David Perez

The use of quality of life data in clinical practice

A large amount of quality of life (QoL) information has been and is being collected in the oncology setting but it is unclear how such data influence decisions about the management of individual patients. A questionnaire designed specifically for the study was mailed to 260 senior oncologists to investigate how QoL data are being used outside the context of cancer clinical trials; replies were received from 154 (59%). Approximately 80% believed QoL information should be collected prior to the commencement of treatment, but less than 50% actually did so. Similarly, less than 50% assessed QoL as a method of monitoring the responses to treatment even when the treatment goal was palliation. The barriers to collecting such data were time and resource constraints, perceived lack of an appropriate instrument and a belief that QoL assessments were unnecessary. Other than making a subjective assessment based on examination and history, 73 (47%) used either standardized questionnaires or a system derived in their unit to assess the QoL of their patients. Given an appropriate instrument the majority believed that QoL data could be collected on a routine basis. The main barriers to collecting QoL data are logistic and the challenge remains to develop a method of collecting and analysing QoL information in a manner which enhances decision making.

SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer

PURPOSE SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Epigenetic silencing in non-neoplastic epithelia identifies E-cadherin (CDH1) as a target for chemoprevention of lobular neoplasia.

Invasive lobular carcinoma (ILC) of the breast is believed to develop from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Down‐regulation of the cell–cell adhesion protein E‐cadherin is a defining feature of lobular breast cancer (LBC) and already occurs in ALH and LCIS. Apart from mutational mechanisms, epigenetic silencing of the E‐cadherin gene (CDH1) is thought to be involved in E‐cadherin down‐regulation and has been observed at a high frequency in ILC. Whether CDH1 promoter methylation is already present in in situ lesions and thus contributes to the initiation of LBC is not established. We thus examined microdissected archived tissue from 20 LBCs by methylation‐specific PCR to determine the CDH1 methylation status of lobular lesions. Nineteen of the 20 LBCs had a hypermethylated CDH1 promoter, including 13/14 ILCs and 13/13 ALHs or LCIS. Bisulphite sequencing indicated that methylation was complete within the investigated promoter fragment. Intriguingly, CDH1 methylation was likewise present in 8/8 adjacent non‐neoplastic epithelia, but not in 6/6 mammary epithelia from healthy subjects. E‐cadherin protein and mRNA were down‐regulated in in situ lesions relative to adjacent epithelia. Together, these results indicate that CDH1 promoter methylation occurs in LBC prior to E‐cadherin down‐regulation and neoplastic formation. We thus propose that epigenetic silencing represents the first of the two hits required to silence both CDH1 alleles for LBC to develop. Because promoter methylation is in principle reversible, our findings suggest that chemoprevention of LBC by epigenetic drugs should be feasible. Furthermore, the presence of CDH1 methylation in pre‐neoplastic epithelia suggests the existence of mammary regions with increased disease susceptibility, providing an explanation for the often multifocal presentation of LBC. Copyright

A longitudinal study of health related quality of life and utility measures in patients with advanced breast cancer

Health related quality of life (HRQOL) measures are now accepted as indicators of efficacy in the palliative treatment of cancer. Utility measures may also provide valuable information yet they have been applied less frequently. To assess the application of a time trade-off (TTO) utility measure and its concordance with the Spitzer uniscale and quality of life index (QLI) 38 women with advanced, symptomatic breast cancer were studied over a 12 month period. The correlation coefficient for QLI and TTO values was 0.54 and for uniscale and TTO 0.62. Using generalized estimating equations the regression of TTO scores on QLI and uniscale scores was significant at baseline. In longitudinal analyses results were significant only for QLI. Although all participants completed the HRQOL measures only 24 (63%) were prepared to trade time. The remaining 14 (32%) stated they felt too well to trade. Those prepared to trade time recorded significantly worse mean HRQOL scores throughout the study compared to those who felt too well to trade and had tumors which showed a poorer response to therapy. In this preliminary study utility and HRQOL scores were generally favorable throughout the 12 month study period and showed fair to moderate concordance. Further research in larger patient groups is required to better define the relationships between utility and HRQOL measures.

A comparison of time trade-off and quality of life measures in patients with advanced cancer

Quality of life (QOL) measures are now accepted as indicators of efficacy in the palliative treatment of cancer. Utility measures may also provide valuable information in this area yet they have rarely been applied. To assess the concordance of QOL and utility scales, 93 patients with advanced, symptomatic cancer completed two QOL instruments, the Spitzer Quality of Life Index (QLI) and Spitzer Uniscale, and a time-trade off (TTO) question reflecting the utility of their health states. The scales were self-administered. All patients completed the QLI and Uniscale but only 37% of participants were prepared to trade time. The remainder comprised 39% who felt too well to trade time and 24% who did not wish to consider trading time at all. Those prepared to trade time had significantly worse scores on both QLI and Uniscale instruments than those who felt too well to trade. However the correlation between time traded and QLI and Uniscale scores was poor. We conclude that the TTO question used in this study, while not strongly related to QOL, provides a measure of the patients attitude to their health state. This may explain why patients differ in their attitude to quantity vs. quality of life.

Increased levels of active c-Src distinguish invasive from in situ lobular lesions.

IntroductionMounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC.MethodsImmunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients.ResultsLevels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold ± 0.24 SD) and nonneoplastic epithelia (1.47 ± 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease.ConclusionsOur data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.

Primary breast cancer of the vulva: case report and literature review.

© 2007 The Authors 77 Journal compilation

Beliefs of New Zealand Doctors About Integrative Medicine for Cancer Treatment

Aims. This study aimed to give an up-to-date description of the views and knowledge that health professionals in New Zealand (NZ) have about complementary and alternative medicine (CAM) and its use in the context of integrative medicine. Study design. A self-administered questionnaire. Methods. Doctors in the Otago region of New Zealand (n = 235 out of 395, 59% response rate) answered questions addressing attitudes toward the principle of integrative medicine, attitudes indigenous Ma-ori holistic views of health, and attitudes about CAM. Information on physician demographics was also gathered. Results. Almost all doctors (95%) agreed that they should address all aspects of a patient’s health, whereas around 60% agreed that CAM can be integrated into a treatment regime to provide the best care for a patient. Most (93%) agreed that in a NZ context, it is important to be aware of Ma-ori holistic views of health. Doctors had many concerns about CAM, and only 26% personally used any CAM therapies themselves. However, many doctors wanted to learn more about CAM (58%) and Ma-ori holistic views of health (62%). Doctors who believed that they “knew enough” about CAM were more likely to ask about it and to recommend it to patients. Conclusion. Integrative medicine is increasingly being accepted in medical practice, although many doctors still do not agree with the use of CAM. There is a need for increased patient–doctor discussions of CAM use. Doctors’ lack of knowledge about CAM may be a barrier to communication and should be addressed with specific medical training.

Is longitudinal functional assessment of cancer therapy-general a useful outcome measure for palliative cancer care?

tant effect to avoid. CONCLUSIONS: These results provide more precise information regarding patient treatment evaluation and satisfaction than that provided by the usual measurement of HRQOL. This information can be used by physicians to employ more precise interventions designed to improve HRQOL in the domains of greatest importance to patients and by all health care professionals to improve patient counseling. ACKNOWLEDGMENT: This research was supported by Pfizer Inc, New York, New York.