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Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may articipate in this CE activity.
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Anita T. Shaffer
Although many treatment options exist for women with ductal carcinoma in situ (DCIS), clinicians often must “guestimate” when it comes to determining the risk of recurrence for patients who choose breast-conserving surgery and how best to manage their care, according to Kimberly J. Van Zee, MS, MD.
In order to help clarify the decision-making process, Van Zee has developed a nomogram that calculates the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery.
Ten clinical and pathological variables are taken into account with the nomogram which thenestimates a 5- and 10-year risk of recurrence in the same breast. Van Zee chose 10 variables that have been correlated with recurrence risk in prior research: age at diagnosis, family history, initial presentation, nuclear grade, necrosis, margin status, number of excisions, year of surgery, radiation therapy, and endocrine therapy. The tool is available free of charge on Memorial Sloan Kettering Cancer Center’s (MSK) website (www.nomograms.org).
The calculator is useful to clinicians and patients alike, said Van Zee, who is an attending surgeon at MSK and a professor of surgery at Weill Medical College of Cornell University. She discussed the nomogram in advance of her presentation on the topic at the 33rd Annual Miami Breast Cancer Conference,held March 13-16, 2016.
The nomogram can help physicians and patients weigh the pros and cons of the many treatment options available for DCIS by estimating the risk associated with each option. Van Zee said she often sits with patients and plugs information into the calculator so that they can understand their own recurrence risks and treatment choices.
“I find that women are often very educated and they’ve done a lot of research. They come in with 20 pages of questions off the Internet and they really relish having some kind of number to compare their options,” said Van Zee. For patients who might not be as comfortable with numbers, Van Zee translates the predictive values into more understandable terms, for example, “1 in 10 women like you.”
Although serious adverse events from radiation in this treatment setting are rare, Van Zee believes the potential harms must be considered because there is no survival benefit from radiation of DCIS. “In my practice, I try to help a woman weigh therisks and benefits of the various treatment optionsaccording to her own values,” said Van Zee. “Oneperson may be very risk averse, both in terms ofany treatment and any risk of recurrence ... On the other hand, there may be a woman who is very risk tolerant and chooses not to have radiation,” Van Zee said. “The nomogram will give her some estimate of her risk with that option so that she can assess if that risk is acceptable to her.”
To create the nomogram, Van Zee and colleagues looked at recurrences among 1868 patients who had undergone breast-conserving surgery for DCIS at MSK from 1991-2006.1
The calculator has since been validated in four external studies in different patient populations, most recently by researchers at Harvard MedicalSchool and Kaiser Permanente, Van Zee said in a presentation at the ASTRO Annual Meeting in October 2015.2,3 The studies calculated how well the nomogram performed in their populations, using a C-index.
The C-index in a perfect model is 1.0, according to Van Zee. The validation studies determined that the DCIS nomogram has a C-index ranging from 0.63 to 0.68, depending on the study, which compares favorably with several commercially available risk-assessment tools.2 Collins et al found that “the overall correlation between 10-year nomogrampredicted recurrences and observed recurrences was 0.95.”3
Van Zee’s next step for the nomogram is toincorporate margin width for women who have undergone surgery for DCIS. She and colleagues have recently published an analysis of marginwidth and risk of recurrence of DCIS, and she hopes that incorporation of these findings will improve the predictive model even further.4
1. Rudloff U, Jacks LM, Goldberg JL, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol. 2010;28(23):3762-3769.
2. Van Zee KJ. Recurrence risk estimation for DCIS treated with breast-conservation: an externally validated DCIS nomogram. Presented at: ASTRO 57th Annual Meeting; October 18-21, 2015; San Antonio, TX.
3. Collins LC, Achacoso N, Haque R, et al. Risk prediction for local breast cancer recurrence among women with DCIS treated in a community practice: a nested, case-control study. Ann Surg Oncol. 2015;22(suppl 3):502-508.
4. Van Zee KJ, Subhedar P, Olcese C, Patil S, Morrow M.The relationship between margin width and recurrence of ductal carcinoma in situ: analysis of 2996 women treated with breast-conserving surgery over 30 years. Ann Surg.2015;;262(4):623-631.
Jason M. Broderick
Among patients with HR-positive/HER2-negative or triple-negative metastatic breast cancer (MBC), nab-paclitaxel (Abraxane) improved time to treatment discontinuation (TTD), time to next treatment (TTNT), and had a favorable safety profile compared with paclitaxel, according to a real-world database analysis presented at the 33rd Annual MiamiBreast Cancer Conference.
