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Background Guidelines for follow-up after locoregional breast cancer treatment recommend imaging for distant metastases only in the presence of patient signs and/or symptoms. However, guidelines have not been updated to reflect advances in imaging, systemic therapy, or the understanding of biological subtype. We assessed the association between mode of distant recurrence detection and survival. Methods In this observational study, a stage-stratified random sample of women with stage II-III breast cancer in 2006-2007 and followed through 2016 was selected, including up to 10 women from each of 1217 Commission on Cancer facilities (n = 10 076). The explanatory variable was mode of recurrence detection (asymptomatic imaging vs signs and/or symptoms). The outcome was time from initial cancer diagnosis to death. Registrars abstracted scan type, intent (cancer-related vs not, asymptomatic surveillance vs not), and recurrence. Data were merged with each patient’s National Cancer Database record. Results Surveillance imaging detected 23.3% (284 of 1220) of distant recurrences (76.7%, 936 of 1220 by signs and/or symptoms). Based on propensity-weighted multivariable Cox proportional hazards models, patients with asymptomatic imaging compared with sign and/or symptom detected recurrences had a lower risk of death if estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative (triple negative; hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.54 to 0.99), or HER2 positive (HR = 0.51, 95% CI = 0.33 to 0.80). No association was observed for ER- or PR-positive, HER2-negative (HR = 1.14, 95% CI = 0.91 to 1.44) cancers. Conclusions Recurrence detection by asymptomatic imaging compared with signs and/or symptoms was associated with lower risk of death for triple-negative and HER2-positive, but not ER- or PR-positive, HER2-negative cancers. A randomized trial is warranted to evaluate imaging surveillance for metastases results in these subgroups.

The National Cancer Institute Division of Cancer Control and Population Science hosted a virtual conference on the Future of Cancer Health Economics Research and included a presentation from a workgroup that considered current challenges and future directions in health economics research centered on cancer treatment. The workgroup identified 3 broad categories of focus: data limitations, opportunities for training for clinicians and health economists interested in collaboration, and the need for prospective economic study of cancer treatment. Within these areas of focus, the workgroup recommended the following: improvement of the availability of key economic measures in data available to researchers, creation of more comprehensive datasets robust to insurance type or coverage, development of cancer care health economics research-focused symposia, instituting clear mechanisms to support integration of economic analyses alongside clinical trials, development of standardized methods to measure the cost of cancer care to health-care systems and patients, and development of standardized evaluations that include measures of social determinants of health.

Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

In almost all clinical settings, patients are at risk for multiple potential events and, in consultation with health-care providers, must weigh the potential benefits and harms across these events when making decisions. As researchers seek to build an evidence base to inform these decisions, they must contend with a choice as to how they will handle the different events. One approach, arguably the standard approach in the literature, is to consider the events individually by conducting analyses and publishing results for each one at a time. Doing so, however, fails to acknowledge or exploit the inherent multivariate nature of the data, represents a lost opportunity, and results in an evidence base that is not aligned with how clinical decision-making is actually performed. The article by Prentice et al. (Am J Epidemiol. 2020;189(9):972–981) in this issue of the Journal moves beyond this standard by illustrating recently developed methods that directly take advantage of information on the co-occurrence of multiple events. Moreover, their article highlights the role of modern methods in deriving additional information and insight from studies of multiple clinical outcomes by making full use of multivariate data, with the goal being to complement, not replace, existing methods.

Objective The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies. Materials and Methods Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission. Results Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term. Discussion Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting. Conclusions Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative.

Data are limited regarding whether the availability of biomarker-directed therapy for lung cancer exacerbates racial and socioeconomic disparities. Patients diagnosed with stage IV lung adenocarcinoma from 2008 to 2013 were identified using Surveillance, Epidemiology, and End Results Program-Medicare. The primary outcome was a Medicare claim for molecular testing within 60 days of diagnosis, analyzed using multivariable logistic regression; the secondary outcome was overall survival, analyzed using multivariable Cox proportional hazards models. All statistical tests were two-sided. Of 5556 patients, 1437 (25.9%) had molecular testing. Testing rates were 14.1% among black, 26.2% among white, and 32.8% among patients of Asian/other descent (adjusted P

A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.

