Reliability and validity of PRO-CTCAE® daily reporting with a 24-hour recall period.

PURPOSE: The standard recall period for the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE®) is the past 7 days, but there are contexts where a 24-hour recall may be desirable. The purpose of this analysis was to investigate the reliability and validity of a subset of PRO-CTCAE items captured using a 24-hour recall. METHODS: 27 PRO-CTCAE items representing 14 symptomatic adverse events (AEs) were collected using both a 24-hour recall (24 h) and the standard 7 day recall (7d) in a sample of patients receiving active cancer treatment (n = 113). Using data captured with a PRO-CTCAE-24h on days 6 and 7, and 20 and 21, we computed intra-class correlation coefficients (ICC); an ICC ≥ 0.70 was interpreted as demonstrating high test-retest reliability. Correlations between PRO-CTCAE-24h items on day 7 and conceptually relevant EORTC QLQ-C30 domains were examined. In responsiveness analysis, patients were deemed changed if they had a one-point or greater change in the corresponding PRO-CTCAE-7d item (from week 0 to week 1). RESULTS: PRO-CTCAE-24h captured on two consecutive days demonstrated that 21 of 27 items (78%) had ICCs ≥ 0.70 (day 6/7 median ICC 0.76), (day 20/21 median ICC 0.84). Median correlation between attributes within a common AE was 0.75, and the median correlation between conceptually relevant EORTC QLQ-C30 domains and PRO-CTCAE-24 h items captured on day 7 was 0.44. In the analysis of responsiveness to change, the median standardized response mean (SRM) for patients with improvement was - 0.52 and that for patients with worsening was 0.71. CONCLUSION: A 24-hour recall period for PRO-CTCAE items has acceptable measurement properties and can inform day-to-day variations in symptomatic AEs when daily PRO-CTCAE administration is implemented in a clinical trial.

A theory of atmospheric oxygen.

Geological records of atmospheric oxygen suggest that pO2 was less than 0.001% of present atmospheric levels (PAL) during the Archean, increasing abruptly to a Proterozoic value between 0.1% and 10% PAL, and rising quickly to modern levels in the Phanerozoic. Using a simple model of the biogeochemical cycles of carbon, oxygen, sulfur, hydrogen, iron, and phosphorous, we demonstrate that there are three stable states for atmospheric oxygen, roughly corresponding to levels observed in the geological record. These stable states arise from a series of specific positive and negative feedbacks, requiring a large geochemical perturbation to the redox state to transition from one to another. In particular, we show that a very low oxygen level in the Archean (i.e., 10-7 PAL) is consistent with the presence of oxygenic photosynthesis and a robust organic carbon cycle. We show that the Snowball Earth glaciations, which immediately precede both transitions, provide an appropriate transient increase in atmospheric oxygen to drive the atmosphere either from its Archean state to its Proterozoic state, or from its Proterozoic state to its Phanerozoic state. This hypothesis provides a mechanistic explanation for the apparent synchronicity of the Proterozoic Snowball Earth events with both the Great Oxidation Event, and the Neoproterozoic oxidation.

Modeling the carbon cycle in Lake Matano.

Lake Matano, Indonesia, is a stratified anoxic lake with iron-rich waters that has been used as an analogue for the Archean and early Proterozoic oceans. Past studies of Lake Matano report large amounts of methane production, with as much as 80% of primary production degraded via methanogenesis. Low δ(13)C values of DIC in the lake are difficult to reconcile with this notion, as fractionation during methanogenesis produces isotopically heavy CO2. To help reconcile these observations, we develop a box model of the carbon cycle in ferruginous Lake Matano, Indonesia, that satisfies the constraints of CH4 and DIC isotopic profiles, sediment composition, and alkalinity. We estimate methane fluxes smaller than originally proposed, with about 9% of organic carbon export to the deep waters degraded via methanogenesis. In addition, despite the abundance of Fe within the waters, anoxic ferric iron respiration of organic matter degrades <3% of organic carbon export, leaving methanogenesis as the largest contributor to anaerobic organic matter remineralization, while indicating a relatively minor role for iron as an electron acceptor. As the majority of carbon exported is buried in the sediments, we suggest that the role of methane in the Archean and early Proterozoic oceans is less significant than presumed in other studies.

