Intensified Radiotherapy Emerging as New Standard

George Rodrigues, MD, PhD

Radiation therapy can be effectively delivered in more focused, intensive, and shorter-course treatment regimens that offer patients at least equivalent—and in some cases superior—outcomes in several tumor types, thus helping to mitigate challenging adverse effects of standard approaches, according to research presented at the 2016 ASTRO Annual Meeting.

Four studies in which innovative strategies using accelerated versus conventional treatment approaches in patients with brain metastases, lung cancer, and prostate cancer were highlighted during the conference, which took place September 25-28 in Boston.

“All 4 presentations detail important randomized controlled data on the topic of hypofractionated radiation treatment that were carried out in several cancer centers,” said George Rodrigues, MD, PhD, who served as moderator during a press briefing where the research was discussed.

“Research about hypofractionated radiation is important to our specialty, our patients, and society in order to provide both convenient and cost-effective care without sacrificing treatment efficacy and while improving toxicity profiles,” said Rodrigues, who is a clinician scientist and radiation oncologist at the Lawson Health Research Institute and London Health Sciences Centre in Canada.

In the first study,¹ researchers at the Mayo Clinic and other sites presented findings that compared stereotactic radiosurgery (SRS) with whole-brain radiotherapy (WBRT) in patients with resected metastatic brain cancer. “In this multi-institutional trial, Mayo Clinic researchers found comparable survival rates, better quality of life, and less cognitive decline following postoperative SRS compared with WBRT,” said Rodrigues.

Similarly, Anita Mahajan, MD, and colleagues found that SRS decreased the rate of local occurrence compared with observation alone following resection in patients with brain metastasis.² “There was no difference in distant metastasis or overall survival (OS) between the 2 groups,” said Mahajan, a professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center.

In the thoracic cancer arena, Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern, Dallas, found that the use of accelerated, hypofractionated radiation therapy can cut treatment time in half compared with conventional therapy with similar efficacy for patients with stage II/III non—small cell lung cancer (NSCLC) who cannot undergo surgery or radiation plus chemotherapy.³

WBRT Versus SRS in Brain Metastases

In the fourth study, Anders Widmark, MD, PhD, of Umeå University in Sweden, presented findings showing that men with intermediate-risk prostate cancer are able to undergo “extremely” hypofractionated radiation therapy without experiencing more adverse events than they would have with conventional therapy.⁴The use of postoperative SRS for patients with resected brain metastases should be considered standard of care because of its equivalent survival, better preservation of function and quality of life, and less toxicity compared with WBRT, said Paul D. Brown, MD, a radiation oncologist at the Mayo Clinic in Minnesota.

Currently, WBRT after resection of brain metastasis to improve local control is the standard of care, but it is fraught with difficult adverse effects including hair loss, fatigue, skin redness, and cognitive impacts, and has shown no survival benefit.

With SRS, surgeons are able to deliver escalated doses of radiation targeted to the tumor while limiting the impact on surrounding tissue. Among clinicians, there has been a growing use of delivering SRS to the surgical cavity to reduce cognitive toxicity but, to date, no level I efficacy data for postoperative SRS have been available.

Brown and colleagues investigated 194 patients with resected brain metastases who were stratified by the number of preoperative brain metastases (1 vs 2-4), histology (lung vs radioresistant vs other), and resection cavity diameter (≤3 cm vs >3 cm). Most of the patients (77%) had a single brain metastasis, with lung cancer as the primary tumor type (59%).

After stratification, patients were randomized to receive either WBRT or SRS. Primary endpoints of the trial included cognitive deterioration—free survival and OS.

The researchers observed no difference in OS between the SRS arm (11.8 months) and the WBRT arm (11.5 months), but noted worse cognitive function over time associated with WBRT (2.8 months) compared with SRS (3.3 months). (Figure).

In addition, surgical bed control was similar, although over the long term it appeared better with WBRT compared with SRS (7.7 vs 7.5 months, respectively).

“This is important because if patients have a recurrence there, it requires treatment. Patients could have excellent surgeons, but there is a high failure rate in this location, especially with high lesions,” said Brown. “Radiosurgery to the surgical cavity after resection of brain metastases should be considered a standard of care and a less-toxic alternative than the historic standard of care—WBRT.”

Brown also emphasized that WBRT requires a 2- to 3-week hospital stay and can result in delays in adding systemic therapy, including immunotherapy, targeted therapy, and standard chemotherapy to the treatment regimen if it is needed.

“Radiosurgery is a 1-day procedure,” he said. “If there’s no survival benefit between SRS and WBRT, but greater cognitive toxicity associated with WBRT, we need to keep this in mind when informing the patient and selecting treatment options. Our trial is the first to demonstrate clearly the efficacy of SRS compared to WBRT in a postoperative setting.”

