Illusions in advanced cancer: The effect of belief systems and attitudes on quality of life

Patients with advanced cancer frequently express positive attitudes and can be unduly optimistic about the potential benefits of treatment. In order to evaluate an illusory domain in the context of advanced cancer, we developed a scale of will to live and characterized the beliefs that patients held about the curability of their cancer, and how committed they were to using alternative treatments. A measure of quality of life was used as the dependent variable in order to assess the association between these attributes. After a preliminary exploration confirmed the presence of an illusory domain, these concepts were prospectively tested in 149 ambulant patients with advanced cancer who attended for palliative systemic treatment, radiation treatment or supportive care. The scale of global quality of life was reliable (Cronbach's alpha coefficient 0.72). The distribution of the scores of will to live was skewed, with no respondent scoring poorly, and the scale was reliable (Cronbach's alpha coefficient 0.82). The scale of belief in curability showed diverse beliefs. In some cases, there was a discrepancy between respondents' beliefs in curability and what they believed to be the report by their doctors. There was also an association between a committed use of alternative treatments and a belief in the curability of the cancer (p

Antiproliferative and phenotype-transforming antitumor agents derived from cysteine

Selective destruction of malignant tumor cells without damaging normal cells is an important goal for cancer chemotherapy in the 21st century. Differentiating agents that transform cancer cells to either a nonproliferating or normal phenotype could potentially be tissue-specific and avoid side effects of current drugs. However, most compounds that are presently known to differentiate cancer cells are histone deacetylase inhibitors that are of low potency or suffer from low bioavailability, rapid metabolism, reversible differentiation, and nonselectivity for cancer cells over normal cells. Here we describe 36 nonpeptidic compounds derived from a simple cysteine scaffold, fused at the C-terminus to benzylamine, at the N-terminus to a small library of carboxylic acids, and at the S-terminus to 4-butanoyl hydroxamate. Six compounds were cytotoxic at nanomolar concentrations against a particularly aggressive human melanoma cell line (MM96L), four compounds showed selectivities of greater than or equal to5:1 for human melanoma over normal human cells (NFF), and four of the most potent compounds were further tested and found to be cytotoxic for six other human cancer cell lines (melanomas SK-MEL-28, DO4; prostate DU145; breast MCF-7; ovarian JAM, CI80-13S). The most active compounds typically caused hyperacetylation of histones, induced p21 expression, and reverted phenotype of surviving tumor cells to a normal morphology. Only one compound was given orally at 5 mg/kg to healthy rats to look for bioavailaiblity, and it showed reasonably high levels in plasma (C-max 6 mug/mL, T-max 15 min) for at least 4 h. Results are sufficiently promising to support further work on refining this and related classes of compounds to an orally active, more tumor-selective, antitumor drug.

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy

Background: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. Methods: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. Results: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. Conclusion: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

Novel renoprotective actions of erythropoietin: New uses for an old hormone

Erythropoietin (EPO) has been used widely for the treatment of anaemia associated with chronic kidney disease and cancer chemotherapy for nearly 20 years. More recently, EPO has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of cytoprotective cellular responses, including mitogenesis, angiogenesis, inhibition of apoptosis and promotion of vascular repair through mobilization of endothelial progenitor cells from the bone marrow. Administration of EPO or its analogue, darbepoetin, promotes impressive renoprotection in experimental ischaemic and toxic acute renal failure, as evidenced by suppressed tubular epithelial apoptosis, enhanced tubular epithelial proliferation and hastened functional recovery. This effect is still apparent when administration is delayed up to 6 h after the onset of injury and can be dissociated from its haematological effects. Based on these highly encouraging results, at least one large randomized controlled trial of EPO therapy in ischaemic acute renal failure is currently underway. Preliminary experimental and clinical evidence also indicates that EPO may be renoprotective in chronic kidney disease. The purpose of the present article is to review the renoprotective benefits of different protocols of EPO therapy in the settings of acute and chronic kidney failure and the potential mechanisms underpinning these renoprotective actions. Gaining further insight into the pleiotropic actions of EPO will hopefully eventuate in much-needed, novel therapeutic strategies for patients with kidney disease.

