumour cells in their action and normal body tissues that contain a large proportion of dividing cells, such as the bone marrow and the epithelium of the gastrointestinal tract, are susceptible to toxici ty. These normal tissues can recover by recruitment of stem cells and so effects on these organs are usually readily reversible on stopping chemotherapy. Loss of whiskers is common in cats receiving chemotherapy (Plate 3.1) some thinning of the coat may also occur. Some agents have specific toxicities Most cytotoxic drugs can cause bone-marrow toxicity (myelosuppression). Vincristine is generally regarded as minimally myelosuppressive in dogs, but has been...

Definition and classification of breast cancer for staging

Breast cancer follow the system of the International Union Against Cancer. This system is based on the tumor, nodes, and metastases (TNM) nomenclature. Definitions for Breast Cancer Staging Classification of Breast Cancer Staging C. The staging of breast cancer dictates not only the prognosis but also directs treatment modality recommendations. The prognosis for women is based on their age, tumor type, initial tumor size, presence of nodes and staging, and hormone-receptor status. The overall 10-year survival rates for the more common breast cancer stages are greater than 90 for stage 0, greater than 75 for stage I, greater than 50 for stage IIA, and approximately 50 for stage IIB.

Intralesional chemotherapy

Two uncontrolled phase II studies have examined the effect of treating intraoral, oropharyngeal and laryngeal AIDS-related KS by intralesional injection of vinblastine.16,17 One obtained a 62 complete response rate (16 26 lesions) in 24 patients with AIDS-associated oropharyngeal or laryngeal KS.16 Lesions were injected with vinblastine, 0-1-0-2 mg ml repeated every 4 to 5 weeks until complete response or stable disease. Side-effects included self-limiting pain, and ulceration. In 11 of 24 patients the pain was not relieved by paracetamol. A similarly high complete response rate was found in another uncontrolled phase II study of intralesional vinblastine as a local treatment for oral-cavity AIDS-associated KS.17 A total of 144 lesions in 50 patients were treated, and the complete response rate was 74 . The most common site of intraoral KS is the hard palate. Intralesional chemotherapy (vinblastine, vincristine or bleomycin) has also been used to treat cutaneous KS lesions, with...

History Of Cancer Chemotherapy And Reflection Thereon

Originally, cancer chemotherapy started with nitrogen mustard, a derivative of poisonous gas yperite, a by-product in World War II. The pharmacological action of nitrogen mustard consists in cytotoxicities (e.g., leukopenia, diarrhea, and stomatitis) to the organism, and attempts were made to utilize these toxicities to obtain anticancer activity. Namely, the modality consisted in cancer therapy using toxicities to the organism that were inherent to nitrogen mustard. From the standpoint of establishing cancer chemotherapy that is ideally based on the premise that only the tumor should be attacked with the least damage to the organism, therefore, we cannot but consider that the approach was the tail wagging the dog (misoriented rescuing). A concept of high-dose chemotherapy, i.e., an anticancer agent fails to be effective unless provoking considerable adverse reactions, still remains at present when half a century has elapsed since the introduction of nitrogen mustard. The concept of...

Singleagent chemotherapy Bleomycin

We found three small uncontrolled phase II trials of bleomycin as single-agent therapy in the treatment of AIDS-related KS and one small non-randomised study comparing singleagent bleomycin with combination ABV chemotherapy.42-45 In one non-randomised phase In a small non-randomised study comparing bleomycin with ABV combination chemotherapy in 24 patients with extensive AIDS-related KS, there were no complete or partial responses in 12 patients who received bleomycin alone. Four of 12 patients who received ABV chemotherapy had a partial response.45 What are the effects of systemic chemotherapy in KS and do liposomal anthracyclines produce higher response rates (by ACTG criteria), with less toxicity, than conventional combination chemotherapy in advanced AIDS-related Kaposi's sarcoma

Family history as an indicator of predisposition to breast cancer

A history of breast cancer among relatives has been found, in epidemiological studies, to be an indication of breast cancer risk. Familial breast cancer is characterized by a younger age at diagnosis than sporadic forms, increasing numbers of affected family members, an increased risk of bilateral breast cancer, and a strong association with ovarian cancer. Table 2.1. Genetic syndromes associated with breast cancer susceptibility Table 2.1. Genetic syndromes associated with breast cancer susceptibility Site-specific hereditary breast cancer If a woman has a first-degree relative (mother, sister or daughter) who has developed breast cancer before the age of 50 years, her own risk of developing the disease is increased two-fold or greater, and the younger the relative the greater is the risk. If a woman has two first-degree relatives with the disease, her risk may be increased four- to six-fold, and again, the younger the relative the greater is the risk (Claus et al., 1996 McPherson et...

ABV or BV chemotherapy versus liposomal anthracyclines

Three large randomised controlled trials have compared liposomal anthracyclines (either doxorubicin or daunorubicin) with standard ABV or BV combination chemotherapy. We found one randomised study comparing liposomal daunorubicin (DaunoXome) with ABV and two randomised trials comparing liposomal doxorubicin with standard combination chemotherapy (either ABV or BV).60-62 All three trials assessed response using modified ACTG response criteria and graded toxicity according to standard criteria. Concurrent antiretroviral

Genes implicated in breast cancer predisposition

More than 500 sequence variations have been identified in BRCA1, and of these, more than 80 of all BRCA1 mutations are frameshift or nonsense mutations that alter the codon reading frame and result in a 'stop' codon producing a premature protein termination (Futreal et al., 1994 Gayther et al., 1995 FitzGerald et al., 1996 Szabo and King, 1997 Liede et al., 1999). Genetic susceptibility to breast cancer is thought to occur when one BRCA1 allele is inactivated in the germline Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have examined multiple families with germline mutations in BRCA1 and BRCA2 to establish the penetrance of mutations in these genes and the risks of other cancers (Ford et al., 1994 Ford et al., 1998 Puget et al., 1999a) (Figure 2.1). These studies suggest that carriers of mutations in BRCA1 have an associated cumulative breast cancer risk of 80-85 by age 80 years. Once affected with a first breast cancer, such gene carriers have a subsequent risk...

Some Basic and Applied Principles of Cancer Chemotherapy

Although our understanding of the basic molecular nature of the neoplastic transformation is still relatively primitive, significant advances have been made during the past three decades in the successful treatment of neoplasms that were not curable by surgery and or radiation alone prior to 1970. The principal modality (used alone or in combination) that has resulted in significant improvement in treating a number of neoplasms, many of which are in persons less than 30 years of age (Chapter 1), is chemotherapy, by use of an increased spectrum of drugs, hormones, and other natural products. Chemotherapy may be defined as the treatment of disease through the use of chemicals. This includes infectious as well as neoplastic disease. Cancer chemotherapy specifically is the treatment of cancer by chemicals that maximize the killing of neoplastic cells while minimizing the killing of most or all other cells of the host. With most malignant neoplasms, the greatest danger to the host results...

Indications for chemotherapy

Chemotherapy should be reserved for malignant tumours that are known to respond to cytotoxic drugs and is indicated for widespread or systemic disease. Examples where chemotherapy would be the first line of treatment are lymphoproliferative and myeloproliferative diseases (lymphoma, myeloma and some leukaemias). Chemotherapy is rarely of value as the sole treatment for solid (non-lymphoid) tumours such as carcinomas, sarcomas or melanomas. Here, surgery or radiotherapy would be the first choice of treatment however, cytotoxic drugs may be useful in an adjuvant setting for the treatment of metastatic disease.

Noninvasive breast cancer

Was evidence of microinvasion, with 4 having lymph node metastases. In addition, there is also a risk of patients with DCIS subsequently developing invasive cancer. Although different estimates of this risk have been reported, approximately 2 of these patients are likely to develop invasive breast cancer each year.

Studies of familial breast cancer

It has been recognized for many years that there is an association in certain families between breast and ovarian cancer. The risk for epithelial ovarian cancer was found to be significantly elevated in patients with first-degree relatives affected with breast cancer (twice the population risk) (Muderspach, 1994 Claus et al., 1996). Similarly, the risk for breast cancer was found to be elevated in patients who had first-degree relatives with ovarian cancer. Following international studies of large families with an excess of both early-onset breast cancer and of ovarian cancers, Mary Clair King's group demonstrated linkage between inherited susceptibility to early-onset breast cancer and a polymorphic marker on chromosome 17q21.3 (Hall et al., 1990). Predisposition to breast and ovarian cancer was also found with this locus in many families around the world, but it was also clear that other families existed with an excess of early-onset breast cancer that did not segregate with this...