In a separate study that explored related questions, Mahajan and colleagues investigated whether the addition of postoperative SRS to the resection cavity resulted in improved local tumor control compared with surgical resection alone. Secondary endpoints included the rate of distant brain metastasis and OS.

In her study, patients were stratified by 1 versus 1 to 2 brain metastases, melanoma versus other primary cancer, and preoperative tumor size ≤3 cm or >3 cm. After stratification, patients were randomized to receive either SRS to the cavity after surgery or observed. If 1 to 2 metastases remained, patients received SRS.

Radiosurgery to the surgical bed significantly increased LC of the resected tumor. At 6 months following treatment, LC rates were 83% for the SRS group and 57% for the observation group. At 12 months, the LC rate was 72% for patients in the SRS arm (HR, 0.46 [0.25-0.85]; 95% CI, 60-87; P = .01) compared with 45% in the observation arm (95% CI, 33-61).

The median time to local recurrence was not reached (NR) for the SRS arm (95% CI, 15.6-NR), as opposed to 7.6 months for the observation arm (95% CI, 5.3-NR).

“In this study, the benefit continued and improved over 2 years,” said Mahajan. The distant brain metastases and OS were not significantly different, said Mahajan, but the initial tumor diameter had an effect.

Researchers observed 91% LC for patients with initial tumors that were ≤2.5 cm in size (n = 40). For patients whose tumors measured 2.6 to 3.5 cm (n = 55), LC was 43%, and for patients whose initial tumor size was >3.5 cm (n = 33), LC was 46%. The results were statistically significant for patients in the ≤2.5-cm group compared with the other 2 groups (combined P = .0004).

“It’s fortuitous that these 2 studies are presented together,” said Rodrigues. “These trials confirm the role of radiotherapy in this patient population, and that SRS is an appropriate modality when managing these patients.”

Non—Small Cell Lung Cancer

Iyengar et al presented interim results of a 226-patient study that sought to determine whether accelerated, hypofractionated radiation therapy can improve survival while halving treatment time in poor performing patients with stage II/III NSCLC who cannot receive surgery, or a combination of radiation and chemotherapy, because of comorbidities.

Cardiac challenges, renal complications, and pulmonary issues often preclude patients from receiving these therapies. Additionally, patients have expressed concern about receiving the combination of radiation and chemotherapy, said Iyengar.

“We had to come up with other ways of treating these patients with just radiation alone,” Iyengar said.

He and his colleagues previously completed a phase I dose escalation study that demonstrated no increased toxicity in treating this patient population with doses reaching 60 Gy/15 fractions, which is half the number of radiation treatments as a standard course.

“If the clinician cannot give the combination therapy, the standard treatment is to give these patients 6 weeks of radiation alone,” Iyengar said.

He warned, however, “that the outcomes are not optimal. That protocol eventually leads to failure at the site of radiation and elsewhere in a short amount of time. Additionally, we were interested in finding out if we were improving their quality of life by halving the time of treatment from 6 weeks to 3 weeks.”

The researchers followed patients for OS, economic impact, time-to-local failure, progression-free survival (PFS), and toxicity and quality of life.

The analysis to date has involved 60 patients, who were an average age of 68 years. The vast majority of enrolled patients (88%, or 53 of 60) presented with stage III NSCLC, and 7 patients presented with stage II disease. The majority of the patients’ lesions (53%) were squamous cell carcinoma, and the remaining 47% were adenocarcinoma.

Patients were randomized to receive either conventional radiotherapy regimens of 60 to 66 Gy/30 to 33 fractions (n = 28) or accelerated, hypofractionated radiotherapy of 60 Gy /15 fractions (n = 32).

Participants undergoing accelerated radiotherapy reported fewer grade 3 toxicities than those who received conventional radiotherapy (6 patients for hypofractionated radiotherapy vs 10 individuals for conventional radiotherapy).

In addition, there was a lower rate of death from hypoxia associated with patients who received the hypofractionated radiotherapy compared with those who received conventional radiotherapy (1 individual for hypofractionated vs 2 patients for conventional). The researchers reported no grade 4 side effects for either group.

Prostate Cancer

“We found that patients in either arm had similar survival rates, and they experienced similar toxicity with either treatment. More importantly, their treatments over time were cut in half,” said Iyengar. “This allowed patients to move on with their lives and to receive other treatments as necessary. We think that up to this point in the trial that we may have a new way of treating these patients that offers equivalent survival, but improved quality of life because of the shorter treatment time.”Prostate cancer has been postulated to have high radiation-fractionation sensitivity, making the use of hypofractionated radiotherapy a potential treatment that could result in patient benefit, said Widmark, lead author of the last trial presented during the press briefing.

