Enthusiasm for IORT in breast cancer tempered by trial designs, recurrence rates

Adjuvant whole-breast external beam radiation therapy serves as the standard of care for women with early-stage breast cancer who undergo lumpectomy.

Adjuvant whole-breast irradiation reduces 5-year recurrence risk by up to 70% and provides a 5% absolute increase in 15-year OS, according to data from the American Society for Radiation Oncology (ASTRO).

However, the time commitment required for a standard course of therapy — 10- to 15-minute radiation sessions 5 days per week for approximately 3 to 6 weeks — can be a treatment barrier, particularly for patients who live in remote or rural areas.

This concern prompted researchers to explore alternative methods for radiation delivery, and some suggest intraoperative radiotherapy (IORT) — a targeted procedure performed concurrently with lumpectomy via a single dose of radiation — may be a practice-changing advance in this setting.

“IORT can treat a woman with all the radiation she needs while she is asleep in the operating room,  only adding about 20 minutes to her total OR time,” Courtney A. Vito, MD, FACS, director of fellowship education and assistant clinical professor in the department of surgical oncology at City of Hope, told HemOnc Today. “A patient can save all of the potential time she would have to take off from work, along with commuting time and the potential hardships involved.”

Two high-profile randomized controlled trials — TARGIT-A and ELIOT — yielded encouraging efficacy and safety results. Further, proponents contend one-time IORT could substantially reduce costs.

However, skeptics have expressed concerns about the designs of these trials, their relatively short follow-up periods and the potentially increased risk for recurrence among women assigned IORT.

HemOnc Today spoke with surgical and radiation oncologists about the promise of IORT, whether trial data support its routine use in clinical practice and which patients are ideal candidates and whether some women with early-stage breast cancer can achieve favorable outcomes without radiation.

Influential study findings

Two randomized controlled trials compared IORT with standard radiotherapy, which traditionally consists of 50 Gy delivered in daily 2-Gy fractions over the course of several weeks, with a 10- to 16-Gy boost to the tumor bed.

The international TARGIT-A trial — results of which appeared in The Lancet Oncology — included 3,451 women with early-stage breast cancer assigned single-dose, targeted IORT (n = 1,721) or fractionated external beam radiotherapy (n = 1,730). Median follow-up was 29 months, and 5-year data indicated IORT met the 2.5% noninferiority threshold.

Researchers reported similar rates of breast cancer mortality between groups (2.6% vs. 1.9%). Significantly fewer women assigned IORT experienced skin complications (P = .029) and non-breast cancer death (P = .0086).

However, significantly more patients in the IORT arm experienced 5-year recurrence in the conserved breast (3.3% vs. 1.3%; P = .042).

Approximately 15% of patients assigned IORT eventually received whole-breast radiation. This risk adaptation — along with the trial design — may prove the trial outcomes are generalizable to the broader breast cancer treatment community, according to Stephen Grobmyer, MD, director of breast services at Cleveland Clinic.

“If patients randomized to [IORT] were found to have higher-risk disease after surgery and pathology, they could then go on to get standard whole-breast radiation therapy,” Grobmyer said. “In those cases, the IORT becomes their boost replacement. That gives us a lot of flexibility in terms of treating patients. In the remaining 80% or so of patients, the initial radiation was all they received.”

The ELIOT trial — conducted in Italy by Veronesi and colleagues and published in The Lancet Oncology — compared whole-breast radiation with electron IORT in 1,305 women.

After a median follow-up of 5.8 years, significantly more patients assigned IORT experienced ipsilateral breast tumor recurrence (4.4% vs. 0.4%; P < .0001). However, 5-year OS was nearly identical between arms (96.8% vs. 96.9%), and significantly fewer patients assigned IORT experienced skin-related adverse events (P = .0002).

David E. Wazer, MD, radiation oncologist-in-chief and chair of the department of radiation oncology at Tufts University School of Medicine, as well as professor and department chair of radiation oncology at Brown University’s Alpert School of Medicine, has been a vocal critic of the TARGIT-A trial design. However, Wazer told HemOnc Today that some aspects of the ELIOT trial could be appealing to radiation oncologists.