Randomized controlled trial of an educational intervention for managing fatigue in women receiving adjuvant chemotherapy for early-stage breast cancer

Purpose To evaluate the efficacy of a psychoeducational intervention in improving cancer-related fatigue. Patients and Methods This randomized controlled trial involved 109 women commencing adjuvant chemotherapy for stage I or II breast cancer in five chemotherapy treatment centers. Intervention group patients received an individualized fatigue education and support program delivered in the clinic and by phone over three 10- to 20-minute sessions 1 week apart. Instruments included a numeric rating scale assessing confidence with managing fatigue; 11-point numeric rating scales measuring fatigue at worst, average, and best; the Functional Assessment of Cancer Therapy-Fatigue and Piper Fatigue Scales; the Cancer Self-Efficacy Scale; the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; and the Hospital Anxiety and Depression Scale. For each outcome, separate analyses of covariance of change scores between baseline (T1) and the three follow-up time points (T2, T3, and T4) were conducted, controlling for the variable's corresponding baseline value. Results Compared with the intervention group, mean difference scores between the baseline (T1) and immediate after the test (T2) assessments increased significantly more for the control group for worst and average fatigue, Functional Assessment of Cancer Therapy-Fatigue, and Piper fatigue severity and interference measures. These differences were not observed between baseline and T3 and T4 assessments. No significant differences were identified for any pre- or post-test change scores for confidence with managing fatigue, cancer self-efficacy, anxiety, depression, or quality of life. Conclusion Preparatory education and support has the potential to assist women to cope with cancer-related fatigue in the short term. However, further research is needed to identify ways to improve the potency and sustainability of psychoeducational interventions for managing cancer-related fatigue.

SCOTROC 2A: Carboplatin followed by docetaxel or docetaxel gemcitabine as first-line chemotherapy for ovarian cancer

The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P = 0.102, P = 0.056, P = 0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% Cl: 10.5 - 20.6); arm B 18.1 months (95% Cl: 15.9 - 20.3); arm C, 13.7 months (95% Cl: 12.8 - 14.6). Neutropenia was the predominant grade 3 - 4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P = 0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approx5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11–12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21–q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3–q4 and 18p11.31 and gains of 6p25.1–p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2–11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

Improving the physical status and quality of life of women treated for breast cancer: A pilot study of a structured exercise intervention

Background and Objectives: This pilot project assessed the acceptability of a mixed-type, moderate-intensity exercise programme following breast cancer treatment, and the impact on presence of lymphoedema, fitness, body composition, fatigue, mood and quality of life. Methods: Ten women completed the programme and measures of fitness (submaximal ergometer test), body composition (bio-electrical impedance), lympoedema (bio-electrical impedance and arm circumferences), fatigue (revised Piper Fatigue Scale), mood (Hospital Anxiety and Depression Scale), quality of life (FACT-B) and general well-being, at baseline, completion of the programme, and 6-week and 3-month follow-up. Results: Participation in the programme caused no adverse effect on the presence of lymphoedema. There was a trend towards reduction in fatigue and improved quality of life across the testing phases. Women rated the programme extremely favourably, citing benefits of the support of other women, trained guidance, and the opportunity to experience different types of exercise. Conclusions: A mixed-type, moderate-intensity exercise program in a group format is acceptable to women following breast cancer treatment, with the potential to reduce fatigue and improve quality of life, without exacerbating or precipitating lymphoedema. This pilot work needs to be confirmed in larger randomised studies. (C) 2004 Wiley-Liss, Inc.

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

Background Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. Methods 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. Findings Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.101 and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. Interpretation Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamouscell tumours.

