Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer.

Aromatase inhibitors (AIs) are well established in the treatment of metastatic hormone-sensitive breast cancer in postmenopausal women. Cyclooxygenase (COX)-2 inhibitors have demonstrated efficacy in reducing cancer risk in animal and human studies. In several preclinical studies, combination AI plus COX-2 inhibitor therapy has shown a synergistic antitumor effect. This review describes the utility of AI plus COX-2 inhibitor therapy and discusses the completed and ongoing clinical trials investigating treatment with the AI exemestane and the COX-2 inhibitor celecoxib in the neo-adjuvant and metastatic breast cancer settings. In general, combination therapy had comparable or better efficacy compared with AI monotherapy using the end points of progression-free survival, overall response rate, clinical benefit rate, time to progression, and duration of clinical benefit. All therapies were well tolerated. There appeared to be a beneficial impact on serum lipid levels for patients receiving combination therapy in a neo-adjuvant trial despite the known cardiovascular toxicity risk associated with COX-2 inhibitors. In conclusion, AIs plus COX-2 inhibitors have shown promising efficacy and safety for the treatment of patients with metastatic breast cancer. Careful monitoring during future trials will be necessary to accurately assess the risk-benefit ratio of combination therapy.

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study.

The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60-100 mg m(-2) on day 1) plus bortezomib (1.0-1.5 mg m(-2) on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n=1) and febrile neutropenia (n=4). The MTD was bortezomib 1.5 mg m(-2) plus docetaxel 75 mg m(-2). All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents.

A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer.

BACKGROUND: This was a feasibility study of the combination of Exemestane and the cyclooxygenase-2 (COX-2) inhibitor Celecoxib in advanced breast cancer. PATIENTS AND METHODS: Post-menopausal women with histologically proven, hormone receptor positive, advanced breast cancer who had progressive disease, normal blood counts, liver and renal function were eligible. Exemestane was given at a dose of 25 mg daily and Celecoxib at a dose of 400 mg bd. Responses were assessed according to RECIST criteria and toxicity was accessed according to CTC. The primary end-point was the percentage of patients who had neither discontinued therapy nor progressed at 6 months ('treatment successes'). RESULTS: Fifty-three eligible patients were enrolled. Of 30 patients with target lesions, 4 (13%) had a complete response (CR), 12 (40%) a partial response (PR) and 5 (17%) stable disease (SD). The best response in 18 of the 23 patients with no target lesions at baseline was stable disease. The clinical benefit (CR, PR+SD) for the whole group was therefore 39/53 (74%). The 'treatment success' rate was 60%. There were two non-malignant deaths which may have been associated with treatment. CONCLUSION: The combination of Exemestane and Celecoxib shows promising activity and tolerability and these results support the use of this combination in phase III clinical trials of short duration treatments.

Acute supraclavicular skin toxicity in patients undergoing radiotherapy for breast cancer: an evaluation of the 'T'-grip method of patient positioning.

AIMS: Supraclavicular fossa (SCF) radiotherapy plays an important part in the adjuvant management of breast cancer but data on acute radiotherapy toxicity are lacking, particularly when differing patient treatment positions are used to allow computed tomography planning or to reduce cardiac doses. MATERIALS AND METHODS: We evaluated SCF and breast/chest wall acute skin toxicity in a cohort of 92 women with breast cancer, who were planned in a 'T'-grip (n = 72) or 90 degrees-grip (n = 20) position, while 'on treatment' and at 6 weeks. The modified Radiation Therapy Oncology Group (RTOG) criteria were used to score toxicity. Data on age, body mass index, smoking history, type of breast operation, prior chemotherapy, radiation dose, number of fields and field size were recorded and correlated with outcome. RESULTS: Maximum SCF reaction score was RTOG 2a, with no moist desquamation observed. SCF reactions were less severe compared with chest wall reactions and no worse than breast reactions. There was significant resolution of toxicity at 6 weeks. SCF radiotherapy in 'T'-grip patients was well tolerated and no worse than the 90 degees-grip group. Pain scores and sore throat occurrences were minimal. Univariate and multivariate analyses showed that smoking was associated with worsening SCF toxicity (odds ratio [OR] 2.92; P = 0.045) and delayed healing. Incremental SCF dose worsened toxicity (OR 3.65; P = 0.023). Smoking worsened breast but not chest wall toxicity. CONCLUSIONS: SCF radiotherapy was at least as well tolerated as breast radiotherapy and better tolerated than chest wall radiotherapy. The 'T'-grip position did not affect toxicity negatively. Smoking and radiation dose affected SCF toxicity.

Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma.

A total of 218 postmenopausal patients were entered in a prospective randomized trial comparing aminoglutethimide (AG) and high-dose medroxyprogesterone acetate (MPA) as second-line hormonal therapy for advanced breast carcinoma. All responses were assessed by the criteria of the International Union Against Cancer. The response rates were 27% (29 of 106 patients) for AG and 31% (35 of 112) for MPA, but if stabilization of previously progressive disease is included, then the overall response rates were 51% (54 of 106) and 54% (61 of 112) for patients receiving AG or MPA, respectively. There was no difference in response to the two drugs at any site of disease, and the durations of response and survival were identical for the two drugs. The time to response was significantly shorter for patients treated with MPA (median, 8.7 wk) than for those treated with AG (median, 15.3 wk) (chi 2 = 9.96, 1 df, P = .0016). The percentage of patients experiencing toxic effects was equivalent in both arms, although the patterns and time courses of these effects were different.

A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer.

Menopausal symptoms are a major survivorship issue for patients treated for breast cancer. There are increasing concerns over the use of hormone replacement therapy (HRT) in this setting and a growing consumer interest in "natural" therapies. It had been suggested that soy phyto-oestrogens might be beneficial in the treatment of menopausal symptoms. Seventy-two patients with a histologically confirmed pre-existing diagnosis of breast cancer who were having menopausal symptoms were randomised between 12 weeks of treatment with soy capsules or placebo. Quality of life and menopausal symptom scores were assessed at baseline, 4, 8 and 12 weeks. There was no statistical difference in menopausal symptom scores or quality of life between the two arms of the study.

A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.

Derivation and application of equations describing the effects of fractionated protracted irradiation, based on multiple and incomplete repair processes. Part I. Derivation of equations.

A general model is developed where the induction and interaction rates of sublethal radiation damage with subsequent irradiation are represented as polynomial functions of the dose-rate. The effect of incomplete multiple repair processes is also included. Equations are evaluated for fractionated protracted irradiation where the dose-rate is constant during each fraction. However, both the dose-rate and the fractional dose are permitted to change from fraction to fraction. The resultant equations show that the apparent alpha/beta ratio derived from the analysis of equivalent protocols may be protocol dependent. Also, the alpha/beta ratio calculated from experimental data, assuming a single repair half-life, will appear to be protocol dependent if in reality more than one repair process is involved in the repair of sublethal damage. It is possible that the effects due to the induction of sublethal damage or its subsequent interaction may be distinguished by designing experiments in which the dose-rate is not constant throughout the whole protocol; also that the underlying processes governing the conversion of sublethal damage may be analysed by fitting experimental data to the equations.

Derivation and application of equations describing the effects of fractionated protracted irradiation, based on multiple and incomplete repair processes. Part 2. Analysis of mouse lung data.

General equations for fractionated protracted irradiation have been applied to the analysis of mouse lung data derived from isoeffect protocols. The data were accrued from a spectrum of different protocols including different radiation qualities, interfraction times and dose-rates. This analysis, based upon two component repair rate processes, suggests that there are possibly two repair-rate processes involved in the repair of sublethal damage in the lung. The two repair half-lives were 0.32 and 1.92 h with a low dose-rate partitioning of 1:0.38 between the amount of lethal damage resulting from rapid and slow sublethal damage repair processes at low dose-rates. The analysis also indicates that there may be a dose-rate amplification of the amount of resultant lethal damage, deriving from sublethal damage, associated with the longer repair process. It is also shown that the alpha/beta ratio is probably independent of the radiation quality and that the ratios of multiple to single event damage for 240kVp X-rays and 60Co are almost identical. However, the absolute values of alpha and beta for 240 kVp X-rays may be greater than for 60Co.