Photo by John Droney.

“The method used in the ELIOT trial calls for a miniature linear accelerator in the operating room, and the electron beam consists of electrons that have a charge and mass,” Wazer said. “Depending upon the energy selected, they will penetrate into tissue to a certain depth and stop. This gives the advantage of being able to control the penetration to a certain degree. Delivering electrons also gives a uniform dose across the entire exposed tissue, which makes sense from a radiation oncologist’s perspective.”

However, Wazer emphasized he does not currently support the standard utilization of either ELIOT or TARGIT-A.

“Neither method allows for image verification that the tissue at risk has actually been irradiated,” Wazer said. “This is all done in a very crude and, very likely, inaccurate manner. This is the primary reason why many of us suspect that [proponents of these techniques] are using ineffective irradiation on patients who are so low risk they need no radiation whatsoever.”

Further, the ELIOT approach may not be feasible in standard operating rooms, Vito said.

“This technique may be more appealing to radiation oncologists because it is closer to what they are used to doing,” Vito said. “As a surgeon, it is much more difficult to use. The applicators for the linear accelerators are bigger and require larger breast incisions, and the patients we can physically accommodate are different. The machines used in TARGIT-A can be more easily applied to smaller breasts, and they can be applied in more creative ways.”

Vito also questioned the design of the ELIOT study.

“Most of the original ELIOT trial data were case reports or accumulated data rather than an organized and randomized trial,” Vito said. “The trial now features a smaller number of patients but, ultimately, the original data that came out of this group were not as well done as the TARGIT trial. In the end, the results are not necessarily any better [with IORT].”

Informed decision-making

In addition to these data, clinicians and patients must consider harms, costs, accessibility and cosmesis when choosing between the two treatment modalities.

Although IORT may seem like a relatively new modality — data from ELIOT were published in 2013 and data from TARGIT-A in 2014 — its history is somewhat mature, according to Alastair M. Thompson, BSC(Hons), MBChB, MD, FRCSEd, professor in the department of breast surgical oncology at The University of Texas MD Anderson Cancer Center.

“This process dates to the 1970s,” Thompson, an investigator on TARGIT-A, told HemOnc Today. “There are multiple methods that this process has been trialed in, including the intrabeam device, intraoperative electron radiation therapy and a process by which a balloon device is inserted into the cavity, which then gives radiation over a period of 5 days down a tube.”

Access can play a key role in therapy selection.

“For most people, the requirements of traditional radiotherapy are an inconvenience — and for some, it is just not possible,” Thompson said. “It is particularly a problem for people who have to travel a distance.”

Beyond convenience, use of IORT may eliminate inappropriate radiation receipt for properly selected patients, Grobmyer said.

“After the surgery, the patient gets to go home. For about 80% of patients, that will be all the radiation she ends up needing,” Grobmyer said. “Select patients with tumors of a certain size or type can elect for this treatment and receive a lot less radiation to normal tissue. In these certain cases, additional radiation does not appear to help.”

Cost also is an issue. Using data from TARGIT-A and ELIOT, Shah and colleagues found IORT saved $3.6 million to $4.3 million per 1,000 patients compared with whole-breast irradiation using 3D-conformation radiotherapy.

Upfront costs for IORT equipment are approximately $425,000, but Alvarado and colleagues determined these costs can be recouped after 3 to 4 years.

Further, cosmesis and treatment length are important to patients, who must consider factors associated with treatment alongside other aspects of their lives, Grobmyer said.

In a single-institution study of IORT following breast-conserving surgery, Yu and colleagues found more than 85% of 75 patients treated with IORT reported favorable cosmetic outcomes, with 43 patients describing their outcomes as “excellent” and 23 as “good.”

The researchers noted adverse events associated with whole-breast irradiation — such as risk for injury to organs like the heart or lungs, as well as atrophy of the irradiated breast — also should be considered.

“When IORT is performed correctly, the risk for skin burns, skin peeling and other effects of whole-breast irradiation are very minimal,” Vito said.

Each these factors must be weighed by patients.

