Clinical Insights: May 2018

Tuesday, May 22, 2018

Release Date: May 22, 2018
Expiration Date: May 22, 2019


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN18May
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Colorectal Cancer

NCCN Recommends Regorafenib Dose Escalation in Metastatic Colorectal Cancer

Jason Harris

The National Comprehensive Cancer Network (NCCN) has updated its colorectal cancer (CRC) guidelines, recommending a weekly regorafenib (Stivarga) dose-escalation strategy beginning at 80 mg and ending at 160 mg for previously treated patients with metastatic CRC (mCRC). The new dosing scheme starts with a dose of 80 mg/daily on days 1 to 7, escalates to 120 mg/daily on days 8 to 14, and concludes with 160 mg/daily on days 15 to 21. For subsequent cycles, the NCCN recommends 160 mg of regorafenib on days 1 to 21 every 28 days.

The updated results are based on findings from ReDOS, a phase II regorafenib dose-optimization study comparing the dose-escalation regimen with the standard dose of 160 mg of regorafenib daily. The median overall survival (OS) was 9.0 months in the dose-escalation arm versus 5.9 months in the standard arm (P = .0943).

The 6-month OS rate was 66.5% (95% CI, 53.8-82.2) in the escalation arm versus 49.8% (95% CI, 37.2-66.8) in the standard arm. Twelve-month OS also favored the dose-escalation arm, at 34.4% versus 26.7%.

Additionally, the median progression-free survival (PFS) favored dose escalation (2.5 vs 2.0 months). The 6-month PFS rate was 12.2% (95% CI, 5.4%-27.5%) in the escalation arm versus 11.8% (95% CI, 5.2%-26.6%) in the standard arm. However, the 12-month PFS rate favored the standard arm, at 5.9% versus 2.4%. Regorafenib was approved by the FDA in 2012 for treating patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy and, if KRAS wild-type, with an anti-EGFR therapy. The approval was based on the phase III CORRECT trial, in which the median OS was 6.4 months in the regorafenib group versus 5.0 months in the placebo group (HR, 0.77; 95% CI, 0.64-0.94; 1-sided P = .0052). Patients in the regorafenib arm received the treatment at 160 mg orally once daily for 3 weeks of every 4-week cycle.

Tanios Bekaii-Saab, MD, professor of medicine at Mayo Clinic in Phoenix, Arizona, presented ReDOS at the 2018 Gastrointestinal Cancers Symposium in January. In an interview with sister publication OncologyLive®, he called the findings “practice changing.”

“The most important aspect of this study is that now we have another option, and I think it is a preferred option, of how to administer regorafenib,” Bekaii-Saab said. “As we get more confirmatory studies, [we might want] to consider regorafenib a little earlier if we want to get the full benefit of the agent, rather than wait until the end, when the patient is literally about to go to hospice. A dose-escalation strategy would make more sense now than the standard 160 mg. We have to become more proactive about how we place our drugs and how to optimize the dose-escalation strategy for regorafenib.”

In ReDOS, 54 patients were assigned to dose escalation, and 62 were assigned to standard dosing. All patients had an ECOG performance status of 0 (37.1%) or 1 (62.9%).

Four patients (7.4%) in the escalation arm had local recurrence, 37 (68.5%) had resected disease, and 13 (24.1%) had unresected disease compared with 1 (1.6%), 44 (71.0%), and 17 (27.4%) in the standard arm, respectively. The median age was 61 (range, 53-68), and a majority of patients were male (61.2%). The percentage with KRAS-mutated or wild-type tumors was nearly identical (46.6% vs 44.0%). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated a third. Patients in the doseescalation arm were more likely to meet that endpoint (43% vs 24%; P = .281). Investigators noted that toxicity was more favorable in the dose-escalation arm, and quality-of-life parameters improved, as well.