Bilateral breast cancers

A second primary cancer in the opposite breast may be found either at the time of the initial presentation (synchronous tumour, 0.5-2 ) or more commonly at a subsequent date (metachronous cancer, 3-9 ). A woman who has a primary breast cancer has a four- to sixfold risk of developing a cancer in the opposite breast. Other risk factors for the The prognosis for patients with bilateral breast cancers depends on the staging of the tumours and treatment should be appropriate for the disease stage. Patients who have a genetic predisposition (mutations of the putative breast cancer gene(s) and associated genomic abnormalities (e.g. loss of het-erozygosity of the p53-suppressor gene)) are at very high risk of developing bilateral breast cancers. In these patients, consideration may be given as to whether prophylactic mastectomy (with or without reconstruction) should be undertaken.

Breast cancer in the male

Cancer of the male breast accounts for 0.5-1 of all breast cancers and less than 1 of all male malignancies. Only 5 of male breast cancers occur before the age of 40 years and the median age of presentation is 68 years (older than that of the female population who develop breast cancer). The aetiology of male breast cancer has not been elucidated but there are risk factors which may predispose to the development of breast cancer. These include increased levels of oestrogens either in the circulation or in the breast tissue (Kleinfelters syndrome, treatment with oestrogens for prostatic cancer), increased prolactin levels, exposure to ionising radiation, genetic predisposition and occupational risk factors (steel and news printing workers). The clinical presentation is usually a lump, most commonly centrally placed or in the upper outer quadrant. Up to 20 of patients may have nipple discharge which can be either serous or sero-sanguineous. Histologically, invasive ductal carcinomas of...

Combination chemotherapy in endemic African Kaposis sarcoma

We found a series of three small randomised comparative studies of chemotherapy in Ugandan patients with endemic (African) KS.71-73 Chemotherapy is an important modality of treatment for endemic KS in developing countries without adequate access to radiotherapy facilities. On the basis of a previous small randomised study which found a higher response rate for actinomycin D than cyclophosphamide in patients with endemic (African) KS, a second randomised study compared actinomycin D with a combination of actinomycin D plus vincristine.71,72 Twelve patients received actinomycin D alone, 0-42 mg m2 day for 5 days every 3-4 weeks, and 14 received this with vincristine, 1-4 mg m2 week until the end of the second course of actinomycin D then on days 1 and 5 of each subsequent course.72 Twenty-four patients were evaluable for response. Two of the 12 patients who received actinomycin D alone died during the first cycle of chemotherapy (Gram-negative sepsis and adrenal failure). A further...

Breast Cancer and Angiogenesis

In solid tumours, growth beyond a millimetre cannot occur without vascular support (Folkman 1996). Transgenic animal tumour model experiments have shown that progression from an in-situ to invasive cancer is accompanied by the onset of angiogenesis (Rak et al. 1995). There are a number of clinical examples where vascularization has been related to tumour progression (e.g., in the change from breast ductal carcinoma in-situ to invasive cancer (Gilles et al. 1995) Bose et al. 1996). Immunohistochemical techniques show changes consistent with this observation for example, expression of the endothelial cell-specific tyrosine kinase receptor, Tie-2 (TEK) is increased during the transition from benign to invasive breast cancer (Bernsen et al. 1998). The most potent pro-angiogenic factor in breast tumours is vascular endothelial growth factor (VEGF), initially termed vascular permeability factor due to its hyperpermeable effect on vessels (Senger et al. 1983). VEGF leads to endothelial cell...

Singleagent versus combination chemotherapy

It is generally accepted that combination chemotherapy is more effective than single-agent chemotherapy. Using a combination of drugs with different mechanisms of action and different toxicities means that the overall tumour response can be enhanced without an increase in toxicity to normal tissues. Each component of a combination protocol should have proven efficacy when used in isolation and ideally the drugs

Late Phase Ii Clinical Trial Of S1 In Breast Cancer

This clinical trial was conducted to examine the antitumor activity and toxicities of S-1. Eligibility required advanced and or recurrent breast cancer which was verified by histopathological or cytological evidence. However, postoperative adjuvant chemotherapy for advanced or metastatic cancer, which was conducted six or more months prior to this clinical trial, was not counted as a regimen. S-1 was administered orally at a dose of 40 mg m2, with at least four courses, each of which consisted of twice-a-day (once each after breakfast and dinner) 28-d consecutive oral administration and of 14-d withdrawal two courses were repeated every 6 wk unless the disease progressed. As shown in Table 10, there were six complete response cases and 28 partial response cases among 81 cases which were evaluable for response, with an overall response rate of 42.0 . As shown in Fig. 14, the median survival time was 910 d. The adverse events that were assessed to be Grade 3 or Response Rate in the Late...

Breast cancer during pregnancy and lactation

Breast cancer presenting during pregnancy or lactation occurs in up to 3 in 10 000 pregnancies, and comprises less than 2 of all breast cancer cases. The median age of these patients is 34 years or less, depending on the series. Earlier studies had suggested that the prognosis was worse in pregnant women with breast cancer, when compared with those who were not pregnant. This is partly due to the fact that presentation tends to be delayed and up to 70 of pregnant women with operable breast cancer have involved axillary nodes. When compared stage for stage with non-pregnant women there appears to be no difference in prognosis. However, in general young women with breast cancer, aged 30 years or less, tend to have a worse prognosis than those aged 35 years or more. The treatment of the breast cancer should be as for the general population. For example, mastectomy can be safely undertaken. Lumpectomy and axillary surgery, if deemed appropriate, may be carried out in the third trimester....

Variables In The Chemotherapy Of Cancer

Although a variety of specific drugs are used in the chemotherapy of cancer, their effects can be quite variable from patient to patient and even within the same patient at different periods of the treatment regimen. Such variability involves different factors, some of which we have discussed above and others of which are noted in Figure 20.6. In this figure, the overall pharmacological-therapeutic process from a drug dose to its therapeutic effect is depicted. However, since neopla-sia is a somewhat specific situation involving cell growth as well as specific humoral effects of the neoplasm on the host (Chapters 17 and 18), other variable factors come into play, some of which are considered here. It is already obvious that drugs used in the chemotherapy of cancer have a variety of toxic effects in the host that may or may not be directly related to its effect on the neoplasm. Thus, in any such situation, the toxicity to normal tissues and the organism as a whole becomes a limiting...

Chemotherapy Regimens For The Treatment Of Leukemias And Solid Neoplasms

With the expansion of the knowledge base for modern chemotherapy of cancer, the efficacy as well as the rationale of the use of combinations of drugs for the therapy of neoplasia became of paramount importance. The ideal situation in which application of the basic knowledge developed to the present time is seen with rapidly growing neoplasms, particularly leukemias, in which neoplastic cells occur systemically but with easy access to the therapeutic agents through the vascular circulation. Here are considered examples of this more idealized treatment as well as the therapy of solid neoplasms, where delivery of the drug to the neoplastic cell becomes a major therapeutic hurdle.

Combination Chemotherapy

A basic limitation of cancer therapy is the resistance of tumors to cytotoxic drugs (I. C. Henderson et al. 1988). Combination chemotherapy developed as a way to overcome resistance. By the 1970s, it had been shown that metastatic breast cancer was moderately sensitive to single-agent chemotherapy (DeVita and Schein 1973). Several groups of cytotoxic agents were identified as active against metastatic breast cancer, including the alkylating agents (cyclophosphamide, thiotepa, L-phenylalanine mustard) the antimetabolites (5-fluorouracil, methotrexate) the vinca alkaloids (vincristine and vinblastine) and the antitumor antibiotics (doxorubicin, mitomycin, and others) (Hortobagyi 2000). Soon after, the superiority of combinations over single-agent drugs was demonstrated. The Cooper regimen, consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) and its derivatives (CMF and CMFP), were generally accepted as active and well tolerated. The...

Metastatic breast cancer

Patients with metastatic disease may present because of symptoms caused by the metastatic deposits. However, up to one-half of patients who present with a loco-regional recurrence of disease either have demonstrable metastatic disease at the time of presentation or shortly thereafter. Once metastatic breast cancer has been diagnosed the mean survival of these patients is approximately 18-24 months. Thus, the primary aim of any treatment is to palliate and improve the quality of life. supportive care relief of debilitating, disabling and distressing symptoms management of pathological fractures correction of disorders of body functions, etc.) and (ii) treatment to retard the growth of the tumour. These latter treatments are either chemotherapy or hormonal therapy.