“Patients are very involved in their treatment decisions, and doctors spend a lot of time outlining to patients what their treatment options are,” Grobmyer said. “Patients are often very educated when they come to us. They know what they want, and they make an informed choice. Without giving patients all of their options, they really cannot be involved in making their best decision.”

The use of IORT also may lessen the strain on facilities that provide traditional radiation services.

“Globally, external beam radiotherapy centers are under a degree of pressure,” Thompson said. “Many more patients are getting cancer and finding themselves in need of radiation treatment, particularly in the breast. Once we get used to doing IORT and everyone is on board, it is a treatment that does not place such demands.”

Still, research letters and public comments have suggested that enthusiasm for IORT is stronger in the surgical community than in the radiation oncology community.

“When you are inside the site, you can aim the radiation directly where the tumor has been taken out,” Thompson said. “You do not have the potential for missing the tumor bed, which occasionally can occur in traditional external beam radiotherapy. All things being equal, one would think that a procedure done at the time of surgery, taking less than an hour, is a great idea.”

Benjamin D. Smith, MD, associate professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, agreed that radiation oncologists might be more hesitant to accept a new therapeutic option on the basis of convenience.

“Surgeons tend to be excited if they can offer patients treatment that is easier and more convenient,” Smith said in an interview. “From a radiation oncology perspective, there are several concerns about IORT that hit home to us more so than to surgeons. That might be why there is a disconnect.”

Target of controversy

Although surgeons generally have heralded results of the TARGIT-A and ELIOT trials as proof of IORT’s potential, others contend the short follow-up and lenient eligibility criteria confound the results.

“It is rare for a randomized trial to create very vocal criticism,” Smith said. “If you have thoughtful people taking the time to say that there are problems, that at least tells you there are some meaningful issues with the trial.”

The criticism of TARGIT-A became so extensive, Anthony Zietman, MD, FASTRO, editor in chief of International Journal of Radiation Oncology, Biology and Physics, wrote a detailed introduction to a special section of correspondence published in the August issue.

“The letters draw on three themes,” Zietman wrote. “The first is the scientific discussion of methodology that focuses on the advantages and pitfalls of noninferiority studies and the importance of mature follow-up. The second regards trial governance: how trials are organized, monitored and overseen. The third is the interpretation of the data. It is in this latter category that the value, or otherwise, of IORT is in the eye of the beholder.”

Wazer has coauthored several articles and research letters that questioned the design and methodology of TARGIT-A. One major concern is the length of follow-up used to validate the findings.

In an editorial published in International Journal of Radiation Oncology, Biology and Physics, Wazer and Jaroslaw Hepel, MD, assistant professor of radiation oncology at Brown University, highlighted specific concerns.

“The median follow-up time for the TARGIT-A cohort of just over 2 years is inadequate to enable conclusions to be drawn regarding risk for local failure or normal tissue toxicity,” they wrote. “For local failure, the distorting effect of short follow-up is particularly applicable to the high proportion of low-risk patients with small, ER-positive tumors. For such a population, local failure will most likely occur after 5 years.”

Thompson agreed concerns regarding follow-up are valid.

“Given that the patients on this trial often had small, mostly ER-positive, node-negative, low-grade cancers — in other words, cancers with a fairly low recurrence risk — we can see why people would say that we need at least 5, maybe 10 years of follow-up,” Thompson said. “However, for patients with the same criteria, the incidence of local recurrence is the same in year 1 as it is in year 20 — about 1% per year, ad infinitum.”

Although ASTRO has not issued formal guidelines on the use of IORT, the society issued a position statement outlining which patients could be considered “suitable.” Suitability criteria included older age, T1 tumor status, absence of BRCA mutations and negative margins.

Because the TARGIT-A trial did not limit enrollment to women who met these criteria, questions arise about recurrence data, Vito said.

“The inclusion criteria for whose tumors would be allowed into the trial was very wide, and it greatly deviates from what we have as our guidelines,” Vito said. “About one-third of patients included in the trial would have been considered suitable. Everybody else would have been ‘cautionary’ or ‘unsuitable.’ The trial included everybody who wanted IORT — even some women who had positive margins. There are women with positive margins who elected not to return to the operating room following IORT, and they are still included in the survival analysis.”

