Release Date: September 22, 2018
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New Standard Established for Frontline Squamous NSCLC
Jason M. Broderick
The immunotherapy agent pembrolizumab (Keytruda), in combination with chemotherapy, is proving effective in treating metastatic squamous non–small cell lung cancer (NSCLC). Findings from the phase III KEYNOTE-407 trial presented at the 2018 ASCO Annual Meeting showed that adding pembrolizumab to frontline carboplatin/paclitaxel or nab-paclitaxel (Abraxane) reduced the risk of death by 36% compared with chemo-therapy alone in this patient population.
The median overall survival (OS) was 15.9 months (95% CI, 13.2-not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0008). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.
Progression-free survival (PFS) also improved with the addition of pembrolizumab. The median PFS was 6.4 months (95% CI, 6.2-8.3) with the PD-1 inhibitor compared with 4.8 months (95% CI, 4.3-5.7) with chemo-therapy alone (HR, 0.56; 95% CI, 0.45-0.70; P<.0001). Although the PFS benefit was also observed across all PD-L1 expression levels, there was a correlation between an increase in PD-L1 level and a greater magnitude of benefit.
The objective response rate (ORR) in the pembrolizumab arm was 57.9%, comprising a complete response (CR) rate of 1.4% and a partial response (PR) rate of 56.5%. In the control arm, the ORR was 38.4%, comprising a CR rate of 2.1% and a PR rate of 36.3%. The duration of response was 7.7 months (range, 1.1+ to 14.7+) versus 4.8 months (1.3+ to 15.8+) in the pembrolizumab versus placebo arms, respectively.
In the pembrolizumab cohort, 28.1% of patients had stable disease, 6.1% had progressive disease, and 2.2% were not evaluable for response. The corresponding rates in the chemotherapy-alone group were 37.0%, 13.9%, and 2.5%, respectively.
In the phase III KEYNOTE-407 trial (NCT- 02775435), 559 treatment-naive patients with metastatic squamous NSCLC received carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks or weekly nab-paclitaxel (100 mg/m2) plus pembrolizumab (200 mg every 3 weeks) or placebo for 4 cycles (each 3 weeks), followed by single-agent pembrolizumab (200 mg every 3 weeks) or placebo for up to 31 cycles, for a potential total of 35 cycles. After the initial 4 cycles, patients randomized to the placebo arm were allowed to cross over to receive pembrolizumab for the potential additional 31 cycles.
In the pembrolizumab cohort, 278 patients were treated; 281 received chemotherapy alone. In the pembrolizumab arm, 121 patients remained on treatment and 157 discontinued primarily due to progressive disease (n = 99) and adverse events (AEs; n = 48). In the chemotherapy-alone arm, 72 patients remained on treatment and 208 discontinued, primarily due to progression (n = 166) and AEs (n = 25).
PD-L1 status was measured by tumor proportion score (TPS). In the pembrolizumab arm, 34.2%, 37.1%, and 26.1% had a PD-L1 TPS status of <1%, 1%-49%, and ≥50%, respectively. The corresponding rates in the placebo arm were 35.2%, 37.0%, and 26.0%.
The HRs for OS were 0.61, 0.57, and 0.64 favoring the pembrolizumab arm in the TPS <1%, <1%-49%, and ≥50% subgroups, respectively. Across the same 3 subgroups, the HRs for PFS favoring the pembrolizumab arm were 0.68, 0.56, and 0.37.
The median treatment duration was 6.3 months in the pembrolizumab arm compared with 4.7 months in the placebo arm. Grades 3 to 5 all-causes AEs occurred in 69.8% versus 68.2%, respectively. Treatment-related AEs (TRAEs) led to discontinuation in 23.4% of the experimental arm versus 11.8% of the control arm. Grades 3 to 5 immune-mediated AEs and infusion reactions occurred in 10.8% versus 3.2%, respectively. Overall, TRAEs led to death in 3.6% versus 2.1% of the 2 arms.