ABV chemotherapy versus doxorubicin

We found one small randomised study of 61 patients with extensive mucocutaneous or visceral AIDS-related KS, comparing ABV combination chemotherapy with doxorubicin alone.74 The overall response rate was 88 for 30 patients who received ABV combination chemotherapy and 48 for the 31 patients who received doxorubicin, 20 mg m2, alone. The response rates differed significantly. Toxicity was similar in both arms, but neutropenia (

Breast Cancer and Its Treatment

It is the second leading cause of cancer death among women (representing 15 of all cancer deaths), compared to 25 of cancer deaths from lung cancer (American Cancer Society ACS 2004). Estimated deaths from breast cancer in 2003 were 39,800 for women and 400 for men. Mortality rates for breast cancer declined significantly in recent years, mostly among young women, both white and black, falling 1.4 annually in 1989-1995 and then at a rate of 3.2 annually. Survival for women with breast cancer varies as a function of the stage of the disease at diagnosis. The ACS data show 5-year relative survival rates of 86 for all stages, 97 for local, 78 for regional, and 23 for distant (or metastasized) cancers. The ACS, relying on the SEER staging system of the National Cancer Institute, defines local-stage tumors as cancers that are confined to the breast regional-stage tumors have spread to surrounding tissue or nearby lymph nodes and distant-stage tumors have...

Cpg Island Hypermethylation In Breast Cancer Progression And Metastasis

Abstract Breast cancer is the most common malignancy in women and comprises 18 of all female cancers. The incidence of breast cancer increases with age and in the western countries the disease is the single most common cause of death among women aged 40-50, accounting for about a fifth of all deaths in this age group. The advent of mammography screening has led to an increased detection of pre-invasive mammary lesions and a better elucidation of the pathological events that precede the development of invasive breast carcinoma. Invasive breast cancer is classified in two main morphological subtypes ductal carcinoma representing about 80 of breast malignancy, and lobular carcinoma that accounts for approximately 10 of breast cancers. Among pre-invasive breast lesions, the hyperplasia of the usual type (HUT) is morphologically and phenotypically heterogeneous, whereas atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are homogenous in cell type and marker expression....

Do ovarian and breast cancer belong to the tumour spectrum of HNPCC

There is no agreement on whether breast cancer belongs to the tumour spectrum of HNPCC. Watson and Lynch (1993) reported 19 cases of breast cancer (mean age 51 years) in 23 HNPCC families (observed expected ratio 0.9, NS). Risinger performed molecular genetic studies in five cases of breast cancer from HNPCC families, one with an identified mutation in MLH1 (Risinger et al., 1996). In three out of the five tumours, widespread MSI was observed, and in the family with the known mutation, expression of only the mutant allele was observed in the breast cancer tissue. Aarnio reported a SIR for breast cancer in 183 mutation carriers of 1.4 (95 CI 0.4-3.7) (Aarnio et al., 1999). Boyd described a male member of a large HNPCC family affected by breast and colorectal cancer (Boyd et al., 1999). This patient was found to harbour a germline mutation of the MLH1 gene, and the breast tumour exhibited reduction to homozygosity for the MLH1 mutation and MSI. Recently, Scott et al. evaluated the...

Combined Locoregional And Systemic Chemotherapy

The rationale for combining locoregional and systemic chemotherapy in advanced col-orectal cancer with metastases to the liver only is based on the following issues 1. Locoregional chemotherapy has a well-defined activity in these patients and is possibly superior, as reported above, to systemic treatment (at least when traditional agents are administered intravenously). 2. Again in Germany, Safi et al. (18) included 45 cases in a small controlled clinical trial in which a combination of intraarterial FUDR (0.2 mg kg d x 14 d every 4 wk) and the same drug given intravenously (0.09 mg kg d in the same period) was evaluated in comparison with FUDR administered only intraarterially at the same dose as above. In this study a response rate of 48 was obtained with the combined strategy and the percentage of extrahepatic spread of cancer during therapy seemed of interest in comparison to that observed with locoregional treatment only (33 vs 61 , even though without statistical significance...

Breast cancer in the elderly

The incidence of breast cancer continues to rise through life with 40 of all cases occurring in patients older than 70 years. A small number of these patients, because of concurrent disease, will be unfit for any form of loco-regional therapy other than tamoxifen (20-40 mg day). With tamoxifen as the sole therapy it has been shown that approximately one-half of the tumours will show a reduction in size and of these, up to 50 will be complete responses (6-12 months of treatment may be required). However, approximately 50 of those tumours which initially responded to tamoxifen will relapse within 2 years, with tumour growth then occurring. It should also be noted that if the tumours are OR negative they are unlikely to respond to tamoxifen and OR status should be established before commencing therapy. In general, therefore, it is recommended that older patients should be treated along the same principles as outlined previously. Stage for stage the results of therapy in women over 65...

TrWeighted Breast Cancer DCEMRI

A large body of literature has shown that breast cancer enhance earlier and to a greater extent than benign breast diseases on Trweighted DCE-MRI. This difference is most marked in the early period (1-3 min) after bolus contrast medium administration (Kaiser and Zeitler 1989 Flickinger et al. 1993 Gilles et al. 1993 Boetes et al. 1994). However, other investigators have demonstrated that there is an overlap in the enhancement rates of benign and malignant lesions (Heywang et al. 1989 Fobben et al. 1995 Stomper et al. 1995). Thus, any kinetic parameter used for tissue characterisation has to take into consideration the relative contrast medium behaviour in different tissues.

High Dose Chemotherapy

The appropriate dosage for cancer chemotherapy has long been debated within oncology. In 1980, Frei and Canellos argued that the importance of the dose of chemotherapy drugs was insufficiently appreciated. Chemotherapy drugs were so toxic that any suggestion that the dose-response curve was not steep or that lower doses were as effective as higher ones led oncologists to administer lower doses. They argued that the toxicity of antitumor agents was strongly dose related for both tumor and normal cells, and that the dose-response curve was steep for the majority of such agents. A few randomized studies had examined dose as a variable, and most had found a dose-response curve, especially for Hodgkin's disease, non-Hodgkin's lymphoma, oat (small) cell carcinoma of the lung, and acute lymphocytic leukemia (Frei and Canellos 1980). Few of the studies in these sensitive cancers had established proof of principle. Even so, higher doses for these sensitive tumors were at most twice that of...

Risk Factors for Breast Cancer

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

Pathology of breast cancers in mutation carriers

There are a number of published studies indicating that breast cancers arising in mutation carriers are of higher grade than sporadic cancers (Bignon et al., 1995 Jacquemier et al., 1995 Eisinger et al., 1996 Marcus et al., 1996). Eisenger et al. studied 27 BRCA1-associated breast cancers from 14 families and compared these to sporadic breast cancers, matching for grade. They found an excess of grade III carcinomas in the BRCA1-associated group. Marcus et al. reported the first large series of the pathology of BRCA1-related tumours. They had 90 BRCA1-related breast cancers assigned to the group on the basis of linkage to chromosomes 17q and or the presence of ovarian cancer and male breast cancer. The control set comprised 187 predominantly non-familial cases. They reported that BRCA1-associated tumours were more likely to be of medullary or atypical medullary type, to be of higher grade, to be aneuploid, and to have a higher tumour cell proliferation rate. When adjusted for age, the...

Recent Modalities In And Potential For Cancer Chemotherapy

Until recent years, the principal direction of cancer chemotherapy has been toward newer and better drugs aimed at affecting cell replication as well as by endocrine-active drugs. A very significant portion of the drugs presently in use were discovered as a result of serendipity or their efficacy is directly related to serendipitous findings. With the dramatic increase in our knowledge of the cellular and molecular biology of living tissues, both normal and neoplastic, it is now reasonable to devise chemotherapeutic agents on the basis of several rationales. Several of these are discussed below. Signal Transduction Pathways as Targets for Chemotherapy With a dramatic increase in our knowledge of molecular mechanisms involved in signal trans-duction and its aberrations in neoplasia, components of this pathway have been suggested as possible targets for chemotherapy (Powis, 1994). Although there are many possibilities, certain specific sites have been targeted by agents developed...

Molecular pathology of BRCAl2associated breast cancers

Since its discovery in 1960, oestrogen receptor (ER) has become an important prognostic and predictive marker for breast cancer (Osborne, 1998). ER expression is inversely correlated with tumour grade (Henderson and Patek, 1998) hence, BRCA-associated tumours, which are more often of a higher grade than those of sporadic breast cancer, would be predicted to be more often ER-negative. Many studies have shown low levels of ER expression in familial breast cancers (Johannsson et al., 1997 Osin et al., 1998a,b Robson et al., 1998 Armes et al., 1999). This is also true when ER expression in fiRCA-associated tumours is compared with a grade-matched control group (Osin et al., 1998a). In contrast, the expression of ER in BRCA2 tumours appears to be similar to that in sporadic breast cancer tumours (Osin et al., 1998a,b). The detection of ERs immunohis-tochemically does not necessarily reflect their functional competence, and a percentage of cancers expressing ER are known to be resistant to...