“Another finding that was very intriguing was the quality of life. The quality of life of patients, when you use the dose-escalating strategy from 80 mg to 120 mg to 160 mg, was not compromised…it was a straight line,” Bekaii-Saab said. “Whereby, with the higher standard dose of 160 mg, we see a drop in the quality of life that readjusts as you readjust the dose of the medication. That difference was consistent across every parameter that was included in the quality of life.”

REFERENCE
Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4):611.
 
Lung Cancer

New Treatments for Lesser-Known Targets in NSCLC Are Emerging

Gina Columbus

Therapeutic strategies to treat less common molecular targets found in non–small cell lung cancer (NSCLC), such as ROS1, NTRK, MET, and HER2, are under development. In a presentation at the 5th Annual Miami Lung Cancer Conference® in March, Sukhmani K. Padda, MD, an assistant professor of medicine at Stanford University in California, reviewed these emerging treatments. “For ROS1, newer-generation tyrosine kinase inhibitors are emerging in the first-line setting, and we are finally also seeing some drugs in the postcrizotinib setting, which also has some efficacy,” Padda said.

In ROS1-rearranged NSCLC, which makes up 1% to 2% of all NSCLCs, researchers have studied agents in treatment-naïve patients, as well as those who progress while on crizotinib (Xalkori), the standard and sole FDA-approved first-line treatment. The March 2016 approval of crizotinib was based on findings of the phase I PROFILE 1001 trial, in which the objective response rate (ORR) was 72% (95% CI, 58%-84%) for patients with advanced ROS1-rearranged disease.1 The median progression-free survival (PFS) was 19.2 months, and the median duration of response (DOR) was 17.6 months.

“These kinds of numbers are quite impressive even when you look at some of the other driver mutations, such as EGFR,” Padda said, adding that other studies have shown similar responses with crizotinib in this population. For example, in EUROS1, a retrospective European study, offlabel use of crizotinib was associated with an 80% ORR and a median PFS of 9.1 months in patients with stage IV lung adenocarcinoma who had a ROS1 rearrangement.2 However, beyond the frontline setting, there are no approved regimens, driving the need for further research, Padda explained.

Ceritinib (Zykadia), which is approved for frontline and second-line therapy in ALK-rearranged NSCLC, also has shown activity in ROS1-rearranged disease. In an openlabel, multicenter phase II study, 32 patients, 30 of whom were crizotinib-naïve, were treated with 750 mg of ceritinib daily. The ORR by blinded independent central review (BICR) was 62% (95% CI, 45%-77%), and the median DOR was 21 months.3

Additionally, the median PFS was 19.3 months and overall survival (OS) was 24 months. The intracranial diseasecontrol rate was 63%.

“The advantage of ceritinib over crizotinib, based on all our experience, is that ceritinib does a better job of crossing that blood-brain barrier,” Padda said.

Entrectinib (RXDX-101), which Padda described as “the new kid on the block,” is another targeted agent being explored in ROS1-rearranged NSCLC. For patients with ROS1 fusion-positive advanced disease, treatment with entrectinib induced an ORR of 68.8% by BICR, which included 2 complete responses (6.3%).4

Resistance mechanisms to crizotinib have been evaluated for ROS1-rearranged NSCLC, which include G2032R, WT, D2033N, and S1986F. Agents under investigation that target these mutations include cabozantinib (Cabometyx) and lorlatinib, Padda said. Phase II data from a multicohort study with lorlatinib showed that the ORR was 36% (95% CI, 23%-52%) and intracranial (IC)-ORR was 56% (95% CI, 35%-76%) for ROS1-positive patients, regardless of prior treatment.5

Beyond ROS1, TRK is an oncogene fusion across several tumor types that is uncommonly expressed in normal or cancerous tissues. TRK fusion drives abnormally high expression and activation of TRK kinase domain. In a phase I/II basket trial of patients with TRK fusion– positive cancers, the novel, highly selective pan-TRK inhibitor larotrectinib (LOXO-101) led to a central-assessed ORR of 75% (95% CI, 61%-85%) and an 80% (95% CI, 67%-90%) investigator-assessed ORR.6 At 1 year, 71% of responses were ongoing and 55% of patients remained progression-free. The median DOR and PFS had not been reached. At a median follow-up of 9.4 months, 86% of those who responded continued treatment or had surgery that was intended to be curative. “This response seems to be across tumor types, regardless of age and TRK gene or fusion partner, so this has made quite a splash,” Padda said.

