Clinical UM Guideline



Subject: Fractionation and Radiation Therapy in the Treatment of Specified Cancers
Guideline #:  CG-THER-RAD-01 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    06/13/2017

Description

This document addresses fractionation and radiation therapy for bone metastases, breast cancer following breast-conserving surgery and non-small cell lung cancer.  Fractionation refers to radiation treatments with each fraction being a discrete appointment to deliver a dose of radiation.  Radiation therapy (also known as radiotherapy), refers to the use of ionizing radiation beams (for instance, x-rays, gamma rays, electron beams, or proton beams) to damage or destroy cancer cells.  External beam radiation therapy (EBRT) for the treatment of various cancers may be administered using various modalities, including but not limited to three-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT).  For additional information on IMRT, refer to THER-RAD.00007 Intensity Modulated Radiation Therapy (IMRT)

This document addresses fractionation and radiation therapy for the following:

  1. Individuals with early-stage breast cancer who do not meet the criteria set forth in the American Society for Radiation Oncology (ASTRO) Fractionation for Whole Breast Irradiation evidence-based guideline (Smith, 2011);
  2. Individuals with bone metastasis who require more than a single dose of radiation therapy; and
  3. Individuals undergoing radiation therapy for the treatment of non-small cell lung cancer.

This document does not address brachytherapy, partial breast irradiation, proton beam radiation therapy or intraoperative radiation therapy.

Note: For information related to additional documents regarding radiation therapy, please see:

Clinical Indications

Medically Necessary:

Whole Breast Irradiation Following Breast-Conserving Surgery

  1. Greater than 16 and up to 28 fractions of whole breast radiation therapy following breast-conserving surgery is considered medically necessary only for individuals with breast cancer who meet any one of the following criteria: *
    1. Age less than 50; or
    2. Tumor greater than 5 cm; or
    3. Positive lymph node involvement requiring treatment of the supraclavicular or internal mammary nodal regions; or
    4. Treatment will be delivered with 3D conformal radiotherapy and the treatment plan results in inhomogeneity of greater than 7% in the central axis (for example, if the plan is normalized to 95%, the maximum dose is >112%).
      * Note: Up to 16 fractions of radiation therapy is considered standard of care for individuals with breast cancer following breast-conserving surgery.  This document does not provide criteria for individuals with breast cancer who were treated with breast-conserving surgery and are treated with or scheduled to receive fewer than 17 fractions of whole breast irradiation.
  2. Up to 8 fractions of boost irradiation to the tumor bed is considered medically necessary when the individual has fulfilled the criteria above (section A).
  3. Up to 5 fractions of boost irradiation to the tumor bed is considered medically necessary for individuals with breast cancer who have undergone breast conserving surgery (lumpectomy) and do not meet the criteria above (section A).

Palliation of Bone Metastases

For the palliation of bone metastasis, greater than 1 and up to 15 fractions of radiation therapy is considered medically necessary in individuals with a fair to good performance status (Karnofsky [KPS] greater than 60 or ECOG status 0-2) and any one of the following: §

  1. A pathologic fracture; or
  2. Soft tissue involvement by tumor; or
  3. Spinal cord compression; or
  4. Spine metastasis; or
  5. Oligometastatic disease (1-5 lesions) with a controlled primary tumor and when the goal of treatment is long term stabilization of disease; or
  6. Weight-bearing bone with cortical erosion.
    § Note: A single fraction of radiation treatment is considered standard of care in individuals with cancer which has metastasized to the bone.  This document does not provide criteria for the palliation of bone metastases when the individuals is being treated with or scheduled to be treated with a single (1) fraction of radiation therapy.

Non-small Cell Lung Cancer

  1. For the treatment of stage I-III non-small cell lung cancer when concurrent chemotherapy and radiation therapy is to be used, up to 30 fractions of radiation therapy is considered medically necessary.
  2. For the palliative treatment of stage IV non-small cell lung cancer, up to 15 fractions of thoracic radiation therapy is considered medically necessary.

Not Medically Necessary: 

Whole Breast Irradiation Following Breast-Conserving Surgery

  1. More than 36 fractions of radiation (total of whole breast irradiation and boost) following breast-conserving surgery for early stage breast cancer are considered not medically necessary.
  2. More than 5 fractions of boost irradiation to the tumor bed are considered not medically necessary for individuals with breast cancer who have undergone breast-conserving surgery (lumpectomy) and do not meet the medically necessary criteria above (section A).

Palliation of Bone Metastases

For the palliation of bone metastases, more than 15 fractions of radiation are considered not medically necessary.