The noninferiority design of the trial has prompted some to question whether IORT truly is equivalent to traditional radiation therapy. In their editorial, Wazer and Hepel wrote that had the 5-year rates of local failure been included in the analysis, the trial would not have met its 2.5% criteria for noninferiority, and external beam radiation would have produced a 2% superiority threshold.

Smith agreed.

“There is a valid concern that the statistics on the TARGIT trial were done in such a way as to lead to a particular conclusion,” Smith said. “Even if you step aside from the issue of study design and look purely at the numbers, the results remain questionable.”

Reactions to TARGIT-A and ELIOT may have advanced a conclusion that was not necessarily substantiated by the study findings, Wazer said.

“The data for TARGIT-A are just not mature enough for us to make any sort of definitive comments,” he said. “The ELIOT trial had good follow-up, but it did show a significantly higher failure rate in the IORT arm.”

The future of IORT

The length of traditional radiation therapy remains a concern for physicians and patients. In addition to IORT, trials are underway to assess a shortened radiotherapy course. Two trials in the United Kingdom are evaluating whether the course can be reduced to as few as 5 days.

“We are looking at a moving set of challenges,” Thompson said. “External beam radiotherapy is not standing still. Instead of 4 or 5 weeks, we are increasingly seeing 3 weeks of radiotherapy. The difference between a single shot of IORT and a very short course of traditional radiotherapy then becomes a slightly different question.”

Still, IORT may remain an enticing choice for appropriate patients, even if the length of external beam radiation is reduced.

“There will be patients who would rather have that small increase in risk that IORT carries than go through a 3-week radiotherapy course,” Thompson said. “Informed patient choice is going to be very important, and I would emphasize the word ‘informed.’ If there is an increased risk for recurrence, patients need to know that.”

Vito agreed, noting that TARGIT-A follow-up continues.

“The trial is not mature, and the technique flies in the face of standard breast cancer treatment,” Vito said. “However, women agonize over the choice of sacrificing their breasts and risking greater complications due to the variety of reasons that radiation might not be an option for them. These are issues that can be addressed with this short, discreet procedure.”

IORT likely will continue to garner support in the broader oncology community, Wazer said.

“There are many advocates for the technique who are very passionate,” he said. “If you have passionate and articulate advocates for anything, you can advance it.”

Still, the next line of research may question whether certain patients with early-stage breast cancer can completely forgo radiation.

“Given that the majority of patients enrolled in these trials also received hormone therapy, we should ask the question of whether they needed radiation therapy,” Wazer said.

Hormone therapy is associated with a 4% 5-year recurrence risk — compared with 1% for whole-breast radiation — among women with early-stage breast cancer, Smith said.

“In that population, you could consider skipping radiation,” Smith said. “Looking at the recurrence risk for TARGIT compared to that data, you have to wonder what the benefit for TARGIT is, and whether TARGIT is doing that much. Maybe these patients would have done just as well with no radiation.” – by Cameron Kelsall

References:

Hepel J and Wazer DE. Int J Radiation Oncol Biol Phys. 2014;doi:10.1016/j.ijrobp.2014.09.019.

Shah C, et al. Ann Surg Oncol. 2014;doi:10.1245/s10434-013-3291-0.

Shah C, et al. Clin Breast Cancer. 2014;doi:10.1016/j.clbc.2013.10.0005.

Silverstein MJ, et al. Ann Surg Oncol. 2014;doi:10.1245/s10434-014-3999-5.

Thompson AM, Yarnold J. Curr Breast Cancer Rep. 2015;doi:10.1007/s12609-014-0174-8.

Vaidya JS, et al. Int J Radiation Oncol Biol Phys. 2015;doi:10.1016/jijrobp.2015.03.022.

Vaidya JS, et al. Lancet. 2014;doi:10.1016/S0140-6736(13)61950-9.

Veronesi U, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70497-2.

Yu W, et al. Am J Cancer Res. 2015;5(7):2249-2257.

Zietman A. Int J Radiation Oncol Biol Phys. 2015;doi:10.1016/j.ijrobp.2015.05.048.