In June, the FDA granted a priority review to the use of pembrolizumab in combination with chemotherapy as a first-line treatment for metastatic squamous NSCLC, regardless of PD-L1 expression. The agency is set to make its decision by October 30, 2018.
Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(suppl; abstr 105). abstracts.asco.org/214/AbstView_214_228023.html.
Kidney Removal May Be Unnecessary With Sunitinib Therapy in Metastatic Kidney Cancer
Sunitinib (Sutent) monotherapy appeared noninferior to cytoreductive nephrectomy and adjuvant sunitinib, the current standard of care for patients with synchronous metastatic renal cell carcinoma (mRCC), according to results from a phase III study presented at the 2018 ASCO Annual Meeting.1
This may impact standard of care moving forward, as the monotherapy appeared to extend survival; however, the trial was only powered to evaluate noninferiority, not superiority.
PHASE III CARMENA TRIAL
In the phase III CARMENA trial (NCT00930033), the median overall survival (OS) was 18.4 months in those who received sunitinib compared with 13.9 months in the standard-of-care arm (HR, 0.89; 95% CI, 0.71-1.10). The prespecified noninferiority margin was ≤1.20 for the upper limit of the confidence interval.
Sunitinib produced similar median OS results for patients with intermediate (23.4 versus 19.0 months; HR, 0.92; 95% CI, 0.68-1.24) and poor prognoses (13.3 versus 10.2 months; HR, 0.85; 95% CI, 0.62-1.17), according to Memorial Sloan Kettering Cancer Center risk groups. Patients with good prognoses were excluded from the trial.
Median progression-free survival (PFS) was 7.2 months (95% CI, 6.2-8.5) with sunitinib alone versus 8.3 months (95% CI, 6.2-9.9) with surgery/sunitinib.
“Sunitinib alone is not inferior to nephrectomy followed by sunitinib,” said lead study author Arnaud Méjean, MD, a urologist at Hôpital Européen Georges-Pompidou—Paris Descartes University. “When medical treatment is required, cytoreductive nephrectomy should no longer be considered the standard of care for these patients with synchronous metastatic disease.”
Patients at 79 centers in France, Norway, and the United Kingdom were assigned to cytoreductive nephrectomy followed by sunitinib 3 to 6 weeks later (n = 226) or 50 mg of once-daily sunitinib for 4 weeks on/2 weeks off (n = 224) from 2009 to 2017. In the surgery arm, 6.7% of patients did not undergo nephrectomy and 22.5% never received sunitinib. In the sunitinib arm, 4.9 % of patients never received sunitinib and 17% had secondary nephrectomy.
At a median follow-up of 50.9 months, investigators found that the overall response rate was 35.9% in both groups and the rate of tumor shrinkage was similar between the treatment groups (27.4% versus 29.1%). The clinical benefit rate in the sunitinib group was 47.9% compared with 36.6% in the surgery group.
The FDA approved sunitinib for the adjuvant treatment of adults at high risk for recurrent RCC following nephrectomy in November 2017 based on results from the multicenter, international, double-blind, placebo-controlled S-TRAC trial.2,3
After a median follow-up of 5.4 years, the median disease-free survival (DFS) was 6.8 years (95% CI, 5.8-not reached) in the sunitinib arm compared with 5.6 years (95% CI, 3.8-6.6) with placebo (HR, 0.76; 95% CI, 0.59-0.98; P = .03). In higher-risk patients, the median DFS was 6.2 years (95% CI, 4.9-not reached) versus 4.0 years (95% CI, 2.6-6.0) in favor of sunitinib (HR, 0.74; 95% CI, 0.55-0.99; P = .04).
ASCO expert Sumanta Kumar Pal, MD, associate clinical professor, Department of Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, California, said that findings from retrospective studies appear to show a benefit associated with nephrectomy. However, the prospective, randomized results from CARMENA show that this may not be the case.
“In the context of the targeted therapy sunitinib, there doesn’t necessarily seem to be a need to remove the kidney in patients with advanced and metastatic disease,” Pal said. “[Dr Méjean has] really sort of flipped the existing paradigm that we have in the management of advanced kidney cancer in this regard.”