Entrectinib has seen encouraging activity in TRK fusion– positive NSCLC, as well as in 2 phase I basket studies, ALKA-372-001 and STARTRK-1. The 1 patient enrolled with NSCLC experienced a complete IC response.7

MET is also a less-common target in NSCLC. Padda’s presentation focused on MET exon 14 skipping mutations, which make up 3% of nonsquamous NSCLCs and 20% to 30% of sarcomatoid lung carcinomas. In an expansion cohort of the PROFILE 1001 trial, crizotinib had activity in these patients in addition to the ROS1-rearranged patients. Additionally, a retrospective analysis of patients who had MET exon 14 skipping mutations showed that treatment with a MET inhibitor led to improved OS (HR, 0.11; 95% CI, 0.01-0.92; P = .04).8

“In general, the message is, if a patient does have a MET exon 14 skipping mutation, they will likely benefit from a MET inhibitor,” Padda said.

HER2 mutations and amplification are also under investigation in NSCLC. In the retrospective European EUHER2 cohort, patients were treated with chemotherapy and/ or HER2-directed agents, including trastuzumab (Herceptin) and ado-trastuzumab emtansine (T-DM1; Kadcyla). The ORR with trastuzumab or T-DM1 was 50.9%, and the median PFS was 4.8 months.9

Though HER2 continues to be a difficult target, strategies are emerging, Padda concluded.

REFERENCE
  1. Shaw A, Rily GJ, Bang YJ, et al. Crizotinib in advanced ROS1-rearranged non-small cell lung cancer. N Eng J Med. 2014;371(21):1963-1971. doi: 10.1056/NEJMoa1406766.
  2. Mazières J, Zalcman G, Crinò L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33(9):992-999. doi: 10.1200/JCO.2014.58.3302.
  3. Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017;35(23):263-2618. doi: 10.1200/JCO.2016.71.3701.
  4. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564.
  5. Solomon BJ, Shaw A, Ignatius Ou S-H, et al. Phase 2 Study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8573.
  6. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.
  7. Drilon A, Siena S, Ou SHI, et al. Safety and antitumor activity of the multi-targeted pan-TRK, ROS1, and ALK inhibitor entrectinib (RXDX-101): combined results from two phase 1 trials (ALKA-372-001 and STARTRK-1) [published online ahead of print February 9, 2017]. Cancer Discov. doi: 10.1158/2159-8290.CD-16-1237.
  8. Awad MM, Leonardi GC, Kravets S, Dahlberg SE, Drilon AE, Noonan S. Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15):8511. doi: 10.1200/JCO.2017.35.15_suppl.8511.
  9. Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27(2):281-286. doi: 10.1093/annonc/mdv573.
 
Brain Cancer

NCCN Recommends TTFields With Temozolomide for Newly Diagnosed GBM

Jason Harris

The National Comprehensive Cancer Network (NCCN) has added the combination of tumor treating fields (TTFields, Optune) and temozolomide (Temodar) to its guidelines for category 1 treatment of newly diagnosed glioblastoma multiforme (GBM) following maximal safe resection and completion of radiation therapy.

TTFields, developed by Novocure, is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Investigators deliver the treatment through 4 transducer arrays with 9 insulated electrodes, each placed on the shaved scalp and connected to a portable device set to generate low-intensity, 200-kHz electric fields within the brain.