BACKGROUND Treatment options for colorectal cancer (CRC) have improved substantially over the past 25 years. Measuring the impact of these improvements on survival outcomes is challenging, however, against the background of overall survival gains from advancements in the prevention, screening, and treatment of other conditions. Relative survival is a metric that accounts for these concurrent changes, allowing assessment of changes in CRC survival. We describe stage- and location-specific trends in relative survival after CRC diagnosis. METHODS We analyzed survival outcomes for 233965 people in the Surveillance Epidemiology and End Results (SEER) program who were diagnosed with CRC between January 1, 1975, and December 31, 2003. All models were adjusted for sex, race (black vs white), age at diagnosis, time since diagnosis, and diagnosis year. We estimated the proportional difference in survival for CRC patients compared with overall survival for age-, sex-, race-, and period-matched controls to account for concurrent changes in overall survival using two-sided Wald tests. RESULTS We found statistically significant reductions in excess hazard of mortality from CRC in 2003 relative to 1975, with excess hazard ratios ranging from 0.75 (stage IV colon cancer; P < .001) to 0.32 (stage I rectal cancer; P < .001), indicating improvements in relative survival for all stages and cancer locations. These improvements occurred in earlier years for patients diagnosed with stage I cancers, with smaller but continuing improvements for later-stage cancers. CONCLUSIONS Our results demonstrate a steady trend toward improved relative survival for CRC, indicating that treatment and surveillance improvements have had an impact at the population level.

Background. The Cancer-Specific Geriatric Assessment (CSGA) is a primarily self-administered paper survey of validated measures. Methods. We developed and tested the feasibility of a computer-based CSGA in patients ≥70 years of age who were receiving treatment for gastrointestinal malignancies at the Dana-Farber Cancer Institute. From December 2009 to June 2011, patients were invited to complete the CSGA at baseline (start of new treatment) and follow-up (at the first of 4 months later or within 4 weeks of completing treatment). Feasibility endpoints were proportion of eligible patients consented, proportion completing CSGA at baseline and follow-up, time to complete CSGA, and proportion of physicians reporting CSGA results that led to a change in clinical decision-making. Results. Of the 49 eligible patients, 38 consented (76% were treatment naive). Median age was 77 years (range: 70–89 years), and 48% were diagnosed with colorectal cancer. Mean physician-rated Karnofsky Performance Status was 87.5 at baseline (SD 8.4) and 83.5 at follow-up (SD 8). At baseline, 92% used a touchscreen computer; 97% completed the CSGA (51% independently). At follow-up, all patients used a touchscreen computer; 71% completed the CSGA (41% independently). Mean time to completion was 23 minutes at baseline (SD 8.4) and 20 minutes at follow-up (SD 5.1). The CSGA added information to clinical assessment for 75% at baseline (n = 27) and 65% at follow-up (n = 17), but it did not alter immediate clinical decision-making. Conclusion. The computer-based CSGA feasibility endpoints were met, although approximately half of patients required assistance. The CSGA added information to clinical assessment but did not affect clinical decision-making, possibly due to limited alternate treatment options in this subset of patients.