Pal noted that the recent approvals of cabozantinib (Cabometyx) for treatment-naïve patients and the combina-tion of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for patients with intermediate- and poor-risk disease may eventually make sunitinib obsolete.
In the phase II CABOSUN trial, first-line cabozantinib reduced the risk for progression or death by 52% compared with sunitinib. The median PFS was 8.6 versus 5.3 months, respectively (HR, 0.48; 95% CI, 0.31-0.74; P = .0008).4
In the phase III CheckMate-214 trial, the combination reduced the risk for death by 32% compared with sunitinib. The risk reduction was 37% in patients with intermediate-and poor-risk RCC, who constituted about 75% of the intent-to-treat population.5
“In the context of these newer therapies, we may potentially have to go back to the drawing board once again and assess the relevance of removing the primary tumor,” Pal concluded.
- Méjen A, Escudier B, Thezenas S, et al. CARMENA: cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. J Clin Oncol. 2018;36(suppl; abstr LBA3). abstracts.asco.org/214/AbstView_214_220283.html
- Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.
- Ravaud A, Motzer RJ, Pandha HS, et al. Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA11. oncologypro.esmo.org/Meeting-Resources/ESMO-2016/Phase-III-trial-of-sunitinib-SU-vs-placebo-PBO-as-adjuvant-treatment-for-high-risk-renal-cell-carcinoma-RCC-after-nephrectomy-S-TRAC
- Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38. academic.oup.com/annonc/article/28/suppl_5/mdx440.032/4109944
- Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/CheckMate-214-Efficacy-and-safety-of-nivolumab-ipilimumab-N-I-v-sunitinib-S-for-treatment-naive-advanced-or-metastatic-renal-cell-carcinoma-mRCC-including-IMDC-risk-and-PD-L1-expression-subgroups
Pancreatic Cancer Survival Improves Significantly With 4-Drug Chemo Combination
Anita T. Shaffer
In a major advance that set a new standard of care in patients with resected pancreatic cancer, a modified FOLFIRINOX (mFOLFIRINOX); (leucovorin [folinic acid], 5-fluorouracil, irinotecan, oxaliplatin) regimen dramatically improved survival compared with standard gemcitabine as postoperative therapy.
Findings from the PRODIGE 24/CCTG PA.6 study showed that with mFOLFIRINOX, median overall survival (OS) was nearly 20 months longer than with gemcitabine (54.4 versus 35.0 months), which represents a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; P = .003).1 The median disease-free survival (DFS) was 8.8 months longer with mFOLFIRINOX than with gemcitabine.
Researchers reporting the findings at the 2018 ASCO Annual Meeting said that mFOLFIRINOX should be the new adjuvant standard of care for those who are fit enough to undergo the chemotherapy combination after surgery.
“The gemcitabine arm is better than in every previous trial, but the median [overall] survival we got with the FOLFIRINOX regimen is the best ever achieved in any previous adjuvant treatment,” said lead author Thierry Conroy, MD, a medical oncologist and director of the Institut de Cancerologie de Lorraine in Nancy, France, when discussing the findings during a press conference.
“FOLFIRINOX was more toxic than gemcitabine, but it’s still a safe regimen with manageable toxicities,” he said. “The FOLFIRINOX regimen should be considered the new standard of care after pancreatic cancer resection in patients with good performance status.”
Andrew S. Epstein, MD, Memorial Sloan Kettering Cancer Center, who was serving as an ASCO expert, noted that “because FOLFIRINOX is a relatively challenging regimen and, as we see, [there are] more toxicities from it compared with single-agent gemcitabine, we need to make sure that we recommend this regimen in the appro-priate people—people who are healthy enough to withstand the rigorousness of the regimen.”