For more information:

Stephen Grobmyer, MD, can be reached at Cleveland Clinic Main Campus, Mail Code A81, 9500 Euclid Ave., Cleveland, OH 44195.

Benjamin D. Smith, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: bsmith3@mdanderson.org.

Alastair M. Thompson, BSc(Hons), MB ChB, MD, FRCSEd, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: athompson1@mdanderson.org.

Courtney A. Vito, MD, FACS, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: cvito@coh.org.

David E. Wazer, MD, can be reached at Tufts Medical Center, 800 Washington St. #359, Boston, MA 02111; email: dwazer@tuftsmedicalcenter.org.

Disclosure: Grobmyer reports research funding and honoraria from Zeiss. Thompson served as an investigator on the TARGIT-A trial. Wazer reports an advisory role with Advanced Radiation Therapy Inc., as well as a leadership position with American Brachytherapy Society. Smith reports research funding from Varian Medical Systems. Vito reports no relevant financial disclosures.

 

 

Should certain women with early-stage breast cancer be given the option to forgo adjuvant radiation therapy?

There may be a subset of women with early-stage invasive or noninvasive breast cancer who can safely avoid radiation.

Adjuvant radiation is considered standard following lumpectomy for early-stage breast cancer, a treatment paradigm called breast conservation. The purpose of radiation is to reduce the risk for an ipsilateral breast tumor recurrence, thus providing equivalent survival to mastectomy. Based on a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) of 17 randomized trials of radiotherapy vs. no radiotherapy after breast-conserving surgery for invasive breast cancer, radiotherapy decreases the 10-year rate of locoregional or distant recurrence from 35% to 19.3% and reduces the 15-year risk for breast cancer death from 25.2% to 21.4%. These data suggest on average about one breast cancer death is avoided for every four recurrences. These results inform us that radiation is an essential component of breast-conserving therapy. However, in an effort to minimize morbidity, contain costs and improve patients’ quality of life, oncologists try to identify patients for whom less aggressive treatment is warranted. The trials included in the EBCTCG meta-analysis varied in terms of patient selection (tumor size, nodal status, age and ER status) and type of surgery performed (lumpectomy vs. quadrantectomy). Thus, there may be a subset of women for whom the benefit of radiation is small and for whom omission of radiation would not compromise survival.

There are two randomized trials of older women with favorable breast cancers treated with lumpectomy and endocrine therapy with or without radiation. CALGB 9343 included 636 women aged 70 years and older who had clinical stage I (T1N0M0) ER-positive breast cancer who were followed for a median of 12.6 years. At 10 years, the local recurrence rate was 2% with radiation vs. 10% without. There was no difference in breast cancer-specific survival or OS. A similar trial from Princess Margaret Hospital included 769 women aged 50 years and older with T1/T2, N0, ER-positive or -negative breast cancers who were randomly assigned after lumpectomy to tamoxifen with or without radiation. The local recurrence rate at 5 years was 7.7% in the tamoxifen group and 0.6% in the tamoxifen plus radiation group (P < .001). Again, there was no significant difference in distant relapse or OS between the groups. Thus, both trials suggested that tamoxifen alone after lumpectomy was a reasonable option for older women.

In summary, radiation benefits all women after lumpectomy by reducing the risk for recurrence; however, the magnitude of this benefit is small for older women with small, ER-positive tumors. In these patients, the reduction in local recurrence provided by radiation does not impact survival. Although radiation is well tolerated — perhaps even better than endocrine therapy — omitting it in these favorable patients could be considered.

 

References:

EBCTCG. Lancet. 2011;doi:10.1016/S0140-6736(11)61629-2.

Fyles AW, et al. N Engl J Med. 2004;351:963-970.

Hughes KS, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.45.2615.

Shelly Bowers Hayes, MD, is director of radiation oncology at Fox Chase Cancer Center in Buckingham, Pa. She can be reached at shelly_hayes@fccc.edu. Disclosure: Hayes reports no relevant financial disclosures.

Radiation therapy remains the best treatment option for the majority of women with early-stage breast cancer.