Two components of repair in irradiated kidney colony forming cells.

Data describing the response of mouse kidney colony-forming cells to fractionated X-irradiation using different interfraction intervals were analysed in order to detect the presence of one or more components of repair. A two-component repair model gave a superior fit, with reference to a single-repair rate model, giving distinct repair halftimes of 0.15 (approximate 95% confidence limits: 0.0, 0.40) and 5.03 (1.23, 8.84) h. These values are the first reported for normal cells in vivo, and they are similar to values calculated for tissue responses in skin, lung and the spinal cord. The slow component of repair is important in radiotherapy, in particular regarding novel hyperfractionation regimens when interfraction intervals much less than 1 day are employed.

Repair kinetics in pig epidermis: an analysis based on two separate rates of repair.

Pig skin was irradiated using 90Sr/90Y plaques and the dose-related incidence of induced moist desquamation was determined. The repair of radiation-induced sublethal damage (SLD) was studied by fitting these response data to the generalized LQ equation for incomplete repair using quasilikelihood methods with binomial statistics, and either a Poisson or logistic link to relate the probability of response to the covariates. A Poisson response analysis based on the assumption that SLD was governed by two repair processes gave estimated repair half-times of 0.20 [(95% confidence limits) 0.12, 0.34] and 6.6 [4.3, 10.0] h. The estimates of the short and long repair half-times were significantly different, although there was no significant difference between the results using the Poisson and logistic modes of analyses. The partition coefficient for the longer repair process was 0.5 [0.34, 0.71] indicating that about 33% of SLD-derived lethal damage is associated with the longer repair process in the case of 'complete repair' protocols. However, this proportionation is, in general, protocol dependent for incomplete repair protocols. A chi2 test on the residual deviance showed that the assumption of two repair processes for SLD gave a superior fit to the data than a single repair process at a significance level >99%. The radiation dose to the assumed target cell population depends upon their depth from the skin surface, due to the relatively short range of the electron emission from the 90Sr/90Y plaques. However, further modelling analyses have shown that the estimated repair half-times were independent of the assumed target cell distribution in the skin. This is in contrast with the alpha/beta ratio, where different (clinically significant) estimates can be obtained depending upon the assumed target cell distribution. If the target cells were at 16 micrometer depth from the surface of the skin, the estimated value for the alpha/beta ratio using the biphasic repair model would be 4.6[3.6, 5.6] Gy(Poisson analysis). However, the estimates decrease with the assumed depth (distribution) of the target cells.

Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy?

Transforming growth factor beta (TGF-beta) is a peptide which has a fundamental role in controlling proliferation of many cell types. Its main effect upon connective tissues in vivo is to stimulate growth. It can result in endothelial cell proliferation but tends to inhibit epithelial cell growth. Damage to the connective tissues and the vasculature are the principal findings in late radiotherapy damage. Following the initial cellular depletion after radiotherapy, an abnormal proliferation of these tissues occurs, which does not respond to normal feedback mechanisms. Immunocytochemical staining for TGF-beta has been performed upon six patients who had received pre-operative radiotherapy and three patients who had surgery alone for large bowel tumours. Transforming growth factor beta was found in relation to the pathological changes of late radiation damage in the non-tumour-bearing tissues of four out of six previously irradiated patients, but in none of the non-irradiated patients. This paper proposes that TGF-beta activity may modulate late post-radiation changes.

Biphasic cellular repair and implications for multiple field radiotherapy treatments.

Data describing the response of several normal tissues to fractionated irradiation, in terms of a biphasic repair of sub-lethal damage, have now been published. Typical results of such analyses have been taken and applied to a conventional radiotherapy protocol of 60 Gy in 30 daily fractions. The effect of using a four field treatment plan is shown to reduce the biological effect of the radiation schedule by increments dependent upon the time interval between each field in a treatment fraction, with a 10% reduction in the extrapolated dose response (ERD) resulting from a 5 min interfield interval. When applied to tissues having the same repair characteristics as pig skin this reduction in ERD is predicted to result in an approximately 25% reduction in the probability of acute morbidity from a protocol of 60 Gy in 30 fractions. These results imply that the basic LQ model, which is unable to correct for interfield intervals, overestimates the effect on normal tissues of radical clinical protocols, most of which use more than a single field. Increasing the interfield interval could be used to reduce the normal tissue side effects from radical radiotherapy when multiple fields are used.