NCCN added TTFields and temozolomide to the Clinical Practice Guidelines in Oncology for Central Nervous System Cancers based on 5-year survival results from the phase III EF-14 trial. Those data, published in Journal of the American Medical Association in December 2017, showed that the combination extended overall survival (OS) and progression-free survival (PFS) by 37% compared with temozolomide alone.

EF-14 included a total of 695 patients with GBM who enrolled at 83 medical centers worldwide from July 2009 to December 2014. Eligible patients had undergone tumor resection or biopsy and completed concomitant radiochemotherapy. Patients were randomly assigned to TTFields plus maintenance temozolomide (n = 466) or temozolomide alone (n = 229). Patients in the TTFields arm received low-intensity alternating electric fields treatment for ≥18 hours per day. All patients received 6 to 12 cycles of 150 mg/m2 to 200 mg/m2 of temozolomide for 5 days in 28-day cycles. More than 90% of patients completed the trial by the December 25, 2016, data cutoff.

Median PFS was 6.7 months with the combination compared with 4 months for the monotherapy (HR, 0.63; 95% CI, 0.52-0.76; P <.001). Median OS was 20.9 months in the TTFields plus temozolomide group versus 16 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P <.001).

In posthoc analyses, TTFields plus temozolomide was associated with an increase in PFS and OS in all subgroups regardless of age, sex, Karnofsky performance score, MGMT promoter methylation status, geographic region, or extent of resection. Investigators found that the OS benefit associated with the combination was consistent across all patient subgroups, including subgroups with the worst prognosis and who had less benefit from previous therapies, such as patients aged ≥65 years (HR, 0.51; 95% CI, 0.33-0.77) and those with methylated and unmethylated MGMT tumors (HR, 0.66; 95% CI, 0.49%-0.85%).

In exploratory analyses, 43% (95% CI, 39%- 48%) of patients were alive at 2 years from randomization, 26% (95% CI, 22%-31%) at 3 years, and 13% (95% CI, 9%-18%) at 5 years in the combination arm compared with 31% (95% CI, 25%-38%; P <.001), 16% (95% CI, 12%-23%; P = .009), and 5% (95% CI, 2-11; P = .004) in the temozolomide-only group.

Six-month PFS was 56% (95% CI, 51%-61%) in the combination arm compared with 37% (95% CI, 30%-44%) with temozolomide monotherapy (P <.001).

Investigators did not see an increase in systemic adverse events (AEs) with the combination (48% vs 44%; P = .58). Patients in the combination arm had a higher number of grade 3/4 AEs, but investigators attributed the difference to the longer duration of temozolomide treatment in this group due to delayed occurrence of progression. These differences disappeared when investigators controlled for duration of treatment, except in the case of higher incidence of localized skin toxic effects beneath the transducer arrays in patients treated with TTFields plus temozolomide.

Fifty-two percent of patients experienced mild to moderate skin irritation, and 2% experienced grade 3 skin involvement. At the interim analysis, difference in anxiety, confusion, insomnia, and headaches, which were reported more frequently, was statistically nonsignificant in patients treated with TTFields. Investigators did not observe those AEs in the final analysis. The incidence of seizures was identical in the 2 groups.

Based on earlier results from the EF-14 trial, the FDA approved a second-generation, lighter version of the device in July 2016.

The first-generation of Optune was most recently approved in 2015 for use in combination with adjuvant temozolomide to treat patients with newly diagnosed GBM following surgery, chemotherapy, and radiation therapy. Optune was initially approved in 2011 for the treatment of recurrent GBM after other surgical and radiation options were exhausted.

REFERENCE
Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306-2316. doi:10.1001/ jama.2017.18718.

