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Journal of Clinical Oncology

Journal of Clinical Oncology RSS feed - Early Release
Journal of Clinical Oncology



Purpose

Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations in individuals with Gorlin syndrome without PTCH1 mutations.

Methods

We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis.

Results

A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma.

Conclusion

We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation–positive individuals, with a risk up to 20x higher in SUFU mutation–positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.





Purpose

Internet support group (ISG) members benefit from receiving social support and, according to the helper therapy principle, by providing support to others. To test the mental health benefits of providing support to others, this trial compared the efficacy of a standard ISG (S-ISG) and an enhanced prosocial ISG (P-ISG).

Methods

A two-armed randomized controlled trial with 1-month pretest and post-test assessments was conducted with women (N = 184) diagnosed in the past 36 months with nonmetastatic breast cancer who reported elevated anxiety or depression. Women were randomly assigned to either the S-ISG or P-ISG condition. Both conditions included six professionally facilitated live chat sessions (90-minute weekly sessions) and access to an asynchronous discussion board; P-ISG also included structured opportunities to help and encourage others.

Results

Relative to the S-ISG, participants in the P-ISG condition exhibited more supportive behaviors (emotional, informational, and companionate support), posted more messages that were other-focused and fewer that were self-focused, and expressed less negative emotion (P < .05). Relative to the S-ISG, participants in the P-ISG condition had a higher level of depression and anxiety symptoms after the intervention (P < .05).

Conclusion

Despite the successful manipulation of supportive behaviors, the P-ISG did not produce better mental health outcomes in distressed survivors of breast cancer relative to an S-ISG. The prosocial manipulation may have inadvertently constrained women from expressing their needs openly, and thus, they may not have had their needs fully met in the group. Helping others may not be beneficial as a treatment for distressed survivors of breast cancer.


Purpose

Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.

Patients and Methods

We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer.

Results

Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients.

Conclusion

IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.


Purpose

Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown.

Patients and Methods

We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage.

Results

In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival.

Conclusion

Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.


Purpose

Pain is a frequent symptom in patients with cancer, with substantial impact. Despite the availability of opioids and updated guidelines from reliable leading societies, undertreatment is still frequent.

Methods

We updated a systematic review published in 2008, which showed that according to the Pain Management Index (PMI), 43.4% of patients with cancer were undertreated. This review included observational and experimental studies reporting negative PMI scores for adults with cancer and pain published from 2007 to 2013 and retrieved through MEDLINE, Embase, and Google Scholar. To detect any temporal trend and identify potential determinants of undertreatment, we compared articles published before and after 2007 with univariable, multivariable, and sensitivity analyses.

Results

In the new set of 20 articles published from 2007 to 2013, there was a decrease in undertreatment of approximately 25% (from 43.4 to 31.8%). In the whole sample, the proportion of undertreated patients fell from 2007 to 2013, and an association was confirmed between negative PMI score, economic level, and nonspecific setting for cancer pain. Sensitivity analysis confirmed the robustness of results.

Conclusion

Analysis of 46 articles published from 1994 to 2013 using the PMI to assess the adequacy of analgesic therapy suggests the quality of pharmacologic pain management has improved. However, approximately one third of patients still do not receive pain medication proportional to their pain intensity.


Purpose

We aimed to assess the impact of spin (ie, reporting to convince readers that the beneficial effect of the experimental treatment is greater than shown by the results) on the interpretation of results of abstracts of randomized controlled trials (RCTs) in the field of cancer.

Methods

We performed a two-arm, parallel-group RCT. We selected a sample of published RCTs with statistically nonsignificant primary outcome and with spin in the abstract conclusion. Two versions of these abstracts were used—the original with spin and a rewritten version without spin. Participants were clinician corresponding authors of articles reporting RCTs, investigators of trials, and reviewers of French national grants. The primary outcome was clinicians' interpretation of the beneficial effect of the experimental treatment (0 to 10 scale). Participants were blinded to study hypothesis.