Promoter Hypermethylation Of Cancer Related Genes In Breast Cancer

Cancer is the result from a multistep process characterized by the accumulation of genetic and epigenetic hits leading to uncontrolled growth and ultimately to the acquisition of metastatic potential (Figure 1B). Three types of genes are involved in carcinogenesis oncogenes, tumor suppressor genes (TSGs) and stability (caretaker) genes. These cancer related genes are involved in a series of pathways that control the basic function of the cell proliferation, communication with neighboring cells and with extra cellular matrix, senescence and programmed cell death (apoptosis) (71, 72). It is now becoming clear that there are many fewer pathways than genes, and they cross talk to one another forming a complex network of intracellular signals (72). Gene silencing by CpG promoter hypermethylation can modulate these pathways by acting directly on tumor suppressor genes and stability genes and indirectly on oncogenes through their regulators (Table 1). The analysis of methylation profiles in...

Screening for breast cancer

Clinical studies have demonstrated that mammographic screening of women can reduce the number of deaths from breast cancer. In particular, studies (USA, Europe) have demonstrated that if women aged 40-74 years of age underwent regular screening there was a decrease in mortality from breast cancer of approximately 25 over 15 years, with the most benefit being found in those women over 50 years of age. In 1988 a UK National Health Service Breast Screening Programme was introduced. The aim of this programme was to reduce deaths from breast cancer by approximately 25 by the year 2000, provided that at least 70 of women in the population being screened attend for mammography. Women aged 50-64 years were invited to attend a screening centre for a single, high-quality mediolateral oblique view mammogram, every 3 years. However, there was concern that a single view mammogram could miss abnormalities that would have been detected if two mammographic views had been taken. Therefore, two views...


Although in Western countries the administration of chemotherapy lies within the province of the non-surgical oncologist, all surgeons must be aware of its advantages and shortcomings. Initially used for the palliation of advanced cancers, the first critical evaluation of the role of chemotherapy in early cancer arose from the observation that the course of acute lymphoblastic leukaemia in children, a uniformly fatal disease, could be dramatically altered by the administration of the folic acid antagonist aminopterin. Although early hopes of 'cure' were not realized, the development of new agents that could be given in combination, recognition of the principles of their action and the ability to objectively monitor response by the marrow aspiration, led to successful and often curative treatment. Although this success has been extended only to a small number of solid tumours - lymphomas, testicular and ovarian cancers, the principles are equally applicable to other forms of cancer and...

Breast cancer

In the scheme proposed for managing varying levels of genetic risk, guidelines might be aimed at the primary care team to ensure that the GP can be confident in reassuring low-risk women (de Bock et al., 1999 Evans and Eccles, 2000). In the hospital-based screening clinic, guidelines and a working knowledge of the relevant literature should allow both patient and clinician to feel confident that a more thorough review of the family tree can help inform a more detailed assessment of risk (The BASO Breast Specialty Group, 1998 Armes et al., 1999) and, if higher risk, in addition to screening, this information can result in onward referral to the genetics specialist. The genetics specialist will use additional information to ensure appropriate use of genetic testing (Couch et al., 1997 Eccles et al., 1998). This, in turn, will allow many of those who appear at first look to be at moderate risk to be reassured that, on closer scrutiny, they appear unlikely to have a significant component...

Abmt Breast Cancer

High-dose chemotherapy with autologous bone marrow transplantation (HDC ABMT) emerged in the late 1980s as a promising new treatment for metastatic breast cancer, then for high-risk breast cancer. Its promise was based on high levels of complete and partial tumor response. In the 1990s, HDC ABMT burst on the oncology scene and was catapulted into widespread use before careful evaluation. The unconfirmed promise of this procedure drove clinical practice, health insurance coverage decisions, court decisions about coverage of individual patients, and federal administrative and state legislative mandates of HDC ABMT as a covered benefit. Entrepreneurial oncology then exploited a lucrative market. In writing this book, we have had two objectives. First, we want to tell the story of the rise and virtual demise of HDC ABMT as a treatment for metastatic and early-stage breast cancer. Second, in telling the story, we aim to draw lessons from it for the evaluation of other medical procedures....

Patient preference and compliance

Glycoprotein Gut Wall

For the majority of metastatic solid tumours, chemotherapy offers at most an improvement in symptom relief and only a modest gain in actual survival. In these palliative treatment regimens, the aspect of quality of life is increasingly being recognised. Surprisingly the patient preference for oral versus intravenous chemotherapy was only recently examined by Liu et al. 6 . Of 103 patients with metastatic cancer, 92 preferred oral chemotherapy, provided that both oral and iv chemotherapy had a similar efficacy. Major reasons for preferring oral chemotherapy were patient convenience, problems with iv access or needles and control of the environment in which patients would receive treatment. The patient preference was not associated with sex, age or prior chemotherapy experiences. Grober et al. did a survey about patient attitudes towards oral and iv therapy in cancer patients with a history of only oral treatment (n 109) and only iv treatment (n 242) 7 . Indeed, orally treated patients...

Nipple retraction inversion

Congenital nipple inversion (of variable degree) occurs in up to one-fifth of all women. This is usually of no clinical significance unless it interferes with breast feeding. The woman may present because of the cosmetic deformity. However, two of the most common causes of nipple retraction are mammary duct ectasia and periductal mastitis. Clinically, this manifests as a transverse depression in the nipple which progresses to complete retraction (there may also be an associated nipple discharge). This process may be intermittent in its early stages and can be present in both breasts. Nipple retraction may also occur in patients with breast cancer. In the latter this is unilateral and there may be an associated breast lump, with or without a nipple discharge (often blood stained). Table 17.2. The risk of breast cancer occurring in patients Risk of developing breast cancer

Health Insurance and Medicine in the 1980s

Elsewhere in health plan evidence of coverage documents, there are often additional exclusionary provisions that not only provide a general exclusion for experimental or investigational services (as specifically defined) but also exclude specific medical interventions or services, such as cosmetic surgery, dental implants, or in some cases during the 1990s, HDC ABMT for breast cancer. A key point is that when coverage is excluded by benefit design (coverage categories) or by specific line item exclusions, medical necessity is irrelevant as coverage will always be excluded. Denials of specific services on the basis of the experimental or investigational exclusion or based on medical necessity, however, could be challenged on the basis of the process and the rationale for the decision. We discuss this in detail regarding HDC ABMT litigation in chapters 3 and 4.

Recombinant vaccines expressing tumor associated antigens

The number of prior chemotherapy regimens was inversely correlated with the ability to generate a T cell response, suggesting that the real clinical impact of vaccination strategies can only be determined in a patient population without immune compromise. A third Phase III study was conducted in the Netherlands involving 254 patients with stage II and stage III colon cancer 34 . This pivotal study differed from the previous clinical trials in that treated patients received a booster with irradiated tumor cells alone, administered 6 months after surgical resection. In contrast to the previous study a centralized manufacturing laboratory supported the 12 participating hospitals, which prepared 98 quality approved vaccines. We showed that 97 of the vaccinated patients had DTH responses greater than 5 mm, suggesting that the centralized method of vaccine manufacturing is very important for vaccine quality. In an intent-to-treat analysis, ASI significantly reduced...

Randomized Clinical Trials Are Authorized

Payment for clinical research was a discussion in the abstract until HDC ABMT came into focus, Sue Gleeson of the BCBSA recalled (Gleeson 2002). A series of meetings in 1988-1990 forged a response to the specific issues raised by the new procedure. The medical directors of the Blue Cross Blue Shield plans met in fall 1988. Guests included Robert Wittes and Mary McCabe from the NCI and Karen Antman of Dana-Farber, who spoke about breast cancer and ABMT (Aronson 2002). Antman's message was that ABMT was an effective therapy that was not being covered and was thus unavailable to patients. Naomi Aronson, then a TEC staff professional and later its director, recalled Antman's presentation as compelling. The NCI was actually in something of a box. Unknown to the insurers, in late June the NCI had asked the cancer cooperative groups to formulate proposals for participation in a high-priority national clinical trial to test the effectiveness of tamoxifen in preventing breast cancer (Cancer...

Ovarian ablation and GnRH analogs

Synthetic GnRH antagonists, which competitively bind to the receptor, have been less extensively investigated. Although devoid of the flare up effect, the clinical use of the first compounds was limited by the occurrence of a severe histaminic skin reaction. More recent drugs, such as cetrorelix, have shown no significant histamine-releasing effect and are under investigation in prostate and in breast cancer 62 . Few data have been reported on the comparison between different methods of ovarian ablation. A couple of randomized studies have compared surgical with medical ablation in premenopausal women with metastatic breast cancer the results were inconsistent but both trials were closed prematurely because of poor accrual, thus leaving the question unresolved 63 . The reversibility of the effect upon discontinuation of treatment represents the major advantage but also a potential limit of medical castration, questioning the optimal duration of the treatment. Studies using GnRH...

