Feature | Radiation Therapy | March 02, 2016 | Jeff Zagoudis

Radiation Therapy Guidelines Keep Evolving

New technologies and techniques are clinically validated and starting to appear in guidelines for lung, prostate and breast cancer

Photo courtesy of Carestream

Like with many other aspects of healthcare, technology has been the driving force behind the evolution of radiation therapy. New advancements have given rise to new, more precise techniques for delivering maximum radiation dose to tumor volumes with minimum effect to surrounding tissue. While still in various stages of clinical testing, many of these new techniques are starting to make their way into clinical guidelines for treatment of various common cancers.

The American Society for Radiation Oncology (ASTRO) and the National Comprehensive Cancer Network (NCCN) are the two main organizations that release guidelines for radiation therapy treatment, but they reach their recommendations in different fashions: ASTRO guidelines are evidence-based, accumulated from systematic literature review, while NCCN guidelines — which are released more frequently — are largely consensus-based. 

Lung Cancer 

ASTRO released an updated guideline for locally advanced non-small cell lung cancer (NSCLC) in May 2015, examining both definitive and adjuvant radiotherapy. 

The guideline for definitive radiotherapy assesses both dose fractionation and treatment timing, which can depend on whether radiotherapy is conducted alone or in combination with chemotherapy. Clinical evidence indicates that radiation therapy alone has been shown to be more effective than observation or chemotherapy in terms of overall survival. However, there was a documented increase in treatment-related side effects, including pneumonitis and esophagitis. As a result, the ASTRO guidelines suggest that definitive radiotherapy alone can be used for patients who may not be able to endure multimodality treatment.1

The recommended dose for this treatment setting is 60 Gy, delivered in 2 Gy fractions. A retrospective study found no differences in local control or overall survival with hypofractionation versus conventional scheduling.1 

An international study presented at the 2015 ASTRO meeting may indicate a solution to the toxicity problem. Comparing intensity-modulated radiation therapy (IMRT) to 3-D conformal radiation therapy (3-D CRT), researchers found that IMRT offered comparable results with lower toxicity rates. A survey found that patients who underwent IMRT were also more likely to complete consolidative chemotherapy, a crucial component of the current standard for lung cancer care.2 

The recommended dose remains the same for concurrent chemoradiation therapy. The ASTRO guideline panel found no evidence that an increased dose at regular intervals or hyperfractionation improved clinical outcomes for concurrent chemoradiation.1

As for the timing of radiation therapy, patients showed higher overall survival, local control and response rate — but also toxicity — with concurrent chemoradiation compared to a sequential approach. As a result, concurrent chemoradiation is currently considered the standard of care. 

Not all patients are able to tolerate concurrent chemoradiation, however, and recent studies suggest that hypofractionation — delivering the radiation dose in fewer treatment sessions — may be an effective option for these cases. “Historically, radiation oncology has not been able to perform these studies because of limitations in the technology for design and delivery of the radiation,” said Bruce Minsky, M.D., professor of radiation oncology at MD Anderson Cancer Center in Houston. “However, changes in the technology now allow us to use much more conformal fields to design therapies that are able to accomplish this.”

A recent trial conducted at Stanford University and the University of Texas Southwestern (UTSW) tested the efficacy of hypofractionation with modern advanced planning and delivery technologies. Patients were administered a dose of 50-60 Gy over the course of 15 treatment sessions in three weeks; the current standard of care is 30-40 treatments for six to eight weeks. Final results indicated hypofractionated treatment was generally well-tolerated, even among the poorest-performing patients. The research team noted this also could lead to a potential treatment cost savings.3 

ASTRO and NCCN guidelines disagree somewhat on the benefit of adjuvant radiotherapy in lung cancer cases. The latest ASTRO guidelines indicate that post-operative radiotherapy does not improve overall survival, but that it may improve local control compared to observation strategies. The guideline panel found no level 1 evidence to support an indication for neoadjuvant (pre-op) RT. 

NCCN, on the other hand, believes that pre-operative radiotherapy could be an option for patients with resectable stage IIIA lung cancer. They also found that post-op radiotherapy significantly improved survival for patients with clinical stage I or II lung cancer that has been upstaged surgically to N2 or above (cancer has spread to the lymph nodes and/or metastasized beyond the lungs). 

Some patients may not be eligible for surgery at all, or may be deemed high-risk for such an approach. For this group, stereotactic body radiotherapy (SBRT) may offer another option, according to Tim Kruser, M.D., assistant professor in the Department of Radiation Oncology at Northwestern University Feinberg School of Medicine. “Recent NCCN guidelines have highlighted the role of this technique for patients who are deemed at high risk for surgical complications for early-stage lung cancer,” he said. “Recent research also suggests SBRT may be an alternative to surgery for patients with early-stage lung cancer, regardless of surgical risk. I think this increased use will be reflected in future NCCN guidelines.” 

Prostate Cancer

The current guidelines for radiation therapy in prostate cancer have been in place since 2013, with input from ASTRO and the American Urological Association (AUA). Prostatectomy has long been the first option for treatment, with radiation therapy employed to attempt to limit recurrence. The long-standing clinical question, according to the guideline, has been whether radiotherapy should be conducted adjuvantly before recurrence or as a salvage therapy after recurrence.

Each argument has its merits. Using salvage radiotherapy avoids unnecessary irradiation of patients who never experience recurrence; however, waiting until the cancer has recurred could allow it to progress to metastasis, especially for high-risk patients. The ASTRO/AUA guidelines conclude that the existing literature cannot generally recommend in favor of one over another for several reasons:

• Lack of randomization in clinical trials;

• Difference in patient characteristics, radiotherapy protocols, failure definitions and follow-up durations; and

• Use of older radiotherapy techniques (external beam radiotherapy), making it unclear whether newer techniques might improve outcomes significantly enough to make a difference. 