STUDY DESIGN AND RATIONALE
The PRODIGE 24/CCTG PA.6 study involved 493 patients with nonmetastatic pancreatic ductal adenocarcinoma treated at 77 French and Canadian centers from April 2012 to October 2016. It was conducted through Unicancer, a network of comprehensive cancer centers in France and a leading clinical trial sponsor in Europe.
To be eligible, patients were required to undergo surgery and have no tumor residue on a postoperative CT scan. Participants had to be between the ages of 18 and 79 years with World Health Organization performance status scores of ≤1.
Three to 12 weeks after surgery, participants were randomized 1:1 to receive mFOLFIRINOX or gemcitabine for 6 months. The mFOLFIRINOX regimen consisted of oxaliplatin, leucovorin, and irinotecan administered intravenously at day 1, followed by 5-fluorouracil via continuous intravenous (IV) infusion over 46 hours, for 12 two-week cycles. Gemcitabine was administered via IV infusion on days 1, 8, and 15 every 28 days for 6 cycles.
The value of postoperative chemotherapy with gemcitabine and/or fluoropyrimidine for patients with pancreatic cancer has been established for 10 years, Conroy said. Nevertheless, most patients still relapse within 2 years.
In 2011, Conroy and colleagues demonstrated that FOLFIRINOX is more effective than single-agent gemcitabine as a first-line treatment in the metastatic setting for patients with pancreatic cancer and a good performance status.2 However, Conroy said the toxicities associated with that regimen made it a difficult choice for adjuvant therapy. Instead, investigators designed the trial with mFOLFIRINOX, which does not include bolus IV 5-fluorouracil and is therefore less likely to result in hematologic toxicities and excessive diarrhea.3
KEY FINDINGS IN TRIAL
The primary endpoint of the PRODIGE 24/CCTG PA.6 study was DFS. After a median follow-up of 33.6 months, patients who received mFOLFIRINOX had a median DFS of 21.6 months compared with 12.8 months with gemcitabine (HR, 0.58; 95% CI, 0.46-0.73; P < .001). The 3-year DFS was 39.7% with mFOLFIRINOX and 21.4% with gemcitabine.
In addition to improved median OS, a secondary endpoint of the study, mFOLFIRINOX demonstrated a superior OS rate (63.4% versus 48.6%) and cancer-specific survival rate (66.2% versus 51.2%) compared with gemcitabine at 3 years.
In terms of safety signals, mFOLFIRINOX resulted in higher rates of grade 3 or 4 adverse events (AEs) than gemcitabine, respectively, for diarrhea (18.6 versus 3.7%), fatigue (11.0% versus 4.6%), vomiting (5.0% versus 1.2%), and mucositis (2.5% versus 0%). There also was a 9.3% rate of grade 3/4 sensory peripheral neuropathy. In the gemcitabine arm, the rate of grade 3/4 AEs was higher for thrombocytopenia (4.5% versus 1.3%) and febrile neutropenia (3.7% versus 2.9%). Patients treated with gemcitabine also experienced significantly higher rates of grades 1 to 4 headache, fever, flu-like symptoms, lymphopenia, and transaminase increases. There was 1 toxic death in the gemcitabine arm, Conroy said.
Although the findings show a significant benefit with mFOLFIRINOX, Conroy said single-agent gemcitabine remains an option for patients who have poor performance status scores 12 weeks after surgery and in those with clear contraindications to the regimen.
Epstein said that the decision would hinge on a patient’s comorbidities. For example, if a patient has neuropathy, he may consider the combination of gemcitabine and capecitabine (Xeloda), which was validated for this population in the ESPAC-4 study last year.4
Next steps for the research include exploring whether mFOLFIRINOX would be beneficial to patients before surgery.
- Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4001. meetinglibrary.asco.org/record/159164/abstract.
- Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi: 10.1056/NEJMoa1011923.
- Mahaseth H, Brutcher E, Kauh J, et al. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. Pancreas. 2013;42(8):1311-1315. doi: 10.1097/MPA.0b013e31829e2006.
- Neoptolemos JP, Palmer DH, Ghaneh P, et al; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6.
