Are differences in stage at presentation a credible explanation for reported differences in the survival of patients with colorectal cancer in Europe?

Popular reporting of a comparison of cancer survival rates across 17 European countries, based on data collected by national and regional cancer registries, has left an impression of inadequate treatment of patients in the UK. A subsequent study has suggested that the poor survival rates reported for the UK can, in large part, be explained by more advanced stage at presentation. We believe this conclusion to be unsound and use this study as an example to illustrate the methodological difficulties which may arise during such international comparisons. As the NHS cancer plan aspires to achieve for the UK parity with the best cancer care in Europe, careful thought needs to be given to identifying countries with which the UK can usefully compare itself and the most appropriate indicators for this comparison.     

Do discordant cancers share familial susceptibility?

AimsCancer syndromes manifest at many sites albeit with variable penetrance. Genome-wide association (GWA) studies have identified susceptibility loci shared by many types of cancer. Yet, a population level search for shared susceptibility between discordant cancers has been hampered because of lacking population sizes.MethodsOver 1.1 million patients in the nation-wide Swedish Family-Cancer Database were analysed for discordant familial cancers covering 33 sites. Standardised incidence ratios (SIRs) were calculated for patients whose family members had a defined cancer compared to those whose family members did not have that cancer. Three independent tests for each pair of cancer sites were done using different family relationships.ResultsLung cancer showed 13 significant discordant associations but most of them were with sites for which smoking is a risk factor. An exception was the clustering of lung cancer and endocrine cancers. Four discordant associations reached a minimal significance level of 5 × 10^–6: colorectum–endometrium, breast–ovary, breast–prostate and melanoma–squamous cell carcinoma of the skin. The association of melanoma and nervous system cancer reached a minimal significance of 10⁻⁴. Discarding lung cancer, all other associations were based on a single test whereby they were liable to be chance associations.ConclusionsThis study showed the extraordinary requirements for statistical power in study of multiple cancer sites. In addition to the smoking related sites, associations between breast and prostate cancers, melanoma and nervous system tumours and lung and endocrine tumours found strong statistical support. Within the present sample size limits, we found no evidence of an overall susceptibility to cancer.     

Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women?

Breast cancer risk is substantially lower in Singapore than in women from the United STATES: Part of the risk discrepancy is probably explained by differences in the production of endogenous estrogens, but differences in the pathway by which estrogen is metabolized may also play a role. We undertook a study to determine whether the ratio of urinary 2-hydroxyestrone (2OHE(1)):16alpha-hydroxyestrone (16alpha-OHE(1)) was higher in Singapore Chinese than in a group of United States (predominantly African-American) women living in Los ANGELES: We also wanted to determine whether any difference in estrogen metabolite ratio between these two groups of women was greater than that in estrone (E(1)), estradiol (E(2)) and estriol (E(3)). The participants in this study were randomly selected healthy, non-estrogen using women participating in the Singapore Chinese Health Study (n = 67) or the Hawaii/Los Angeles Multiethnic Cohort Study (n = 58). After adjusting for age and age at menopause, mean urinary 2-OHE(1) was only 23% (P = 0.03) higher in Singapore Chinese than in United States women, and there were no statistically significant differences in 16alpha-OHE(1) levels or in the ratio of 2-OHE(1):16alpha-OHE(1) between the two groups. The adjusted mean 2-OHE(1):16alpha-OHE(1) ratio was 1.63 in Singapore Chinese and 1.48 in United States women (P = 0.41). In contrast, the adjusted mean values of E1, E2, and E3 were 162% (P < 0.0001), 152% (P < 0.0001), and 92% (P = 0.0009) higher, respectively, in United States women than in Singapore Chinese women. Our study suggests that urinary E1, E2, and E3 reflect the differences in breast cancer risk between Singapore Chinese and United States women to a stronger degree than the estrogen metabolites 2OHE(1) and 16alpha-OHE(1) or the ratio of 2OHE(1):16alpha-OHE(1.)     

Do differences in target volume definition in prostate cancer lead to clinically relevant differences in normal tissue toxicity?