Uncovering the Neoproterozoic carbon cycle.

Interpretations of major climatic and biological events in Earth history are, in large part, derived from the stable carbon isotope records of carbonate rocks and sedimentary organic matter. Neoproterozoic carbonate records contain unusual and large negative isotopic anomalies within long periods (10-100 million years) characterized by δ(13)C in carbonate (δ(13)C(carb)) enriched to more than +5 per mil. Classically, δ(13)C(carb) is interpreted as a metric of the relative fraction of carbon buried as organic matter in marine sediments, which can be linked to oxygen accumulation through the stoichiometry of primary production. If a change in the isotopic composition of marine dissolved inorganic carbon is responsible for these excursions, it is expected that records of δ(13)C(carb) and δ(13)C in organic carbon (δ(13)C(org)) will covary, offset by the fractionation imparted by primary production. The documentation of several Neoproterozoic δ(13)C(carb) excursions that are decoupled from δ(13)C(org), however, indicates that other mechanisms may account for these excursions. Here we present δ(13)C data from Mongolia, northwest Canada and Namibia that capture multiple large-amplitude (over 10 per mil) negative carbon isotope anomalies, and use these data in a new quantitative mixing model to examine the behaviour of the Neoproterozoic carbon cycle. We find that carbonate and organic carbon isotope data from Mongolia and Canada are tightly coupled through multiple δ(13)C(carb) excursions, quantitatively ruling out previously suggested alternative explanations, such as diagenesis or the presence and terminal oxidation of a large marine dissolved organic carbon reservoir. Our data from Namibia, which do not record isotopic covariance, can be explained by simple mixing with a detrital flux of organic matter. We thus interpret δ(13)C(carb) anomalies as recording a primary perturbation to the surface carbon cycle. This interpretation requires the revisiting of models linking drastic isotope excursions to deep ocean oxygenation and the opening of environments capable of supporting animals.

Use of high technology imaging for surveillance of early stage breast cancer.

Guidelines do not support utilization of high technology radiologic imaging (HTRI) for surveillance after curative treatment for early stage breast cancer. Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data were used to identify 25,555 women diagnosed with stage I-II breast cancer between 1998 and 2003 who survived ≥ 48 months from diagnosis without evidence of second primary or recurrent cancer in this interval. HTRI utilization (computerized tomography scanning (CT), bone scan (BS), breast magnetic resonance imaging, and positron emission tomography scans) was measured in months 13-48 post-diagnosis. Cases were individually matched to 75,669 female Medicare enrollees without cancer. Factors associated with HTRI utilization were evaluated. Forty percent of women with stage I-II breast cancer and 25% of controls had ≥ 1 HTRI during the surveillance interval (P < 0.001). High utilization rates were observed for CT (30%) and BSs (19%). The proportion of women who had a CT during the surveillance period increased in both cancer survivors and controls. Among breast cancer cases age <80, higher comorbidity index, stage II disease, and more recent diagnosis were independently associated with receipt of HTRI. Paralleling patterns observed in controls, HTRI utilization for surveillance following diagnosis of early stage breast cancer has steadily increased among Medicare beneficiaries. Strategies to foster judicious utilization of HTRI should be a priority.

Dynamic contrast enhanced-MRI for the detection of pathological complete response to neoadjuvant chemotherapy for locally advanced rectal cancer.