Variation in the probability of cardiac complications with radiation technique in early breast cancer.

Cardiac damage is recognized to be a potentially serious side effect of breast cancer radiotherapy, the risk of which may be reduced by the choice of appropriate radiotherapy technique. We have previously described variation in physical dose to the heart dependent upon radiotherapy technique. In this paper we report the calculated improvement in normal tissue complication probability (NTCP) (for cardiac damage) achievable by these methods. Cardiac doses were calculated from dose-volume histograms (DVHs) using a "Helax" planning system for 11 patients with left-sided tumours and 5 patients with right-sided tumours. The DVH reduction algorithm of Lyman and Wolbarst [1989] was applied to each DVH to produce a value for the NTCP. For left-sided tumours, mean NTCP with the standard technique was 7.4 +/- 5.6% (range 0.6-17%) and for the optimum technique mean NTCP was 0.3 +/- 0.6% (range 0-2%) (p < 0.003 for the difference between the two techniques): a predicted reduction in late cardiac complications of 23-fold, which is not clearly evident from viewing the DVH raw data.

The influence of the number of fractions and bi-exponential repair kinetics on biological equivalence in pulsed brachytherapy.

A linear-quadratic radiobiological model incorporating single or bi-exponential repair kinetics has been used to show the following and other features when a continuous low dose rate (CLDR) 70 Gy/140 h brachytherapy protocol is replaced by a radiobiologically equivalent pulsed dose rate (PDR) system using 140 fractions for reasons of dosage homogeneity. (1) For equivalent effects in late-reacting tissues, the PDR dose (at 5 or 0.05 Gy min-1) x 1 h intervals needs to be reduced by up to only 3%. Progressively further reductions in dose are required when fewer larger fractions are used. (2) When equivalence using pulsed doses is achieved for one normal tissue type, and extrapolated response doses (ERD) are calculated for other tissue types in the irradiated volume, values of the ERD remain within 5% of each other using the above PDR protocol and associated parameters. (3) For tumours with alpha/beta = 10 Gy and a single repair halftime of 0.1-1.0 h, there is no significant loss of therapeutic benefit using the PDR protocol equivalenced for late normal tissue reactions. The strategy of replacing an LDR boost protocol of about 24 Gy by a PDR protocol gives similar levels to the 70 Gy PDR protocol for the expected percentage increase in the biological dose to normal tissues (due to the PDR protocol alone). These calculations also highlight the importance of the values assumed for the conventional alpha/beta ratio and the repair kinetics when estimating equivalent PDR protocols. The use of an inappropriate radiobiological parameterization will lead to erroneous conclusions with the potential to advocate PDR protocols which will, in practice, lead to an increase in late complications.

Reducing cardiac dose in post-operative irradiation of breast cancer patients: the relative importance of patient positioning and CT scan planning.

Left-sided post-operative radiotherapy fields for the treatment of breast cancer inevitably encompass the heart within the treatment volume, resulting in late mortality which may negate the cause-specific survival advantage of the therapy. The effect of positioning was studied in 11 patients with left-sided tumours and five with right-sided tumours receiving routine post-operative radiotherapy to the breast or chest wall as part of primary therapy for breast cancer. Using the same arrangement of glancing fields for each patient treatment position, the optimum patient positioning resulted in a reduction in cardiac dose compared to our standard patient treatment position. On the left side the reduction in mean cardiac dose was 60% (p < 0.001) and the reduction in maximum dose was 32% (p < 0.001); on the right it was 17% and 31%, respectively. The volume of cardiac tissue irradiated was also reduced for all patients. Using this optimum treatment position, cardiac dose was investigated in a further 10 patients with left-sided tumours and our standard glancing field set-up was compared with 3-dimensional planning. A further reduction of 12% in the mean cardiac dose was achieved. 5 of 10 patients had a further small reduction of 4.6% in the maximum dose and one patient had a further reduction in maximum dose of 58%. In conclusion, sophisticated radiotherapy planning can reduce cardiac doses, but optimum patient positioning is of greater importance. The general application of such relatively simple measures could have a significant positive effect on overall survival from breast cancer.