PURPOSE: Many studies have described the quantitated differences between clinicians in target volume definition in prostate cancer. However, few studies have looked at the clinical effects of this. We aimed to assess the relevance and sequelae of such differences. METHODS AND MATERIALS: Five experienced radiation oncologists were given the clinical details of 5 patients with early-stage prostate cancer and asked to define the clinical target volume, consisting of the prostate and seminal vesicles (CTV1) and the prostate alone (CTV2), on specified planning CT scans of the pelvis. Planning target volumes (PTV1) were generated by automatic expansion of the CTV1 by a 1-cm margin. The PTV2 was defined as the CTV2. The rectum and bladder were defined by a single experienced clinician for each plan without knowledge of the involved clinician marking the CTVs. The Pinnacle planning system was used to generate the plans, using four-field conformal radiotherapy, to deliver 64 Gy in 32 fractions to the PTV1 followed by a boost of 10 Gy to the PTV2 (Medical Research Council RT01 trial protocol). Dose-volume histograms were generated for the whole bladder and rectum for each plan and the volume receiving a specific percentage of the dose (e.g., V(90)) calculated for 74 Gy, followed by estimates of normal tissue complication probabilities (NTCPs) for the bladder and rectum. RESULTS: Statistically significant differences were found in the CTV1 and CTV2 and, consequently, the PTV1 among the 5 clinicians (p < 0.0005). Most of the discrepancies occurred at the delineation of the prostatic apex and seminal vesicles, with the smallest variance noted at the rectum-prostate and bladder-prostate interfaces. No statistically significant differences were found among clinicians for the rectal V(90), V(85), V(80), V(70), or V(50) or for the bladder V(85), V(80), V(70), or V(50). A difference was noted among consultants for the bladder V(90) (p = 0.015), although no correlation was found between the bladder V(90) and the size of the outlined volumes. No statistically significant differences were found between the estimates of bladder (p = 0.1) and rectal (p = 0.09) NTCPs. CONCLUSION: The statistically significant difference in outlined volumes of the CTV1, CTV2, and PTV1 among the 5 clinicians is in keeping with the findings of previous studies. However, the interclinician variability did not result in clinically relevant outcomes with respect to the irradiated volume of rectum and bladder or NTCP. This may have been because the outlined areas in which interclinician differences were smallest (the rectal-prostate and prostate-bladder interfaces) are the areas that have the greatest effect on normal tissue toxicity. For the areas in which the interclinician correlation was lowest (the prostatic apex and distal seminal vesicles), the effects on normal tissue toxicity are smallest. The results of this study suggest that interclinician outlining differences in prostate cancer may have less clinical relevance than was previously thought.     

Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3β (GSK3β) by serine 9-dephosphorylation. Strikingly, GSK3β-mediated survival was restricted to leukemic progenitors from female patients. GSK3β inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of α(5)β(1)-integrin engagement, was specifically upregulated and controlled GSK3β activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3β-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3β as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy.     

Estrogen receptor positive tumors: Do reproductive factors explain differences in incidence between black and white women?

Purpose

The incidence of estrogen receptor positive (ER+) breast cancer is higher among white women relative to black women. In two large prospective cohorts, the Black Women’s Health Study (BWHS) and the Nurses’ Health Study II (NHSII), we investigated whether reproductive factors explain the difference.

Methods

During 1,582,083 person-years of follow-up of 140,914 women observed from 1995 to 2007, 327 ER+ breast cancers were identified among black women in BWHS and NHSII and 1,179 among white women in NHSII. Cox proportional hazards regression models, stratified by race and pooled, were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association of race, parity, age at first birth, and lactation in relation to risk of ER+ cancer with adjustment for age and other breast cancer risk factors.

Results

Age at first birth differed markedly in the two groups, with 66 % of parous black women having their first child before age 25 as compared with 36 % of white women. Each additional year of age at first birth was associated with a 4 % increased risk of ER+ breast cancer among both racial groups. Relative to nulliparous women, parous women were at decreased risk of ER+ breast cancer (HR 0.59, 95 % CI 0.20, 1.77), in black women and (HR 0.63, 95 % CI 0.45, 0.87) in white women. The HR for the association of black race with ER+ cancer was 0.67 (95 % CI 0.53, 0.84) in a model that adjusted for age only, 0.77 (95 % CI 0.61, 0.99) in a model that controlled for parity, age at first birth, and other reproductive/hormonal factors, and 0.83 (95 % CI 0.70, 0.98) in a model that additionally controlled for other breast cancer risk factors such as alcohol consumption and use of hormone supplements. Similar associations were seen among premenopausal women and in an analysis restricted to ER+PR+ tumors.