Hormone therapy is the mainstay of adjuvant treatment for hormone receptor positive (HR-positive) nonmetastatic breast cancer. We evaluated adjuvant hormone therapy (AHT) initiation among Medicaid-insured women aged 21-64 years with stage I-III HR-positive breast cancer. We used multivariable logistic regression to identify independent predictors of AHT initiation. Within 1 year of diagnosis, 68% (1049/1538) initiated AHT; by 18 months, 80% (1168/1461) initiated AHT. In multivariable analysis, women less likely to initiate AHT had more comorbidity (≥ 2 vs none: adjusted odds ratio (AOR) = 0.55; 95% CI = 0.32 to 0.97), more advanced disease (stage III vs I: AOR = 0.27; 95% CI = 0.18 to 0.39), and no radiation after breast conserving surgery (AOR = 0.15; 95% CI = 0.10 to 0.22). Race, age, and history of mental health disorders were not independently associated with initiation of AHT. Among initiators of AHT, 58% (604/1049) were adherent to treatment for the year after initiation. Despite comprehensive prescription coverage, only 39% (604/1538) received optimal AHT including prompt initiation and adherence for the year after treatment. Partnerships between Medicaid programs and cancer registries may help identify at-risk women and facilitate the implementation of quality improvement strategies.

Background. Because poverty is difficult to measure, its association with outcomes for serious illnesses such as hematologic cancers remains largely uncharacterized. Using Medicaid enrollment as a proxy for poverty, we aimed to assess potential disparities in survival after a diagnosis of acute myeloid leukemia (AML) or Hodgkin's lymphoma (HL) in a nonelderly population. Methods. We used records from the New York (NY) and California (CA) state cancer registries linked to Medicaid enrollment records for these states to identify Medicaid enrolled and nonenrolled patients aged 21–64 years with incident diagnoses of AML or HL in 2002–2006. We compared overall survival for the two groups using Kaplan–Meier curves and Cox proportional hazards analyses adjusted for sociodemographic and clinical factors. Results. For HL, the adjusted risk for death for Medicaid enrolled compared with nonenrolled patients was 1.98 (95% confidence interval [CI], 1.47–2.68) in NY and 1.89 (95% CI, 1.43–2.49) in CA. In contrast, for AML, Medicaid enrollment had no effect on survival (adjusted hazard ratio, 1.00; 95% CI, 0.84–1.19 in NY and hazard ratio, 1.02; 95% CI, 0.89–1.16 in CA). These results persisted despite adjusting for race/ethnicity and other factors. Conclusions. Poverty does not affect survival for AML patients but does appear to be associated with survival for HL patients, who, in contrast to AML patients, require complex outpatient treatment. Challenges for the poor in adhering to treatment regimens for HL could explain this disparity and merit further study.

The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the "PRO-CTCAE." The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI's cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self-reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials.

Background The learning curve for surgery — i.e., improvement in surgical outcomes with increasing surgeon experience — remains primarily a theoretical concept; actual curves based on surgical outcome data are rarely presented. We analyzed the surgical learning curve for prostate cancer recurrence after radical prostatectomy. Methods The study cohort included 7765 prostate cancer patients who were treated with radical prostatectomy by one of 72 surgeons at four major US academic medical centers between 1987 and 2003. For each patient, surgeon experience was coded as the total number of radical prostatectomies performed by the surgeon before the patient ’ s operation. Multivariable survival – time regression models were used to evaluate the association between surgeon experience and prostate cancer recurrence, defined as a serum prostatespecific antigen (PSA) of more than 0.4 ng/mL followed by a subsequent higher PSA level (i.e., bio che mical recurrence ), with adjustment for established clinical and tumor characteristics. All P values are two-sided. Results The learning curve for prostate cancer recurrence after radical prostatectomy was steep and did not start to plateau until a surgeon had completed approximately 250 prior operations. The predicted probabilities of recurrence at 5 years were 17.9% (95% confidence interval [CI] = 12.1% to 25.6%) for patients treated by surgeons with 10 prior operations and 10.7% (95% CI = 7.1% to 15.9%) for patients treated by surgeons with 250 prior operations (difference = 7.2%, 95% CI = 4.6% to 10.1%; P