Results

Three hundred clinicians were randomly assigned using a Web-based system; 150 clinicians assessed an abstract with spin and 150 assessed an abstract without spin. For abstracts with spin, the experimental treatment was rated as being more beneficial (mean difference, 0.71; 95% CI, 0.07 to 1.35; P = .030), the trial was rated as being less rigorous (mean difference, –0.59; 95% CI, –1.13 to 0.05; P = .034), and clinicians were more interested in reading the full-text article (mean difference, 0.77; 95% CI, 0.08 to 1.47; P = .029). There was no statistically significant difference in the clinicians' rating of the importance of the study or the need to run another trial.

Conclusion

Spin in abstracts can have an impact on clinicians' interpretation of the trial results.


Purpose

The National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) provide guidelines for surveillance after surgery for renal cell carcinoma (RCC). Herein, we assess the ability of the guidelines to capture RCC recurrences and determine the duration of surveillance required to capture 90%, 95%, and 100% of recurrences.

Patients and Methods

We evaluated 3,651 patients who underwent surgery for M0 RCC between 1970 and 2008. Patients were stratified as AUA low risk (pT1Nx-0) after partial (LR-partial) or radical nephrectomy (LR-radical) or as moderate/high risk (M/HR; pT2-4Nx-0/pTanyN1). Guidelines were assessed by calculating the percentage of recurrences detected when following the 2013 and 2014 NCCN and AUA recommendations, and associated Medicare costs were compared.

Results

At a median follow-up of 9.0 years (interquartile range, 5.7 to 14.4 years), a total of 1,088 patients (29.8%) experienced a recurrence. Of these, 390 recurrences (35.9%) were detected using 2013 NCCN recommendations, 742 recurrences (68.2%) were detected using 2014 NCCN recommendations, and 728 recurrences (66.9%) were detected using AUA recommendations. All protocols missed the greatest amount of recurrences in the abdomen and among pT1Nx-0 patients. To capture 95% of recurrences, surveillance was required for 15 years for LR-partial, 21 years for LR-radical, and 14 years for M/HR patients. Medicare surveillance costs for one LR-partial patient were $1,228.79 using 2013 NCCN, $2,131.52 using 2014 NCCN, and $1,738.31 using AUA guidelines. However, if 95% of LR-partial recurrences were captured, costs would total $9,856.82.

Conclusion

If strictly followed, the 2014 NCCN and AUA guidelines will miss approximately one third of RCC recurrences. Improved surveillance algorithms, which balance patient benefits and health care costs, are needed.



Purpose

We examined racial and ethnic disparities in patient-provider communication (PPC), perceived care quality, and patient activation among long-term cancer survivors.

Methods

In 2005 to 2006, survivors of breast, prostate, colorectal, ovarian, and endometrial cancers completed a mailed survey on cancer follow-up care. African American, Asian/Pacific Islander (Asian), Hispanic, and non-Hispanic white (white) survivors who had seen a physician for follow-up care in the past 2 years (n = 1,196) composed the analytic sample. We conducted linear and logistic regression analyses to identify racial and ethnic differences in PPC (overall communication and medical test communication), perceived care quality, and patient activation in clinical care (self-efficacy in medical decisions and perceived control). We further examined the potential contribution of PPC to racial and ethnic differences in perceived care quality and patient activation.

Results

Compared with white survivors (mean score, 85.16), Hispanic (mean score, 79.95) and Asian (mean score, 76.55) survivors reported poorer overall communication (P = .04 and P < .001, respectively), and Asian survivors (mean score, 79.97) reported poorer medical test communication (P = .001). Asian survivors were less likely to report high care quality (odds ratio, 0.47; 95% CI, 0.30 to 0.72) and reported lower self-efficacy in medical decisions (mean score, 74.71; P < .001) compared with white survivors (mean score, 84.22). No disparity was found in perceived control. PPC was positively associated with care quality (P < .001) and self-efficacy (P < .001). After adjusting for PPC and other covariates, when compared with whites, Asian disparities remained significant.

Conclusion

Asian survivors report poorer follow-up care communication and care quality. More research is needed to identify contributing factors beyond PPC, such as cultural influences and medical system factors.


Purpose

Traditional disease-free survival (DFS) does not reflect changes in prognosis over time. Conditional DFS accounts for elapsed time since achieving remission and may provide more relevant prognostic information for patients and clinicians. This study aimed to estimate conditional DFS among patients with ovarian cancer and to evaluate the impact of patient characteristics.

