As we begin 2017, members of Congress are taking steps that could lead to the repeal of the Patient Protection and Affordable Care Act (ACA). The ACA, which was passed in 2010, made sweeping changes to healthcare law and patients’ access to care. How has the ACA changed the way oncologists treat their patients?

 To answer that question I would like to explain a little bit about my practice here in New Mexico. New Mexico has a Republican governor, and we did expand Medicaid to people who were between 100% and 137% of the Federal Poverty Level. We created a not-for-profit insurance company to be able to provide individually owned insurance for patients. In New Mexico, we have long had a high-risk pool, but it is unaffordable for many patients and does not have the ability to get patients what they need in a timely manner. In fact, we have a several-year waiting list for people to get into the high-risk pool. Obviously, for cancer patients, you can’t wait a couple of years to treat your cancer. The high-risk pool wasn’t helping.

When the ACA was enacted, our Republican governor expanded Medicaid and we started the community-oriented and -operated plan that we call New Mexico Health Connections. We were able to drop our uninsured rate from 24% to about 16%. Sixteen percent is still too high, but what this meant for me as an oncologist taking care of patients is that I would be able to bring patients into the practice and be able to purchase the drugs that they need. I can see a patient in an exam room, and I could potentially even do that for free, but nobody other than the insurance companies can afford to purchase expensive chemotherapy for patients. The ACA allowed us to get these patients on treatment. To me, that was a very important event. It is heartbreaking to have a patient whom you know you could treat, but economic barriers prevent you from doing so. The ACA took away at least some of those.

.There seems to be a divide in the medical community about whether the ACA is really an effective program, or if it just puts more burden on the treating physician. What do you think is the reason for this difference of opinion?

 I do think that it was overpromised and underfunded to a great extent. When you have individuals who have never had insurance before and they sign up for the cheapest possible plan-a Bronze plan-they would find that their deductible could be as high as $6,400 when they tried to use the insurance for care. Patients with cancer would come into my practice, needing treatment, and I would have to explain that the first $6,400 comes out of their pocket. These are people living at 150% of the Federal Poverty Level. They have-and the average American has-on hand about $500 to use for an emergency. They don’t have $6,400.

The patients then become angry with the practice because we must explain to them that their plan requires that they pay this money upfront before the real insurance part of it kicks in. That puts a huge burden on the physician, and it means that we are at risk of providing the first $6,400 worth of services for which we will never be able to collect payment. These people simply do not have the money. Also, if they stop paying their premiums, they have a 3-month grace period in which they are still covered, but the insurance companies have the ability to stop paying us even though they are telling us the patient is covered. We don’t have a good mechanism to know that this patient is really on the plan or not on the plan. It puts us in the situation of being at risk for expensive therapies that we never get paid for, trying to police our patients to see if they are paying their premium bills, or ending up having to abandon patients midway through a cycle because now they are uninsured and we cannot as a practice afford to purchase the drugs or turn on the linear accelerator if we are not going to get paid for the cost of those services. That is a significant problem for us.

Some of the features of the ACA that worked well were preventing insurance companies from being able to reject patients for coverage because of preexisting conditions, and letting children be covered on their parents’ plans until age 26.

If Congress repeals the ACA, this may mean that preexisting conditions, including cancer, soon may not be covered by medical insurance. If this occurs, how will it impact oncology practice, specifically community oncology practices?

If a patient receives a cancer diagnosis and his or her insurance gets canceled due to the repeal of the ACA, then we are in the same position as treating someone who is uninsured because the cancer is now a preexisting condition that disqualifies that person from obtaining insurance. In a process called rescission, patients with a new diagnosis of cancer would have to deal with the insurance companies going back through their previous applications and finding that they forgot to mention that they had seen a dermatologist for a squamous cell skin cancer that was frozen off in the office, and they would say, “Ah-ha! You had a preexisting condition and now you are not covered for your cancer today.”

We would end up spending a huge amount of time writing letters, trying to get patients reinstated so that we would be able to treat them. That would be painful. Painful for the patients, and painful for doctors who have to try to help patients file an appeal with insurance companies.

Another concern about one of the current suggestions for how the ACA might be replaced is that patients would be allowed to buy insurance across state lines. My problem with that is when we get a patient from out of state, insurers often don’t pay us for the care we give. I recently had a patient from out of state who needed a particular drug. We called the insurance company and they said that we did not need a prior authorization, so we gave the drug and then when the bill was sent, the patient’s insurance company said that the drug was supposed to go through a specialty pharmacy and wouldn’t pay for it. If we are practicing across state lines with patients who have insurance from another state and we are taking care of the only patient they have in our area, why on earth would they pay us? They can just find some reason to deny the claim, and no community oncologist can afford to fight every single denial from health plans all across the country. You can’t be in-network with all of these insurance companies. That policy would certainly affect oncology practices.

Unless the current requirement that preexisting conditions cannot be a reason to deny insurance is preserved under a replacement plan, it would mean that any patient we see, even if he or she had a thyroid cancer with a very high rate of being cured, would struggle to get insurance. I generally remind oncologists and the general public that 10% of cancers occur in people who have had a previous cancer. That means that all of those patients will be uninsured. We know from years of data that patients who are uninsured live sicker and die younger than patients who have insurance. It will very much affect oncology practices because it will limit the number of people that we are able to help.

The possible repeal of the ACA has many cancer patients worried that they will no longer be able to afford the treatments they need. What is your advice to those people, and what steps should they take to protect themselves?

The first thing we are telling people to do right now in our state is to talk to the New Mexico Health Insurance Exchange and see if they can get on a plan. President Trump has stated that he does not intend to throw anybody who currently has insurance, off insurance.

We are encouraging people in the open enrollment period to get on insurance and make sure that they pay their premiums. One of the possible insurance remedies that is being considered as the “replace” part of “repeal and replace” is that if anybody misses a payment they are uninsured for a year. This would kill a cancer patient. I know how easy it is, from personal experience, to miss a bill and then pay it later when you find it-even if it is not your intent to ever do that. I worry about what that might do to our patients, and how community oncologists are going to manage this if we have patients halfway through a course of chemotherapy and then all of a sudden their insurance gets dropped because they were sick and missed the bill coming in the mail.

I tell patients to work with a caregiver to make sure that they are signed up for insurance, and to make sure they keep those premiums coming. Unfortunately, we are not allowed to help patients when they need help with their premiums. We can do that for insured patients who had employer-based coverage and have a COBRA payment. We can assist them with that, but we can’t, as a practice, assist them with premiums for the ACA policies.

Patients also need to get their preventive services taken care of as soon as possible. Get that colonoscopy done while it is free under the ACA. Make sure your mammograms are up to date. These things are important for people to do to protect themselves.

Many experts say that repealing the ACA without a sufficient replacement would be “catastrophic” to people’s health and to the health insurance market. Do you agree?

The responsible thing for the new administration to do is to come up with a replacement plan so that we can reassure millions of Americans that they will not be without coverage, especially cancer patients who cannot wait for the wheels of bureaucracy to turn. I remember a patient I took care of who was a Marine and never thought he would need health insurance because he was so healthy, until he developed Hodgkin disease, which is curable-but with expensive medications. We were able to get him on an individual plan and he was able to get treated without having to go into bankruptcy.

I look at health insurance as an essential function. None of us, except for the 0.001%, can afford to pay for acute leukemia treatment out of our pockets. We need to have our risk pooled so that if you are the unlucky one who gets cancer, then you have insurance that will pay for treatment. That is the basic premise of insurance.

We absolutely have to have insurance markets that accurately address what the premiums should be, and that pay the claims in an expeditious way so that practices can stay in business. If we, for example, got rid of a preexisting condition requirement without requiring that everybody get insurance, we would end up with people getting insurance as soon as they get sick. A patient would go to the doctor, get a blood count, and if the doctor was worried about leukemia, the patient would run home and sign up for insurance. That doesn’t work for an insurance market. Insurance companies have to be able to predict their future expenses in order to price their policies in a way that allows them to stay in business.