Progression-free survival (PFS) is increasingly used as an endpoint for cancer clinical trials. Disease progression is typically assessed on the basis of radiologic testing at scheduled time points or after a fixed number of treatment cycles. The date of the radiologic evaluation at which progression is first evident is used as a proxy for the true progression time. The true progression time actually lies somewhere within the time interval between two assessments, a situation that results in interval-censored data. An analysis that ignores this interval censoring and uses the detection date as the date of progression unavoidably results in an overestimation of median PFS. This overestimation can erroneously result in a result being described as clinically significant when in fact a longer median PFS may just be a consequence of the length of the surveillance interval. Furthermore, if surveillance intervals are heterogenous within a disease group, comparisons of median PFS across studies may not be meaningful. The decision to use PFS as a primary endpoint should be made carefully when designing clinical trials, and investigators focused on a particular disease should develop consensus standards and strive for consistent surveillance intervals.

Background Strong associations between provider (i.e., hospital or surgeon) procedure volumes and patient outcomes have been demonstrated for many types of cancer operation. We performed a population-based cohort study to examine these associations for ovarian cancer resections. Methods We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify 2952 patients aged 65 years or older who had surgery for a primary ovarian cancer diagnosed from 1992 through 1999. Hospital- and surgeon-specific procedure volumes were ascertained based on the number of claims submitted during the 8-year study period. Primary outcome measures were mortality at 60 days and 2 years after surgery, and overall survival. Length of hospital stay was also examined. Patient age at diagnosis, race, marital status, comorbid illness, cancer stage, and median income and population density in the area of residence were used to adjust for differences in case mix. All P values are two-sided. Results Neither hospital- nor surgeon-specific procedure volume was statistically significantly associated with 60-day mortality following primary ovarian cancer resection. However, differences by hospital volume were seen with 2-year mortality; patients treated at the low-, intermediate-, and high-volume hospitals had 2-year mortality rates of 45.2% (95% confidence interval [CI] = 42.1% to 48.4%), 41.1% (95% CI = 38.1% to 44.3%), and 40.4% (95% CI = 37.4% to 43.4%), respectively. The inverse association between hospital procedure volume and 2-year mortality was statistically significant both before (P = .011) and after (P = .006) case-mix adjustment but not after adjustment for surgeon volume. Two-year mortality for patients treated by low-, intermediate-, and high-volume surgeons was 43.2% (95% CI = 40.7% to 45.8%), 42.9% (95% CI = 39.5% to 46.4%), and 39.5% (95% CI = 36.0% to 43.2%), respectively; there was no association between 2-year mortality and surgeon procedure volume, with or without case-mix adjustment. After case-mix adjustment, neither hospital volume (P = .031) nor surgeon volume (P = .062) was strongly associated with overall survival. Conclusion Hospital- and surgeon-specific procedure volumes are not strong predictors of survival outcomes following surgery for ovarian cancer among women aged 65 years or older.

BACKGROUND For many diseases, specialized care (i.e., care rendered by a specialist) has been associated with superior-quality care (i.e., better outcomes). We examined associations between physician specialty and outcomes in a population-based cohort of elderly ovarian cancer surgery patients. METHODS We analyzed the Medicare claims, by physician specialty, of all women aged 65 years or older who underwent surgery for pathologically confirmed invasive epithelial ovarian cancer between January 1, 1992, and December 31, 1999, while living in an area monitored by the Surveillance, Epidemiology, and End Results (SEER) program to assess important care processes (i.e., the appropriate extent of surgery and use of adjuvant chemotherapy) and outcomes (i.e., surgical complications, ostomy rates, and survival). All statistical tests were two-sided. RESULTS Among 3067 ovarian cancer patients who underwent surgery, 1017 patients (33%) were treated by a gynecologic oncologist, 1377 patients (45%) by a general gynecologist, and 673 patients (22%) by a general surgeon. Among patients with stage I or II disease, those treated by a gynecologic oncologist (60%) were more likely to undergo lymph node dissection than those treated by a general gynecologist (36%) or a general surgeon (16%). Patients with stage III or IV disease were more likely to undergo a debulking procedure if the initial surgery was performed by a gynecologic oncologist (58%) than by a general gynecologist (51%) or a general surgeon (40%; P < .001) and were more likely to receive postoperative chemotherapy when operated on by a gynecologic oncologist (79%) or a general gynecologist (76%) than by a general surgeon (62%, P < .001). Survival among patients operated on by gynecologic oncologists (hazard ratio [HR] of death from any cause = 0.85, 95% confidence interval [CI] = 0.76 to 0.95) or general gynecologists (HR = 0.86, 95% CI = 0.78 to 0.96) was better than that among patients operated on by general surgeons. CONCLUSIONS Ovarian cancer patients treated by gynecologic oncologists had marginally better outcomes than those treated by general gynecologists and clearly superior outcomes compared with patients treated by general surgeons.