OBJECTIVE: To determine the ability of dynamic contrast enhanced (DCE-MRI) to predict pathological complete response (pCR) after preoperative chemotherapy for rectal cancer. METHODS: In a prospective clinical trial, 23/34 enrolled patients underwent pre- and post-treatment DCE-MRI performed at 1.5T. Gadolinium 0.1 mmol/kg was injected at a rate of 2 mL/s. Using a two-compartmental model of vascular space and extravascular extracellular space, K(trans), k(ep), v(e), AUC90, and AUC180 were calculated. Surgical specimens were the gold standard. Baseline, post-treatment and changes in these quantities were compared with clinico-pathological outcomes. For quantitative variable comparison, Spearman's Rank correlation was used. For categorical variable comparison, the Kruskal-Wallis test was used. P ≤ 0.05 was considered significant. RESULTS: Percentage of histological tumour response ranged from 10 to 100%. Six patients showed pCR. Post chemotherapy K(trans) (mean 0.5 min(-1) vs. 0.2 min(-1), P = 0.04) differed significantly between non-pCR and pCR outcomes, respectively and also correlated with percent tumour response and pathological size. Post-treatment residual abnormal soft tissue noted in some cases of pCR prevented an MR impression of complete response based on morphology alone. CONCLUSION: After neoadjuvant chemotherapy in rectal cancer, MR perfusional characteristics have been identified that can aid in the distinction between incomplete response and pCR. KEY POINTS: Dynamic contrast enhanced (DCE) MRI provides perfusion characteristics of tumours. These objective quantitative measures may be more helpful than subjective imaging alone Some parameters differed markedly between completely responding and incompletely responding rectal cancers. Thus DCE-MRI can potentially offer treatment-altering imaging biomarkers.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Lifestyle prescriptions for cancer survivors and their communities.

Current cancer care focuses on procuring the most up-to-date therapy to prevent cancer death. However, the majority of cancer survivors will not die from cancer but from cardiovascular disease.A cancer diagnosis presents a 'teachable moment' for lifestyle behavior change.Changes in key behavioral risk factors reduce cardiovascular risk; yet, this potential for primary prevention of cardiovascular disease among cancer survivors is often overlooked.Evidence now exists for both individual clinic-based approaches and complementary community-based strategies to induce successful behavior change.We propose a systematic re-alignment of clinical and research focus to complement cancer surveillance and adjuvant treatments with key patient-and community-based strategies to improve lifestyles in cancer survivors [added].

Meeting the 12 lymph node (LN) benchmark in colon cancer.

BACKGROUND: Examining >or=12 LN in colon cancer has been suggested as a quality metric. The purpose of this study was to determine whether the 12 LN benchmark is achieved at NCCN centers compared to a US population-based sample. METHODS: Patients with stage I-III disease resected at NCCN centers were identified from a prospective database (n = 718) and were compared to 12,845 stage I-III patients diagnosed in a SEER region. Age, gender, location, stage, number of positive nodes were compared for NCCN and SEER data in regards to number of nodes evaluated. Multivariate logistic regression models were developed to identify factors associated with evaluating 12 LNs. RESULTS: 92% of NCCN and 58% of SEER patients had >or=12 LN evaluated. For patients treated at NCCN centers, factors associated with not meeting the 12 LN target were left-sided tumors, stage I disease and BMI >30. CONCLUSIONS: >or=12 LN are almost always evaluated in NCCN patients. In contrast, this target is achieved in 58% of SEER patients. With longer follow-up of the NCCN cohort we will be able to link this quality metric to patterns of recurrence and survival and thereby better understand whether increasing the number of nodes evaluated is a priority for cancer control.

Subsurface characterization of methane production and oxidation from a New Hampshire wetland.

We measured the carbon isotopic composition of pore water carbon dioxide from Sallie's Fen, a New Hampshire poor fen. The isotope profiles are used in combination with a one-dimensional diffusion-reaction model to calculate rates of methane production, oxidation and transport over an annual cycle. We show how the rates vary with depth over a seasonal cycle, with methane produced deeper during the winter months and at progressively shallower depths into the summer season. The rates of methane production, constrained by the measured delta(13)C(dic) profiles, cannot explain high methane emission during the summer. We suggest that much of the methane produced during this time comes either from the unsaturated peat, or from the top 1-3 cm of saturated peat where episodic exchange with the atmosphere makes it invisible to our method.

Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in stage II colon cancer.

BACKGROUND: Failing to meet the benchmark of 12 lymph nodes in resection specimens is an indication for adjuvant chemotherapy in stage II colon cancer. METHODS: Among consecutive eligible patients with pathologic stage II colon cancer treated at eight NCI-designated comprehensive cancer centers between September 1, 2005 and February 19, 2008, we analyzed receipt of adjuvant chemotherapy, with less than 12 versus 12+ lymph nodes removed and examined the primary explanatory variable of interest. RESULTS: Among 258 patients, 46% received adjuvant chemotherapy. An oxaliplatin-containing regimen was used 67% of the time. Younger age (<50 years, P < 0.001), presence of lymphovascular invasion (P = 0.007), and higher T stage (P = 0.007) were independently associated with adjuvant chemotherapy use. There was significant inter-institutional variability in practice with the proportion receiving treatment ranging from 17% to 64% (P < 0.05). Notably, presence of less than 12 lymph nodes in the surgical specimen was a strong predictor of treatment (P = 0.008). CONCLUSIONS: Adjuvant chemotherapy use after resection of stage II colon cancer is common, but by no means standard practice at National Comprehensive Cancer Network (NCCN) institutions. More attention to achieving the recommended benchmark for lymph node dissection has the potential to decrease exposure to the toxicity of adjuvant treatment.

Young age influences treatment but not outcome of colon cancer.

BACKGROUND: Early age at onset is often considered a poor prognostic factor for colon cancer. The aim of this study was to determine the association between age, clinicopathologic features, adjuvant therapy, and outcomes following colon cancer resection. METHODS: A prospective database of 1,327 surgical stage I-III colon cancer patients operated on from 1990-2001 was evaluated, and patients grouped by age. RESULTS: Sixty-eight patients (5%) were diagnosed at age 40 (older). Younger patients were more likely to have left-sided tumors (66% vs 51%, P = .02), but no more likely to present with symptomatic lesions, more advanced tumors, or have worse pathologic features. Younger patients were noted to have more nodes retrieved in their surgical specimens than older patients (median 18 vs 14, P = .001), although the numbers of total colectomies were similar in both groups. Younger patients were also more likely to receive adjuvant chemotherapy, and this was most pronounced in the stage II cohort: 39% vs 14%, P = .003. With a median follow-up of 55 months, 5-year disease-specific survival (DSS) was similar in both study groups: 86% vs 87%, but 5-year overall survival (OS) was significantly higher in the younger patient cohort (84% vs 73%, P = .001). CONCLUSION: Younger patients undergoing complete resection of stage I-III colon cancer had DSS similar to older patients. However, younger patients had more nodes retrieved from their specimens and were more likely to receive adjuvant therapy, especially for node-negative disease. These factors may have contributed to their overall favorable outcome.

Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation.

Patients who develop respiratory failure requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT) have very high mortality. Several investigators have identified prognostic features that can be used to identify a subset of these patients who are virtually certain to die, yet these have never been prospectively assessed. The objectives of this study were to determine the accuracy of published prognostic features for mortality and to determine the survival of patients who recover from respiratory failure. A systematic review of the literature was undertaken to identify reported poor prognostic features and survival rates. The study validated the reported poor prognostic features on a prospective, multicenter inception cohort of 226 patients with respiratory failure requiring mechanical ventilation after HSCT. The main outcome measures were determination of a baseline probability of death, drawn from literature review; likelihood ratio of mortality for each prognostic feature determined from the validation cohort; conditional probability of death in the presence of each feature; and 6-month survival of those who recover. Patients requiring mechanical ventilation after HSCT have a baseline probability of death of 82% to 96%. In the setting of combined hepatic and renal dysfunction, the probability of death rises to 98% to 100%. Other previously reported prognostic features are less strongly associated with mortality. For patients who recover from respiratory failure, the proportion surviving 6 months or longer ranges from 27% to 88%. It was concluded that in patients requiring mechanical ventilation after HSCT, the presence of combined hepatic and renal dysfunction is highly predictive of death. The presence of this feature may justify the recommendation to withdraw life-sustaining measures.