The best thing, not only for the people who need insurance, but for the insurance market and for physicians and physician practices, is to have a replacement plan available before the ACA is repealed, so that practices, as small businesses, can figure out how to manage under the new system and survive, make payroll, keep the lights on, and keep delivering healthcare.

Articles

In this interview we discuss how the ACA, which was passed in 2010, changed the way oncologists treat their patients, and how a repeal of the law would affect patients’ access to care.

Barbara McAneny on How the Repeal of the ACA Without a Replacement Threatens the Health of Patients and the Success of Community Practices

Accelerated partial breast irradiation (APBI) should not be used routinely in the treatment of breast cancer. Whole-breast irradiation (WBI) has an established local control benefit,[1] which has been shown to confer a survival benefit not only in invasive cancer,[2] but also in a subset of patients with ductal carcinoma in situ.[3] Breast cancer recurrence increases linearly with time, and both radiotherapy (RT) and systemic therapy continue to reduce local failure beyond 5 years after diagnosis. Therefore, robust follow-up data are needed before the routine use of any therapy that may compromise local control and subsequently survival.

APBI is not expected to provide better local control than WBI, so its use should be considered only if it might offer some other tangible benefit to women. Proponents of APBI cite the increased convenience of this technique, the promise of lower toxicity, and the hope that this technique will allow more women to receive radiation.[4] Currently, breast-conserving surgery (BCS) rates nationally are only 46% in seemingly eligible women,[5] and APBI has been proposed as a modality that may increase the use of BCS. To address this issue thoroughly, we will explore the validity of the claims of efficacy, convenience, toxicity, and access surrounding APBI.

Early practice of APBI had unacceptably high local recurrence rates.[6,7] These trials included patients with node-positive disease and larger tumors, no uniform clinical target volume margin, variable radiation techniques, and suboptimal methods of tumor bed localization that undoubtedly contributed to the observed high rates of failure. More recently, APBI has demonstrated much more favorable results. Despite promising prospective studies of highly selected patients,[8,9] randomized trials with adequate follow-up are lacking. The populations included in the current randomized trials have tumors that are predominantly estrogen receptor (ER)-positive[10] and luminal A subtype.[11] The natural history of these tumors is indolent, and they remain under the effect of endocrine therapy,[12] which makes the present follow-up inadequate to determine long-term efficacy.

Routine use of APBI would require that it could be applied to a broad population. Not only is the long-term efficacy of APBI uncertain, but there are also concerning data that suggest that local failure rates are high in women with ER-negative disease and other biologically adverse subtypes when a partial breast approach is used.[13,14] Therefore, a partial breast approach is not reasonable for routine use, but only for highly selected postmenopausal women with small tumors and no adverse pathologic features.[15]

APBI is convenient. However, hypofractionated (HF) WBI is also a convenient option. With a treatment course of 15 fractions rather than 10, the UK Standardisation of Breast Radiotherapy (START) and Canadian phase III randomized trials have shown equivalent local control and reduced adverse effects with HF-WBI when compared with conventional fractionation (CF) WBI with long-term follow-up.[16,17] A randomized trial of HF- vs CF-WBI demonstrated significantly lower rates of acute grade 2 or higher toxicity and improved physical well-being and fatigue in the HF arm.[18] Rates of pneumonitis remain extremely low[19]; cardiac doses are modest, with minimal impact on outcomes[20-22]; and cosmesis is excellent with modern techniques.[23]

In an effort to further expedite treatment, the UK FAST-Forward trial, which is testing two 5-fraction regimens over 1 week vs HF-WBI, was launched at the end of 2011.[24] If the 1-week regimen is found to be noninferior to HF-WBI, it may eliminate the convenience advantage of APBI.

Although the convenience of APBI may be enticing, there are troubling toxicity reports in the APBI literature. Cosmetic results of the external beam technique have been reported to be inferior,[25-27] although this has not been uniformly found.[28,29] While the multicatheter-based interstitial brachytherapy literature has not echoed these findings, there are equipment and skill needs that prevent routine use of this technique.[30] Balloon-based brachytherapy is also associated with significant toxicity to the chest wall, as well as softtissue necrosis.[31,32] Although the exact reasons for mastectomy in this setting are not clear, women who receive APBI with balloon-based brachytherapy have double the rate of mastectomy, as well as a higher risk of breast pain, fat necrosis, rib fracture, and postoperative complications, compared with women who receive WBI.[33] Based on these data, the allegation that APBI always results in less toxicity than WBI is inaccurate.

No data support the notion that partial breast irradiation will allow more eligible women to undergo BCS. In fact, the available data conflict with this hypothesis. The rate of mastectomy rose by 36% from 2005 to 2013,[34] despite an increase in the use of APBI from 8% in 2005 to 17% in 2008.[35] Although access is a cited reason for promoting APBI, rural living areas were independently associated with less utilization of APBI.[35] The reasons behind women’s selection of mastectomy are complex, and various factors influence their decision, including the use of MRI,[36] physician advice, and fear of future recurrence. Other initiatives have found that clinician education can increase rates of BCS[37]; however, to date APBI has not been shown to increase utilization of BCS or radiation following BCS.[38]

We know that breast cancer represents a spectrum of diseases, with variation in prognosis, and that RT can range from highly complex treatments to the breast and regional lymph nodes, to complete avoidance of radiation. The challenge will be to select the most appropriate treatment for the individual patient and to personalize RT based on tumor biology.[39]

The standard treatment for breast cancer patients at low risk for recurrence is conservative surgery followed by WBI. The APBI concept, developed more than 20 years ago, may be an option in carefully selected patients. However, the ideal patient profile for APBI is still not clearly identified, as evidenced by the heterogeneity of the inclusion criteria of the continuing APBI trials. The ongoing French SHARE trial will randomize 2,800 patients to three arms: APBI using three-dimensional conformal RT (1 week), CF-WBI (6.5 weeks), and HF-WBI (3 weeks).[40] Results of this trial should give us more insight into the optimal therapy for women with early-stage breast cancer.

Until long-term follow-up data are available, APBI should be used with caution in selected patients at low risk for ipsilateral breast tumor recurrence only, after careful informed consent is obtained. HF-WBI is a clinically proven alternative to APBI and CF-WBI for women who desire a shorter course of RT without potentially compromising local control and survival.

The authors have no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. For the sake of transparency, it should be noted that Dr. Evans’s institution receives funding from 21st Century Oncology for research in which she is involved

 Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet. 2011;378:1707-16.

 Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-106.

 Sagara Y, Freedman RA, Vaz-Luis I, et al. Patient prognostic score and associations with survival improvement offered by radiotherapy after breast-conserving surgery for ductal carcinoma in situ: a population-based longitudinal cohort study. J Clin Oncol. 2016;34:1190-6.

 Wallner P, Arthur D, Bartelink H, et al. Workshop on Partial Breast Irradiation: State of the Art and the Science, Bethesda, MD, December 8–10, 2002. J Natl Cancer Inst. 2004;96:175-84.

 Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol. 2001;19:2254-62.

 Ribeiro GG, Magee B, Swindell R, et al. The Christie Hospital breast conservation trial: an update at 8 years from inception. Clin Oncol (R Coll Radiol). 1993;5:278-83.

 Dodwell DJ, Dyker K, Brown J, et al. A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol (R Coll Radiol). 2005;17:618-22.

 PolgÃ¡r C, Major T, Fodor J, et al. Accelerated partial-breast irradiation using high-dose-rate interstitial brachytherapy: 12-year update of a prospective clinical study. Radiother Oncol. 2010;94:274-9.

 Strnad V, Hildebrandt G, PÃ¶tter R, et al. Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2011;80:17-24.

 Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016;387:229-38.

 Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015;51:451-63.

 Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor–positive tumors. N Engl J Med. 1989;320:479-84.

 Wilder RB, Curcio LD, Khanijou RK, et al. Results with accelerated partial breast irradiation in terms of estrogen receptor, progesterone receptor, and human growth factor receptor 2 status. Int J Radiat Oncol Biol Phys. 2010;78:799-803.

 Wilkinson JB, Reid RE, Shaitelman SF, et al. Outcomes of breast cancer patients with triple negative receptor status treated with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;81:e159-e164.

 Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.

 Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086-94.

 Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-20.

 Shaitelman SF, Buchholz TA, Hunt KK, et al. Hypofractionated whole breast irradiation results in less acute toxicity and improved quality of life at six months compared to conventionally fractionated whole breast irradiation: results of a randomized trial. Int J Radiat Oncol Biol Phys. 2014;90:1264.

 Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16.

 Patt DA, Goodwin JS, Kuo YF, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol. 2005;23:7475-82.

 Giordano SH, Kuo YF, Freeman JL, et al. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97:419-24.

 Rutter CE, Chagpar AB, Evans SB. Breast cancer laterality does not influence survival in a large modern cohort: implications for radiation-related cardiac mortality. Int J Radiat Oncol Biol Phys. 2014;90:329-34.

 Mukesh MB, Barnett GC, Wilkinson JS, et al. Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-year results confirm superior overall cosmesis. J Clin Oncol. 2013;31:4488-95.

 Coles CE, Brunt AM, Wheatley D, et al. Breast radiotherapy: less is more? Clin Oncol (R Coll Radiol). 2013;25:127-34.

 Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol. 2013;31:4038-45.

 Liss AL, Ben-David MA, Jagsi R, et al. Decline of cosmetic outcomes following accelerated partial breast irradiation using intensity modulated radiation therapy: results of a single-institution prospective clinical trial. Int J Radiat Oncol Biol Phys. 2014;89:96-102.

 Hepel JT, Tokita M, MacAusland SG, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2009;75:1290-6.

 RodrÃ­guez N, Sanz X, Dengra J, et al. Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2013;87:1051-7.

 Wolmark N, Curran WJ, Vicini F, et al. Response to “Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation” (Int J Radiat Oncol Biol Phys 2010;76:71-78) and “Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation” (Int J Radiat Oncol Biol Phys 2009;75:1290-1296). Int J Radiat Oncol Biol Phys. 2010;77:317; author reply 318.

 Wojcicka JB, Lasher D, Bialkowski M, et al. Clinical and dosimetrical experience with MammoSite based brachytherapy under RTOG-0413 protocol. In: World Congress on Medical Physics and Biomedical Engineering 2006. Vol 14. Berlin, Germany: Springer; 2007. p. 1928-31.

 Rosenkranz KM, Tsui E, McCabe EB, et al. Increased rates of long-term complications after MammoSite brachytherapy compared with whole breast radiation therapy. J Am Coll Surg. 2013;217:497-502.

 Brashears JH, Dragun AE, Jenrette JM. Late chest wall toxicity after MammoSite® breast brachytherapy. Brachytherapy. 2009;8:19-25.

 Smith GL, Xu Y, Buchholz TA, et al. Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA. 2012;307:1827-37.

 Steiner CA, Weiss AJ, Barrett ML, et al. Trends in bilateral and unilateral mastectomies in hospital inpatient and ambulatory settings, 2005-2013: statistical brief #201. In: Healthcare Cost and Utilization Project (HCUP) statistical briefs. Rockville, MD: Agency for Healthcare Research and Quality; 2006.

 Gold HT, Shao H, Hayes MK, Tousimis E. Diffusion of accelerated partial breast radiotherapy in the United States: physician-level and patient-level analyses. Med Care. 2014;52:969-74.

 Bleicher RJ, Ciocca RM, Egleston BL, et al. Association of routine pretreatment magnetic resonance imaging with time to surgery, mastectomy rate, and margin status. J Am Coll Surg. 2009;209:180-7.

 Elward KS, Penberthy LT, Bear HD, et al. Collaborative initiatives in the care of early stage breast cancer: reduction in variation of breast-conserving therapy. Breast J. 2000;6:108-14.

 Wang EH, Park HS, Rutter CE, et al. Association between access to accelerated partial breast irradiation and use of adjuvant radiotherapy. Cancer. 2016 Sep 22. [Epub ahead of print]

 Bellon JR. Personalized radiation oncology for breast cancer: the new frontier. J Clin Oncol. 2015;33:1998-2000.

 Belkacemi Y, Bourgier C, Kramar A, et al. SHARE: a French multicenter phase III trial comparing accelerated partial irradiation versus standard or hypofractionated whole breast irradiation in breast cancer patients at low risk of local recurrence. Clin Adv Hematol Oncol. 2013;11:76-83.

We know that breast cancer represents a spectrum of diseases, with variation in prognosis, and that RT can range from highly complex treatments to the breast and regional lymph nodes, to complete avoidance of radiation.

Accelerated Partial Breast Irradiation for Breast Cancer: Not Ready for Routine Use

To paraphrase a deep philosophical question: if an important, long-awaited phase III prospective randomized trial from Europe is published[1] and no one pays attention, does it make a sound?

For many years, the leaders in accelerated partial breast irradiation (APBI) research have heard from skeptics: “Despite the large number of single-institution studies, large registry reports, and a mature prospective phase II Radiation Therapy Oncology Group (RTOG) trial, we really need to see a head-to-head comparison of the standard 6 weeks of whole-breast irradiation (WBI) vs 4 or 5 days of partial breast irradiation before we can embrace APBI as an acceptable treatment option for selected breast cancers.” Although the data are robust and the results of the European randomized trial of APBI are positive, the “sound” does not seem to be reverberating through radiation oncology centers in the United States-and the impact is muffled.

What does it take for an innovative treatment to be accepted as a new standard of care? Can you imagine the uproar in the radiation scientific community if a similar randomized trial demonstrated positive outcomes for intensity-modulated radiotherapy? Sentinel node mapping for breast cancer was adopted as a standard with fewer supporting data than APBI has now. Prostate brachytherapy became a viable and accepted treatment option without 

 randomized data, as did laparoscopic cholecystectomy and indeed many therapies now considered as “standard of care.”

The evolution of the scientific evidence for APBI is a model for how medicine should advance. Twenty-five years ago, the first patient was treated at the Ochsner Clinic in New Orleans with wide-volume brachytherapy using modern techniques and a target volume defined as 2 cm beyond the lumpectomy cavity. Since then, significant advances have occurred in the technology, methods of delivery, and data accumulation.

The original hypothesis-that selected breast cancers can be successfully treated by hypofractionated twice-daily targeted brachytherapy or external beam radiotherapy to the tissue at highest risk for microscopic tumor cells after breast-conserving surgery-was supported by pathology studies that showed a decreasing malignant cell gradient as the distance from the lumpectomy cavity edge increased. Under this hypothesis, covering all breast tissue in remote quadrants of the breast is unnecessary for selected breast cancers. This concept was also supported by randomized clinical trials of lumpectomy alone vs lumpectomy and WBI, which showed no difference in the subsequent rate of “elsewhere recurrence,” defined as a new tumor in a different quadrant of the breast or at least 4 cm away.