We report that patients treated with cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), occasionally develop a magnesium wasting syndrome with inappropriate urinary excretion. We first observed this phenomenon in a 34-year-old male patient with metastatic colorectal cancer who developed profound fatigue and symptomatic hypocalcemia and hypomagnesemia while on cetuximab plus irinotecan therapy. Other medications with the potential to cause magnesium wasting had not been administered. Intravenous magnesium supplementation was required for the duration of cetuximab therapy, but electrolyte abnormalities resolved after discontinuation of treatment. This case prompted review of serum chemistry reports for a consecutive case series of 154 colorectal cancer patients treated with cetuximab. Thirty-four patients (22%) had at least one serum magnesium measurement during cetuximab treatment, and six had grade 3 (< 0.9 mg/dL) and two had grade 4 (< 0.7 mg/dL) hypomagnesemia. Because EGFR is strongly expressed in the kidney, particularly in the ascending limb of the loop of Henle where 70% of filtered magnesium is reabsorbed, EGFR blockade may interfere with magnesium transport. Because symptoms may be rapidly ameliorated with supplementation, we suggest that, when fatigue or hypocalcemia is encountered during cetuximab therapy, serum magnesium level be measured and repleted as necessary.

Background: Patients diagnosed with superficial bladder cancer who have not undergone total cystectomy are at high risk for recurrence, and bladder surveillance with cystoscopy is recommended for such patients every 3–6 months. We examined the degree to which bladder cancer patients undergo the recommended surveillance procedures and identified patient and primary care provider characteristics associated with nonadherence to these recommendations. Methods: We used information obtained from the Surveillance, Epidemiology, and End Results (SEER) Program– Medicare-linked database to identify 6717 patients aged 65 years or older who were diagnosed with superficial bladder cancer from 1992 through 1996 and who survived for at least 3 years after diagnosis but did not have a total cystectomy. We used information obtained from Medicare claims forms to examine the frequency with which these patients had a surveillance examination of the bladder during each of five contiguous 6-month intervals from month 7 to month 36 following diagnosis. We examined characteristics of patients and their physicians that were associated with low-intensity surveillance (defined as having an examination during fewer than two of the five possible follow-up intervals). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were twosided. Results: Only 40% of the entire cohort had an examination during all five intervals; 1216 patients (18.1%) had low-intensity surveillance. Patient characteristics that were independently associated with low-intensity surveillance were being age 75 years or older (adjusted OR = 1.54, 95% CI = 1.35 to 1.74), nonwhite (adjusted OR = 1.94, 95% CI = 1.57 to 2.40), and having favorable tumor histology (adjusted OR = 0.59, 95% CI = 0.48 to 0.72 for poorly differentiated versus referent well-differentiated tumor grade) and high comorbidity (adjusted OR = 1.72, 95% CI = 1.30 to 2.27). Residence in an urban area or in a census tract with low median income was also associated with low-intensity surveillance. Conclusions: The actual practice of surveillance for patients with superficial bladder cancer differs substantially from the standards recommended in clinical guidelines. [J Natl Cancer Inst 2003;95:588–97]