Non-small Cell Lung Cancer

  1. For the treatment of stage I-III non-small cell lung cancer when concurrent chemotherapy and radiation therapy is to be used, more than 30 fractions of radiation therapy are considered not medically necessary.
  2. For the palliative treatment of stage IV non-small cell lung cancer, more than 15 fractions of radiation therapy are considered not medically necessary.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CPT  
77385 Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386 Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; complex
77402 Radiation treatment delivery, >1 MeV; simple
77407 Radiation treatment delivery, >1 MeV; intermediate
77412 Radiation treatment delivery, >1 MeV; complex
77427 Radiation treatment management, 5 treatments
   
HCPCS  
G6003 Radiation treatment delivery, single treatment area, single port or parallel opposed ports, simple blocks or no blocks: up to 5 MeV
G6004 Radiation treatment delivery, single treatment area, single port or parallel opposed ports, simple blocks or no blocks: 6-10 MeV
G6005 Radiation treatment delivery, single treatment area, single port or parallel opposed ports, simple blocks or no blocks: 11-19 MeV
G6006 Radiation treatment delivery, single treatment area, single port or parallel opposed ports, simple blocks or no blocks: 20 MeV or greater
G6007 Radiation treatment delivery, 2 separate treatment areas, 3 or more ports on a single treatment area, use of multiple blocks: up to 5 MeV
G6008 Radiation treatment delivery, 2 separate treatment areas, 3 or more ports on a single treatment area, use of multiple blocks: 6-10 MeV
G6009 Radiation treatment delivery, 2 separate treatment areas, 3 or more ports on a single treatment area, use of multiple blocks: 11-19 MeV
G6010 Radiation treatment delivery, 2 separate treatment areas, 3 or more ports on a single treatment area, use of multiple blocks: 20 MeV or greater
G6011 Radiation treatment delivery,3 or more separate treatment areas, custom blocking, tangential ports, wedges, rotational beam, compensators, electron beam; up to 5 MeV
G6012 Radiation treatment delivery,3 or more separate treatment areas, custom blocking, tangential ports, wedges, rotational beam, compensators, electron beam; 6-10 MeV
G6013 Radiation treatment delivery,3 or more separate treatment areas, custom blocking, tangential ports, wedges, rotational beam, compensators, electron beam; 11-19 MeV
G6014 Radiation treatment delivery,3 or more separate treatment areas, custom blocking, tangential ports, wedges, rotational beam, compensators, electron beam; 20 MeV or greater
   
ICD-10 Diagnosis  
C34.00-C34.92 Malignant neoplasm of bronchus and lung
C50.011-C50.929 Malignant neoplasm of breast
C79.51-C79.52 Secondary malignant neoplasm of bone
D05.00-D05.92 Carcinoma in situ of breast
Z85.118 Personal history of other malignant neoplasm of bronchus and lung
   
Discussion/General Information

Breast Cancer
Breast cancer is the most common cancer diagnosed in women and the second most common cause of cancer death in women.  Based on 2010-2012 data, approximately 12.3% of women in the United States will be diagnosed with breast cancer at some point during their lifetime.  The management of women with early-stage breast cancer (confined to the breast and nearby lymph nodes) has changed over time.  Historically, the majority of women with early-stage breast cancer underwent a total mastectomy.  However, studies confirmed that long-term overall survival (OS) is equivalent using breast-conserving treatment (removal of the portion of the breast containing the tumor followed by radiation treatment to the remaining breast tissue) compared with mastectomy.  Studies have also demonstrated that the quality of life is enhanced with women who undergo breast-conserving treatment.  Consequently, breast-conserving treatment has become a standard treatment option for women with early breast cancer (James, 2010; Seer, 2015). 

Radiation Therapy for the Treatment of Breast Cancer
Radiation therapy is treatment with high-energy rays or particles that destroy cancer cells.  Radiation to the breast is often given after breast-conserving surgery to help lower the chance that the cancer will come back in the breast or nearby lymph nodes.  Radiation is also used to treat cancer that has spread to other areas, for example to the bones or brain.  Radiation therapy can be given externally (external beam radiation) or internally (brachytherapy).  This document does not address brachytherapy.  For information on brachytherapy, refer to THER-RAD.00001 Brachytherapy for Oncologic Indications.