With this in mind, the ASTRO/AUA document does offer some guidance for each procedure. Under these auspices, adjuvant radiotherapy is indicated for patients with adverse pathological features following prostatectomy — including positive surgical margins, seminal vesicle invasion and extraprostatic extension — with no detectable prostate-specific antigen (PSA) recurrence. Salvage radiotherapy is indicated for patients with adverse pathological features who do demonstrate detectable PSA recurrence (but no evidence of distant metastatic disease). 

A phase 2 clinical trial published in the September/October issue of the ASTRO journal, Practical Radiation Oncology, examined the potential of image-guided IMRT post-prostatectomy.4 Currently, treatment plans are devised based on computed tomography (CT) scans of the organ or area in question, but imaging can only be performed so frequently in order to avoid giving too much extra radiation dose to the patient. Image-guided radiation therapy (IGRT), on the other hand, combines imaging and radiation delivery in one machine, “so we’re able to both track tumor movement as well as re-plan patients on a periodic basis while they’re being treated,” said Minsky. 

For this particular image-guided study, the research team was interested in treatment-related toxicities, health-related quality of life (HRQoL) factors and biochemical outcomes for 68 patients treated with image-guided intensity modulated radiation therapy (IG-IMRT). Fifty-three patients received salvage radiation therapy and 15 received adjuvant radiotherapy; all patients received a dose of 66 Gy in 33 fractions. Treatment was delivered with IMRT and daily cone beam computed tomography (CBCT) guidance, with routine follow-up every three to six months during the first five years. Reported toxicities did not exceed grade 2 under the National Cancer Institute’s Common Terminology Criteria for Adverse Events, and only transient impacts to genitourinary and sexual performance HRQoL factors were noted.4   

Breast Cancer

At present, radiation therapy is indicated in breast cancer treatment following mastectomy to remove cancerous tissue. In most cases, whole breast irradiation (WBI) is utilized, followed by a boost dose to the tumor bed. Treatment is typically delivered over a total of five to six weeks. This treatment path can be difficult for patients, however, both in terms of radiation dose received and time spent traveling to and from treatment sessions. Several alternatives have been explored in recent years, with treatment guidelines beginning to reflect these options. 

For this reason, breast cancer guidelines have been among the first to recommend hypofractionation. A study published in the December 2014 International Journal of Radiation Oncology — Biology — Physics found that hypofractionated whole-breast irradiation (HF-WBI) for early-stage breast cancer increased 17.4 percent from 2004 to 2011, with HF-WBI patients showing similar disease-free and overall survival rates to those treated with conventionally fractionated WBI.5 The 2014 guideline from ASTRO and the Society of Surgical Oncology for whole breast irradiation in stages I and II invasive breast cancer referenced two other large randomized clinical trials that illustrated comparable long-term efficacy and toxicity data for the shorter schedule, suggesting it is a viable alternative.6 

Regardless of the dose or delivery schedule, whole breast irradiation can result in greater toxicity to surrounding healthy tissue. For patients who cannot or choose not to undergo this treatment, accelerated partial breast irradiation (APBI) offers a more targeted option, delivering the entire radiation dose directly to the tumor bed and sparing surrounding tissue. 

One particular APBI technique that has seen recent growth is brachytherapy, when radioactive seeds are implanted and release the radiation directly inside the tumor cavity. This method can be used as a boost for conventional WBI or as a standalone therapy, allowing treatment completion in one day. Research presented at the 2015 ASTRO meeting found APBI using multicatheter brachytherapy was as effective in local control, disease-free and overall survival rates. The phase III study included 1,184 patients aged 40 or older with early-stage breast cancer who had undergone breast-conserving surgery. Patients were randomized to 50 Gy WBI for seven weeks with a 10 Gy tumor bed boost, or APBI for five days. Prior studies had indicated APBI for patients in their 50s and 60s, but this was the first study to suggest it is appropriate for patients in their 40s.7 

The current ASTRO guideline for APBI, published in 2009, says the treatment is suitable for patients 60 and above (provided they meet other criteria); patients 50-59 are deemed cautionary, and patients 49 or younger are deemed unsuitable for APBI. The NCCN follows similar age brackets, but prescribes a dose of
34 Gy in 10 fractions delivered twice per day with brachytherapy. APBI with external beam radiation therapy has a prescribed dose of 38.5 Gy in 10 fractions, delivered twice daily.8  

References

1. Rodrigues, G., et al. “Definitive radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.” Practical Radiation Oncology, May 2015.  

2. “IMRT for Lung Cancer Associated With Fewer Side Effects, Better Chemotherapy Tolerance.” www.itnonline.com, Oct. 28, 2015. 

3. “Precision Hypofractionated Radiotherapy Effective in Locally Advanced Non-small Cell Lung Cancer.” www.itnonline.com,
Jan. 26, 2016.

4. “Post-prostatectomy Image-guided IMRT.” www.itnonline.com,
Nov. 11, 2015. 

5. “Use of Hypofractionated Whole-Breast Irradiation for Early-Stage Breast Cancer Patients Increasing.” www.itnonline.com, Dec. 16, 2014.

6. Moran, Meena S., et al. “Society of Surgical Oncology - American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer.” International Journal of Radiation Oncology Biology Physics, March 2014. 

7. “APBI With Multicatheter Brachytherapy Effective for Low-Risk Patients After Breast Conserving Surgery.” www.itnonline.com,
Oct. 19, 2015.

8. Smith, Benjamin D., et al. “Accelerated Partial Breast Irradiation Consensus Statement from the American Society for Radiation Oncology (ASTRO.” International Journal of Radiation Oncology Biology Physics, July 2009. 

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