The impact of rehabilitation support services on health-related quality of life for women with breast cancer

As the number of women surviving breast cancer increases, with implications for the health system, research into the physical and psychosocial sequelae of the cancer and its treatment is a priority. This research estimated self-reported health-related quality of life (HRQoL) associated with two rehabilitation interventions for breast cancer survivors, compared to a non-intervention group. Women were selected if they received an early home-based physiotherapy intervention (DAART, n = 36) or a group-based exercise and psychosocial intervention (STRETCH, n = 31). Questionnaires on HRQoL, using the Functional Assessment of Cancer Therapy - Breast Cancer plus Arm Morbidity module, were administered at pre-, post-intervention, 6- and 12-months post-diagnosis. Data on a non-intervention group (n = 208) were available 6- and 12-months post-diagnosis. Comparing pre/post-intervention measures, benefits were evident for functional well-being, including reductions in arm morbidity and upper-body disability for participants completing the DAART service at one-to-two months following diagnosis. In contrast, minimal changes were observed between pre/post-intervention measures for the STRETCH group at approximately 4-months post-diagnosis. Overall, mean HRQoL scores (adjusted for age, chemotherapy, hormone therapy, high blood pressure and occupation type) improved gradually across all groups from 6- to 12-months post-diagnosis, and no prominent differences were found. However, this obscured declining HRQoL scores for 20-40% of women at 12 months post-diagnosis, despite receiving supportive care services. Greater awareness and screening for adjustment problems among breast cancer survivors is required throughout the disease trajectory. Early physiotherapy after surgery has the potential for short-term functional, physical and overall HRQoL benefits.

RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin

Targeted inhibition of oncogenes in tumor cells is a rational approach toward the development of cancer therapies based on RNA interference (RNAi). Tumors caused by human papillomavirus (HPV) infection are an ideal model system for RNAi-based cancer therapies because the oncogenes that cause cervical cancer, E6 and E7, are expressed only in cancerous cells. We investigated whether targeting HPV E6 and E7 oncogenes yields cancer cells more sensitive to chemotherapy by cisplatin, the chemotherapeutic agent currently used for the treatment of advanced cervical cancer. We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway. The loss of E6 and E7 resulted in a reduction in cellular viability concurrent with the induction of cellular senescence. Interference was specific in that no effect on HPV-negative cells was observed. We demonstrate that RNAi against E6 and E7 oncogenes enhances the chemotherapeutic effect of cisplatin in HeLa cells. The IC50 for HeLa cells treated with cisplatin was 9.4 mu M, but after the addition of a lentivirus-delivered shRNA against E6, the IC50 was reduced almost 4-fold to 2.4 mu M. We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone. Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels.

Which drug combination for hormone-refractory prostate cancer

Patients with metastatic hormone-refractory prostate cancer have a progressive disease with a median survival of similar to 11 months, and currently no treatment offers a survival advantage. The standard drug treatment is a corticosteroid and chemotherapy with mitoxantrone. In a comparison of docetaxel every 3 weeks and prednisone, versus mitoxantrone and prednisone, with a follow-up of similar to 21 months, there were less deaths in the docetaxel group than in the mitoxantrone group (166 of 335 patients and 201 of 337 patients, respectively). Docetaxel also prolonged the duration of survival compared with mitoxantrone (18.9 and 16.5 months, respectively). When given with prednisone, docetaxel was also shown to reduce pain and serum prostate specific antigen levels and improve quality of life compared with mitoxantrone/prednisone. In another trial in hormone-resistant prostate cancer patients, which compared docetaxel and estramustine with mitoxantrone and prednisone during a median follow-up of 32 months, there were fewer deaths with docetaxel/estramustine than with mitoxantrone/prednisone, which were 217 of 338 and 235 of 336 patients, respectively. Median survival was also longer in the docetaxel and estramustine group than in the mitoxantrone/prednisone group (17.5 and 15.6 months, respectively). In conclusion, two combinations (docetaxel/prednisone and docetaxel/estramustine) have been shown to be superior to mitoxantrone/prednisone in hormone-refractory prostate cancer and both should be considered for use. With the present information, there is little to distinguish between these combinations.