Apalutamide Reduces Risk of PSA Progression by 94% in Nonmetastatic CRPC
Jason M. Broderick
Apalutamide (Erleada) lowered the risk of prostate-specific antigen (PSA) progression by 94% in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to a posthoc analysis from the phase III SPARTAN trial presented at the 2018 American Urological Association (AUA) Annual Meeting.1
The median time to PSA progression was not reached in the apalutamide arm compared with 3.71 months in the placebo group (HR, 0.064; 95% CI, 0.052-0.080; P <.0001). A separate retrospective cohort study presented at AUA underscored the significance of these apalutamide data by confirming prior observations of the link between faster PSA doubling time (PSADT) and poorer metastasis-free survival (MFS) and overall survival (OS).2
“Patients with nonmetastatic castration-resistant prostate cancer are at risk for metastases and mortality. In these patients, PSA doubling time is an important predictor of outcomes, including time to developing metastases or symptoms from their cancer,” Eric Small, MD, co-principal investigator of the SPARTAN study, said in a statement.
“This analysis further underscores the efficacy of apalutamide therapy and helps us understand how PSA changes in these patients are associated with clinical outcomes,” added Small, who is a professor of medicine, chief of the Division of Hematology and Oncology, and deputy director of the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco.
In February 2018, the FDA approved apalutamide for the treatment of patients with nonmetastatic CRPC, based on MFS data from the SPARTAN trial. The median MFS was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).
The SPARTAN trial evaluated the safety and efficacy of apalutamide versus placebo in 1207 patients with nonmetastatic CRPC and a rapidly rising PSA level despite receiving continuous androgen deprivation therapy. Nonmetastatic status was determined by a negative bone scan and a negative CT of the pelvis, abdomen, chest, and brain. Patients were required to have a PSA doubling time of ≤10 months.
Patients were randomized in a 2:1 ratio to 240 mg of apalutamide daily (n = 806) or placebo (n = 401). The median baseline PSAs were 7.78 and 7.96 ng/mL in the 2 arms, respectively, and the corresponding average baseline PSA doubling time was 4.4 versus 4.5 months. Patients who developed metastases were allowed to receive abiraterone acetate (Zytiga) plus prednisone.
Beyond the primary MFS endpoint, secondary endpoints included time to metastasis, progression-free survival, time to symptomatic progression, and OS. For patients who developed metastases, the researchers also evaluated the time between randomization to first treatment for metastatic CRPC and subsequent progression.
According to the posthoc data presented at AUA, a confirmed PSA response was reported for 90 percent of the apalutamide arm versus 2% of the placebo arm (relative risk, 40.09; 95% CI, 20.99-76.58; P <.0001). Among patients receiving apalutamide, the median time to PSA response was 29 days (range, 8-310).
At 12 weeks following randomization, the median PSA in the apalutamide group deceased by 90% compared with a 40% increase in patients receiving placebo. Additionally, 66% of patients in the apalutamide arm achieved a 90% maximum decline in PSA from baseline at any time point on the trial compared with only 1% in the placebo group.
The retrospective analysis of PSADT presented at AUA used data from 84,479 patients with prostate cancer from the Optum integrated electronic health records and claims database accrued between 2007 and 2017. Patients were considered high risk if they had a PSADT ≤10 months and low risk if their PSADT was >10 months.
Surgical and/or medical castration was administered to 15,431 patients. Among this group, 947 developed nonmetastatic CRPC, with 504 meeting criteria for continuous medical castration. The median patient age was 78.0 years at the onset of nonmetastatic CRPC.
PSADT was evaluable in 393 patients, of whom 38.2% (n = 150) were high risk and 61.8% (n = 243) were low risk. The median MFS was 15.2 versus 30.5 months in the high- versus low-risk populations, respectively (P < .0001). The median OS was 36.0 versus 57.6 months, respectively (P = .0092).