Nab-paclitaxel is approved by the FDA for use in patients with MBC following the failure ofcombination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.
The approval was based on a pivotal phase IIItrial that showed an overall response rate of 33%with nab-paclitaxel versus 19% with paclitaxel inthe frontline or later settings. The median time toprogression was 5.3 months versus 3.9 months.
Despite this approval, there is a paucity ofcomparative effectiveness data in the real-world setting for subsets of patients with MBC who are HR+/HER2- or triple-negative. For this reason,Fadi Braiteh, MD, of the University of Nevada School of Medicine, and colleagues conducted aretrospective analysis comparing use of nabpaclitaxel versus paclitaxel in these subtypes.
Braiteh et al examined data from an electronic medical record platform (Navigating Cancer).Their analysis included patients with HR+/HER2- (n = 446) or triple-negative MBC (n = 228)who received first- or second-line treatment withnab-paclitaxel or paclitaxel between December 1,2010, and October 1, 2014.
The analysis included only patients treated in a real-world setting, not in clinical trials. Monotherapywas preferred, but patients were still included if they received combination regimens with a targeted agent.
Patients received at least 2 doses of nab-paclitaxelor paclitaxel. Nab-paclitaxel was administeredat the FDA-approved dose of 260 mg/m2 every 3 weeks, or 100 mg/m2 or 150 mg/m2 once per week for 3 of 4 weeks. Patients received paclitaxel at 175 mg/m2 every 3 weeks or 80 mg/m2 weekly.
In the HR+/HER2- group, TTD was significantly longer with nab-paclitaxel at 4.5 months versus 2.9 months with paclitaxel. The median TTNT was significantly improved with nab-paclitaxel at 6.9 versus 5.3 months, respectively. The TTD was also significantly longer with nab-paclitaxel in the triple-negative breast cancer (TNBC) cohort at 3.3 versus 2.8 months with paclitaxel. The median TTNT with nab-paclitaxel was numerically higher; however, the difference was not statistically significant: 6.2 versus 5.4 months.
Across both the HR+/HER2- and TNBC cohorts, neuropathy rates were lower and antiemetics and treatments for allergic reactions to doses were used less frequently among patients receiving nab-paclitaxel. Treatment for bone loss, granulocyte colony-stimulating factor, and hydrating agents were used less frequently with paclitaxel versus nab-paclitaxel.
In the HR+/HER2- arm, notable all-grade adverse events (AEs) with nab-paclitaxel versus paclitaxel included anemia (26% vs 33%), neutropenia (19% vs 14%), nausea and vomiting (12% vs 10%), pain (1% vs 11%), neuropathy (3% vs 8%), and dehydration (9% vs 7%).
The all-grade AE rates were comparable for nab-paclitaxel versus paclitaxel in the TNBC arm: anemia (24% vs 35%), neutropenia (18% vs 12%), nausea and vomiting (12% vs 5%), pain (5% vs 7%), neuropathy (1% vs 11%), and dehydration (15% vs 5%).
Tony Berberabe, MPH
Men with prostate cancer treated with radiotherapy were at higher risk for developing second malignancies in the bladder, colon, and rectum compared with men who were not exposed to radiotherapy,according to a systemic reviewand meta-analysis from theUniversity of Toronto.
Overall, 21 studies were selected for analysis. Robert K. Nam, MD, MSc, of the Division of Urology and colleagues reported an increased risk of cancers of the bladder (4 studies; adjusted HR, 1.67, 95% CI 1.55-1.80), colorectum (3 studies; adjusted HR, 1.70; 95% CI 1.34-2.38), and rectum (3 studies; adjusted HR, 1.79; 95% CI 1.34-2.38).
In contrast, secondary hematologic cancers (1 study) or lung cancers (2 studies) were not associated with exposure to radiotherapy. In addition, the researchers found that patients who received external beam radiotherapy had higher odds of developing a second malignancy as compared with patients who received brachytherapy. The researchers reported that the absolute rates, however, were low.
“We found a positive risk association,” said Nam. “This study clearly shows that physicians need to discuss the possibility of a second cancer after radiation treatment.”
The researchers focused on sites that are closest to the prostate gland: bladder, rectum, and colon. “Those are the vulnerable areas that are susceptible to radiation exposure when treating the prostate gland. We also looked at distant areas that could be susceptible because of radiation scatter. These sites include the bone and lung. Our study did not show an association for those distant sites.”
Treatment options for patients with a diagnosis of prostate cancer can include surgery or radiotherapy. Each option is associated with side effects including urinary incontinence and erectile dysfunction. Secondary cancers related to treatment represent perhaps the most serious of all complications, but previous studies have led to conflicting results.