Fractionation Schemes for Whole-Breast Irradiation following Breast-Conserving Surgery
The use of radiotherapy as an adjunct to breast-conserving surgery has been proven to reduce the risk of local-regional recurrence (LRR) and to improve long-term breast cancer-specific and OS.  "Conventionally fractionated" (CF) radiotherapy following breast-conserving surgery is generally delivered to the whole breast and regional lymph nodes utilizing daily radiation doses ranging from 1.8-2 Gray (Gy) over 4.5 to 6 weeks for a total dose of 45-50 Gy, with or without a subsequent radiation boost to the tumor bed.  Historically, CF-whole breast irradiation (CF-WBI) has been recommended based on the theory that small, as opposed to large, daily fraction sizes lower the risk of late normal tissue toxicity without diminishing cancer control.  However, due to geographic limitations, individual preferences and financial considerations, some individuals do not undergo or complete the prescribed course of CF-WBI following breast-conserving surgery.  As an alternative to CF-WBI, researchers have explored the efficacy and toxicity of hypofractionated whole breast irradiation (HF-WBI) in which the radiation dose delivered per fraction is slightly increased (exceeding 2 Gy), but the number of treatments (fraction schedule) is decreased (typically reduced to 3-4 weeks).  The hypofractionated approach is based on the model that a larger dose per fraction given over a shorter period of time is equally effective as the traditional longer schedule.  HF radiotherapy approaches have been proposed to make the regimen less burdensome for individuals undergoing treatment for cancer by decreasing the number of weeks the individual would undergo daily radiation treatment as well as decreasing the cost of treatment (both direct health care expenditures and opportunity costs to the affected individual and society due to time away from home and work).

Individuals with early-stage breast cancer are commonly treated with CF-WBI; however, several large randomized trials carried out in Canada and the United Kingdom and Canada have demonstrated HF-WBI has similar efficacy and reduced toxicity compared with CF-WBI (Haviland, 2013; Owen, 2006; START A Trial, 2008; START B Trial, 2008; Whelan, 2002; Whelan, 2010; Yarnold, 2005).  The most recent report from the UK START trials as well as the meta-analysis have demonstrated that some hypofractionated regimens yielded improved cosmetic outcome including reduced incidence of breast shrinkage, telangiectasias and breast edema in the HF-WBI recipients compared to those individuals who underwent conventional fractionation.  After conducting a systematic review of the peer-reviewed literature, the ASTRO task force identified a population of individuals in which hypofractionation is an appropriate treatment option.  According to ASTRO, suitable candidates include women greater than 50 years of age treated with breast-conserving surgery but not adjuvant chemotherapy, with node-negative breast cancer and tumors less than 5 cm in size.  The task force agreed that for this population it is appropriate to treat with HF-WBI regimen in 16 fractions to a total dose of 42.5 Gy.  ASTRO advised that homogeneous doses should be achieved, with no inhomogeneity greater than ± 7% and treatment fields should avoid the heart completely (Smith, 2011).

In spite of the excellent local control and cosmetic results of the above-described studies, there is still a lack of consensus in the medical community regarding the use of hypofractionation in individuals who were either excluded or under-represented in the studies mentioned above.  The ASTRO Task Force could not reach consensus for some individuals who did not satisfy all of these criteria and "therefore chose not to render a recommendation either for or against hypofractionated whole breast irradiation in this setting" (Smith, 2011).

The whole breast irradiation criteria set forth in this Clinical UM Guideline are limited to those individuals with early-stage breast cancer treated with breast-conserving surgeries who do not meet the criteria set forth in the ASTRO guideline (Smith, 2011).  As such, the whole breast irradiation criteria in this document do not apply to women who have undergone breast-conserving surgery for breast cancer and are 50 years of age or greater, have a tumor less than or equal to 5 cm or negative lymph node involvement.  In these individuals, up to 16 fractions of whole breast irradiation and up to 5 fractions of boost irradiation are considered appropriate.

Bone Metastases
Metastasis to the bony skeleton is a common site of spread for many solid tumors including breast, lung and prostate cancers.  Bone metastases can be seen with any cancer histology and affects more than 250,000 individuals per year in the United States (Li, 2012; Schulman, 2007).  It has been estimated that as many as 80% of individuals with solid tumors will develop painful bone metastases to the pelvis, spine or extremities during the course of their illness (Nielsen, 1999).  Bone metastases can cause accelerated bone breakdown which may result in pain, hypercalcemia, pathologic fractures, myelosuppression, and spinal cord compression with subsequent progressive immobility.  Laboratory abnormalities may include hypercalcemia.  The currently available therapies provided include but are not limited to radiation therapy, opioid-based analgesia and bisphosphonates.  Radiation therapy has long been used to palliate pain and other symptoms of bone metastases with excellent results.  Radiation therapy is a time-efficient and successful method by which to prevent the morbidity of bone metastases or to palliate pain.