Nurse Perspective

 Marlon Garzo Saria, PhD, RN,AOCNS, FAANMarlon Garzo Saria, PhD, RN, AOCNS, FAAN
Major, Nurse Corps, US Air Force Reserve


For a diagnosis with limited treatment options, new therapies with proven adequate safety and efficacy profiles are often embraced by mainstream medical practices. Such was not the case for tumor treating fields (TTFields), referred to as the fourth cancer treatment modality, (when chemotherapy and immunotherapy/biotherapy are categorized as 1 modality under pharmacotherapy). Reasons may include skepticism about the efficacy of a novel unconventional therapy from patients and providers alike or lack of availability of the new technology. The recent addition of the combination of TTFields and temozolomide (Temodar) in the National Comprehensive Cancer Network guidelines as a category 1 treatment of newly diagnosed glioblastoma multiforme (GBM) following maximal safe resection and completion of radiation therapy will hopefully serve as the tipping point for a much needed practice change in the field of neuro-oncology.

Oncology nurses can make an impact in improving neuro-oncology outcomes by recognizing and managing dose-limiting toxicities of cancer treatment, adverse effects that deny patients the optimal efficacy of the full prescribed dose of cancer treatment. Minimal systemic toxicities and recent evidence that TTFields increase radiation treatment efficacy support the use of TTFields in combination with any of the previously established GBM treatment modalities. In addition, oncology nurses can optimize outcomes by encouraging and inspiring patient adherence to treatment. Oncology nurses need to emphasize the impact of adherence to TTFields therapy, particularly in terms of proper electrode application and the optimal daily duration of treatment.

 
Immunotherapy

T-Cell Fuel Source, Chemotherapy Exposure Reduce Potential to Develop CAR T Therapy

Kristie L. Kahl

Both prior chemotherapy and a dependence on glycolysis appear to reduce the potential to develop T cells into chimeric antigen receptor (CAR) T-cell therapy. Oxygen consumption rate (OCR) analysis revealed a poor spare respiratory capacity (SRC) in the T-cell samples that go on to perform poorly as CAR T cells. Nanostring RNA profiling of metabolic pathways showed that the poor performers were more likely to use glycolysis rather than fatty acids as a fuel source.

Investigators at Children’s Hospital of Philadelphia (CHOP) found that solid tumors are especially likely to produce T cells with poor potential. “Many of our solid tumors, osteosarcoma, and Ewing sarcoma, have very poor T-cell performance,” said David M. Barrett, MD, PhD, assistant professor of pediatrics at CHOP. “This gives me great concern as we try to make cell therapies for these cancers in the future.”

In results presented at the American Association for Cancer Research (AACR) Annual Meeting 2018, Barrett showed that although chemotherapy, especially cyclophosphamide- and doxorubicin-containing regimens, exacerbates the problem, these T cells are poor starting material, even before treatment. “This is an outgrowth of the work we were doing at Children’s Hospital on chimeric antigen receptor T cells for pediatric cancer,” he said. “We treated a number of children between 2012 and 2014, and one of the things that became very clear was that it was quite challenging to make an effective CAR T-cell product.”

Investigators realized that some patients could not be treated because their T cells died in the lab prior to processing. To develop CAR T cells, the patient’s T cells must be healthy enough to survive processing in the lab, then retain enough energy to kill tumor cells after reintroduction to the body, Barrett added. He and his team wanted to determine why some children have poor-quality T cells and establish the characteristics of viable starting material for CAR manufacture.

“What is the quality of the T cells that we collect from patients with cancer before they’ve gotten chemotherapy? I think everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells, but I really wanted to know what is the potential at diagnosis,” Barrett said. “As we think about expanding CAR T-cell therapy to other cancers besides leukemia and lymphoma, we really want to know what are our challenges.”

Investigators at CHOP collected peripheral blood samples from 157 pediatric patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma at diagnosis and after each cycle of chemotherapy. They then depleted the adherent cells from this collection, quantified the CD3+ population using flow cytometry, and expanded these T cells using CD3/CD28 stimulatory beads as in CAR T-cell manufacturing.