Laryngeal and hypopharyngeal cancer

Hypopharyngeal Cancer

Is cord fixation or extension of disease into the hypopharynx or when hypopharynx cancer causes fixation of the hemilar-ynx, total laryngectomy is usually required. Hypopharyngeal cancer requires partial or total pharyngectomy in addition to laryngectomy. Reconstruction of the pharyngeal defect is by regional myocutaneous flap (based on the latissimus dorsi or the pectoralis major muscle), free forearm flap (Fig. 20.14), free jejunal segment or gastric pull up. Extrathoracic gastric pull up or colon interposition is required to reconstruct the oesophagus when total oesophagectomy is carried out for upper cervical oesophageal disease (Fig. 20.18). Voice rehabilitation is by learning oesophageal speech, use of an elec-trolarynx or by creation of a tracheo-oesophageal fistula for insertion of a Blom-Singer prosthesis. Advanced stage laryn-geal hypopharyngeal cancer often requires concomitant neck dissection for a clinically positive neck followed by postoperative radiotherapy. Induction...

Colorectal Cancer Background and aetiology

Each year colorectal cancer affects 32 000 people in the UK and is responsible for around 22 000 deaths. In males it is second only to lung cancer and in females it falls third behind lung and breast cancer. In the developed world, life-time risk of colorectal cancer is around 1 25 and this is increased by genetic predisposition and certain conditions such as chronic colitis. Colorectal cancer is mainly a disease of the elderly with a marked rise in incidence after age 70 years, however, 10 of individuals are under age 55 years at diagnosis.

Prodrugs of anthracyclines

Any strategy by which a cytotoxic drug is targeted to the tumor, thus increasing the therapeutic index of the drug, is a way of improving cancer chemotherapy and minimizing systemic toxicity. Low- or high-molecular weight pro-drugs hold promise as tumor selective drug delivery systems. Expected advantages of such formulations are a preferable tissue distribution, a prolonged half-life of the drug in the plasma, and a controlled drug release at the tumor site by adjustment of the chemical properties of the bond between the drug and the linker. In the past, the design of prodrugs with antitumor agents has focused on strategies that allow the drug to be released by extracellular or intracellular proteases or at the low pH values present in lysosomes and endo-somes, respectively.

Dosage and administration

In case of severe elevated liver enzymes and bilirubin the administration of a full dose of doxorubicin cannot be recommended because metabolism and excretion via the bile is severely hampered. There is no really good algorithm how to manage such a patient. For example, for a young breast cancer women with a complete diffuse metastatic infiltration of the liver at the time of diagnosis it is feasible to start with weekly DOX application as first line therapy with flat doses, e.g., 20 mg. If the patient tolerates this well, the drug dose can be escalated to 25 and 30 mg depending on the course of the liver enzymes. If therapy with DOX is satisfactory, a normalization will occur and a switch from a weekly schedule to a 3-week schedule can be considered. The normalization of the drug dose by use of body surface area is a matter of debate 125 . The reason why all anthracyclines doses including DOX are normalized by use of BSA, can only be seen in a historical context. The first studies in...

Immunodeficiency and cancer

Immunocompromised individuals such as patients after radiotherapy or chemotherapy, transplant patients on immunosuppressive drugs or those with an AIDS are at an increased risk of developing cancer. The risk is particularly for lymphoproliferative and cutaneous malignancies, which

Arbitrary and Capricious Standard in FEHBA and Champus Cases

Courts interpreted the arbitrary and capricious standard more strictly in FEHBA cases than in ERISA cases, perhaps because most of the insurance plans provided by carriers with which the OPM contracts explicitly excluded coverage of HDC ABMT for breast cancer. As a result of this strict interpretation, courts consistently upheld the OPM's denials of coverage. (Of the two cases in which courts found for the plaintiff under a FEHBA policy, one was reversed on appeal, and the other was a state court decision.) In Caudill v. Blue Cross & Blue Shield of North Carolina, the court upheld the district court's decision granting summary judgment to the insurer, noting, t here is nothing to suggest that OPM's interpretation of the contract at issue here was irrational. But even if the court would have come to a different conclusion, it must not substitute its judgment for that of the administrative agency with a decision under review. 86 Even in cases in which the OPM made no explicit factual...

The Story in Brief A Fateful Branching

Autologous Bone Marrow Transplant

What do these cases illustrate They indicate the intense hope and fear that drove women with a diagnosis of breast cancer to seek an experimental treatment presumed to offer better prospects than conventional therapy. They suggest the dependence of women on the advice they receive from their physicians, especially when a treatment is characterized as the only chance for a cure. The cases show how the demands of these women were expressed forcefully to and through families, physicians, clergy, employers, and newspaper and television reporters. They demonstrate that lawyers often translated these demands into litigation against health insurers. They indicate that insurers often provoked litigation by denying coverage of the highdose chemotherapy with autologous bone marrow transplantation (HDC ABMT) procedure on the grounds that the procedure was experimental. An important underlying consideration was that the procedure was very expensive, significantly more than conventional therapy....

Analytical epidemiology

In an experimental or interventional study, individuals are randomly allocated to be included in a study group, which is exposed to a factor under study or allocated to a non-exposed control group. Such studies offer the most direct and conclusive method of establishing a causal relationship between a risk factor and a cancer. Although the introduction of a suspected risk factor may happen opportunistically, as in irradiation following the atomic bombs in Japan, the introduction of harmful measures (or withdrawal of beneficial ones) from random sections of the population is not ethical. Although this study design is standard for assessing the effects of treatment, it is applicable only to epidemiological studies of primary or secondary prevention for example vaccination against hepatitis B or screening for breast cancer. Such large and expensive population studies will become more frequent as chemoprevention becomes a reality.

Clear Exclusions by Insurers

In response to the rulings in favor of breast cancer patients seeking coverage for HDC ABMT, insurers quickly began to draft their policies in ways that made the exclusion of the treatment hard to dispute, even under the de novo standard (as described in the section ERISA Standards of Review ). By 1993, circuit courts had faced a number of so-called clear-drafting cases (ERISA Litigation Reporter 1996). In one case, the plan did not include breast cancer in its list of specific cancers for which HDC ABMT was covered and stated that s ervices or supplies for or related to surgical transplant procedure for artificial or human organ tissue transplants not listed as specifically covered were excluded from the policy.60 The court held that the Office of Personnel Management's (OPM's) exclusion of HDC ABMT was the only logical interpretation of the policy. 61 In another case, the plan excluded coverage for treatment provided as part of a phase 1, 2, or 3 clinical trial because the...

Assessing the status of ErbB receptors in human tumours

Immunohistochemical staining of HER2 overexpression in breast cancer tissue is also becoming part of the standard diagnostic work-up. This staining is scored semiquantitatively, with a 3+ positive staining being considered to be positive. In many centres, a 2+ positive staining in combination with a positive FISH test, however, is also considered to be positive.

Magnetic resonance mammography

Characteristic appearances of a breast cancer on mammography. Figure 17.9. Characteristic appearances of a breast cancer on mammography. primary chemotherapy and there are trials which are evaluating its use as a screening technique, particularly in its role in younger women.

EGFR Inhibition Via lyrosine Kinase Inhibitors

In randomised studies comparing chemotherapy to a combination of chemotherapy and trastuzumab in patients with metastatic breast cancer over-expressing HER2, increased response rates and increased time to disease progression were observed with the combination 8 . Studies exploring the role of trastuzumab in the adjuvant disease setting have recently demonstrated impressive clinical benefit in HER2-neu overexpressing tumors 9-11 . Trastuzumab is currently approved for treatment in patients with metastatic breast cancer, either as a single agent or in combination with non-antracycline cytotoxic chemotherapy, both as first-line and second-line treatment.

Recognition of a New Procedure

In the case of HDC ABMT for breast cancer, the new treatment became visible to insurers quickly as it was substantially more costly than existing treatments, and the number of potential patients was very large. As early as 1988, some patients, assisted by transplanters, had begun to seek insurance coverage for HDC ABMT, and some physicians had begun to bill insurers for the procedure. As is often true for new procedures, billing used existing procedure codes or components of existing procedures. Often, there was legitimate confusion on how to bill. Some billings revealed to insurers that a new and expensive procedure was being used to treat breast cancer patients. Dr. Wade Aubry, then senior vice president and medical director for Blue Shield of California, recalls receiving the first requests for ABMT coverage in late 1988 (Aubry 2002). Initially, these requests were not recognized as ABMT some were seen as high-dose chemotherapy, some as harvesting of bone marrow, and some as...