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

Background: Composite endpoints (CEP), such as progression-free survival, are commonly used in cancer research. Notwithstanding their popularity, however, CEP analyses suffer from a number of drawbacks, especially when death is combined with a nonterminal event (ie, progression or recurrence), exemplifying the semicompeting risks setting. We investigated the semicompeting risks framework as a complementary analysis strategy that avoids certain drawbacks of CEPs. Methods: The illness-death model under the semicompeting risks framework was compared with standard analysis approaches: CEP analyses and (separate) univariate analyses for each component endpoint. Data from a previously published phase III randomized clinical trial in metastatic colon cancer including 1419 participants in the N9741 trial (conducted between 1997 and 2003) were used to determine the impact of the loss of information associated with combining multiple endpoints, as well as of ignoring the potentially informative role of death. A simulation study was conducted to further explore these issues. Results: Failure to account for critical features of semicompeting risks data can lead to potentially severely misleading conclusions. Advantages of semicompeting risks analyses include a clear delineation of treatment effects on both events, the ability to draw conclusions about a patient’s joint risk of the two events, and an assessment of the dependence between the two event types. Conclusions: Embedding and analyzing component outcomes in the semicompeting risks framework, either as a supplement or alternative to CEP analyses, represents an important, underutilized, and feasible opportunity for cancer research.

Author Summary Background. Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. Methods. Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. The primary endpoint was 2-month progression-free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients. Results. Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment-related grade 3/4 adverse events were lymphopenia (n = 1) and elevated alanine aminotransferase (n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3-II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3-II in patient lymphocytes demonstrated inconsistent autophagy inhibition. Conclusion. Mouse studies identified LC3-II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy.

Background. Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). Methods. The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. Results. Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3–4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9–3.6 months) and 5.6 months (95% CI: 4.4–10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). Conclusions. The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.

BACKGROUND Laparoscopic colectomy has been shown to have equivalent oncologic outcomes to open colectomy for the management of colon cancer, but its adoption nationally has been slow. This study investigates the prevalence and factors associated with laparoscopic colorectal resection at National Comprehensive Cancer Network (NCCN) centers. METHODS Data on patients undergoing surgery for colon and rectal cancer at NCCN centers from 2005 to 2010 were obtained from chart review of medical records for the NCCN Outcomes Project and included information on socioeconomic status, insurance coverage, comorbidity, and physician-reported Eastern Cooperative Oncology Group (ECOG) performance status. Associations between receipt of minimally invasive surgery and patient and clinical variables were analyzed with univariate and multivariable logistic regression. All statistical tests were two-sided. RESULTS A total of 4032 patients, diagnosed between September 2005 and December 2010, underwent elective colon or rectal resection for cancer at NCCN centers. Median age of colon cancer patients was 62.6 years, and 49% were men. The percent of colon cancer patients treated with minimally invasive surgery (MIS) increased from 35% in 2006 to 51% in 2010 across all centers but varied statistically significantly between centers. On multivariable analysis, factors associated with minimally invasive surgery for colon cancer patients who had surgery at an NCCN institution were older age (P = .02), male sex (P = .006), fewer comorbidities (P ≤ .001), lower final T-stage (P < .001), median household income greater than or equal to $80000 (P < .001), ECOG performance status = 0 (P = .02), and NCCN institution (P ≤ .001). CONCLUSIONS The use of MIS increased at NCCN centers. However, there was statistically significant variation in adoption of MIS technique among centers.