Patients and Methods

Patients were recruited as part of the Hormones and Ovarian Cancer Prediction case-control study and were included in the current study if they had achieved remission after a diagnosis of cancer of the ovary, fallopian tube, or peritoneum (N = 404). Demographic and lifestyle information was collected at enrollment; disease, treatment, and outcome information was abstracted from medical records. DFS was calculated using the Kaplan-Meier method. Conditional DFS estimates were computed using cumulative DFS estimates.

Results

Median DFS was 2.54 years (range, 0.03-9.96 years) and 3-year DFS was 48.2%. The probability of surviving an additional 3 years without recurrence, conditioned on having already survived 1, 2, 3, 4, and 5 years after remission, was 63.8%, 80.5%, 90.4%, 97.0%, and 97.7%, respectively. Initial differences in 3-year DFS at time of remission between age, stage, histology, and grade groups decreased over time.

Conclusion

DFS estimates for patients with ovarian cancer improved dramatically over time, in particular among those with poorer initial prognoses. Conditional DFS is a more relevant measure of prognosis for patients with ovarian cancer who have already achieved a period of remission, and time elapsed since remission should be taken into account when making follow-up care decisions.


Purpose

Patients with cancer commonly use complementary and alternative medicine, including herbs and supplements (HS), during cancer treatment. This national survey explored oncologists' knowledge, attitudes, and practice patterns regarding HS use by their patients.

Methods

A survey was sent by mail and e-mail to a random sample of 1,000 members of the American Society for Clinical Oncology. The questions covered several topics: communication patterns, attitudes about HS, education about HS, response to HS use among hypothetical patients with cancer, knowledge of HS adverse effects, and demographic information.

Results

Among eligible oncologists, 392 (42%) responded to the questionnaire. Most were white (75%) men (71%), with a mean age of 48 years (standard deviation, 9.8 years). On average, oncologists discussed use of HS with 41% of their patients; only 26% of discussions were initiated by the oncologist. Two of three oncologists indicated they did not have enough knowledge to answer questions from patients regarding HS, and 59% had not received any education about the topic. Physician factors associated with having initiated discussions with patients about the use of HS included female sex, higher self-reported knowledge, prior education about HS, increased knowledge about HS adverse effects and interactions, and estimating that > 40% of one's patients with cancer use HS.

Conclusion

Fewer than one half of oncologists are initiating discussions with patients about HS use, and many indicate that lack of knowledge and education is a barrier to such discussions. Improving physician education about HS may facilitate more physician-patient communication about this important topic.


Purpose

The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS.

Patients and Methods

Premenopausal women with axillary node-negative, hormone receptor–positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were disease-free survival (DFS) and overall survival (OS). Secondary end points included toxicity and patient-reported outcomes. Patient-reported outcome data included health-related quality of life, menopausal symptoms, and sexual function. These were evaluated at baseline, 6 months, 12 months, and then annually for up to 5 years after registration.

Results

In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for DFS (5-year rate: 87.9% v 89.7%; log-rank P = .62) or OS (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up.

Conclusion

When added to tamoxifen, OFS results in more menopausal symptoms and sexual dysfunction, which contributes to inferior self-reported health-related quality of life. Because of early closure, this study is underpowered for drawing conclusions about the impact on survival when adding OFS to tamoxifen.


Purpose

Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions.

Patients and Methods

Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST.

Results

Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10.

Conclusion

Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.


Purpose

To assess the effectiveness of a telephone-based peer-delivered intervention in reducing distress among women with a BRCA1 or BRCA2 gene mutation. The intervention involved trained peer volunteers contacting women multiple times over a 4-month period to provide informational, emotional, and practical support.

Methods

Three hundred thirty-seven participants completed the baseline questionnaire, and those reporting interest in talking to other mutation carriers were randomly assigned to either the usual care group (UCG; n = 102) or the intervention group (IG; n = 105). Participants and researchers were not blinded to group allocation. Two follow-up questionnaires were completed, one at the end of the intervention (4 months after random assignment, time 2) and one 2 months later (time 3). Outcomes included breast cancer distress (primary outcome), unmet information needs, cognitive appraisals about mutation testing, and feelings of isolation.