Meta-analysis cannot establish cause and effect, but those involving observational research are useful for pulling evidence together. These results were consistent when the researchers restricted analyses to studies using 5- or 10-year lag periods between treatment and the development of a secondary cancer. The researchers noted in the analysis that odds ratios for bladder and rectal cancer increasedwith a longer lag time (odds ratio at 5-year lag vs10-year lag: 1.3 vs 1.89 for bladder cancer and1.68 vs 2.2 for rectal cancer), suggesting a potentialassociation between radiotherapy and the development of secondary malignancy of the bladder and rectum.
“This information could be particularly important to a large proportion of patients in which treatment is recommended and according to treatment guidelines in which surgery or radiation would be equal options for them to choose,” said Nam.
Armed with this information from the study, urologists are in a better position to discusstreatment options with their patients, said Nam. “Informed decision making is so important. It’s important for patients to be aware of this risk and to understand the complications that could arise from treatment.”
Nam explained that for patients who are at low risk and candidates for active surveillance, second malignancies are not an issue. At the other end of the spectrum, those patients with high-risk,aggressive disease will likely die from it before the development of a second malignancy.
“But the group who might require treatment, where treatment provides long-term cancer control,these survivors could suffer the ill effects of radiation treatment. It is these patients who are at risk for developing these types of cancers, and it’s important for urologists to discuss the risk with them.”
Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systemic review and meta-analysis. BMJ. 2016;352:i851.
Pamela Ann Hall, RN, OCN, BSN
Jason M. Broderick
Patients with advanced ovarian cancer harboring mutations in homologous recombination (HR) genes, including BRCA1/2, had improved survival versus patients without HR mutations, according to a mutational analysis of the phase III GOG 218 study presented at the 2016 Society of Gynecologic Oncology (SGO) Annual Meeting. Abstract 1
In the primary GOG 218 analysis, add-on bevacizumab (Avastin) followed by maintenance bevacizumab improved progression-free survival (PFS) by 3.8 months versus chemotherapy alone in the frontline setting for patients with stage III/IV ovarian cancer. (N Engl J Med. 2011;365(26):2473-2483).
The analysis presented at SGO showed that among patients with BRCA1, BRCA2, and non-BRCA HR mutations, respectively, the reduction in the risk of death, regardless of the treatment received, was 26%, 64%, and 33%, compared with patients without HR mutations. The risk of disease progression was decreased by 20%, 48%, and 27%, respectively.
The findings also demonstrated that HR mutations did not mitigate the benefit of adding bevacizumab to standard care.
“All 3 mutation-carrier groups had significantly better progression-free and overall survival when compared to those with no mutations,” said lead author Barbara S. Norquist, MD, a gynecologic oncologist at the University of Washington, who presented the results at the meeting. The double-blind, phase III GOG-218 trial included 1873 patients with untreated stage III/IV ovarian cancer who had undergone debulking surgery. Patients were randomized to carboplatin (AUC 6) and paclitaxel (175 mg/m2) with placebo (n = 625), bevacizumab initiation from cycles 2 through 7 (n = 625), or bevacizumab continuation starting at cycle 2 and continuing throughout the study (n = 623). Bevacizumab was administered at 15 mg/kg every 3 weeks.
Using the BROCA-HR assay, Norquist et al sequenced germline and/or somatic DNA from 1195 women (63.8%) who participated in GOG 218. The researchers identified germline or somatic BRCA1, BRCA2, or non-BRCA HR mutations in 12.4% (n = 148), 6.5% (n = 78), and 6.8% (n = 81), of patients, respectively. No HR mutations were detected in 74.3% of the population.
In the primary GOG-218 analysis, the median PFS with bevacizumab continuation was 14.1 months compared with 10.3 months with chemotherapy alone (HR, 0.717; 95% CI, 0.625-0.824; P <.001). The bevacizumab-initiation arm did not demonstrate a statistical difference compared with placebo (HR, 0.908; P = .16). A significant difference in overall survival (OS) was not observed between the arms.
Using proportional hazard models, Norquist et al estimated the hazard ratios for OS and PFS for the HR mutation subgroups versus the non-mutation population. The median OS was 55.3 months, 75.2 months, and 56.0 months in the BRCA1, BRCA2, and non-BRCA HR mutation subgroups, respectively, compared with 42.1 months in the group without HR mutations. The median PFS was 15.7 months, 21.6 months, and 16.0 months in the BRCA1, BRCA2, and non-BRCA HR mutation subgroups, spectively, compared with 12.6 months in the group without HR mutations.