The Ochsner Clinic and the William Beaumont Hospital in Michigan both executed prospective phase II trials with matched-pair analyses that demonstrated no significant difference between 4- or 5-day interstitial brachytherapy APBI and 6-week WBI, with long-term follow-up.[2,3]

The RTOG conducted the phase II multi-institutional clinical trial 95-17.[4] This prospective trial took 2 years to develop, because new quality assurance measures had to be created and selection criteria were extensively debated in committees. Eligible participants included women of all ages with invasive nonlobular carcinomas who had pathologic tumors of ≤ 3 cm that were excised with margins exhibiting no ink on tumor, and who were node-negative or had 1 to 3 positive nodes without extracapsular extension. Grade 3 and estrogen receptor (ER)-negative tumors were allowed. Twenty percent of patients had positive nodes, and human epidermal growth factor receptor 2 status was not assessed at that time. One hundred patients signed informed consent, but one patient was deemed ineligible because she had sentinel node mapping instead of axillary dissection. All patients were treated with low- (45 Gy in 3 to 5 days) or high-dose-rate (34 Gy in 10 twice-daily fractions, separated by at least 6 hours) interstitial brachytherapy. With 12.5 years’ median follow-up, the ipsilateral breast tumor recurrence (IBTR) rate was only 6.2% at 10 years. Note that the patients in this study were not the more favorable subsets that have been included in many subsequent studies.

In 2002, the US Food and Drug Administration approved the MammoSite balloon catheter, which greatly simplified brachytherapy by creating a single-entry device that surgeons could place using local anesthesia in an office setting. Radiation oncologists would then deliver 34 Gy in 10 fractions over 5 days using a high-dose-rate iridium-192 robot. Later, the multichannel Contura balloon catheter and the multistrut SAVI (strut-adjusted volume implant) applicator were added to the armamentarium, and APBI is now used to treat approximately 15% of early-stage breast cancers in the United States. Each of these devices has been studied in large registry trials, with favorable tumor control and low toxicity profiles. More than 40 single-institution reports have been published.

The PROMIS registry study includes more than 1,500 patients treated with interstitial brachytherapy APBI at 6 institutions. With a median follow-up of over 6 years, the 7-year actuarial IBTR rate is 6% overall and 5% for ductal carcinoma in situ (DCIS).[5]

Despite the large number of publications, the scientific community awaited level 1 evidence. The first randomized prospective trial came from Hungary.[6] The small number of participants hindered statistical strength, but equivalent tumor control was reported, with a trend to better cosmetic outcomes with interstitial brachytherapy APBI.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/RTOG 0413 phase III trial randomized 4,214 women to 5 days of APBI or 5 to 6 weeks of WBI.[7] In the APBI arm, three techniques were allowed: interstitial brachytherapy, single-entry brachytherapy, and three-dimensional conformal external beam APBI. More than 70% of patients received the last treatment option. At over 8 years’ median follow-up, the number of events in the two arms has not met statistical criteria for release of the data.

Single-dose intraoperative lumpectomy cavity irradiation has been studied in two randomized trials. The Italian electron beam intraoperative radiotherapy (ELIOT) phase III trial demonstrated a higher recurrence rate in the electron beam arm but has been criticized for lacking clearly defined target volume and quality assurance measures.[8] The UK-based Targeted Intra-Operative Radiotherapy (TARGiT) trial used soft 50-kV x-rays and also showed a higher recurrence rate in the intraoperative radiation therapy (IORT) arm.[9] This study has been criticized for delivering a tumoricidal dose to only 2 mm of tissue beyond the lumpectomy edge. A thin layer of blood, air, or seroma potentially blocks any significant dose to breast tissue at risk for recurrence.

The results of the Groupe EuropÃ©en de CuriethÃ©rapie–European Society for Radiotherapy and Oncology (GEC-ESTRO) phase III trial were presented by Professor Strnad at a plenary American Society for Radiation Oncology (ASTRO) session and immediately published in the 

.[1] Interstitial brachytherapy was directly compared with conventional WBI. At 5 years, this study demonstrated the noninferiority of APBI by this method. A trend toward lower toxicity in the APBI arm was noted.

Thus, over a period of 25 years, brachytherapy APBI has been one of the most studied treatments in medical history. The hypothesis that only the affected part of the breast, with a clearly defined margin, needs to be treated in selected breast cancers has been supported by many single-institution and registry trials, a national prospective phase II RTOG clinical trial, and now the phase III GEC-ESTRO trial, as well as the positive but less powerful original Hungarian randomized trial.

What does it take for a treatment to be accepted as a standard of care?[10] How much evidence is necessary? Is it acceptable to extrapolate from the rich and plentiful data supporting interstitial brachytherapy to three-dimensional conformal external beam APBI, single-entry devices, or IORT? With a skill-dependent procedure such as interstitial brachytherapy, what credentialing is necessary before it may be performed at various medical institutions around the United States or the world?

These are difficult questions to answer. Brachytherapy APBI now has level 1 evidence supporting it, which complements 25 years of research by numerous institutions and cooperative groups worldwide. There is enough evidence at this point to add interstitial brachytherapy as an option for the treatment of selected breast cancers.

The definition of “selected” would be the topic of another article, but most investigators include women older than age 50 with DCIS or invasive breast cancers of ≤ 3 cm who are node-negative. One particularly risky group, according to the PROMIS data, consists of women younger than age 50 who are ER-negative. Since the NSABP B39/RTOG 0413 randomized trial has a substantial number of high-risk women enrolled, answers should be forthcoming.

Dr. Kuske has an unrestricted educational grant from Elekta for the PROMIS registry trial and minor stock options in Cianna Medical. 

 King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg. 2000;180:299-304.

 Shah C, Antonucci JV, Wilkinson JB, et al. Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother Oncol. 2011;100:210-4.

 Arthur DW, Winter K, Kuske RR, et al. A phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radiat Oncol Biol Phys. 2008;72:467-73.

 Kamrava M, Kuske R, Anderson B, et al. Outcomes of breast cancer patients treated with accelerated partial breast irradiation via multicatheter interstitial brachytherapy: the pooled registry of multicatheter interstitial sites (PROMIS) experience. Ann Surg Oncol. 2015;22(suppl 3):abstr 404.

 PolgÃ¡r C, Fodor J, Major T, et al. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108:197-202.

 Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14:1269-77.

 Vaidya JS, Wenz F, Bulsara M, et al; on behalf of the TARGIT trialists’ group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383:603-13.

 Kuske RR, Young SS. Breast brachytherapy versus whole-breast irradiation: reported differences may be statistically significant but clinically trivial. Int J Radiat Oncol Biol Phys. 2014;88:266-8.

To paraphrase a deep philosophical question: if an important, long-awaited phase III prospective randomized trial from Europe is published and no one pays attention, does it make a sound?

Accelerated Partial Breast Irradiation for Breast Cancer: An Innovative Option for Selected Early-Stage Cancers

The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and immunotherapies. Advances in the understanding of cancer biology and therapeutic strategies have resulted in increasing numbers of new drug applications and approvals. Consequently, practicing oncologists need to learn how the newly available agents function and what toxicities to watch for, as well as ways to optimize the use of both new drugs and previously approved drugs with new indications. In 2016, the US Food and Drug Administration approved three novel drugs for the treatment of solid malignancies-olaratumab in selected patients with soft-tissue sarcoma, atezolizumab for the treatment of bladder cancer, and rucaparib for the treatment of ovarian cancer; also in 2016, the use of previously approved anticancer agents (including atezolizumab) was expanded into 11 new patient populations. The diversity of options for patients is evident in the broad range of the 2016 approvals, which include immune checkpoint inhibitors, targeted therapies, monoclonal antibodies, and traditional cytotoxic agents. This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning.

Advances in our understanding of the cancer genome and our ability to harness the patient’s immune system to fight cancer continue to translate into US Food and Drug Administration (FDA) approval of new agents for the treatment of cancer. In 2016, three novel drugs were approved to treat patients with solid malignancies; in contrast, 16 new molecular entities were approved in 2015 and 9 were approved in 2014.[1,2] Among the new approvals is the first-in-class programmed death ligand 1 (PD-L1) inhibitor atezolizumab, which was also granted a second indication in 2016. In addition to the two new approvals for this novel agent, two new indications have emerged for the previously approved programmed death 1 (PD-1) inhibitor pembrolizumab, and one new indication has emerged for nivolumab, highlighting that immunotherapy continues to transform cancer care. There were a total of 11 new indications that expanded the use of previously approved anticancer agents into new patient populations (Table 1).