Fractionation Schemes for Palliative Treatment of Bone Metastases 
Numerous prospective randomized clinical, retrospective trials and systematic reviews have explored whether a single or multiple fraction scheme provides the best palliative treatment in individuals experiencing painful bone metastases (Chow, 2012; Dennis, 2013; Foro, 2008; Bone Pain Trial Working Party, 1999; Hartsell, 2005; Jeremic, 1998; Kaasa, 2006; Nielsen, 1998; Steenland, 1999; Sze, 2004; van der Linden, 2006; Wu, 2003).  ASTRO has published a guideline providing recommendations for palliative radiotherapy as a treatment for bone metastases (Lutz, 2011).  ASTRO's recommendations were based on the findings of their systematic review of the peer-reviewed literature on palliative radiotherapy for bone metastases combined with the expert opinion of the Task Force members.  With regards to the most effective fractionation scheme for the treatment of painful and/or the prevention of morbidity from peripheral bone metastases, the ASTRO task force indicated that:

"Multiple prospective randomized trials have shown pain relief equivalency for dosing schema, including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, and a single 8-Gy fraction for patients with previously unirradiated painful bone metastases.  Fractionated RT courses have been associated with an 8% repeat treatment rate to the same anatomic site because of recurrent pain vs. 20% after a single fraction; however, the single fraction treatment approach optimizes patient and caregiver convenience."

With regard to radiation therapy for the treatment of painful and/or prevention of morbidity from uncomplicated bone metastases involving the spine or other critical structures, ASTRO indicated that while many of the peer-reviewed studies did not make a distinction between treatment relief of spinal vs. nonspinal metastases, the task force was able to conclude that there was no evidence to suggest that a single 8-Gy fraction was less effective in providing pain relief than a more prolonged radiotherapy course in painful spinal sites.  The authors also concluded that there were not "any suggestions from the available data that single-fraction therapy produces unacceptable rates of long-term side effects that might limit this fractionation schedule for patients with painful bone metastases" (Lutz, 2011).

The ASTRO evidence-based guideline on palliative radiotherapy for bone metastases does not stipulate which individuals should be considered for fractionated treatment stating only that the "longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers" (Lutz, 2011). 

The American College of Radiology (ACR) Appropriateness Criteria® for both spinal and non-spinal bone metastases indicate that randomized clinical trials have demonstrated equivalent pain relief utilizing several fractionation regimens including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or a single 8 Gy fractions (Expert Panel on Radiation Oncology Bone Metastases, 2013; Kim, 2015). 

The guidelines by German Society for Radiation Oncology (DEGRO) and members of the Working Party of Gynecologic Oncology (AGO) Breast Committee recommend that when radiation therapy is intended to provide pain reduction, a fractionation scheme of a single dose of radiation (8 Gy) is appropriate.  For individuals in reduced overall condition and pain, complex irradiation techniques are, in general, not of improved value due to prolonged treatment times as well as higher needs for precise immobilization and positioning.  Instead, simple techniques with short daily treatment times may be preferred when analgesia is the main goal of treatment.  When the goal of radiation therapy is to provide stabilization and the individual has a good prognosis, and in cases of oligometastases, an extended fractionation scheme (more than a single fraction) may be preferred (Souchon, 2010).

The National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer recommend that 8 Gy as a single dose be used instead of 30 Gy in 10 fractions for non-vertebral metastases (NCCN, 2017c).

Re-treatment for Bone Metastases
Following initial treatment with radiotherapy for bony metastasis, some individuals may develop recurrent or progressive symptoms for which additional radiotherapy is indicated.  Because re-treatment of bone metastases may expose the heart, kidneys, bowel and bladder to unsafe cumulative doses, the effect of prior irradiation on the surrounding normal tissues must be taken into consideration.  This is especially important when treating vertebral lesions where the cumulative dose to the spinal cord should be minimized.  The generally accepted maximum cumulative dose to the spinal cord is 50 Gy in 2 Gy fractions (or equivalent).  If repeat radiation using 2D or 3D techniques would result in a cumulative dose to the spinal cord greater than 50 Gy in 2 Gy fractions then consideration may be given to intensity modulated radiation therapy or stereotactic body radiation therapy.  For additional information, refer to:

The ASTRO guideline also gave consideration to the use of repeat radiation therapy in individuals with uncomplicated bone metastases and painful spinal metastases.  The authors found that while no specific trial was identified that provided criteria for the repeat treatment of individuals with recurrent symptoms of metastatic disease, most of the studies reviewed included the option for repeat radiation treatment and that the rate of repeat treatment has been 20% with single-fraction palliative radiotherapy schedules compared with 8% with lengthier radiotherapy courses (Lutz, 2011).  

