Is there an association between PONV and chemotherapy-induced nausea and vomiting?

BACKGROUND: Drug-induced nausea and vomiting, both post-operatively and following chemotherapy, is often distressing for the patients. Our clinical impression is that certain patients are not prone to but instead protected against both post-operative and chemotherapy-induced nausea and vomiting (CINV). If support for this hypothesis could be generated, it might be easier to identify such patients as low-risk patients and judge all other patients as high-risk patients by default. METHODS: All patients scheduled for breast cancer surgery at Danderyd Hospital, Stockholm, Sweden during 1 year (March 2003-March 2004) were asked to participate in this prospective, observational study. A number of women went on to receive adjuvant chemotherapy. Post-operatively, patients were assessed for 24 h with regard to the occurrence of post-operative nausea and vomiting (PONV). CINV was assessed for 5 days after start of chemotherapy. RESULTS: A total of 275 women were included, 33% were classified as PONV and 67% as non-PONV. Sixty-one of the 275 women included were later subjected to adjuvant chemotherapy. In the non-PONV group, 95% of the patients did not experience CINV, whereas the association between PONV and subsequent CINV was only 38%. CONCLUSIONS: A substantially stronger interrelationship was found between non-PONV and non-CINV than between both PONV and CINV. This may suggest that certain patients, instead of being prone to nausea and vomiting, in fact in some way are protected against these unpleasant side effects.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial.

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(®)) and paclitaxel (Taxol(®)) alone (ET) or in combination with capecitabine (Xeloda(®), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Prevention of tumour cell dissemination in diagnostic needle procedures.

BACKGROUND: A side effect of diagnostic needle biopsies is the possibility to disseminate tumour cells into the needle track, which may cause concern in certain malignant tumour types. METHODS: In order to prevent tumour cell dissemination we developed a technology that uses radiofrequency (RF) pulses to sterilise the needle track and denaturate tumour cells. To determine feasibility, we applied this technology to fine needle aspiration biopsy (FNAB) and used breast cancer as a model tumour. Routine FNAB was performed in 88 patients with adenocarcinoma and blood droplets passing the skin orifice were cytomorphologically analysed for the presence of tumour cells. RESULTS: The analysis showed the presence of tumour cells in 65/88 cases (74%). When using an experimental anti-seeding device in a subset of patients viable tumour cells were found in 0/31 cases (P<0.001). In all 31 patients blood passing the skin orifice was sparse. No degrading effect on the cytological sample inside the needle was detected and pain caused by the RF pulses was comparable to that of the biopsy procedure itself. CONCLUSION: The herein presented method has the potential to prevent the dissemination of viable tumour cells in the needle track and minimize bleeding without additional pain or degradation of the aspirate.

Deletions on chromosome 16 in primary familial breast carcinomas are associated with development of distant metastases.

Genetic alterations that occur in human breast cancers are believed to be of importance for initiation as well as progression of the disease. In order to find a genetic alteration that may be used as a prognostic marker, 82 familial breast carcinomas were analyzed for loss of constitutional heterozygosity at polymorphic loci on all chromosomes. Frequently occurring allele losses were compared to estrogen receptor expression, lymph node metastases, tumor size at the time of operation, and distant metastases at the time of follow-up 2-15 years later. Loss of heterozygosity (LOH) on the long arm of chromosome 16 in the tumor at the time of operation was significantly correlated (P < 0.001) with the occurrence of distant metastases 1-13 years after the operation. In addition, LOH at 16q was not correlated with estrogen receptor status, lymph node positivity, or tumor size, nor was the occurrence of distant metastases correlated with any of these parameters. The results suggest the existence of a tumor suppressor gene on 16q that facilitates hematogenic spread of breast cancer and that LOH at this locus is an independent prognostic marker in breast cancer.

Loss of heterozygosity in familial breast carcinomas.

Three loci have been implicated in the etiology of familial breast cancer; the BRCA1 locus on 17q, the p53 gene on 17p, and the androgen receptor gene on the X chromosome. However, it has been estimated that in approximately 50% of all breast cancer families the predisposing genetic defect is not linked to any of these three loci. In an attempt to identify chromosomal regions harboring putative breast cancer genes we performed allelotyping in 82 familial breast carcinomas. Polymorphic markers representing 45 different loci were analyzed and the most frequently involved chromosomal arms were 8p, 16q, 17p, 17q, and 19p.

Structure-function relationships of glutamine synthetases.