Sponsors of oncology drugs continued to make use of the FDA’s expedited approval programs as pathways to approval in 2016 (Table 2). The Breakthrough Therapy designation is granted to drugs that, based on preliminary clinical evidence, may yield substantial improvement of a clinically significant endpoint, compared with other available therapies. Among the 2016 approvals in solid malignancies, 10 of 14 (71%) were granted Breakthrough Therapy designation, including all three of the new drugs. The Priority Review designation is granted for drugs that, if approved, would provide a significant improvement over the standard-of-care therapies in terms of treatment safety or effectiveness. Priority Review was granted to 13 of 14 approvals (93%), including all three of the novel drugs granted Breakthrough Therapy designation.

In this article we review the three newly approved drugs indicated for use in the oncology population and discuss the new indications of already approved agents. We will focus on pivotal trial data for each agent, as well as the drug’s indication, mechanism of action, pertinent toxicities, use in special populations, and the appropriate clinical context for treatment planning.

Olaratumab is a human immunoglobulin (Ig) G1 antibody directed against platelet-derived growth factor receptor Î± (PDGFR-Î±). This novel agent received accelerated FDA approval on October 19, 2016 for advanced soft-tissue sarcoma, and had already been granted Priority Review status in May 2016. The drug is specifically approved in combination with doxorubicin for adult patients with soft-tissue sarcoma subtypes for which an anthracycline-based regimen is appropriate and for which curable options are not available. Treatment options are limited for soft-tissue sarcoma and typically involve doxorubicin, administered either alone or in combination. Doxorubicin was combined with olaratumab in the pivotal trials.

The accelerated approval of olaratumab was based on the results from an open-label phase Ib trial and randomized phase II trial of adult patients with locally advanced or metastatic soft- tissue sarcoma who had not previously received doxorubicin. The phase Ib portion enrolled 15 patients who received olaratumab at a dose of 15 mg/kg IV on days 1 and 8 concurrently with doxorubicin at 75 mg/m

 on day 1 of each 21-day cycle, for a maximum of 8 cycles (with dexrazoxane permitted for cardioprotection), followed by continuation of olaratumab maintenance, until disease progression. The phase II portion of the trial randomized 133 patients in a 1:1 ratio to either the combination using the phase Ib dosing regimen or to single-agent doxorubicin. Patients who initially received single-agent doxorubicin could later receive single-agent olaratumab following evidence of disease progression. The primary endpoint of the phase Ib trial was safety, and for the phase II trial was progression-free survival (PFS). The phase II trial was designed with a planned sample size of 130 patients to have 80% power and a two-sided significance level of 0.20 that was adjusted to 0.1999 following the planned interim analysis. The most common soft-tissue sarcoma histology in this group was leiomyosarcoma (36%), followed by undifferentiated pleomorphic sarcoma (15%), liposarcoma (12%), and angiosarcoma (6%). The median PFS in the phase II portion favored the combination of olaratumab and doxorubicin (6.6 months) compared with doxorubicin alone (4.1 months; stratified hazard ratio [HR], 0.67; 95% CI, 0.44–1.02; 

 = .0615). More notably, the median overall survival (OS) was significantly improved by 11.8 months in the patients who received combination therapy (OS, 26.5 months) compared with patients randomized to doxorubicin alone (OS, 14.7 months; stratified HR, 0.46; 95% CI, 0.30–0.71; 

 = .003). This survival benefit was consistent across histologic subtypes, number of prior therapies, and PDGFR-Î± status. There was no correlation between response and tumor positivity for PDGFR-Î±.[3]

Grade 3/4 adverse events (AEs) associated with doxorubicin and olaratumab included neutropenia (53%), leukopenia (36%), anemia (13%), and fatigue (9%). ANNOUNCE (ClinicalTrials.gov identifier: NCT02451943) is an ongoing phase III randomized trial of doxorubicin and olaratumab in combination vs doxorubicin plus placebo that will help to validate the results of previous trials.

Atezolizumab, for the treatment of bladder cancer and non–small-cell lung cancer (NSCLC): two approvals

Atezolizumab is an anti–PD-L1 monoclonal IgG1 antibody. It was granted both first approval and a new indication by the FDA in 2016, and is the first FDA-approved PD-L1 inhibitor. The initial indication was for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression either during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In October 2016, atezolizumab joined nivolumab and pembrolizumab as approved immune checkpoint inhibitors for treatment of metastatic NSCLC that had progressed during or following platinum-based chemotherapy. Atezolizumab was also approved in advanced NSCLC that has progressed during or after treatment with epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors. The FDA also approved the complementary VENTANA PD-L1 (SP142) immunohistochemistry assay for patients with metastatic urothelial cancer or NSCLC who are candidates for treatment with atezolizumab.[4-6] Although PD-L1 expression is not required for initiation of therapy, higher levels of expression are associated with an increased likelihood of response to atezolizumab.

As an immune checkpoint inhibitor, atezolizumab selectively binds PD-L1, preventing interaction with PD-1 and CD80 (also called B7-1), while sparing interaction between programmed death ligand 2 (PD-L2) and PD-1. This ultimately results in inhibition of T-cell suppression while potentially preventing autoimmunity, which would reduce the occurrence of immune-related AEs.[7,8] The mechanism of PD-L1 inhibition by atezolizumab differs from that of previously approved immunotherapies that block PD-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4; ipilimumab), although there is overlap in efficacy and toxicity.

The study supporting FDA approval of atezolizumab in urothelial carcinoma was a single-arm, multicenter, phase II trial of 310 patients with locally advanced or metastatic bladder cancer who had previously been treated with platinum-based therapy.[4,9,10] Atezolizumab was dosed at 1,200 mg IV on day 1 of each 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the immune-modified RECIST criteria (irRECIST).[11] Patients were prospectively stratified by levels of PD-L1 expression. In comparison with a historic ORR of 10%, the ORR was 15% (

 < .0058), and higher response rates correlated with higher levels of PD-L1 expression. The 12-month OS rate was 29% in patients with no PD-L1 expression and 48% in those with the highest expression. After a median follow-up of 11.7 months, 84% of responders had ongoing responses, with complete responses (CRs) in 5.5% of patients overall.[4] In conjunction with an exploratory outcome evaluation, this study also used a targeted exome-sequencing panel to correlate the degree of mutational load as a predictor of atezolizumab response. The median mutational load was 12.4 mutations/Mb in the responders compared with 6.4 mutations/Mb in the nonresponders (

 < .0001), results similar to outcomes reported for pembrolizumab-treated patients with melanoma.[12]

 The pivotal POPLAR and OAK trials were the basis for FDA approval of atezolizumab in NSCLC. The POPLAR trial was a phase II randomized controlled trial of 287 patients with NSCLC who progressed on post-platinum chemotherapy.[13] Patients were randomized in a 1:1 ratio to atezolizumab at a dosage of 1,200 mg IV every 3 weeks or docetaxel at 75 mg/m

 every 3 weeks. They were stratified based on the status of PD-L1 tumor-infiltrating immune cells, histology, and number of previous lines of therapy. The primary endpoint was OS in the intention-to-treat population and PD-L1 subgroups. The median OS durations in the POPLAR trial were 12.6 months and 9.7 months for the atezolizumab and docetaxel arms, respectively (HR, 0.73; 95% CI, 0.53–0.99; 

 = .04). Patients with nonsquamous disease had increased OS durations-15.5 months and 10.9 months for the atezolizumab and docetaxel arms, respectively-compared with those who had squamous disease, for whom OS was 10.1 months and 8.6 months in the two arms, respectively. PFS was similar, at 2.7 months and 3.0 months for the atezolizumab and docetaxel arms, respectively.