Leanne Schimke MSN, CRNP, FNP-C, CUNP
- Small EJ, Lee JY, Lopez-Gitlitz A, et al. Prostate-specific antigen (PSA) outcomes in patients (PTS) with nonmetastatic castration-resistant prostate cancer (NMCRPC) treated with apalutamide (APA): results from phase 3 SPARTAN study. Presented at: AUA Annual Meeting; May 18-21, 2018; San Francisco, CA. Abstract PD10-11. jurology.com/article/S0022-5347(18)39931-2/fulltext
- Saad F, Mehra M, Small EJ, et al. A population-based study of the association of prostate-specific antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (NMCRPC) patients (PTS). Presented at: AUA Annual Meeting; May 18-21, 2018; San Francisco, CA. Abstract PD10-04. jurology.com/article/S0022-5347(18)39924-5/pdf.
Advanced Prostate Cancer Clinic
Patients with nonmetastatic castration-resistant prostate cancer had limited treatment options until the approval of apalutamide (Erleada). Treatment consisted of androgen-deprivation therapy until metastatic disease was detected. Apalutamide opens up a new horizon.
It is important as nurses to educate and monitor our patients for significant adverse events (AEs) related to apalutamide. The most common AEs are fatigue, rash, falls and fractures, hypothyroidism, hypertension, peripheral edema, and hot flushes. Seizure risk is 0.2%.
The rash is macular-maculopapular and occurs within the first 3 months of therapy. Treatment consists of a topical steroid cream and antihistamines along with holding apalutamide for 2 to 3 weeks until the rash resolves. In the trial, 4% required oral steroids for resolution. Hypothyroidism occurred with elevated thyroid-stimulating hormone (TSH) in 25% of patients, requiring initiation or adjustment of thyroid medication. In the SPARTAN clinical trial, TSH levels were checked every 4 months, with median onset of elevated levels at 113 days after initiation of apalutamide. For the first year of therapy, expert opinion is to check the TSH level every 4 months then once yearly as long as the patient is on drug therapy.
The increased risk of falls (16%) and fractures (12%) in the clinical trial with only 10% of the patients treated for bone health indicates an area that should be monitored. As nurses, we need to be assessing the patients for their fall risk and they should be on bone health medication to help prevent fractures.
Overall, apalutamide was very well tolerated with no changes in quality of life indices. Apalutamide therapy in the right population is another step forward in the treatment of advanced prostate cancer.
Trial Induces “Best Ever” Survival Data Among Young Patients With Certain T-Cell Cancers
Jason M. Broderick
Adding nelarabine (Arranon) to escalating-dose methotrexate (C-MTX) increased the 4-year disease-free survival (DFS) rate to 91% in pediatric and young adult patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL), according to results from the phase III AALL0434 trial.
The study, presented at the 2018 ASCO Annual Meeting, included 3 other treatment arms comprising C-MTX alone, high-dose MTX (HD-MTX) alone, or HD-MTX plus nelarabine, a chemotherapy drug. All patients initially received the COG-augmented Berlin-Frankfurt-Munster (aBFM) multidrug chemotherapy regimen.
Among 1545 evaluable patients, the 4-year results included an overall survival rate of 90.2% and an event-free survival rate of 84.1%. The 4-year DFS rates were 88% among patients receiving a nelarabine combination versus 83% for patients receiving HD-MTX or C-MTX alone. Additionally, the number of central nervous system relapses was lower among patients receiving nelarabine, and there was no difference in neurotoxicities between treatment arms.
“AALL0434 is the largest clinical trial for children and young adult patients with T-ALL/T-LL ever conducted [and] has the best ever survival data [in this population],” lead study author Kimberly Dunsmore, MD, professor, Virginia Tech Carilion School of Medicine, said in a presscast held in advance of the meeting.
“T-cell ALL is a disease that requires the use of a very intense and complex chemotherapy regimen. Historically, about 80% of people live at least 4 years after being treated for their disease, but we felt we could and must do better. Our trial shows that we could further increase survival rates by about 10%, which is very encouraging,” Dunsmore explained in a statement.