Those of us in large chaotic health-care systems, like that in the United States, look with particular interest at the experience in smaller more contained health systems, like that in The Netherlands, to glean how we might apply rational principles to organizing care delivery. In classical epidemiology, we have learned a tremendous amount by examining the experiences of those in The Netherlands and other countries, such as Scandinavia, who couple meticulous records on the vital status and health of their populations with high-quality cancer registries. Similarly, in clinical epidemiology and health services research, we gain enormously from evaluating the experiences of other health-care systems with different models of care delivery. It is therefore with great interest that we examine the study from The Netherlands by Vernooij et al. ( 1 ) that compares delivery of ovarian cancer care among generalized, semispecialized, and specialized hospitals. The authors sought to obtain information as to whether ovarian cancer patients who receive their care in specialty cancer hospitals have superior survival outcomes compared with those who receive their care in semispecialized or general hospitals. Using tumor registry data, they compared survival outcomes for the 40% of Dutch women who received ovarian cancer care at general hospitals with that of the 40% who received care at hospitals with some cancer expertise and the 20% who received care at specialty cancer centers. They found a 5-year relative survival of 38% at general hospitals, 39.4% at semispecialized hospitals, and 40.3% at specialty hospitals. They relied on 5-year relative survival — that is, the ratio of the observed survival to the survival that was expected based on the age- and period-specifi c mortality of the general population — as a proxy for cancer-specifi c survival, which is not reliably tracked by the cancer registry that they used. The limitations of the analysis by Vernooij et al. (1) and by others ( 2 – 4 ) are those that are inherent in their data source — population-based tumor registries. Although tumor registries in The Netherlands and elsewhere collect meticulous high-quality data on cancer site, histology, and stage, several critical pieces of information that infl uence both choice of treatment and cancer outcomes are missing. In particular, there is no information about comorbidity or performance status. Consequently, it is exceedingly diffi cult, if not impossible, to determine whether the survival differences reported are due to differences in the quality of care or to underlying systematic differences in the characteristics of patients who seek care at general vs specialty hospitals. This potential for selection bias is the bugaboo of scores of articles on regionalization of specialty cancer care as well as the related voluminous literature on volume – outcome relationships in cancer surgery. In the analysis of Vernooij et al. (1), we note that patients treated at general hospitals were an average of 5 years older and were substantially less likely to undergo primary surgical reduction or to receive systemic chemotherapy than those treated at more specialized centers. It is of course not possible to know whether the patients who did not undergo debulking surgery and chemotherapy would have received these interventions had they gone to a specialty center or whether these interventions would have improved their outcomes. However, both the age of the patients and the treatment differences strongly indicate that Dutch ovarian cancer patients who seek care at specialized hospitals have different characteristics from those who seek care at general hospitals. This potential for confounding makes it impossible to know whether the superior outcomes at specialty centers are a result of the patients’ underlying attributes and disease severity or of the care they received. Therefore, this analysis in and of itself does not justify regionalization of ovarian cancer surgery in The Netherlands to specialty centers. Although there are many reasons that explain why the care may be superior in specialty centers, the survival differences are quite modest and there is considerable evidence of selection when it comes to hospital choice. The data presented hint that generalized hospitals in The Netherlands may treat the very old and infi rm, who do not undergo surgery at all, as well as patients with early-stage uncomplicated disease, who generalist gynecologists may be more comfortable managing. Such a heterogeneous mixture of patients would attenuate differences in survival outcomes between generalized and specialized centers. The optimal strategy to mitigate selection bias is randomization. If women could be randomly assigned to receive their care in particular hospitals and systematic differences in their outcomes were evident, then we would have convincing evidence about how to organize care. However, the practical obstacles to randomly