The OAK trial enrolled 1,225 patients with advanced NSCLC who had progressed on a prior platinum-containing regimen, or had experienced disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or combined modality with curative intent. Enrolled patients were randomized 1:1 to atezolizumab (at 1,200 mg IV every 3 weeks) or docetaxel (at 75 mg/m

 every 3 weeks). The median OS duration was 13.8 months in the atezolizumab arm compared with 9.6 months in the docetaxel arm (

 = .0003). Improvement in OS was seen regardless of PD-L1 expression; however, OS was significantly greater in the groups with the highest PD-L1 expression (median OS, 20.5 months with atezolizumab vs 8.9 months with docetaxel; HR, 0.41; 

 < .0001). In 425 intention-to-treat patients, the ORRs in the atezolizumab vs the docetaxel arms were similar at 13.6% and 13.4%, respectively. However, the duration of response was 16.3 months with atezolizumab vs 6.2 months with docetaxel. The PFS durations were 2.8 months in the atezolizumab arm vs 4.0 months in the docetaxel arm.[14]

Within the POPLAR, OAK, and urothelial carcinoma trials, atezolizumab was well tolerated; consistent with previous studies, its safety profile was favorable in comparison with docetaxel.[14] In the pivotal trial for urothelial carcinoma, AEs were reported in 16% of all patients treated with atezolizumab. Fatigue was the most common grade 3/4 AE (2% of patients). Immune-related AEs reported in at least 5% of patients included pneumonitis, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, rash, and dyspnea. Among patients treated with atezolizumab, 4% discontinued therapy because of AEs.[4] Within the POPLAR trial, in patients treated with atezolizumab, the most common grade 3/4 AE (≥ 2%) was dyspnea (~ 9%). Significant immune-related AEs for patients receiving atezolizumab included pneumonitis, hepatitis (elevated AST and ALT), and colitis. Among patients treated with atezolizumab, 8% discontinued therapy because of AEs, vs 22% of patients treated with docetaxel. Within the OAK trial, grade 3/4 AEs occurred in 15% of patients treated with atezolizumab, with no associated deaths. The FDA warnings/precautions in atezolizumab product labeling concern immune-mediated reactions that are class-
specific to immunotherapy.

Atezolizumab represents the first approved anti–PD-L1 therapy, a new member of the evolving group of immunotherapy options for a variety of malignancies, including bladder and lung cancer. Individualized clinical information, such as strength of PD-L1 positivity, may guide the decision of whether or not atezolizumab should be considered as treatment; there also may be situations in which caution should be exercised-for example, in patients with autoimmune disease.[15] The search for clinically useful biomarkers to help determine who is most likely to benefit from these immune therapies is ongoing, with increasing consideration of their relative costs and toxicities.

Rucaparib, new approval for pretreated ovarian cancer patients with BRCA mutations

Rucaparib is a novel inhibitor of the enzyme poly (ADP-ribose) polyermase (PARP), which is involved in DNA repair through mechanisms that include base excision repair. The genes 

 encode tumor suppressors also involved in DNA repair through homologous recombination.[16] The PARP inhibitors exert their effect through synthetic lethality, in which a mutation in just one gene (ie

) does not result in cell death, but inhibition of both pathways of DNA repair (ie, base excision repair via BRCA1 and homologous recombination via PARP) and will result in cell death.[17] Patients with 

 mutations in either their germline or tumor samples have been shown to have increased sensitivity to inhibitors of PARP.

Rucaparib received accelerated FDA approval on December 19, 2016 for patients with advanced ovarian cancer who had received therapy with two or more chemotherapy agents and who also have deleterious germline and/or somatic 

 mutations. To determine the presence of a deleterious mutation in 

, a required companion diagnostic test was also approved. The FoundationFocus CDx

 test utilizes next-generation sequencing to determine the presence of insertion alterations > 4 nucleotides and deletions > 10 nucleotides in either 

 in formalin-fixed, paraffin-embedded ovarian tumor tissue, without distinguishing between germline vs somatic mutations.[18]

The evidence supporting this accelerated approval was based on two multicenter, phase II, single-arm trials in 106 patients with advanced 

-mutant ovarian cancer following progression after two or more prior platinum-based chemotherapy regimens. The majority of patients had deleterious germline 

 mutations, although 17% had somatic mutations only. Patients received rucaparib at 600 mg orally each day. The ORR was 54%, with 9% CRs and 45% partial responses (PRs). The median duration of response was 9.2 months.[19] In a population of 206 patients enrolled in the ARIEL2 trial, the most common grade 3/4 toxicities were anemia and elevated levels of liver enzymes.[20]

Rucaparib now joins the approved PARP inhibitor olaparib for the treatment of advanced ovarian cancer. Whereas olaparib was specifically assessed and approved for patients with deleterious germline 

 mutations, rucaparib is approved for patients with both germline and/or somatic mutations. Additional trials are ongoing to further define the role of PARP inhibitors in cancer management, including assessment of rucaparib in the treatment of ovarian cancer and other cancers related to alterations in DNA damage pathways.

New Indications for Already Approved Drugs

In addition to newly approved drugs, several agents that were previously approved by the FDA received additional indications in 2016. These include the immune checkpoint inhibitors pembrolizumab and nivolumab; the cytotoxic agent eribulin; the monoclonal antibody bevacizumab; and the oral targeted inhibitors crizotinib, cabozantinib, lenvatinib, palbociclib, and everolimus. These expanded approvals are reviewed below.

Expanded approvals of anti–PD-1 agents: pembrolizumab and nivolumab in head and neck squamous cell carcinoma (HNSCC) and pembrolizumab in NSCLC. 

Pembrolizumab and nivolumab are anti–PD-1 monoclonal IgG4 antibodies. Pembrolizumab was previously approved for the treatment of metastatic melanoma, and nivolumab was previously approved for the treatment of patients with metastatic melanoma, NSCLC, and renal cell carcinoma. In 2016, the approved indications for each of these new agents were expanded into new patient populations. Pembrolizumab was approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy, and for two new indications in the treatment of patients with metastatic NSCLC.

One new indication for pembrolizumab is for its use as initial therapy in patients whose tumors express PD-L1 with a tumor proportion score (TPS) ≥ 50%, and who are ALK/EGFR-negative and have not received prior systemic chemotherapy. The other indication is for use as subsequent therapy in patients whose tumors express PD-L1 with a TPS ≥ 1%, and who have disease progression during treatment with a platinum-containing chemotherapy regimen (or anti-ALK/EGFR therapy in patients with those genetic mutations). Prior to administration of pembrolizumab, TPS must be determined by an FDA-approved test such as the concurrently approved companion PD-L1 IHC 22C3 pharmDx assay.[21,22] Nivolumab was approved for the treatment of recurrent or metastatic HNSCC with disease progression on or after platinum-based chemotherapy.[23]

Pembrolizumab and nivolumab block PD-1, preventing the interaction between PD-1 and its ligands PD-L1 and PD-L2. Blocking the PD-1/PD-L1 pathway prevents immune suppression of cytotoxic T cells. This therapy may be particularly effective in tumor types that rely on upregulation of the PD-1/PD-L1 pathway as a survival strategy.[21,24,25]

The approval of pembrolizumab in patients with metastatic HNSCC was based on the demonstration of a durable ORR in KEYNOTE-012, a nonrandomized, open-label, multicenter study. The trial enrolled 60 patients with recurrent or metastatic HNSCC who had a PD-L1 TPS ≥ 1% and disease progression during or after treatment with platinum-containing chemotherapy. Pembrolizumab was administered at a dosage of 10 mg/kg every 2 weeks. The primary endpoints were ORR and assessment of safety. The ORR was 18% overall, 25% for human papillomavirus–positive patients, and 14% for human papillomavirus–negative patients. After a median follow-up of 14 months, 16% of patients had a PR, 2% had a CR, and 18% had stable disease. The median PFS duration was 2 months. Median OS was 13 months, with 51% of patients surviving at 12 months.[22] Pembrolizumab showed greater effectiveness, as measured by ORR (