The prevalence of menopausal symptoms in patients treated for breast cancer.

A survey has been performed to discover the prevalence of menopausal symptoms in 108 patients successfully treated for breast cancer. Patients were assessed by them answering a custom designed questionnaire, and the use of the Hospital Anxiety and Depression (HAD) scale and the Greene Climacteric Scale. During the first year after treatment 70% of women suffered such symptoms; overall 60% of women surveyed were affected. Adjuvant hormonal treatment was the largest contributing factor in the development of symptoms. There was a relationship with borderline cases of anxiety, but not with definite cases of anxiety, as measured by the HAD scale. The high proportion of women shown to be affected means that treatment of menopausal symptoms should be incorporated into randomized trials of adjuvant therapy.

A randomized trial to assess the efficacy of 5-aminosalicylic acid for the prevention of radiation enteritis.

Sulphasalazine is an effective treatment for diarrhoea occurring during pelvic radiotherapy. We report the results of a trial to assess the value of its active moiety, 5-aminosalicylic acid, (5-ASA) in a prophylactic setting. Seventy-three patients planned for external beam radiotherapy to the pelvis were randomized on a double-blind basis to receive prophylactic 5-ASA or placebo. The severity of the acute radiation bowel reaction was documented by a weekly questionnaire. Surprisingly, diarrhoea occurred in a higher proportion of patients in the 5-ASA arm than the placebo arm (91.2% versus 73.7%, P = 0.070). The maximum change in both the severity of diarrhoea and the number of days per week on which diarrhoea occurred (from pre-radiotherapy level to the worst level at any time during treatment) were both significantly greater in patients taking 5-ASA than those taking placebo (P = 0.014 and P = 0.026, respectively). The average change (the sum of the weekly scores divided by the number of weeks of treatment, minus the pre-radiotherapy score) for both severity and days per week of diarrhoea were again greater in the 5-ASA than the placebo arm, but failed to reach statistical significance (P = 0.095 and P = 0.079, respectively). The use of anti-diarrhoeal medicines was significantly greater in the 5-ASA arm (P = 0.011). Constipation was more common in the placebo arm but this did not reach significance (P = 0.20). 5-ASA thus has no protective effect against acute radiation enteritis and appears to worsen it. Possible reasons for this surprising finding are discussed.

Carboplatin, 5-fluorouracil and folinic acid: a 48-hour chemotherapy regimen in advanced and recurrent squamous carcinoma of the head and neck.

Eighty patients with advanced squamous carcinoma of the head and neck were entered into a study using a 2-day, inpatient, intravenous regimen. Folinic acid 200 mg/m2, 5-fluorouracil (5-FU) 500 mg/ m2 bolus followed by 5-FU 500 mg/m2 in a 22-hour infusion were given on days 1 and 2, with carboplatin 300 mg/m2 on day 2. The whole was repeated every 21 days. Forty-three patients had advanced disease with no prior treatment; 37 had recurred following radical treatment. Fifty-eight patients were male and the median age was 60 years. In total, 275 cycles of chemotherapy were given. The major toxicity was haematological, which delayed 65 cycles of chemotherapy and contributed to the death of two patients. Non-haematological toxicity was mild, with less than 8% of patients experiencing any toxicity greater than WHO grade 2. The patients who had had no previous treatment had a 65% response rate (95% confidence interval (95% CI) 48-80). Those who had been previously treated had a 37% response rate (95% CI 21-55). The overall response rate was 52% (95% CI 40-64), of whom 5% were complete responders. The median survival time was 36 weeks (95% CI 29-45), with the majority of patients dying with progressive disease. We conclude that this chemotherapy regimen was well tolerated and produced minimal toxicity, while maintaining an acceptable response rate of 52%.