As a highly regulated enzyme at the core of nitrogen metabolism, glutamine synthetase has been studied intensively. We review structural and functional studies of both bacterial and eukaryotic glutamine synthetases, with emphasis on enzymatic inhibitors.

Adequate locoregional treatment for early breast cancer may prevent secondary dissemination.

PURPOSE: To analyze different events that determine event-free survival (EFS) in a randomized trial on adjuvant radiotherapy in early breast cancer patients with more than 15 years of follow-up evaluation. PATIENTS AND METHODS: The trial included 960 patients with a unilateral, operable breast cancer. Surgery consisted of a modified radical mastectomy. The trial compared three arms, as follows: preoperative radiotherapy, postoperative radiotherapy, and no adjuvant treatment. Events were analyzed by a competing-risk approach. A proportional hazards multiple regression model was used to analyze the effects of radiotherapy on the risk of distant metastasis. Similar analyses were performed separately for node-negative [N(-)] and node-positive [N(+)] patients in the two groups that did not include preoperative radiotherapy. RESULTS: Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001). In N(+) patients, postoperative radiotherapy decreased the risk of distant dissemination (relative risk, 0.63). When local recurrence was introduced in the model as a time-dependent covariate, this factor was predictive of distant dissemination (P < .0001) and nullified the effect of postoperative radiotherapy. This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence. A similar effect was found in models that used overall survival as an end point. CONCLUSION: This study shows that postmastectomy radiotherapy in N(+) breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination.

Individuals with an increased risk of colorectal cancer: perceived benefits and psychological aspects of surveillance by means of regular colonoscopies.

PURPOSE: To evaluate the psychological consequences of genetic counseling followed by a surveillance program using colonoscopy among individuals with increased risk of colorectal cancer. PATIENTS AND METHODS: Two hundred sixty-five individuals, participating in a surveillance program with colonoscopy, were mailed a survey questionnaire that assessed their experience of the surveillance program and their perception of the risk of colorectal cancer. The Hospital Anxiety and Depression scale and the Swedish Short Form-36 Health Survey was also included. RESULTS: Two hundred forty individuals completed the questionnaire and were divided into the following risk groups: risk group 1, an individual with a mutation in hMLH1 or hMSH2 and a lifetime colorectal cancer risk of 80% (n = 28); risk group 2, a lifetime colorectal cancer risk of 40% (n = 129); and risk group 3, a lifetime colorectal cancer risk of 20% (n = 83). Among all individuals, the mean for perceived benefit was 8.0, and the perception of discomfort was 3.3 on the visual analog scale (1-10). In risk group 1, 61% underestimated personal risks as being 40% or less. Approximately 50% of the subjects in risk groups 2 and 3 either under- or overestimated their lifetime risk. According to the Swedish Short Form-36 Health Survey and the Hospital Anxiety and Depression scale, the study sample resembled the reference population. CONCLUSION: A majority of the study sample understood why they were under surveillance, and regular colonoscopies were well-tolerated. The wide range of risk perception as well as low-risk perception in mutation positive subjects is acceptable, as long as these individuals adhere to surveillance programs and do not demonstrate increased levels of anxiety or depression.

The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer.

The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.

Post-mastectomy megavoltage radiotherapy: the Oslo and Stockholm trials.

The ability of adjuvant radiotherapy to prevent distant metastasis and to prolong survival in patients with early breast cancer is much debated. The paper presents a joint analysis of long-term results (13-16 years' follow-up) from the Oslo and Stockholm randomised trials of post-operative megavoltage radiotherapy versus surgery alone. Among node-positive patients there was a significant 37% relative reduction of distant metastases with radiation (P less than 0.01) and an overall survival difference in favor of the irradiated patients which corresponded with a 22% relative reduction of deaths of borderline significance (P less than 0.06). No significant benefit with radiation in terms of distant metastasis-free survival or overall survival was observed among node-negative patients. The results show that effective local treatment can prevent distant dissemination in some patients and contradict the contention that node-positive breast cancer invariably is a systemic disease already at primary diagnosis.

Intravenous clodronate for the treatment of hypercalcaemia in breast cancer patients with bone metastases--a prospective randomised placebo-controlled multicentre study.