Although numerous randomized trials have demonstrated substantial reductions in the relative risk for locoregional recurrence with adjuvant radiation therapy after lumpectomy, not all patients attain the same absolute benefit. Tremendous advances in screening, surgery, pathologic assessment and systemic therapy have lowered the absolute risks, and this reduces the gain from radiation therapy for some patients. Because radiation also involves toxicity, burden and expense, it is important to identify patients who might safely omit radiation therapy.

Meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group have suggested that the survival benefit from radiotherapy appears to be restricted to patients who reap a large absolute reduction in recurrence risk from treatment, rather than those in whom the absolute benefit in recurrence risk reduction is under 10%, or even between 10% and 20%. Numerous prior studies have sought to identify patients with a low baseline risk for recurrence, in whom further reduction would be unexpected to influence survival.

Unfortunately, most studies demonstrated unacceptably high rates of local failures without radiotherapy, even after the development of effective endocrine therapy. For example, in the NSABP B-21 trial, women with invasive breast cancers up to 1 cm in size had an 8-year risk for ipsilateral breast tumor recurrence of 16.5% after lumpectomy and tamoxifen alone, compared with 9.3% with radiation and 2.8% with both, leading the authors to conclude that adjuvant radiotherapy was necessary even in patients with small tumors. Similarly, the overall findings of a Canadian multicenter trial of patients aged at least 50 years with T1/T2, N0 tumors who received radiation with or without tamoxifen were disappointing, with unacceptably high rates of local recurrence (7.7% at 5 years and 18% at 8 years). Even in the subgroup with T1N0 ER-positive tumors, the 8-year rate of local recurrence was 15.2%. Studies restricted to elderly patients have been more promising. In the CALGB 9343 trial, women aged 70 years or older with clinical stage T1N0M0, ER-positive invasive cancers received lumpectomy with negative margins (with or without axillary assessment) and tamoxifen for 5 years, and received whole-breast radiation or observation. Although the difference in local recurrence rates with radiation (2%) and without radiation (10%) was statistically significant, this study has been widely interpreted as justifying omission of radiation in older women with favorable cancers. Similar findings, albeit with much shorter follow-up, have been suggested by the recently published PRIME II study conducted in women aged 65 and older. Ultimately, decision-making regarding omission of radiotherapy in older patients must weigh patients’ values and preferences. Such decisions must consider the patient’s willingness to receive endocrine therapy and her overall life expectancy. For certain older patients similar to those on these trials, omission of radiotherapy may reasonably be considered. For others, the increasing array of less burdensome treatment options for radiation administration may be more appropriate.

Recent advances have broadened our appreciation that breast cancer is a heterogeneous disease in which tumor biology is at least as important in predicting behavior and outcomes, if not more so, than classical clinical and pathologic features. Several studies have suggested that rates of locoregional recurrence vary by biologic subtype of breast cancer, not only in patients receiving radiotherapy but also in those treated with surgery alone. Ongoing prospective cohort studies, including the LUMINA study in Canada (which uses assessment of Ki-67 in addition to consideration of ER, PR and HER-2–negative status to identify patients with favorable, Luminal A tumors) and the IDEA study in the United States (which relies on the Oncotype DX 21-gene recurrence score to identify patients with favorable biology), will help to shed further light on these issues.

In the meantime, radiation therapy remains the standard of care after lumpectomy for most patients, but enrollment of willing patients on open protocols should help to advance our understanding and hopefully create a greater array of evidence-based options for patients in the future.

 

References:

EBCTCG. Lancet. 2011;doi:10.1016/S0140-6736(11)61629-2.

Fisher B, et al. J Clin Oncol. 2002;doi:10.1200/JCO.2002.11.101.

Fyles AW, et al. N Engl J Med. 2004;351:963-970.

Hughes KS, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.45.2615.

Kunkler IH, et al. Abstract S2-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2013; San Antonio.

Reshma Jagsi, MD, PhD, is associate professor and deputy chair for faculty and financial operations in the department of radiation oncology at University of Michigan Health System. She can be reached at rjagsi@med.umich.edu. Disclosure: Jagsi reports no relevant financial disclosures.