Government agencies provide regular reports on progress in the fight against cancer, and these reports are viewed with great interest by researchers and by the media (1). The primary measures of the cancer burden are cancer incidence rates and cancer mortality rates. The latter are derived from state death certificates, which are completed by physicians, medical examiners, coroners, and funeral directors, and collated by the National Center for Health Statistics (NCHS) (2). The data from death certificates are compiled using the World Health Organization schema to determine the underlying cause of death. The classification rules are changed periodically; most recently in 1999 with the adoption of the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) (3). This general approach leads to the designation of a unitary “underlying” cause for each death. In practice, a death may be precipitated by multiple causes. Recently, the NCHS has developed a system for processing multiple classifications, including the use of relevant free text from the death certificate (2). However, the National Cancer Institute continues to report death rates using deaths for which cancer is designated as the sole underlying cause. In this issue of the Journal, Welch and Black (4) raise the concern that cancer death rates are systematically underestimated, in that many patients who die as a result of cancer treatment do not have cancer recorded as the underlying cause of death. The authors assembled data on the reported cause of death for all patients in the Surveillance, Epidemiology, and End Results (SEER) program from 1994 through 1998 who died within 1 month of cancer-directed surgery for one of 19 common solid tumors. They found that for 41% of these deaths, the cause was not attributed to cancer. The authors speculate that cancer treatment is the probable underlying cause for essentially all of these deaths and, as a result, the cancer mortality rate is underestimated by 0.9%. Welch and Black (4) also suggest that many deaths subsequent to 1 month after cancer-directed surgery may be similarly miscoded, leading to further underestimation. We note that the terminology related to death rates can be confusing. The term “cancer mortality rate” is used conventionally to represent a cancer death rate in the total population— where the denominator includes all people in the population with or without the cancer of interest. Thus, the metric is comparable to the “cancer incidence rate” in the population. By contrast, the term “cancer survival” usually refers to the mortality experience (survival rather than death) among patients with a cancer diagnosis. However, in studies of postoperative outcomes, the terms “operative mortality” or “surgical mortality” are often used, although the denominator includes only cancer surgery recipients. To calibrate their calculations throughout their article, Welch and Black (4) used population-based rates. The misattribution of cancer deaths is a long-studied issue (5–8). Welch and Black (4) appear to be especially concerned about systematic underestimation in the context of greater use of cancer screening tests. Greater use of cancer-directed surgery in patients with small, early-stage lesions leading to, presumably, more deaths following a cancer diagnosis that are not attributed to cancer could exaggerate the benefits of screening. Welch and Black (4) propose that for all deaths following cancer treatment—including radiotherapy, chemotherapy, and surgery— cancer should be designated as the underlying cause of death. They propose the development of “simple” though arbitrary rules, such as the designation of any death within 1 month of treatment as a cancer death. Although we agree that continued efforts to refine and improve the classification and reporting of cancer mortality statistics are worthwhile, and indeed are being pursued in the government agencies responsible for reporting vital statistics, the specific ideas proposed by Welch and Black (4) appear to us to be impractical and may themselves introduce inaccuracies. Consider first the proposal to designate all deaths within 1 month of surgery as cancer deaths, and take, as an example, the use of radical prostatectomy for prostate cancer. We know that the 1-month death rate following this procedure in men over 65 years of age is 0.49% (9). Welch and Black (4) would, by their convention, designate all of these deaths as cancer deaths. However, in an elderly population of this nature (i.e., men over age 65 years), the underlying force of mortality is strong. In fact, using death rates for men in the United States from the NCHS (2), adjusted to the age distribution of the surgery patients receiving prostatectomy, the underlying probability of death in any given month for this cohort of men is 0.28%. That is, of the operative deaths that occur, 57% are expected in the absence of the procedure. When viewed from this context, the observation by Welch and Black (4) that 75% of deaths within 1 month of prostatectomy are not attributed to cancer appears only modestly exaggerated. To be sure, patients who receive surgery are a selected group, because surgeons will generally not operate on patients who appear to be at imminent risk of death or are otherwise seriously medically compromised. Nonetheless, many deaths do occur suddenly and unpredictably. For procedures with much higher operative mortality than prostate cancer— such as pancreatectomy, esophagectomy, or lung resection—we agree that a higher proportion of the operative deaths are likely to be caused by the procedure. However, these are among the sites for which the reclassification proposed by Welch and Black (4) would have the least impact, because relatively few incident cases receive surgery, and the mortality rate of the disease is high relative to the incidence rate. Welch and Black (4) also propose greater efforts to educate individuals who prepare death certificates on basic strategies for ensuring that treatment-related deaths are attributed to cancer. However, this would appear to be a daunting and complex task, with uncertain payoff in improved accuracy, given the vast num