 = .020), in patients whose tumors expressed higher levels of PD-L1.[22,26]

Approval of nivolumab in HNSCC was based on results from the phase III CheckMate-141 clinical trial, which showed a longer median OS-7.5 months-with nivolumab at a dosage of 3 mg/kg every 2 weeks IV, compared with a median OS of 5.1 months using investigator’s choice of standard single-agent therapy (HR, 0.70; 97.73% CI, 0.51–0.96; 

 = .01). Single-agent choices included cetuximab at an initial dosage of 400 mg/m

 IV weekly. The 1-year OS rate was 36.0% with nivolumab compared with 16.6% with standard therapy. The median PFS with nivolumab was 2.0 months compared with 2.3 months with standard therapy (HR, 0.89; 95% CI, 0.70–1.13; 

 = .32), with a response rate of 13.3% in the nivolumab group compared with 5.8% in the group that received standard therapy. Grade 3/4 AEs were significantly reduced with nivolumab (13.1%) compared with standard therapy (35.1%). The most common grade 3/4 AEs in the nivolumab group included fatigue (2.1%) and anemia (1.3%), and the most common grade 3/4 AEs in the group treated with standard therapy were neutropenia (7.2%) and anemia (4.5%).[23]

The expanded approvals for pembrolizumab in the lung cancer population were based on several of the KEYNOTE trials. KEYNOTE-001, a dose-escalation phase Ib trial, established a TPS ≥ 50% as the threshold value for PD-L1 expression associated with clinical benefit.[27]

The phase III KEYNOTE-024 trial was designed to assess the benefit of pembrolizumab compared with one of five platinum-based standard first-line chemotherapy regimens in previously untreated stage IV NSCLC without sensitizing 

 translocations. All patients were required to have a PD-L1 TPS ≥ 50%. Patients were randomized in a 1:1 ratio to receive treatment with either pembrolizumab at 200 mg IV every 3 weeks for 35 cycles or 4 to 6 cycles of the investigator’s choice of platinum-based combination chemotherapy. The primary endpoint was PFS. Pembrolizumab was associated with a significantly longer median PFS of 10.3 months, compared with 6.0 months in the chemotherapy group. The estimated rate of OS at 6 months was likewise significantly greater among the patients who received pembrolizumab (OS rate, 80.2% with pembrolizumab vs 72.4% in the chemotherapy group). OS was significantly longer in the pembrolizumab group than in the chemotherapy group (HR for death, 0.60; 95% CI, 0.41–0.89; 

KEYNOTE-010 was designed to assess the benefit of pembrolizumab compared with docetaxel in previously treated patients with stage IV NSCLC. This three-arm phase II/III trial enrolled 1,033 patients whose tumors had a PD-L1 TPS ≥ 1%. Patients were randomized 1:1 to receive treatment with pembrolizumab at two different doses (2 mg/kg or 10 mg/kg, every 3 weeks) or treatment with docetaxel. The primary endpoints were OS and PFS. The median OS durations were 10.4 months, 12.7 months, and 8.5 months for pembrolizumab at 2 mg/kg, pembrolizumab at 10 mg/kg, and docetaxel at 75 mg/m

, respectively. Compared with patients in the docetaxel treatment group, OS was significantly longer for patients treated with pembrolizumab at 2 mg/kg (

 < .0001). In 442 patients with elevated PD-L1 expression in tumor cells (TPS ≥ 50%), median OS durations were 14.9 months for patients treated with pembrolizumab at 2 mg/kg, 17.3 months for patients who received the 10-mg/kg dose of pembrolizumab, and 8.2 months for patients treated with docetaxel at 75 mg/m

KEYNOTE-012 and KEYNOTE-024 both demonstrated acceptable toxicity profiles for pembrolizumab, with fewer AEs than the chemotherapy regimens with which it was compared. In KEYNOTE-012, AEs of any type were seen in 63% of patients with HNSCC treated with pembrolizumab, with the most common being fatigue (22%), pruritus (12%), rash (7%), diarrhea (4%), and musculoskeletal pain (4%). Grade 3 AEs were seen in 17% of patients, the most common of which included elevated AST and ALT levels, and hyponatremia, each seen in 3% of patients.[22,26] In KEYNOTE-024, there was a lower frequency of treatment-related AEs in the pembrolizumab group (73.4%) vs the chemotherapy group (90.0%). The most common grade 3–5 AE was diarrhea (3.9%). Immune-related AEs of any grade occurred in 29.2% of patients, with hypothyroidism (9.1%) being the most common. AEs led to discontinuation of pembrolizumab in 7.1% of patients, compared with 6.0% of patients who received alternate chemotherapy. One treatment-related death occurred in the pembrolizumab group and three deaths occurred in the group treated with alternate chemotherapy.[28]

National Comprehensive Cancer Network (NCCN) guidelines for HNSCC have classified both pembrolizumab and nivolumab as single-agent therapies for use upon disease progression during or after therapy with platinum-containing regimens. Both have shown clinically sigificant activity, and to date there has not been a study directly comparing pembrolizumab with nivolumab.[30] NCCN guidelines for NSCLC classify pembrolizumab as an agent to be used as subsequent therapy for patients with metastatic nonsquamous or squamous cell NSCLC if PD-L1 expression levels are 1% or higher.[31] Pembrolizumab may be used as first-line therapy for patients whose tumors have PD-L1 expression levels of 50% or higher and who are negative for 

 rearrangements. HNSCC and NSCLC both have associations with smoking, a contributing factor for high tumor mutation burden, a metric shown to correlate with the effectiveness of immunotherapy.[4,21,29,32,33] Further assessment of tumor mutation burden to identify patients who will derive the greatest benefit from these agents is an ongoing effort.

Palbociclib, approved for advanced or metastatic hormone receptor–positive breast cancer, in combination with fulvestrant. 

Palbociclib is an orally available inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). It was approved by the FDA for use in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.[34] Palbociclib is a first-in-class-and currently the only-FDA-approved inhibitor of CDK4/6. It was initially approved on February 3, 2015 for use in combination with letrozole as initial endocrine-based therapy in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

As a CDK4/6 inhibitor, palbociclib exerts its anticancer effects by blocking progression from the G1 phase to the S phase of the cell cycle; the resulting loss of retinoblastoma protein phosphorylation prevents DNA synthesis.[35] HR-positive breast cancers, in particular those that have developed resistance to prior endocrine therapy, have demonstrated reliance upon CDK4/6 activity.[36-38] Based on mechanistic, preclinical, and clinical evidence supporting the synergistic effect of hormonal therapy plus palbociclib in HR-positive breast cancer, the pivotal PALOMA-3 trial was conducted utilizing the estrogen receptor antagonist fulvestrant.[39,40]

PALOMA-3 was a multicenter, double-blind, randomized, phase III study that compared the combination of fulvestrant plus palbociclib at 125 mg daily for 21 consecutive days followed by 7 days off treatment vs fulvestrant plus placebo in women with HR-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy. The major results were reported across three articles: the first article described the initial results; the second presented a final analysis with extended follow-up, including subgroup and biomarker analyses; and the most recent one provided a detailed safety analysis.[41-43] In total, 521 patients were randomized (2:1) to receive treatment until disease progression or unacceptable toxicity. Stratification was based upon sensitivity to previous hormonal therapy, menopausal status, and presence or absence of visceral metastasis. The primary endpoint was investigator-assessed PFS according to RECIST.[41,42] After a median follow-up of 8.9 months, median PFS was 9.5 months in the combination group compared with 4.6 months in the group randomized to fulvestrant with placebo (HR, 0.46; 95% CI, 0.36–0.59; 

 < .0001). At the time of publication, the OS data were not fully mature.[42]

The safety of palbociclib plus fulvestrant was evaluated in the 345 patients in PALOMA-3 who were treated with this combination. Neutropenia was the most common AE in this group, with grade 3 neutropenia reported in 55% of patients and grade 4 neutropenia reported in 10%.[43] In total, 34% of patients had at least one dose reduction during the study and 4% of patients discontinued therapy due to AEs.[42] The most common grade 1–4 AEs, other than neutropenia, occurring in at least 10% of patients were leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia.