Results

There was a greater decrease in breast cancer distress scores in the IG than UCG at time 2 (mean difference, –5.96; 95% CI, –9.80 to –2.12; P = .002) and time 3 (mean difference, –3.94; 95% CI, –7.70 to –0.17; P = .04). There was a greater reduction in unmet information needs in the IG than UCG (P < .01), with unmet needs being lower in the IG than UCG at time 2. There was a greater reduction in Cognitive Appraisals About Genetic Testing stress subscale scores in the IG than UCG (P = .02), with significantly lower scores among the IG than UCG at time 2 (P < .01).

Conclusion

The intervention is effective in reducing distress and unmet information needs for this group of women. Identifying strategies for prolonging intervention effects is warranted.


Purpose

To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL).

Patients and Methods

In the SMARTE-R-CHOP-14 trial, rituximab 375 mg/m2 was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6xR-CHOP-14), on days –4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6xR-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial.

Results

The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index [IPI], 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients.

Conclusion

Extended rituximab exposure compared with eight 2-week applications in combination with 6xR-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6xR-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted.








Purpose

Although disparities in colorectal cancer (CRC) with regard to race, socioeconomic status, and geography are well documented, the extent to which these factors contribute to premature death resulting from CRC nationwide and by state is unknown.

Patients and Methods

We calculated age-standardized CRC death rates for three broad educational categories as a marker of socioeconomic status by race/ethnicity and state among individuals age 25 to 64 years from 2008 through 2010. We also calculated the proportion of premature death resulting from CRC that could potentially be averted in each state by applying the average death rate for the five states with the lowest rates among the most educated whites (Connecticut, North Dakota, Utah, Vermont, and Wisconsin) to all populations.

Results

Compared with those with the most education, those with the least education had significantly higher CRC death rates in virtually all states for each racial/ethnic group. For example, rate ratios ranged from 1.15 (95% CI, 0.66 to 2.01) in Delaware to 3.18 (95% CI, 2.01 to 5.05) in New Mexico among whites. Overall, half the premature deaths resulting from CRC that occurred nationwide from 2008 through 2010, or 7,690 deaths annually, would have been avoided if everyone had experienced the lowest death rates of the most educated whites. More premature deaths could be averted in southern states (60% to 70%) than in northern and western states (30% to 40%). Restricting the analyses to persons age 50 to 64 years, for whom CRC screening is recommended, resulted in similar findings.

Conclusion

The majority of premature deaths from CRC in southern states and half these deaths nationwide are due to racial/ethnic, socioeconomic, and geographic inequalities.




Purpose

Clinical practice guidelines (CPGs) and consensus statements (CSs) are used to apply evidence-based medicine or expert recommendations to clinical practice. Here we explore author financial conflicts of interest (FCOIs), sources of guideline funding, and their relationship with endorsement of specific drugs.

Methods

An electronic search of MEDLINE was conducted to identify CPGs and CSs for common solid cancers published between January 2003 and October 2013. The search was restricted to articles evaluating systemic therapy. We extracted data on self-reported author FCOIs, funding sources, use of manuscript writers, and endorsement of specific drugs in the abstract of the article.

Results

Of 142 articles evaluated, 64% were CPGs, and 36% were CSs. The proportion of articles reporting FCOIs improved from 11% in 2003 to 93% in 2013 (P for trend < .001). Only 45% of articles explicitly reported funding sources. Of these, 65% disclosed partial or full industry sponsorship. Use of manuscript writers was declared in 13%, but many articles did not explicitly report the role of authors in the writing of the manuscript. Endorsement of specific drugs was significantly associated with author FCOIs (odds ratio [OR], 7.29; P = .001), but not with industry funding (OR, 0.95; P = .37).

Conclusion

Reporting of FCOIs in CPGs and CSs has improved over time. Despite prevalent funding of guideline development by industry, such funding is not associated with endorsement of specific drugs. Author FCOIs are prevalent, and endorsement of a specific drug seems to be more common when authors have FCOIs with the pharmaceutical company marketing that drug.





Purpose

Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.

Methods

Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.

Results

Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.

Conclusion

In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.


Purpose

Data on smoking and second cancer risk among cancer survivors are limited. We assessed associations between smoking before first cancer diagnosis and risk of second primary smoking-associated cancers among survivors of lung (stage I), bladder, kidney, and head/neck cancers.