Conclusions

Reproductive factors explained some of the higher incidence of ER+ tumors among white women as compared to black women.     

Do children and adults differ in survival from medulloblastoma? A study from the SEER registry

Studies investigating whether adults have diminished survival from medulloblastoma (MB) compared with children have yielded conflicting results. We sought to determine in a population-based registry whether adults and children with MB differ in survival, and to examine whether dissimilar use of chemotherapy might contribute to any disparity. 1,226 MB subjects were identified using the Surveillance Epidemiology and End Results (SEER-9) registry (1973–2002) and survival analysis performed. MB was defined strictly to exclude non-cerebellar primitive neuro-ectodermal tumors. Patients were stratified by age at diagnosis: <3 years (infants), 3–17 years (children) and ≥18 years (adults). Because the SEER-9 registry lacks treatment data, a subset of 142 patients were identified using the San Francisco-Oakland SEER registry (1988–2003) and additional analyses performed. There was no significant difference in survival between children and adults with MB in either the SEER-9 (P = 0.17) or SFO (P = 0.89) cohorts but infants fared worse compared to both children (P < 0.01) and adults (P < 0.01). In the SFO sample, children and adults who received chemotherapy plus radiation therapy (XRT) did not differ in survival. Among patients treated with XRT alone, children showed increased survival (P = 0.04) compared with adults. Children and adults with MB do not differ with respect to overall survival, yet infants fare significantly worse. For children and adults with MB treated with both XRT and chemotherapy, we could not demonstrate a survival difference. Similar outcomes between adult and childhood MB may justify inclusion of adults in pediatric cooperative trials for MB.     

Do all locally advanced rectal cancers require radiation? A review of literature in the modern era

Potentially curable rectal cancer is primarily treated with surgical resection. Adjuvant or neoadjuvant radiotherapy is often utilized for patients deemed to be at unacceptable risk for local recurrence. The purpose of this article is to review the pertinent literature and elucidate the role of radiotherapy in patients with an intermediate risk of local recurrence. The addition of chemoradiotherapy is recommended in the majority of patients with transmural or node positive rectal cancer. However, some patients with favorable characteristics may have only a small incremental benefit from the addition of radiotherapy. The decision to treat or not to treat should take into consideration the patient and physician tolerance of risk of recurrence and risk of treatment related toxicity. The primary factors identified for determining low risk patients are circumferential radial margin (CRM), location within the rectum, and nodal status. Patients at lowest risk have widely negative CRM (>2mm), proximal lesions (>10cm from the anal verge), and no nodal disease. Patients with all three low risk factors have an absolute reduction in local recurrence that is <5% and may be eligible to forego radiotherapy. Additional factors identified which may impact local recurrence risk are elevated serum CEA level, lymphovascular space invasion, pathologic grade, and extramural space invasion.     

Are inflammatory cytokines the common link between cancer-associated cachexia and depression?

The prevalence of depression among patients diagnosed with cancer is higher than among the general medical population and is associated with faster tumor progression and shortened survival time. Cancer-related depression often occurs in association with anorexia and cachexia, although until recently the relationship between these conditions has not been well understood. Cachexia is associated with poorer quality of life and survival outcomes and is theeventual cause of death in approximately 30% of all patients with cancer. Recent evidence has linked elevated levels of inflammatory cytokines with both depression and cachexia, and experiments have shown that introducing cytokines induces depression and cachectic symptoms in both humans and rodents, suggesting that there may be a common etiology at the molecular level. Therapeutic agents targeting specific cytokine molecules, such as interleukin-6 or tumor necrosis factor-alpha, are currently being evaluated for their potential to simultaneously treat both depression and cachexia pharmacologically. This review summarizes the available data suggesting a dual role for cytokines in the development of cancer-related depression and cachexia and describes how biologic therapies targeting specific cytokines may improve outcomes beyond depression and cachexia, such as survival and quality of life.     

Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?

Familial Cancer - Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the...     

Is England closing the international gap in cancer survival?