Historically, results from randomized studies investigating the efficacy and side effects of moderately hypofractionated schedules have been reported, notably in the phase III CHHiP trial,⁵ in which hypofractionated radiotherapy using 60 Gy/20 fractions was demonstrated to be noninferior to conventional fractionation using 74 Gy/37 fractions for men with localized prostate cancer.

In the HYPRO trial,⁶ hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. And in the RTOG 0415 trial,⁷ the efficacy of 70 Gy/28 fractions over 5.6 weeks was not inferior to 73.8 Gy/41 fractions over 8.2 weeks for men with low-risk prostate cancer.

In their study, Widmark and colleagues sought to determine the impact of extreme hypofractionation (E-HF) on men with intermediate-risk prostate cancer (T1c-T3a; PSA ≤20; Gleason score ≥7). In all, the phase III trial randomized 1200 men to receive either conventional fractionation (CF) or E-HF.

CF consisted of 78 Gy of image-guided radiotherapy to the prostate in 39 treatments of 2 Gy each over 8 weeks; E-HF consisted of 42.7 Gy in 7 treatments of 6.1 Gy each over 2.5 weeks. Most patients (80%) received 3-dimensional conformal radiotherapy, and the remaining patients received volumetric arc therapy. Androgen deprivation therapy was not allowed among study participants.

Rates of physician-reported grade ≥2 toxicities at 2 years following treatment did not differ significantly between treatment arms. Urinary side effects were reported for 5.4% of E-HF patients and 4.6% of CF patients (P = 0.59).

“We see there is no significant difference at 2 years, which is around 5%,” said Widmark. “There is a small increase around 3 months, but this is likely due to the short time after ending radiotherapy. In the CF arm, it’s only 1 month, and in the E-HF arm, it was 2.5 months.”

Bowel side effects were reported for 2.2% of E-HF patients and 3.7% of CF patients (P = .20). Impotence at 2 years post treatment was reported in 34% in both groups compared with 16% among all participants at baseline. Patient-reported outcomes at 2 years following treatment also did not differ significantly between treatment groups for overall bother from urinary (P = .17), bowel (P = .12), or sexual function (P = .71) symptoms.

Patient-reported bowel function at the conclusion of radiotherapy was also significantly worse following E-HF than following CF for 7 of 10 symptoms assessed, although these differences dissipated at 3 and 6 months’ follow-up. At 1-year post treatment, patient-reported urinary function was significantly worse among E-HF patients for 4 of the 14 symptoms measured.

“The trial was designed to have equal late toxicity, so although there were some differences in shorter-term side effects, the results for long-term toxicity were precisely what we hoped to find,” said Widmark. “Our plan moving forward is to analyze primary endpoint data and present updated toxicity results approximately 1 year from now.”

“This is a timely presentation given, all the data that we have in moderate hypofractionation,” said Rodrigues. “There are many cooperative groups exploring extreme hypofractionation with various treatment schedules. We can now start looking at some of the longer-term outcomes to see if these treatments are equivalent to standard therapy.”

References

1. Brown PD, Ballman KV, Cerhan J, et al. N107C/CEC.3: a phase III trial of post-operative stereotactic radiosurgery (SRS) compared with whole brain radiotherapy (WBRT) for resected metastatic brain disease. Presented at: 2016 ASTRO Annual Meeting; September 25-28, 2016; Boston, MA. LBA-1.
2. Mahajan A, Ahmed S, Li J, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: results of a prospective randomized study. Presented at: 2016 ASTRO Annual Meeting; September 25-28, 2016; Boston, MA.
3. Iyengar P, Westover KD, Court LE, et al. A phase III randomized study of image guided conventional (60Gy/30fx) vs accelerated, hypofractionated (60Gy/15fx) radiation for poor performance status stage II and III NSCLC patients—an interim analysis. Presented at: 2016 ASTRO Annual Meeting; September 25-28, 2016; Boston, MA.
4. Widmark A, Gunnlaugsson A, Beckman L, et al. Extreme hypofractionation vs. conventionally fractionated radiotherapy for intermediate risk prostate cancer: early toxicity results from the Scandinavian randomized phase III trial “HYPO-RT-PC.” Presented at: 2016 ASTRO Annual Meeting; September 25-28, 2016; Boston, MA. LBA-5.
5. Dearnaley D, Syndikus I, Mossop H, et al. CHHiP Investigators. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060. doi:10.1016/S1470-2045(16)30102-4.
6. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061-1069. doi: 10.1016/S1470-2045(16)30070-5.
7. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325-2332. doi:10.1200/JCO.2016.67.0448.