Methods

Data were pooled from 2,552 patients with stage I lung cancer, 6,386 with bladder cancer, 3,179 with kidney cancer, and 2,967 with head/neck cancer from five cohort studies. We assessed the association between prediagnostic smoking and second smoking-associated cancer risk with proportional hazards regression, and compared these estimates to those for first smoking-associated cancers in all cohort participants.

Results

Compared with never smoking, current smoking of ≥ 20 cigarettes per day was associated with increased second smoking-associated cancer risk among survivors of stage I lung (hazard ratio [HR] = 3.26; 95% CI, 0.92 to 11.6), bladder (HR = 3.67; 95% CI, 2.25 to 5.99), head/neck (HR = 4.45; 95% CI, 2.56 to 7.73), and kidney cancers (HR = 5.33; 95% CI, 2.55 to 11.1). These estimates were similar to those for first smoking-associated cancer among all cohort participants (HR = 5.41; 95% CI, 5.23 to 5.61). The 5-year cumulative incidence of second smoking-associated cancers ranged from 3% to 8% in this group of cancer survivors.

Conclusion

Understanding risk factors for second cancers among cancer survivors is crucial. Our data indicate that cigarette smoking before first cancer diagnosis increases second cancer risk among cancer survivors, and elevated cancer risk in these survivors is likely due to increased smoking prevalence. The high 5-year cumulative risks of smoking-associated cancers among current smoking survivors of stage I lung, bladder, kidney, and head/neck cancers highlight the importance of smoking cessation in patients with cancer.


Purpose

Distinguishing independent primary tumors from intrapulmonary metastases in non–small-cell carcinoma remains a clinical dilemma with significant clinical implications. Using next-generation DNA sequencing, we developed a chromosomal rearrangement–based approach to differentiate multiple primary tumors from metastasis.

Methods

Tumor specimens from patients with known independent primary tumors and metastatic lesions were used for lineage test development, which was then applied to multifocal tumors. Laser capture microdissection was performed separately for each tumor. Genomic DNA was isolated using direct in situ whole-genome amplification methodology, and next-generation sequencing was performed using an Illumina mate-pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction.

Results

A total of 41 tumor samples were sequenced (33 adenocarcinomas [ADs] and eight squamous cell carcinomas [SQCCs]), with a range of three to 276 breakpoints per tumor identified. Lung tumors predicted to be independent primary tumors based on different histologic subtype did not share any genomic rearrangements. In patients with lung primary tumors and paired distant metastases, shared rearrangements were identified in all tumor pairs, emphasizing the patient specificity of identified breakpoints. Multifocal AD and SQCC samples were reviewed independently by two pulmonary pathologists. Concordance between histology and genomic data occurred in the majority of samples. Discrepant tumor samples were resolved by genome sequencing.

Conclusion

A diagnostic lineage test based on genomic rearrangements from mate-pair sequencing demonstrates promise for distinguishing independent primary from metastatic disease in lung cancer.


Purpose

To analyze rate, risk factors, and costs associated with 30-day readmission after ovarian cancer surgery.

Patients and Methods

The SEER-Medicare linked database (1992 to 2010) was used to evaluate readmission rates within 30 days of index surgery in patients with stage IIIC/IV ovarian, primary peritoneal, or fallopian tube cancer. Multivariable logistic regression was used to identify factors associated with readmission.

Results

Of 5,152 eligible patients, 1,003 (19.5%) were readmitted within 30 days of discharge. Mean patient age was 75 years. Diagnoses associated with readmission included infection (34.7%), dehydration (34.3%), ileus/obstruction (26.2%), metabolic/electrolyte derangements (23.1%), and anemia (12.3%). In multivariable analysis, year of discharge was significantly associated with 30-day readmission (1996 to 2000: odds ratio [OR], 1.32; 95% CI, 1.01 to 1.71; 2001 to 2005: OR, 1.58; 95% CI, 1.24 to 2.0; 2006 to 2010: OR, 1.73; 95% CI, 1.35 to 2.21; referent years 1992 to 1995), as were length of index hospital stay more than 8 days (OR, 1.39; 95% CI, 1.18 to 1.64) and discharge to a skilled nursing facility (OR, 1.3; 95% CI, 1.04 to 1.63). Patients readmitted within 30 days had a significantly greater 1-year mortality rate compared with patients not readmitted (41.1% v 25.1%, respectively; P < .001). The median cost of readmission hospital stay was $9,220 in year 2010 dollars, with a total cost of $9.3 million over the study period.