Antiidiotype antibody vaccines

The murine monoclonal antibody CEA Vac mimics a highly restricted CEA epitope that has no cross-reactivity with CEA expressed by normal human tissues. This antibody acts as a surrogate tumor antigen, inducing anti-CEA antibody responses and specific T cell responses, and was demonstrated to have a major antitumor effect in a murine tumor model 20 . In a study in 23 patients with advanced colorectal cancer, 17 generated anti-anti-idiotype responses, and 13 of these were proven to be true anti-CEA responses 21 . However, none of the patients had objective clinical responses and toxicity was limited to local swelling and minimal pain at vaccination site. CEA Vac has also been evaluated in the setting of adjuvant therapy of high risk colorectal cancer 22 . 32 patients were included in this study, 4 stage II, 11 stage III, 11 completed resected stage IV and nine stage IV patients with minimal residual disease. 15 patients received 5-FU-based chemotherapy, simultaneously with the CEA Vac....

Marrow transplantation

The potentially lethal problems associated with intensive chemotherapy are infection and haemorrhage due to destruction of marrow cells. Initially these were countered by intensive antibiotic treatment, laminar-flow isolation and granulocyte and platelet transfusions, but with the development of marrow transplantation a more lasting solution evolved. Supralethal cytoreductive therapy followed by salvage allogeneic marrow transplantation, when practised during the initial remission of acute leukaemia, results in a high proportion of disease- and treatment-free survivors. During developmental studies in experimental animals it was noted that stem cells from the buffy coat of the peripheral blood, when injected into recipients, can repopulate marrow spaces. Following the discovery of the colony-stimulating factors, CSF and GCSF, which control the proliferation of granu-locytes, monocytes, macrophages and related haemopoietic cells in human marrow, it became practical to 'shift' stem...

The Ambivalent Commitment of Medicine to the Gold Standard

Documented the complex process by which randomized trials came to be adopted as a guide to clinical practice in oncology, especially in the challenge by Bernard Fisher to the Halstead radical mastectomy in breast cancer. Phase 3 randomized trials are clearly difficult to mount (as we discuss in chapter 8). An oft-cited figure is that only 3 -5 of adult cancer patients are entered into randomized clinical trials. This is due to many factors, prominent among them patient resistance to randomization. On the one hand, ineffective standard therapy may encourage patients to seek experimental treatment outside of trials. Patients with a terminal illness, such as stage IV breast cancer, may say that they have nothing to lose from seeking access to new treatments, further complicating efforts to conduct randomized trials. On the other hand, some patients may be unwilling to risk exposure to the experimental procedure within a trial, viewing the untested negatively. Physician incentives to...

Cases Subject to State

Only policies negotiated directly between the patient and an insurance underwriter are governed by the law of the state in which the agreement is consummated. State courts have traditionally viewed health insurance policies as contracts of adhesion rather than negotiated agreements and therefore have construed ambiguous coverage provisions in favor of the policyholder (Giese 1996, pp. 215-216). As such, state court decisions reviewing denial of coverage for HDC ABMT tended to favor the policyholder. For example, in Taylor v. Blue Cross Blue Shield of Michigan, a Michigan appellate court held that the exclusion clause in the policy was ambiguous because the terms experimental and research in nature could be interpreted in different ways.94 Furthermore, the plaintiff had introduced evidence that HDC ABMT was an effective treatment for breast cancer and thus not experimental. Likewise, in Tepe v. Rocky Mountain Hospital and Medical Services, a Colorado appellate court held that the...

Upper Gi Malignancy Oesophageal carcinoma

Tumours are suitable for resection if pre-operative staging suggests no more than T3 disease, N0 or N1 lymph node status, and no distant metastases (i.e. T3, N1, M0, or better). Unfortunately, only 20 of patients who present with oesophageal cancer are suitable for resection, mainly because the presenting symptom, dysphagia, often occurs late in the disease process. Recent studies in the UK, Holland, and America have suggested survival benefits in certain patients receiving neo-adjuvant chemotherapy, and current practice in the UK is to offer this to patients with T2 and T3 tumours.

EGFR tyrosine kinase inhibitors

Gefitinib was the first compound to be tested clinically after it had shown growth inhibitory activity towards a range of human tumour cell lines expressing EGFR. In addition to this single-agent activity, additive and even synergis-tic antitumour activity with various frequently used cytotoxic antitumour agents and radiation therapy was demonstrated in these models. Gefitinib demonstrated promising clinical activity and patient benefit in Phase I and II trials in patients with non-small-cell lung cancer (NSCLC). Based on these results, gefitinib has meanwhile been approved and licensed for the third-line treatment of this disease. To determine the potential role of gefitinib in combination with chemotherapy in first-line treatment in patients with metastatic NSCLC, two large Phase III trials with gefitinib in combination with two of the most frequently used regimens in these patients have been performed. Somewhat surprisingly, both studies failed to show any clinical benefit of...

A new paradigm and novel therapies

This model, which is derived from the need to destroy invading microorganisms, may not necessarily apply to cancer cells which are derived from their host. It has been suggested that the malignant cell should be regarded as part of a biological communications network where processes of cell growth, division and migration take place in an environment of impaired regulation. While conventional antineo-plastic approaches, such as surgery, radiation therapy and cytotoxic chemotherapy, still play a part in treatment, the essential need is to reassert normal controlling mechanisms so that re-regulation of critical processes in the growth, invasion and metastatic process can occur. This will entail reversal of inducing and promoting events, blocking the action of defective or false transmitters, overriding inefficient enzymes or receptors and inducing alternative metabolic pathways. Palliative care, is commonly regarded as synonymous with terminal care that is, the...

Bone Marrow Transplantation

Bone marrow transplantation is an offshoot of whole organ transplantation.2 Allogeneic BMT involves infusing marrow cells from an immunologically compatible donor to the patient being treated. It had been applied therapeutically mainly to hematologic disorders and was described as curative for severe immunodeficiency, aplastic anemia, thalassemia, and leukemia and lymphoma (Hansen et al. 1989). Autologous BMT involves extracting a patient's marrow, preserving it through a freezing process, treating the patient's cancer with HDC, and reinfusing the patient's marrow cells in the hope that the hematologic and immunological capability depleted by chemotherapy will be restored. The success of allogeneic transplantation in dealing with acute leukemia resistant to standard chemotherapy led investigators to use autologous transplantation against other cancers responsive to chemotherapy and radiation. Canellos (1985) compared the relative merits of allogeneic versus autologous BMT for treating...

Fat protein and calories

Evidence for a positive interaction between dietary fat and cancer (particularly of the colon and breast) is supported by experimental studies and geographical correlations between fat intake and incidence, but large cohort studies of detailed dietary habits provide little support. Individual fatty acids may be more relevant than total fat intake. A high intake of monounsaturated fatty acids is associated with a reduced risk of breast cancer, which possibly explains the low incidence of breast cancer in Mediterranean countries where olive oil is widely consumed. a-linoleic acid is also believed to have a protective effect on breast cancer risk. In animal models, reduction in total caloric intake explains much if not all of the potentiating effect of dietary fat on experimental tumour induction. Low-calorie diets inhibit tumour formation and this is possibly one reason for the lower incidence of breast and colorectal cancer in those of poorer socioeconomic status. There is increasing...

Sentinel lymph node biopsy

In recent years, sentinel lymph node (SLN) mapping and biopsy have been well established for intermediate to thick melanoma and clinically node-negative breast cancer. In a study of 114 patients (from Emory University School of Medicine) with thick melanoma (s4 mm), 32.5 had a positive SLN biopsy, half of which had a single-positive lymph node after dissection. The overall 3-year survival for SLN-negative patients was 82 versus 57 for node-positive patients.

Health Insurers and Randomized Clinical Trials

Health insurers were not ambivalent about the need for randomized trials to provide the evidence that HDC ABMT was effective treatment. Their assessments of the medical literature concluded that the existing data did not justify the provision of HDC ABMT outside clinical trials. Most were adamant that they had no obligation to pay for patient care costs of such trials. Whereas costs for standard chemotherapy for metastatic breast cancer might run as high as 30,000 to 40,000 per patient, HDC ABMT charges could easily run as high as 150,000, with a potential for going much higher if complications occurred, as they required weeks and sometimes months of hospitalization, more highly trained professional staff, and the complicated administration of bone marrow transplantation.