In a double blind randomised multicentre study the effect of intravenous clodronate plus hydration was compared with placebo plus hydration in the treatment of hypercalcaemia in breast cancer patients with bone metastases. The patients were treated either with hydration plus clodronate 300 mg/day or hydration plus placebo, up to 7 days or until serum ionised calcium was below 1.4 mmol/l. 25 patients received clodronate and 19 placebo. A significant difference in favour of clodronate was observed in the time to reach normocalcaemia (P = 0.004) and in the number of patients achieving normocalcaemia (P = 0.0003). 17 patients of 21 evaluable patients on clodronate achieved normocalcaemia compared with 4 of 19 patients on placebo. The only adverse event clearly associated with clodronate was symptomatic hypocalcaemia in 1 patient. Thus, clodronate seems to be a safe and highly efficacious drug for the treatment of hypercalcaemia in breast cancer patients.

Influence of radiation therapy on the lung-tissue in breast cancer patients: CT-assessed density changes and associated symptoms.

The relative electron density of lung tissue was measured from computer tomography (CT) slices in 33 breast cancer patients treated by various techniques of adjuvant radiotherapy. The measurements were made before radiotherapy, 3 months and 9 months after completion of radiation therapy. The changes in lung densities at 3 months and 9 months were compared to radiation induced radiological (CT) findings. In addition, subjective symptoms such as cough and dyspnoea were assessed before and after radiotherapy. It was observed that the mean of the relative electron density of lung tissue varied from 0.25 when the whole lung was considered to 0.17 when only the anterior lateral quarter of the lung was taken into account. In patients with positive radiological (CT) findings the mean lung density of the anterior lateral quarter increased 2.1 times 3 months after radiotherapy and was still increased 1.6 times 6 months later. For those patients without findings, in the CT pictures the corresponding values were 1.2 and 1.1, respectively. The standard deviation of the pixel values within the anterior lateral quarter of the lung increased 3.8 times and 3.2 times at 3 months and 9 months, respectively, in the former group, as opposed to 1.2 and 1.1 in the latter group. Thirteen patients had an increase in either cough or dyspnoea as observed 3 months after completion of radiotherapy. In eleven patients these symptoms persisted 6 months later. No significant correlation was found between radiological findings and subjective symptoms. However, when three different treatment techniques were compared among 29 patients the highest rate of radiological findings was observed in patients in which the largest lung volumes received the target dose. A tendency towards an increased rate of subjective symptoms was also found in this group.

Long term effects on the immune system following local radiation therapy for breast cancer. I. Cellular composition of the peripheral blood lymphocyte population.

Local radiation therapy for breast cancer depletes the blood of various subsets of lymphocytes. Previous studies showed that the recovery is still incomplete at 30 months. To further elucidate the recovery we examined blood lymphocyte counts of 138 disease-free women and various lymphocyte subsets in 102 of these patients. These patients, 5-6 and 10-11 years earlier, had entered a clinical trial in which preoperative irradiation (45 Gy) was evaluated against postoperative irradiation (45 Gy) or surgery only. Patients who had undergone surgery only served as controls. Total lymphocyte counts of the irradiated patients were still significantly reduced 10-11 years after treatment. This reduction was mainly attributable to a subnormal level of T-cells as determined by the monoclonal antibody Leu-1 and the ability to form rosettes with sheep erythrocytes, whereas the number of non-T cells, expressing C'3 receptors, did not differ significantly from the controls. Within the T-cell population a subset with helper/inducer phenotypes, detected by Leu-3a antibodies, was significantly reduced even 10-11 years after irradiation. T-cells with suppressor/cytotoxic phenotypes, stainable with Leu-2a antibodies, however, had already recovered 5-6 years after irradiation. The duration of the radiation induced reductions of different lymphocyte subsets may be related to the physiological turn-over of the cells or a changed distribution of cells in the body.

Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials.