Conclusion

Early readmission after surgery for ovarian cancer is common. There is a significant association between 30-day readmission and 1-year mortality. These findings may catalyze development of targeted interventions to decrease early readmission, improve patient outcomes, and control health care costs.


Purpose

Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort.

Patients and Methods

Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs).

Results

Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically.

Conclusion

The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.


Purpose

To examine the influence of age and conditioning with total-body irradiation (TBI) on the trajectory of cognitive functioning after treatment with pediatric hematopoietic stem-cell transplantation (SCT).

Patients and Methods

Pediatric patients who were scheduled to undergo a SCT were eligible for the study, with 315 patients completing a baseline assessment. Of these, 183 patients (58.1%) were alive at 1 year after SCT and completed additional assessments at 1, 3, and 5 years after SCT. Half of the long-term sample (52.1%) received TBI during conditioning. Cognitive functioning was assessed via age-appropriate standardized measures.

Results

At baseline, there were no differences in intelligence quotient (IQ) based on age. At 5 years after SCT, the youngest patients (< 3 years old at baseline) who received TBI demonstrated a significantly lower IQ than those who did not receive TBI (P = .05). Longitudinal analyses (piecewise linear mixed-effects models with a knot at 1 year after SCT) revealed a significant impact of age and TBI over time. The youngest patients evidenced declines in cognitive functioning during the first year; however, patients who did not receive TBI largely recovered their functioning in subsequent years. In contrast, young patients who received TBI failed to recover the losses experienced during the first year after SCT, demonstrating stability in their functioning, but at a lower level.

Conclusion

Our findings clarify the relationship between TBI and age on cognitive outcomes in pediatric SCT survivors. Young patients who receive TBI may benefit from early intervention efforts to minimize cognitive losses during the first year after SCT and to maximize potential recovery.


Purpose

Therapies that target overexpression of human epidermal growth factor receptor 2 (HER2) rely on accurate and timely assessment of all patients with new diagnoses. This study examines HER2 testing of primary breast cancer tissue when performed with immunohistochemistry (IHC) and additional in situ hybridization (ISH) for negative cases (IHC 0/1+). The analysis focuses on the rate of false-negative HER2 tests, defined as IHC 0/1+ with an ISH ratio ≥ 2.0, in eight pathology centers across Canada.

Patients and Methods

Whole sections of surgical resections or tissue microarrays (TMAs) from invasive breast carcinoma tissue were tested by both IHC and ISH using standardized local methods. Samples were scored by the local breast pathologist, and consecutive HER2-negative IHC results (IHC 0/1+) were compared with the corresponding fluorescence or silver ISH result.

Results

Overall, 711 surgical excisions of primary breast cancer were analyzed by IHC and ISH; HER2 and chromosome 17 centromere (CEP17) counts were available in all cases. The overall rate of false-negative samples was 0.84% (six of 711 samples). Interpretable IHC and ISH scores were available in 1,212 cases from TMAs, and the overall rate of false-negative cases was 1.6% (16 of 978 cases).

Conclusion

Our observation confirms that IHC is an adequate test to predict negative HER2 status in primary breast cancer in surgical excision specimens, even when different antibodies and IHC platforms are used. The study supports the American Society of Clinical Oncology/College of American Pathologists and Canadian testing algorithms of using IHC followed by ISH for equivocal cases.


Purpose

To determine whether any tumor biomarkers could account for the survival advantage observed in the LNH 03-2B trial among patients with diffuse large B-cell lymphoma (DLBCL) and low-intermediate risk according to the International Prognostic Index when treated with dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) compared with standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP).

Patients and Methods

Using immunohistochemistry, expression of CD10, BCL6, MUM1, MYC, and BCL2 and coexpression of MYC/BCL2 were examined. The interaction effects between each biomarker and treatment arm on survival were studied in a restricted model and a full model incorporating clinical parameters.