When combining the 3 groups of patients with HR mutations and comparing them with the non-HR mutation population, bevacizumab provided a similar improvement in PFS, regardless of mutation status. In the non-HR mutation group, the median PFS was 15.7 months in the bevacizumab continuation arm (n = 281) versus 10.6 months with chemotherapy alone (n = 300), representing a 5.1-month PFS benefit.
Among the combined group of patients with HR mutations, the median PFS was 19.6 months in the bevacizumab-continuation arm (n = 120) versus 15.4 months with chemotherapy alone (n = 108), representing a 4.2-month PFS benefit.
Summarizing the findings she presented, Norquist remarked, “This is important prognostic information for patients and highlights the importance of knowing genetic status in clinical trials in ovarian cancer.”
Marieta Branis, DNP, ANP, NP-C
Lauren M. Green
An investigational extended-release formulation of the antiemetic granisetron achieved a complete response (CR) more often than did ondansetron among patients with cancer receiving highly emetogenic cisplatin-based chemotherapy, a new analysis of a randomized trial showed. Abstract 5988
The proportion of patients who had complete response in the delayed phase of chemotherapy administration was 64.8% with APF530 compared with 56.3% of patients randomized to ondansetron.
Secondary endpoints—including complete response in the acute phase and overall; complete control, and total response—all favored the investigational antiemetic, as reported at the Society of Gynecologic Oncology meeting in San Diego.
The findings were consistent with those of the overall trial, which showed a statistically significant improvement in complete response with APF530. As a post-hoc analysis, the results in the cisplatin-treated subgroup lacked statistical power to demonstrate significant differences between treatment groups.
“Relatively few studies have looked at management of chemotherapy-induced nausea and vomiting (CINV) in patients treated with platinum-based regimens,” said Lee Schwartzberg, MD, a medical oncologist at the West Clinic in Memphis, Tennessee.
“The data from this trial provided an opportunity to do that, and we found that the results were the same as in the overall trial, which was driven by a majority of patients who were receiving AC (doxorubicin/cyclophosphamide) chemotherapy.”
“APF530 is the only 5-HT3 receptor antagonist to demonstrate superiority over another as part of the guideline-recommended regimen in a three-drug versus three-drug phase III efficacy trial.”
APF530 consists of 2% granisetron in a proprietary viscous bioerodible vehicle that undergoes controlled hydrolysis after administration to effect extended release of granisetron for prevention of acute and delayed CINV.
A single subcutaneous dose of APF530 has been shown to achieve and maintain therapeutic levels of granisetron for at least 5 days (Cancer Manag Res. 2015; 7:83-92).
Schwartzberg and colleagues reported findings from a subgroup analysis of the phase III MAGIC trial, which compared APF530 and ondansetron—each in combination with the neurokinin-1 receptor antagonist fosiprepitant and dexamethasone—in 942 patients receiving highly emetogenic chemotherapy regimens.
The trial had a primary endpoint of CR, defined as no emesis and no use of rescue medication for CINV during the delayed phase (24-120 hours).
As reported at the 2015 meeting of the American Society of Clinical Oncology, the primary analysis showed that the APF530 treatment group had a significantly higher rate of CR: 64.7% versus 56.6% (P = .014).
The posthoc subgroup analysis involved 251 patients treated with cisplatin-based chemotherapy, the most common combination being cisplatin plus gemcitabine (27.1%). The type of cancer for the indicated chemotherapy was not recorded.
As in the overall trial, the primary endpoint for the subgroup analysis was CR during the delayed phase. Secondary endpoints included CR in the acute phase and overall; complete control (CR plus no more than mild nausea); and total response (CR and no nausea).
The analysis yielded a primary outcome (8.5% absolute difference in favor of APF530) almost identical to that of the overall trial (8.0% absolute difference).
Acute-phase CR rates were 84.0% with APF530 and 80.2% with ondansetron, and overall CR rates were 60.8% and 54.8%. For the endpoint of complete control, all comparisons favored the APF530 group: delayed phase (61.6% vs 53.2%), overall (58.4% vs 50.8%), and acute phase (84.0% vs 76.2%).
Total response rates were 48.0% for APF530 and 45.2% for ondansetron in the delayed phase, 48.0% versus 44.4% overall, and 81.6% versus 73.8% during the acute phase.
Among women treated with cisplatin-based chemotherapy (45% of the subgroup), most of the endpoints were numerically greater for APF530 as compared with the total subgroup. Absolute differences in CR were 10.3% in the delayed phase, 10.0% overall, and 8.9% in the acute phase.
Kristin Barber, RN, MSN,APRN