They determined that the CAR T-cell potential of the T cells was very poor in all tumor types except ALL and Wilms tumor in the prechemotherapy samples. More than 90% of patients with standard- and high-risk ALL had very high-quality T cells at diagnosis, which may explain why this CAR T-cell therapy has been so successful in pediatric ALL, Barrett said. Patients with Wilms tumor, the only other class to show good performance, produced potentially successful cells more than 50% of the time.

Researchers observed a decline in CAR T-cell potential with cumulative chemotherapy in all cancer types, but the effect was particularly significant in children aged younger than 3 years.

Certain types of chemotherapy were especially harmful to the T cell’s SRC, a measure of energy reserve. Cyclophosphamide- and doxorubicin-containing regimens were strongly associated with severely depleted CAR T-cell potential. The 2 drugs were associated with mitochondrial dysfunction after chemotherapy both in vitro and in patient T cells after in vivo chemotherapy.

“These T cells seem to be exhausted, probably by the tumor or the chemo. We can now predict who is going to do well and not do well [on CAR T-cell therapy],” said Michael Caligiuri, MD, AACR president and president and physician-in-chief of City of Hope National Medical Center in Duarte, California.

“If you think about subjecting people to these clinical trials, the cost involved, the notion now—which we will pursue, I’m sure—is creating alternate strategies, different chemotherapies, different preparatory regimens that decrease the injury to the T cells’ metabolic pathway, if not reversing that metabolic pathway, and seeing if that predicts for a great outcome with the immune therapy,” Caligiuri added.

Barrett suggested that the T cells from solid tumor patients may need different manufacturing protocols to be successful. Results from preliminary experiments showed that it was possible to force T cells to use fatty acids such as palmitate to restore SRC in chemotherapy-exposed T cells.

REFERENCE
Das RK, Storm J, Barrett DM. T cell dysfunction in pediatric cancer patients at diagnosis and after chemotherapy can limit chimeric antigen receptor potential. Presscast presented at: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL.

 
Breast Cancer

Endocrine Therapy May Eliminate Need for Surgery or Chemotherapy for Some Patients With Breast Cancer

Tony Hagen

Endocrine therapy can reduce tumor size in patients with estrogen receptor (ER)–positive breast cancer, helping some patients avoid chemotherapy or even surgery. Deciding how long to continue this therapy can be tricky, though, according to Hyman B. Muss, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“[Endocrine therapy] can improve the probability of breast preservation for women who would appropriately fit in [related] studies and don’t have very high-grade or aggressive tumors,” Muss said during a presentation at the 2018 Miami Breast Cancer Conference®. “The optimal duration is 3 to 6 months. I think it’s [also] worth considering this in postmenopausal women with larger tumors.

“A lot of studies compare primary treatment with drugs—like tamoxifen—with surgery in operable candidates, and suffice it to say that now, with long-term data, although surgery is better for controlling local disease, overall survival is the same,” Muss continued. Not only is endocrine therapy potentially very helpful in shrinking tumors, he added, it’s also very effective as adjuvant therapy.

Based on available evidence, the current National Comprehensive Cancer Network guidelines indicate that preoperative endocrine therapy alone may be considered for patients with ERpositive disease, based on comorbidities or lowrisk luminal status.

In a randomized phase II trial, neoadjuvant endocrine therapy has shown similar efficacy as chemotherapy in 239 patients.1 A partial response (PR) was achieved in roughly 65% of patients in both groups, and 10% had no palpable mass, with no statistically significant difference between the groups. “And these are all stage IIb, IIIb, and IIIa patients,” Muss said.

For breast conservation, data favored endocrine therapy (33% vs 24%). Pathological complete response (pCR) percentages were low—6% for endocrine therapy versus 3% for chemotherapy— but “very few of these patients get pCRs,” Muss said. “When I talk about neoadjuvant and endocrine therapy in hormone receptor–positive patients, I don’t build up the pCR as such an important thing, because then when you don’t get it, patients are petrified.”