Other Claims for Relief

A few plaintiffs tried more creative approaches in their efforts to enjoin their insurer from denying coverage, albeit not with great success. In Reger v. Espy, the plaintiff argued that denial of coverage of HDC ABMT violated Title VII of the Civil Rights Act of 1964 in that exclusion of the treatment has a disparate impact on females.105 The court rejected that argument, noting that i t is clear from the language of the Plan . . . that HDC-ABMT benefits are not available for most types of cancers, only one of which is breast cancer. 106 The court also found the exclusion to be facially neutral and the decision not to provide HDC-ABMT benefits for all but the five listed diagnoses affect s both men and women equally. 107 In Dodd v. Blue Cross & Blue Shield Association, the plaintiff claimed that excluding coverage of HDC ABMT for breast cancer runs afoul of the Rehabilitation Act of 1973 and the Americans with Disabilities Act of 1993 (ADA) because the treatment is provided for some...

Oncology Legitimates an Experimental Procedure

The limited commitment to randomized trials was reflected in several statements that emanated from the AMA. Its Diagnostic and Therapeutic Technology Assessment (DATTA) program solicited the opinions of clinicians rather than systematically reviewing the literature. In an early 1990 poll of 45 oncologists on ABMT, an overwhelming majority rated the safety and effectiveness of ABMT as established or promising (AMA DATTA 1990). Although the report limited itself to acute lymphocytic leukemia, acute myelogenous leukemia, and lymphoma, it would be used to support coverage for HDC ABMT as a breast cancer treatment. The then-director of the DATTA program, Dr. Elizabeth Brown, would write In summary, the DATTA panelists considered the harvesting, cryopreservation and reinfusion of autologous bone marrow an appropriate method for managing bone marrow hypoplasia aplasia in patients undergoing treatment for cancer (Brown 1990a, p. 1). She would make no mention of those cancers for which the...

Stamp I Stamp Ii Stamp Iii Stamp Iv Stamp V

A The letter sequence in a combination regimen corresponds to the sequence in which the individual chemotherapy drugs are administered. disease, suggesting that the dose-response curve would be steeper in the adjuvant (or early-stage) setting than in the metastatic setting. This appeared to be true for the CMF regimen in breast cancer treatment, but results differed for pre- and postmenopausal women (Hortobagyi 2000, p. 588). Dose intensification received a powerful stimulus from several articles published in the mid-1980s. In 1984, Hryniuk and Bush lamented Combination chemotherapy has failed to cure advanced disease, patients who have received adjuvant chemotherapy continue to relapse, and chemotherapy has not dramatically increased survival in Stage IV disease. Manipulations of doses, schedules, and combinations do not seem to improve results. Combination chemotherapy of breast cancer appears to have reached an impasse (1984, p. 1281). Their review of metastatic breast cancer...

Resolution and Postscript

In 1999, several randomized controlled studies reported that HDC ABMT was no more effective than standard-dose chemotherapy (e.g., Stadtmauer et al. 2000 see also chapter 8). An editorial accompanying one study concluded as follows T o a reasonable degree of probability, this form of treatment for women with metastatic breast cancer has been proved to be ineffective and should be abandoned in favor of well-justified alternative approaches (Lippman 2000, p. 1120). Predictably, requests for the procedure declined, as did the attendant litigation, although a few courts are still dealing with the issue. Most recently, a federal district court in Michigan held that the insurer's denial of coverage for HDC PSCR or HDC ABMT for stage II breast cancer for which fewer than 10 lymph nodes were affected was arbitrary and capricious.111 In that case, Reed v. Wal-Mart Stores, Inc., Wal-Mart denied the plaintiff's request for coverage of the treatment because ' b ased on the medical information...

Cytoplasmic oncogenes

A number of classes of cytoplasmic oncogenes have been described. Some are homologous to growth factors, for example sis and platelet-derived growth factor (PDGF), his and int-2 and fibroblast growth factor (FGF) others activate growth factors, for example ras and TGF-a, a member of the epidermal growth factor (EGF) family. Some have receptor tyrosine kinase activity, the most prominent of which is erb-B2 which codes for the EGF protein others may code for non-receptor PKCs. Most have no role in human cancers three, ras, erb-B2 and abl, have been implicated in colon and breast cancer and leukaemia.

Litigation Trends and Lessons Learned

Others involve only a handful of the cases for example, among those cases favoring the plaintiff, several emphasize the fact that the treatment was generally accepted by oncologists. Second, as noted, many of the opinions focused largely on the proper standard of review (de novo vs. arbitrary and capricious) rather than on the merits of the case. Finally, the fact that these cases were driven largely by the specific facts of the case, such as the exact policy language at issue, makes it somewhat difficult to compare the cases. In many instances, virtually the only constant between two cases is that they both involved HDC ABMT as a treatment for breast cancer. As Judge Sweet of the Southern District of New York noted, many courts have addressed the 'experimental' nature of HDC-ABMT for the treatment of Stage IV breast cancer, but t hose cases provide little assistance since, by virtue of the task, they each are specifically focused on the particular contract language...

Clinical features

Staging of breast cancer UICC staging. above). Locally advanced cancers are characterised by oedema, skin infiltration, satellite skin nodules, ulceration, fixity to the chest wall and or large fixed axillary nodes (N2) (Fig. 17.27). Some patients may also have oedema of the ipsi-lateral arm. However, not all cancers have these features and occasionally some may be difficult to differentiate clinically from benign tumours such as fibroadenomas. Other breast cancers may present as a diffuse nodularity, with no localised lump being found, and up to 10 of patients with breast cancer may present with pain as the predominant complaint.

Litigation Issues and Trends

After their health insurers refused to pay for HDC ABMT on the grounds that there was no evidence that HDC ABMT was superior to standard-dose chemotherapy, many women responded by seeking insurance coverage of the procedure through the judicial system. In most cases, they filed a motion for a preliminary injunction to compel their insurer to provide coverage in advance of the treatment. In other cases, the women underwent the therapy, and then they or, all too often, their estate sued their insurer to recover the cost of the procedure. Most cases were settled out of court to avoid the expense and publicity of a jury trial, but numerous others were litigated to the appellate level. The remainder of this chapter reviews the HDC ABMT cases, highlighting the major issues facing those courts called on to adjudicate a coverage dispute between a breast cancer patient and her health plan. It explains how the cases differed depending on the type of policy at issue (ERISA, non-ERISA, Civilian...

Primary breast tumour

The treatments initially advocated for breast cancer were based on the belief that cancer cells spread in a centrifugal pattern - from the tumour to the regional-draining lymph nodes and then sequentially to the vascular system and distant metastatic sites. Thus, it was recommended that a radical mastectomy (which includes removing the pectoralis major muscle) should be undertaken. However, in the 1920s and 1930s this approach was challenged and surgeons began to realise that less radical surgery was associated with good results. Indeed, Geoffrey Keynes in the UK had treated early breast cancers by local excision of the tumour and implantation of a radioactive source (radium seeds) at the site of the excised tumour 'bed'. Randomised-controlled trials (both Europe and the USA) evaluated more precisely the role of breast conservation surgery versus mastectomy in the treatment of patients with breast cancer. It was demonstrated that if the clinical size of the tumour was 2 cm or less...

The Courts Initial Response

The first cases challenging insurers' refusal to cover the procedure were filed in the late 1980s, shortly after HDC ABMT initially attracted interest as a therapy for breast cancer but before much was known about it. Consequently, it is not surprising that in these early cases (before 1990) courts supported the insurers' determination that the treatment was experimental.29 These relatively short opinions focused on the fact that HDC ABMT was still in phase 3 clinical trials (in which the efficacy of the treatment is studied), and that it had not yet been generally recognized throughout the medical profession as an appropriate treatment for high-risk or metastatic breast cancer. For example, Janice Thomas was diagnosed with breast cancer in 1984.30 After a chest x-ray revealed that the cancer had spread to her lungs, she began chemotherapy to no avail. Her oncologist referred her to Vanderbilt University Medical Center, where doctors recommended HDC ABMT. Before Ms. Thomas was...

The Evaluation of New Treatments

Cancer chemotherapy drugs are evaluated somewhat differently from other drugs. Determinations about effectiveness require judgment about how much damage to normal cells can be tolerated in the effort to kill cancerous cells. Consequently, phase 1 studies in oncology, which test the allowable level of toxicity, typically involve patients with a cancer for which no effective treatment exists or for whom treatment has failed (or predictably will fail). Healthy volunteers are ruled out on ethical grounds as most chemotherapy drugs are toxic and cause harm. Phase 2 studies of new anticancer agents test for therapeutic effect, typically tumor response, in sick patients for whom standard therapy is known to be ineffective or nonexistent. Phase 3 studies in cancer, usually large, randomized trials, evaluate the risk-benefit relationship between toxicity and outcomes of treatment, which include tumor response (both complete response and partial response), overall survival, event-free or...