Background:

We provide an up-to-date international comparison of cancer survival, assessing whether England is ‘closing the gap'' compared with other high-income countries.

Methods:

Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995–2012. Trends during 1995–2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends.

Results:

Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005–2009. For some cancers, survival improved more in England than in other countries between 1995–1999 and 2005–2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1-year survival rising to 2% during 2010–2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995–1999 and 2005–2009.

Conclusions:

Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap.     

Chromosomal radiosensitivity as a marker of predisposition to common cancers?

We previously found that 40% of breast cancer patients showed enhanced sensitivity to X-ray induced chromosome damage in G(2)lymphocytes and suggested that this might indicate a low penetrance predisposition to breast cancer, for which there is good epidemiological evidence. We have now tested the hypothesis that elevated G(2)radiosensitivity is a marker of such predisposition to other common cancers. We tested patients with colorectal cancer, for which there is also good epidemiological evidence of inherited risk in a substantial proportion of cases, and patients with cancers having a strong environmental aetiology (lung and cervix). We also repeated our study of breast cancer cases and tested patients with chronic diseases other than cancer. The results support our hypothesis, in that 30% (12/37) of colorectal cases showed enhanced sensitivity compared with 9% (6/66) of normal healthy controls (P = 0.01), whereas the proportions of sensitive cervix (11%, 3/27, P = 0.72) and lung cancer cases (23%, 8/35, P = 0.07) were not significantly above normals. We confirmed the enhanced sensitivity of 40% (12/31, P = 0.001) of breast cancer patients and found that patients with non-malignant disease had a normal response in the assay (12%, 4/34, P = 0.73). We suggest that enhanced G(2)chromosomal radiosensitivity is a consequence of inherited defects in the ability of cells to process DNA damage from endogenous or exogenous sources, of a type that is mimicked by ionizing radiation, and that such defects predispose to breast and colorectal cancer.     

What is the future burden of HPV-related cancers in Spain?

Purpose

The aim of this study is to analyze mortality trends of HPV-related cancers in Spain by gender, during the period 1996–2010, and make predictions until the year 2025.

Methods

All deaths registered as cervical cancer were registered (ICD-10 code: C53), as well as vulvar and vaginal (C51 and C52), anal (C21), penile (C60), and oropharyngeal (C02, C09, C10). Adjusted rate calculations for each year were used to study the trends through the regression program Joinpoint. Predictions were made using the Nordpred program, utilizing the age–period–cohort model.

Results

In men, a statistically significant increase was observed in mortality by anal cancer, a reduction was observed in oropharyngeal cancer mortality and penile cancer rates were stable. In women, a statistically significant decreasing trend was observed for cervical, vulvar and vaginal cancers. In the predictions, the annual change relative to risk or population changes (size and structure) revealed a reduction in death risk by oropharyngeal cancer in men, and a reduction in death risk by anal cancer in women, although stable adjusted rates were verified for anal cancer in women.

Conclusions

Although an increase was identified in the number of deaths for both genders, rates indicate gender differences in the trends, with increased rates for anal cancer and reduced rates for oropharyngeal cancer in men. Women presented reduced rates for cervical, vulvar, and vaginal cancers. For penile cancer and anal cancer in women, stable trends were verified.     

Do pathological fractures influence survival and local recurrence rate in bony sarcomas?

The influence of pathological fracture on surgical management, local recurrence and survival was established in patients with high grade, localised, extremity osteosarcoma (n=484), chondrosarcoma (n=130) and Ewing's sarcoma (n=156). Limb salvage was possible in 79% of patients with a fracture compared to 84% of patients without a fracture (p=0.17). No difference in local recurrence was found between fracture and control groups. In univariate analysis, survival in the fracture group was lower than in the control group for osteosarcoma (34% versus 58%, p<0.01) and chondrosarcoma (35% versus 63%, p=0.04), but not for Ewing's sarcoma (75% versus 64%, p=0.80). In multivariate analysis, fracture remained a significant predictor of survival for osteosarcoma, but not for chondrosarcoma, where dedifferentiated subtype appeared to be decisive. Pathological fracture independently predicts worse survival in osteosarcoma, but not chondrosarcoma and Ewing's sarcoma. Limb saving surgery seems safe, if adequate resection margins are achieved.