Who gets adjuvant treatment for stage II and III rectal cancer? Insight from surveillance, epidemiology, and end results--Medicare.

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer. PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively. RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P <.001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor. CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.

The influence of hospital volume on survival after resection for lung cancer.

BACKGROUND: Among patients who have undergone high-risk operations for cancer, postoperative mortality rates are often lower at hospitals where more of these procedures are performed. We undertook a population-based study to estimate the extent to which the number of procedures performed at a hospital (hospital volume) is associated with survival after resection for lung cancer. METHODS: We studied patients 65 years old or older who received a diagnosis of stage I, II, or IIIA non-small-cell lung cancer between 1985 and 1996, resided in 1 of the 10 study areas covered by the Surveillance, Epidemiology, and End Results Program, and underwent surgery at a hospital that participates in the Nationwide Inpatient Sample (2118 patients and 76 hospitals). RESULTS: The volume of procedures at the hospital was positively associated with the survival of patients (P<0.001). Five years after surgery, 44 percent of patients who underwent operations at the hospitals with the highest volume were alive, as compared with 33 percent of those who underwent operations at the hospitals with the lowest volume. Patients at the highest-volume hospitals also had lower rates of postoperative complications (20 percent vs. 44 percent) and lower 30-day mortality (3 percent vs. 6 percent) than those at the lowest-volume hospitals. CONCLUSIONS: Patients who undergo resection for lung cancer at hospitals that perform large numbers of such procedures are likely to survive longer than patients who have such surgery at hospitals with a low volume of lung-resection procedures.

Age and adjuvant chemotherapy use after surgery for stage III colon cancer.

BACKGROUND: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. METHODS: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. RESULTS: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values <.001). CONCLUSIONS: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment.

Influence of hospital procedure volume on outcomes following surgery for colon cancer.

CONTEXT: Survival following high-risk cancer surgery, such as pancreatectomy and esophagectomy, is superior at hospitals where high volumes of these procedures are performed. Conflicting evidence exists as to whether the association between hospital experience and favorable health outcomes also applies to more frequently performed operations, such as those for colon cancer. OBJECTIVE: To determine whether hospital procedure volume predicts survival following colon cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of data from the Surveillance, Epidemiology and End Results-Medicare linked database on 27 986 colon cancer patients aged 65 years and older who had surgical resection for primary adenocarcinoma diagnosed between 1991 and 1996. MAIN OUTCOME MEASURES: Thirty-day postoperative mortality and overall and cancer-specific long-term survival, by hospital procedure volume. RESULTS: We found small differences in 30-day postoperative mortality for patients treated at low- vs high-volume hospitals (3. 5% at hospitals in the top-volume quartile vs 5.5% at hospitals in the bottom-volume quartile). However, the correlation was statistically significant and persisted after adjusting for age at diagnosis, sex, race, cancer stage, comorbid illness, socioeconomic status, and acuity of hospitalization (P<.001). The association was evident for subgroups with stage I, II, and III disease. Hospital volume directly correlated with survival beyond 30 days and also was not attributable to differences in case mix (P<.001). The association between hospital volume and long-term survival was concentrated among patients with stage II and III disease (P<.001 for both). Among stage III patients, variation in use of adjuvant chemotherapy did not explain this finding. CONCLUSION: Our data suggest that hospital procedure volume predicts clinical outcomes following surgery for colon cancer, although the absolute magnitudes of these differences are modest in comparison with the variation observed for higher-risk cancer surgeries.