Research Methodologies

We relied greatly on the published scientific literature. Typically, we would conduct a Medline search for all citations to a particular clinician-investigator. From that list, which included abstracts, we selected papers pertaining to HDC ABMT for breast cancer and obtained and read the papers. Interviewees often identified important papers and interpreted their importance for us. In addition to the published literature, we obtained and reviewed many documents memoranda, letters, unpublished reports not easily categorized by Medline and that may not be readily accessible to the public. Such documents have sometimes been described as fugitive literature. We interpreted these in the context of when, where, and why they were generated, often relying on our interviewees for help in answering these questions. Cynthia Farquhar, with a research assistant, conducted the analyses of the Health Care Utilization Project database about the utilization of HDC ABMT during 1993-2001. The database...

Carcinoma Of The Breast Introduction

Breast cancer accounts for approximately 24 of all malignancies occurring in the female population in industrialised western societies and 18 of deaths in women due to malignant disease. In the UK there are approximately 117 cases per 100 000 women (34 000 new cases per annum). Thus, 1 at least 12 women will develop breast cancer during their lifetime and the incidence is rising by approximately 2 per annum. Breast cancer rarely occurs in women under the age of 25 years. Thereafter, the incidence increases steadily until at the time of the menopause, where the incidence plateaus out. After the menopause there is again a steady increase in

Principles Of Cancer Treatment Curability

Stage at which many tumours presented to surgeons, but also because it was believed that there were two distinct stages in the natural history of a cancer a 'primary stage' when the cancer is confined to its organ or other site of origin and their regional lymphatics, and a 'secondary stage' when it is disseminated to distant sites. Only when the natural defences of the lymph nodes draining the primary site is overridden was such secondary spread believed to occur. Haematogenous spread was regarded as a late phenomenon. This concept has been replaced by evidence that invasive cancer disseminates early in its course by both lymphatic and blood systems to form micrometastases in regional lymph nodes and in systemic organs and tissues. Although it may be many years before these micrometastases become clinically evident, the effective treatment of invasive cancer now includes not only the control of local disease by surgery and or radiotherapy but also of systemic disease by chemotherapy...

Microarchitectural changes

This is characterised by prominent intralobular fibrosis and proliferation of small ductules or acini. The fibrosis may be extensive resulting in dense spiculated strands with prominent architectural distortion of the normal breast pattern. Complex sclerosing lesions are variants of this but are associated with prominent epithelial hyperplasia. In addition, there may be an increase in the myoepithelial component. As a result of the accumulation of dense fibrous tissue these lesions may be difficult to differentiate clinically and mam-mographically from breast cancers. This is characterised by hyperplasia of the epithelium lining the terminal ducts and acini. The proliferation of epithelium may result in a solid mass with obliteration of the ducts or it may take the form of epithelial projections which grow into the ducts (ductal papillomatosis). The morphological appearance of the epithelial cells can vary and different degrees of atypia may be seen. A variant is atypical lobular...

Assessment Of Effectiveness

There are two methods of determining clinical effectiveness. The first is clinical audit and the second is research, usually in the form of clinical trials. It is important to note that a treatment is not proved to be effective just because it has been used for a long time and is regarded as the standard approach. Mastectomy was regarded in the UK for many years as the only acceptable treatment for breast cancer but when the question was examined in clinical trials it was found that breast conservation was an acceptable alternative. This raises questions over the increasing trend towards the development of clinical guidelines which are often derived on the basis of consensus, unless that consensus is based on independent verifiable evidence.


Experimental studies in mouse leukaemia indicated that chemotherapy acted in a logarithmic fashion on cancer cells according to 'first-order kinetics'. A given dose of drug kills the same fraction, not the same number, of cells. The fractional reduction of tumour cells following chemotherapy is constant, irrespective of the size of the tumour burden. The amount of treatment required to effect a 99 reduction of a tumour of 1 mg (from 106 to 104 cells) is the same as that for one of 1 kg (from 1012 to 1010 cells). This finding suggests that the induction of an apparent complete remission is only the first step in treatment. To eradicate all leukaemia cells and maintain remission, more intensive, prolonged and potentially lethal therapy is required. This in turn requires measures to counteract its effects.


Combinations of chemotherapeutic drugs are more effective than single agents and their scheduling is of primary importance to the duration of their effect. Resistance to cytotoxic chemotherapy is well established in the laboratory and it is believed that similar mechanisms may operate in some human tumours.

Other symptoms

During the past decade there has been increasing concern that the success of treatment of cancer cannot be measured only in terms of freedom from disease and survival. Of equal importance to the patient is the quality of well-being during remaining life. This is of particular importance to those with advanced cancer, in whom the unpleasant side-effects of treatment must never exceed potential benefit. The advent of adjuvant cytotoxic chemotherapy has made quality of life assessment relevant in early disease. To allow quantitation of quality of life with survival, a novel approach has been developed by the International Breast Cancer Study Group, the quality adjusted survival analysis or Q-TWisT. TWisT refers to Time without Symptoms and Toxicity, which is calculated by subtracting from the survival time that time during which the patient has experienced toxicity, local and systemic relapse of the disease. A function has been developed for quality-adjusted survival related to TWisT,...


In clinical practice, one variable (e.g. the risk of developing breast cancer) may be related to a number of other variables. Multiple regression allows examination of the effect of several independent variables on the dependent variable simultaneously. If more than one variable is likely to affect the dependent variable, then multiple regression should be performed rather than a series of linear regressions as there may be interaction between the independent variables which will not otherwise be detected. Often a variable will have an association in univariate analysis but will not be found to be significant in the multivariate analysis because its effect is contained within the effect of another variable.


The realisation that clinically important results might be being obscured because trials were too small led to the development of new statistical techniques to allow the results from trials to be combined. It is not possible to take the results of different trials and merely add them together but the sample means are normally distributed around the population mean so, given a large enough number of sample means, it is possible to calculate the true mean and standard deviation of the population. This technique has been very successfully applied to adjuvant chemotherapy for breast cancer and is now being widely used in other settings. Once again, care must be taken in the interpretation of the results. Statistical significance does not necessarily mean clinical importance.

Critical reading

There is currently a fashion for developing consensus guidelines and it is being recommended that management decisions should be based on these guidelines. Unless these guidelines are backed by proper studies, they may do more harm than good and may actually inhibit progress. After all, the consensus in the UK until the 1980s was that mastectomy was the only safe procedure for women with primary breast cancer.


Has little effect since most T-cells have matured and populated the secondary lymphoid organs by this time. Adult thymec-tomy could result in T-cell deficiencies if T-lymphocytes are subsequently destroyed by chemotherapy or whole-body irradiation, for replenishment of secondary lymphoid tissue by new mature T-cells will not be possible.

Aplastic anaemia

Aplastic anaemia is caused by depletion or dysfunction of the bone marrow pluripotential stem cell. The result is a reduction in the numbers of all blood cell precursors in the marrow as well as a circulating pancytopaenia. There are numerous causes of aplastic anaemia, but a surgeon is most likely to encounter primary (idiopathic) aplastic anaemia or aplastic anaemia secondary to chemotherapy, ionizing radiation, idiosyncratic drug reactions or infection. Bone marrow transplantation is the treatment of choice if no treatable underlying cause can be found.


Because of its broad spectrum of antitumor activity, topoisomerase I and II inhibitors are clearly among the most important anticancer drugs developed in the last few decades. Their pharmacokinetic behavior has been explored extensively in recent years, which has been of fundamental importance in our understanding of their clinical effects. In addition, a wealth of information has yielded valuable insight into the mechanism of action, the mechanisms of tumor resistance, toxicities, and considerations of dosage and schedule and route of drug administration. However, only through further investigations that may allow better definition of the biochemistry and pharmacologic profiles of these agents can their rational optimization of therapy be achieved. This need has become even more important in light of the current clinical use of camp-tothecins and epipodophyllotoxins in combination regimens with other anti-neoplastic drugs or agents specifically administered to modify toxicity...

Hepatic tumours

Treatment options for HCC include surgical resection, tumour ablation, and chemotherapy. Surgery may involve partial hepatectomy, or total hepatectomy and transplantation. Liver resection in cirrhotic patients carries increased risk of morbidity and mortality, and this risk increases with the Childs grade (see Table 12.10). Childs C patients would not be offered surgery, and the risks in Childs A are still significant. Numerous methods of ablating liver tumours when surgery is not appropriate have been developed, including ethanol injection, cryotherapy, radio-frequency ablation, microwave, and electrolysis. Chemotherapy is only of value if given transarterially, and combined with emboli-sation of the feeding artery (chemo-embolisation).