Based on the results of PALOMA-3, palbociclib is now indicated, in combination with fulvestrant, for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who experienced disease progression following endocrine therapy. Clinicians now have a variety of options for the treatment of HR-positive breast cancer, including several endocrine drug therapies that are recommended for patients with recurrent or metastatic disease. The NCCN assigned a category 1 recommendation to use of the palbociclib/fulvestrant combination as endocrine therapy for postmenopausal or premenopausal women with recurrent or metastatic HR-positive, HER2-negative breast cancer who are undergoing ovarian suppression with a luteinizing hormone–releasing hormone agonist, and whose disease had progressed on prior endocrine therapy. While the impact of this novel combination on OS is still to be determined, there is clear consensus that the addition of palbociclib to conventional endocrine therapy represents a significant improvement. The search for biomarkers or other features to identify patient-selection strategies is a focus of ongoing clinical trials.

Eribulin, approved for advanced liposarcoma following treatment with an anthracycline.

 Eribulin mesylate is a synthetic analog of halichondrin B that inhibits microtubule dynamics, ultimately leading to G2/M-phase cell-cycle blockade and apoptosis. Eribulin’s unique mechanism of action is distinct from the other microtubule inhibitors-including the vincas, taxanes, and epothilones-and early studies indicate that it may maintain activity in disease that has progressed on these agents.[44] This agent was initially approved in November 2010 for the treatment of metastatic breast cancer that had progressed on at least two prior treatment regimens, including an anthracycline and a taxane. On January 28, 2016, eribulin also gained FDA approval for therapy of unresectable or metastatic liposarcoma following treatment with a prior anthracycline-containing regimen.

The evidence supporting approval of eribulin in liposarcoma was from a randomized, open-label, multicenter, phase III trial of eribulin vs dacarbazine in adult patients with previously treated advanced liposarcoma or leiomyosarcoma. Patients were randomized 1:1 to either eribulin at 1.4 mg/m

 IV on days 1 and 8 (n = 228) or dacarbazine (n = 224), with the dosing based on the site of enrollment. They were stratified by disease type (liposarcoma or leiomyosarcoma), number of prior treatment regimens, and geographic region. The primary endpoint was OS, which was improved in patients who received eribulin compared with those receiving dacarbazine (13.5 months vs 11.5 months, respectively; HR, 0.77; 95% CI, 0.62–0.95; 

The survival benefit appeared to be limited to patients with liposarcoma, since those treated with eribulin had a median OS duration of 15.6 months, compared with 8.4 months in the patients who received dacarbazine (HR, 0.51; 95% CI, 0.35–0.75; 

 = .001), although the study was not powered to assess this comparison. Median PFS in the liposarcoma patients was 2.9 months in those treated with eribulin and 1.7 months in those treated with dacarbazine (HR, 0.52; 

 = .002). In the whole patient population, the median PFS was similar between the treatment groups (2.6 months in each group). Grade 3/4 AEs were rare, with the exception of neutropenia (35%), leukopenia (10%), and anemia (7%). Discontinuation of eribulin secondary to AEs occurred in 8% of patients, and dose reduction was required in 26%.[45]

Part of the rationale for investigating eribulin in the soft-tissue sarcoma population was related to effects of this drug on vascular remodeling that may enhance the tumor response to subsequent chemotherapy.[46] This may explain the OS benefit without clinically meaningful improvement in median PFS observed in the trial discussed previously, since 69% of patients who received eribulin went on to receive subsequent chemotherapies. The phase III approval trial restricted enrollment to liposarcoma and leiomyosarcoma due to evidence from a prior phase II trial demonstrating that only these two sarcoma histologies met the threshold endpoint of at least 30% of patients being progression-free at 12 weeks.[47] The place for eribulin in the treatment of liposarcoma is still being determined in light of the newer approvals of trabectedin and olaratumab, although it will likely remain a later-line option.

 Crizotinib is an oral small-molecule tyrosine kinase inhibitor of 

. It was initially approved in January 2011 for patients with metastatic NSCLC whose tumors are ALK-positive; however, given the similarity between the kinase domains of 

, it was also found to inhibit the latter.[48] On March 11, 2016, crizotinib was approved for the treatment of metastatic NSCLC positive for 

 rearrangements are rare in NSCLC, occurring in about 1% of all lung adenocarcinomas, with a higher prevalence in younger patients who are nonsmokers. Rearrangements with 

 typically involve the same portion of the 

 gene fusing with one of at least 11 partners, ultimately resulting in constitutively active ROS1 fusion protein.[49] The initial clinical evidence supporting the use of crizotinib in NSCLC with 

 rearrangements was derived from a case report of a 31-year-old male never-smoker, who was found to be 

-positive and had near complete response of his multifocal lung tumor at 8 weeks; the patient continued to receive treatment with crizotinib for more than 6 months, with no evidence of recurrence.[49]

The support for the approval of crizotinib in 

-positive NSCLC came primarily from an expansion cohort of the original phase I crizotinib trial: 50 adult patients diagnosed with NSCLC who harbored a 

 rearrangement. The patients received crizotinib at a dosage of 250 mg by mouth twice daily. The ORR was 72%, with 3 patients having CRs and 33 having PRs. The median duration of response was 17.6 months, and median PFS was 19.2 months. There was no correlation between response and the type of 

Very few grade 3 toxicities were reported, and included neutropenia (10%) and hypophosphatemia (10%).[50] These data are similar to results from the retrospective cohort of 32 

-positive NSCLC patients enrolled in the EUROS1 trial who received the same regimen of crizotinib and demonstrated an ORR of 80%, including 5 CRs.[51] Based on the high rates of response reported, crizotinib is indicated by the NCCN as the preferred first-line therapy for 

Everolimus, for progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine tumors.

 Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR), a kinase composed of two protein complexes-mTOR complex 1 and mTOR complex 2-that is activated by numerous upstream receptor tyrosine kinases. Everolimus is an oral allosteric inhibitor of mTOR complex 1.[52] Everolimus is approved for several indications, including progressive neuroendocrine tumors of pancreatic origin. On February 26, 2016, this approval was expanded to include progressive, nonfunctional GI and lung neuroendocrine tumors.

Neuroendocrine tumors originate from the neuroendocrine cells of the body, with about half arising from the GI tract, 27% from the lungs, and only 6% from the pancreas. They are classified as functional if they are associated with hormonal hypersecretion symptoms, or nonfunctional if they are not.[53] Somatostatin analogs, such as octreotide, are effective for malignancies involving hormonal syndromes; however, effective options for the treatment of nonfunctional neuroendocrine tumors, especially in the GI tract and lungs, are very limited. Based on data from studies of pancreatic neuroendocrine tumors and combination trials with octreotide in functional neuroendocrine tumors, everolimus was assessed specifically in patients with nonfunctional neuroendocrine tumors of the GI tract and lungs.[54]

This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning.

Oncology Vol 31 No 2

Barbara McAneny on How the Repeal of the ACA Without a Replacement Threatens the Health of Patients and the Success of Community Practices

Accelerated Partial Breast Irradiation for Breast Cancer: Not Ready for Routine Use

Accelerated Partial Breast Irradiation for Breast Cancer: An Innovative Option for Selected Early-Stage Cancers

Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management

Novel and Expanded Oncology Drug Approvals of 2016-PART 2: New Options in the Management of Hematologic Malignancies