The paper summarizes up-dated results of three randomized adjuvant trials from the Stockholm Breast Cancer Group. The objective of all studies included an evaluation of the role of megavoltage radiation in the primary management of patients with early breast cancer. The first trial was started in 1971 and included 960 pre- and postmenopausal patients with operable disease. The study compared adjuvant radiotherapy with surgery alone. All patients were treated with a modified radical mastectomy. There was a sustained improvement of the recurrence-free survival with radiotherapy (p less than 0.001). Among node positive cases radiation reduced the frequency of both loco-regional recurrence (p less than 0.001) and distant metastasis (p less than 0.01). This observation indicates that distant dissemination in subgroups of patients can originate from uncontrolled local deposits of tumor cells, for instance in the regional lymph nodes. No adverse effect from radiation on long-term survival was observed. The second study was started in 1976 and compared postmastectomy radiation with adjuvant chemotherapy in pre- and postmenopausal high-risk patients. At a mean follow-up of 6 1/2 years there was no significant difference in recurrence-free survival between the two treatments. However, postmenopausal patients fared better with radiotherapy (p less than 0.01). In this subgroup, radiation was more effective than adjuvant chemotherapy in reducing both distant metastases (p less than 0.01) and loco-regional recurrences (p less than 0.001). In the third trial--which only included postmenopausal patients--2 years of adjuvant tamoxifen was compared with no adjuvant endocrine treatment. The number of treatment failures was significantly reduced with tamoxifen (p less than 0.01) but there was no significant overall survival benefit. Subset analysis indicated that tamoxifen improved the recurrence-free survival among patients treated with adjuvant chemotherapy (p less than 0.01) but only to a level close to that achieved with radiotherapy alone. Addition of tamoxifen to radiotherapy failed to further increase the recurrence-free survival.

GroupBuild: a fragment-based method for de novo drug design.

A novel method for de novo drug design, GroupBuild, has been developed to suggest chemically reasonable structures which fill the active sites of enzymes. The proposed molecules provide good steric and electrostatic contact with the enzyme and exist in low-energy conformations. These structures are composed entirely of individual functional groups (also known as "building blocks" or "fragments") which the program chooses from a predefined library. User-selected enzyme seed atom(s) may be used to determine the area(s) in which structure generation begins. Alternatively, GroupBuild may begin with a predocked "inhibitor core" from which fragments are grown. For each new fragment generated by the program, several thousand candidates in a variety of locations and orientations are considered. Each of these candidates is scored based on a standard molecular mechanics potential function. The selected fragment and orientation are chosen from among the highest scoring cases. Tests of the method using HIV protease, FK506 binding protein, and human carbonic anhydrase demonstrate that structures similar to known potent inhibitors may be generated with GroupBuild.

Long-term effects on the immune system following local radiation therapy for breast cancer. 4. Proliferative responses and induction of suppressor activity of the blood lymphocyte population.

The long-term effect of local irradiation for breast cancer on the blood lymphocyte population was examined in 149 women who had been disease-free for 5-6 and 10-11 years. The patients were included in a clinical trial aiming at determining the value of pre- and post-operative irradiation (45 Gy) compared to surgery only. It was observed that the relative mitogen responses of lymphocytes to phytohaemagglutinin (PHA) and Concanavalin (Con A) and in a mixed lymphocyte culture (MLC) were significantly lower in irradiated compared to unirradiated patients at least a decade after treatment. The prolonged reductions of mitogen responses after irradiation could partly be due to an increased proportion of lymphocytes which may express suppressor function since the Con A-inducible suppressor activity of lymphocytes was significantly higher in irradiated compared to unirradiated patients.

Possible role of prostaglandin producing monocytes in the depression of mitogenic responses of blood lymphocytes following radiation therapy.

Previous studies have shown that the depression of mitogenic responses of cultured blood lymphocytes following radiation therapy can largely be explained by immunosuppressive cells. In this investigation we have shown that the addition of silica, a monocyte toxic agent, to the cultures enhance the PHA- and PPD-responses of the cells at completion of irradiation. Such an effect, however, was not noted before radiation treatment was started. Similar results were obtained by adding indomethacin, an inhibitor of prostaglandin synthesis, to the cultures. The results thus indicate that immunosuppressive monocytes which mediate their activity by prostaglandins are involved in the reductions of mitogen responses of blood lymphocytes following irradiation.

In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer.

Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation we have compared nine different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. Five of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150%. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation.

Blood lymphocyte subsets in operable breast-cancer - relation to extent of tumor disease and prognosis.

Previously we have reported that a high frequency of E-rosette forming cells (T-cells) in the blood of newly diagnosed breast cancer patients was associated with the development of distant metastases and a short survival. In the present investigation, comprising 204 untreated breast cancer patients, we showed that the proportion of the total T-cell population (CD2 and CD3 positive cells) and the proportion of helper/inducer T-cells (CD4 positive) was positively linked to spread of cancer cells to axillary nodes which in turn Was strongly correlated to prognosis. The latter subset also correlated significantly to time to development of distant metastases. Cox multivariate regression analysis showed that the frequency of these lymphocytes, independently of other variables, predicted prognosis. Our present as well as our previous results do not support the view that a high proportion of T-cells in the blood forecast a good prognosis.