It’s often unclear how much preoperative endocrine therapy should be used before resorting to more aggressive treatment, according to Muss: “The real question on this—the frequently asked question—is, if you do it, how long should you give it, and how will you know when to bail out early?”

A study coauthored by Michael J. Dixon, MD,2 could help answer the question of duration, Muss noted. In the 182-patient trial, clinical complete response (CR) and PR rates at 3 months were 70% with neoadjuvant letrozole. After 3 months, 63 patients elected to continue the drug, and they achieved an 84% CR + PR rate. From there, 33 women at a mean age of 83 years remained on letrozole. At 3 years, median time to treatment failure had not been reached. “A lot of older people did great on this neoadjuvant therapy and then stayed on it without surgery, so I would say that you need at least 3 to 4 months, but one of the seminal trials that we’re doing to help us with the chemotherapy question is 6 months. It’s tough for a lot of patients to take a little pill with a mass in their breast that they can feel and wait 6 months for surgery. You’ve got to cheer them along,” Muss said.

In a study reported in 2008, the Preoperative Endocrine Prognostic Index (PEPI) was used to determine how relapse risk could help with decisions about additional treatment options for patients who have received neoadjuvant endocrine therapy.3 Investigators concluded that patients with breast cancer with pathological stage I or 0 disease and a PEPI score of 0 were at very low risk of relapse and unlikely to benefit from adjuvant chemotherapy.

“They looked at relapsed survival at 5 years, and these data were very impressive by the PEPI scores. But very few of these patients had pCR, pathologically, so it’s a very skewed group, but this scoring system worked impressively well,” Muss said. PEPI, Allred, and Ki67 scoring results indicate that “you don’t have to rush,” Muss said. “If you have these grade 1, hormone-receptive tumors, they’re more likely to respond, and this is verified by genomic assays and other assays.”

REFERENCE
  1. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110(2):244-254. doi: 10.1002/cncr.22789.
  2. Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat. 2009;113(1):145-151. doi: 10.1007/s10549-008-9915-6.
  3. Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. Natl Cancer Inst. 2008;100(19):1380-1388. doi: 10.1093/jnci/djn309.

Nurse Perspective

 Emily Mason Beard, RN, OCN, CBCNEmily Mason Beard, RN, OCN, CBCN
Coordinator, Women’s Oncology Program, Northside Hospital Cancer Institute, Atlanta, GA


With so much emerging data guiding treatment plans for breast cancer, for many patients and their families, the decisions on what evidence-based choices are best and when to make them can be overwhelming. There is no longer a predictable stepwise approach—surgery, chemotherapy, and radiation followed by adjuvant endocrine therapy—to planning treatment, and this can confuse patients who make assumptions that surgical removal of a tumor will forever be the gold standard of treatment. Individualizing care requires shared decision-making conversations, close monitoring of responses, and ongoing communication about adverse effects and compliance.

I was recently speaking with a 78-year-old patient about her treatment for stage IIb breast cancer. Prior to beginning taxane-based chemotherapy, this retired teacher was living an active lifestyle, driving herself to appointments and attending 2 dance classes a week. After 3 cycles of neoadjuvant chemotherapy, debilitated by fatigue and neuropathy, she had to move in with a relative and was very distressed about the impact on her quality of life, especially her independence.

“That first meeting with my oncologist I said I wanted to be aggressive with this, and now I regret saying that,” she said. “I wish there was something other than chemotherapy for me to take. I wish I had some better options.”

Given the results of these recent trials, it seems reasonable that the future standard-of-care for patients with early-stage disease and favorable prognostic indicators could include neoadjuvant endocrine therapy, with or without surgery, to achieve clinical responses similar to those of cytotoxic therapy but without the harshest side effects. Having choices and options, even to change the course of treatment midstream based on response or stability of disease, has benefits and impact on quality of life.

 

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