Results

Among the 379 patients analyzed in the trial, 229 tumors were evaluable for germinal center B-cell–like (GCB)/non-GCB subclassification according to the Hans algorithm. Among all the biomarkers, only the interaction between the Hans algorithm and the treatment arm was significant for progression-free survival (PFS) and overall survival (OS) in univariable (PFS, P = .04; OS, P = .01) and multivariable (PFS, P = .03; OS, P = .01) analyses. Non-GCB tumors predicted worse PFS (hazard ratio [HR], 3.21; 95% CI, 1.29 to 8.00; P = .01) and OS (HR, 6.09; 95% CI, 1.37 to 27.03; P = .02) among patients treated with R-CHOP compared with patients who received R-ACVBP, whereas there were no significant survival differences between these regimens among patients with GCB tumors.

Conclusion

The survival benefit related to R-ACVBP over R-CHOP is at least partly linked to improved survival among patients with non-GCB DLBCL. Therefore, the Hans algorithm could be considered a theragnostic biomarker for selecting young patients with DLBCL who can benefit from an intensified R-ACVBP immunochemotherapy regimen.


Purpose

Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC.

Patients and Methods

A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m2 intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m2 IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety.

Results

Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes.

Conclusion

Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.


Purpose

Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA.

Patients and Methods

In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20).

Results

For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer.

Conclusion

These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.



Purpose

To endorse the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guideline on adjuvant and salvage radiotherapy after prostatectomy. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines developed by other professional organizations.

Methods

The guideline on adjuvant and salvage radiotherapy after prostatectomy was reviewed for developmental rigor by methodologists. An ASCO endorsement panel then reviewed the content and recommendations.

Results

The panel determined that the guideline recommendations on adjuvant and salvage radiotherapy after prostatectomy, published in August 2013, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorsed the guideline on adjuvant and salvage radiotherapy after prostatectomy, adding one qualifying statement that not all candidates for adjuvant or salvage radiotherapy have the same risk of recurrence or disease progression, and thus, risk-benefit ratios are not the same for all men. Those at the highest risk for recurrence after radical prostatectomy include men with seminal vesicle invasion, Gleason score 8 to 10, extensive positive margins, and detectable postoperative prostate-specific antigen (PSA).

Recommendations

Physicians should discuss adjuvant radiotherapy with patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invasion, positive surgical margins, extraprostatic extension) and salvage radiotherapy with patients with PSA or local recurrence after prostatectomy. The discussion of radiotherapy should include possible short- and long-term adverse effects and potential benefits. The decision to administer radiotherapy should be made by the patient and multidisciplinary treatment team, keeping in mind that not all men are at equal risk of recurrence or clinically meaningful disease progression. Thus, the risk-benefit ratio will differ for each patient.




Purpose

To determine whether the addition of advanced-practice nurse (APN) telephone counseling to a printed survivorship care plan (SCP) significantly increases the proportion of at-risk survivors who complete cardiomyopathy screening.

Patients and Methods

Survivors age ≥ 25 years participating in the Childhood Cancer Survivor Study who received cardiotoxic therapy and reported no history of cardiomyopathy screening in the previous 5 years were eligible for enrollment. The 472 participants (mean age, 40.1 years; range, 25.0 to 59.0; 53.3% women) were randomly assigned to either standard care, consisting of an SCP summarizing cancer treatment and cardiac health screening recommendations (n = 234), or standard care plus two APN telephone counseling sessions (n = 238). The primary outcome—completion of cardiomyopathy screening within 1 year—was validated by medical records and compared between the two arms using adjusted relative risks (RRs) with 95% CIs.

Results

Participants in the standard and APN counseling groups were not statistically different by demographic or clinical characteristics. At the time of 1-year follow-up, 107 (52.2%) of 205 survivors in the APN group completed screening compared with 46 (22.3%) of 206 survivors in the non-APN group (P < .001). With adjustment for sex, age (< 30 v ≥ 30 years), and Children's Oncology Group–recommended screening frequency group (annual, 2 years, or 5 years), survivors in the APN group were > 2x more likely than those in the control group to complete the recommended cardiomyopathy screening (RR, 2.31; 95% CI, 1.74 to 3.07).

Conclusion

The addition of telephone counseling to an SCP with cardiac health screening recommendations increases cardiomyopathy screening in at-risk survivors.