Between January 2007 and July 2014, the phase III AALL0434 trial enrolled 1895 patients with newly diagnosed T-ALL (94%) or T-LL (6% of patients). Patients were aged 1 to 30 years.
The study used a 2 x 2 pseudo-factorial randomization. All patients enrolled on the 4-arm trial initially received COG aBFM chemotherapy. They were then randomized to receive HD-MTX plus leucovorin rescue or C-MTX without leucovorin rescue plus pegaspargase.
A second randomization was done for patients with T-ALL or T-LL who had an intermediate or high risk of recurrence. These patients were randomized to no nelarabine or six 5-day courses of 650 mg/m2 of nelarabine daily. Thus, the 4 treatment arms were HD-MTX alone, C-MTX alone, HD-MTX plus nelarabine (intermediate-and high-risk patients), and C-MTX plus nelarabine (intermediate- and high-risk patients).
Prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation was also administered to the intermediate- and high-risk patient with T-ALL. Additionally, patients with T-ALL in whom induction therapy failed were assigned nonrandomly to receive HD-MTX plus nelarabine. Compared with the 91% 4-year DFS rate with nelarabine plus C-MTX, the rate was 89.8% (+/- 3.0%) with C-
MTX alone. Among patients randomized to nelarabine plus HD-MTX, the 4-year DFS was 86.2% (+/- 3.2%) versus 78.0% (+/- 3.7%) with HD-MTX alone. The 4-year DFS rate was 54% for patients who did not achieve induction remission, which Dunsmore said was “more than double” previously reported rates.
There was no added benefit with nelarabine for high-risk patients with T-LL, with a 4-year DFS rate of 85.0% (+/- 5.6%) for those receiving the additional drug compared with 89.0% (+/- 4.7%) for those who did not.
Regarding safety, Dunsmore et al wrote in their abstract, “Overall toxicity and neurotoxicity were acceptable and not significantly different between all 4 arms.”
Commenting on future directions for the research, Dunsmore said, “Next steps [are] to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation to decrease long-term neurologic side effects. We think this may be possible, since nelarabine [led to] fewer CNS relapses.”
Nelarabine was approved by the FDA in October 2005 for the treatment of patients with relapsed/refractory T-ALL or T-LL following 2 or more chemotherapy regimens.
“Nelarabine, the drug employed here, is approved for relapsed or recurrent disease. And in this particular setting, moving it upfront closer to the initial treatment improved the outcomes for those patients,” ASCO President Bruce E. Johnson, MD, FASCO, said during the presscast.
Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: a randomized trial testing nelarabine in newly diagnosed t-cell malignancy. J Clin Oncol. 2017;36(suppl; abstr 10500). abstracts.asco.org/214/AbstView_214_218959.html
Belinda Mandrell, PhD, RN
Director, Nursing Research
St. Jude Children’s Research Hospital
Although numerous options have been added to treatment regimens for precursor B-cell acute lymphocytic leukemia, treatment advancements for T- cel l acute lymphocytic leukemia (T-ALL) and T-cell lymphocytic lymphoma (T-LL) remain limited. Disease-free survival (DFS) and overall survival (OS) for children with T-cell disease are lower than B-cell disease. In 2005, nelarabine (Arranon) was approved for patients with relapsed or refractory T-ALL and T-LL receiving ≥2 chemotherapy regimens.
The recent findings from Dunsmore et al’s Children’s Oncology Group (COG) multi-institutional, randomized study have significant implications for children and adolescents with T-ALL and T-LL. Nelarabine not only improved OS but also DFS for patients not achieving induction remission. Patients receiving nelarabine had few central nervous system relapses, prompting COG to consider removing cranial irradiation in future studies.
Although overall toxicity and neurotoxicity profiles were acceptable and not different between arms, nurses need to consider potential toxicities such as ataxia, vertigo, peripheral neuropathy, and reversible somnolence. In patients with T-cell disease, nelarabine improves outcomes and has few toxicities, with benefits of eliminating prophylactic cranial irradiation and associated neurocognitive deficits.