Circumstances Requiring Extended Fractionation Schedules
Some circumstances have been identified where more prolonged fractionation may be preferable.  These include individuals with soft tissue involvement causing neuropathic symptoms, oligometastatic disease, lesions of the bony spine and impending or outright spinal cord compression.  Most of these trials exploring different radiation fractionation schemes for bony metastases have excluded subjects with spinal cord compression or pathologic fracture at presentation. 

Soft Tissue Involvement (Tumor)
Roos and colleagues (2005) explored dose fractionation for the palliation of neuropathic pain resulting from bone metastases in a randomized setting.  The researchers compared outcomes in individuals who received a single fraction (8 Gy/1 fraction) versus those who received multiple fractions (20 Gy/5 fractions). Although it did not reach statistical significance (P=0.056), a comparison of the time to treatment failure curves suggested that treatment using a single fraction was not as effective as multiple fractions.  However, individuals with decreased performance status (PS), shorter expected survival and/or various comorbidities that would very likely not be amenable to multiple hospital visits may benefit from a single fraction.

Spinal Cord Compression and/or Pathologic Fracture
Radiation therapy is commonly utilized as a treatment for metastatic spinal cord compression.  As much as 40% of individuals with cancer suffer metastases to the spine with 2.5% experiencing symptoms of spinal cord compression which can cause sensory and motor deficits as well as bowel and bladder incontinence.  More specifically, approximately 20% of individuals with breast cancer suffer from bone metastases and skeletal involvement is present in more than half of the cases with distant metastases.  Fewer than 10% of the individuals with bone metastases will develop metastatic spinal cord compression, typically late in the course of the disease.  It has been estimated that more than 80% of the cases involving metastatic spinal cord compression involve bone metastases to the vertebral column which results in the mechanical compression of the myelon (Souchon, 2010).

Treatment options generally include corticosteroids and EBRT, with spinal decompression surgery reserved for specific clinical conditions in which the affected individual has adequate performance status to tolerate surgery, and a sufficient life expectancy to warrant the necessary post-operative healing and rehabilitation.  The available peer-reviewed literature suggests that surgery does not prevent the need for post-operative EBRT in individuals with spinal cord compression.  

The indication for a surgical intervention prior to radiation therapy depends on the stability of the bone and the prognosis of the affected individual.  Radiation therapy is generally administered more generously in lesions of the weight-bearing lower extremities.  However, the lack of a validated set of criteria to determine bony, and in particular spinal, instability makes the selection of individuals for surgical intervention more difficult.  Postoperative radiation therapy may be administered following surgical stabilization in order to prevent progression of the bony destruction and to improve remineralization.  Because the surgical resection of bone metastases is almost never complete, postoperative radiation therapy is essential to provide local tumor control (Souchon, 2010).

The decision to perform surgical decompression is generally made by an interdisciplinary team including a neurosurgeon, after giving consideration to PS, primary tumor site, extent and distribution of metastases, expected survival and the desire of the affected individual.  The ASTRO task force recommends surgical decompression and post-operative radiotherapy for spinal cord compression or spinal instability in highly selected individuals with sufficient PS and life expectancy but does not stipulate the number of fractions considered appropriate to treat spinal cord decompression.  The Task Force also indicates that the optimal dosing of post-operative EBRT cannot be determined from the available data, though longer schedules, like 30 Gy in 10 fractions, are most commonly used because the intent is to eradicate microscopic residual disease rather than relieve symptoms through partial tumor regression with single fraction palliative radiation.  The most frequently employed fractionation scheme for metastatic spinal cord compression is 30 Gy in 10 fractions (Lutz, 2011). 

According to the Updated Systematic Review and Clinical Practice Guideline for the Management of Malignant Extradural Spinal Cord Compression, all individuals who are not treated with primary surgery should receive radiation therapy with or without steroids.  For individuals with a poor prognosis, a single fraction of 8 Gy is recommended as opposed to more protracted courses of radiation therapy.  The authors also indicate that outside of a clinical trial, in individuals with a good prognosis, radiation therapy comprised of 30 Gy in 10 fractions could be considered, especially when local control is of high value and/or close follow-up is burdensome (Loblaw, 2012).

Spine Metastases
Lam and colleagues (2015) explored factors affecting adverse outcomes in 299 individuals receiving palliative radiotherapy for uncomplicated spine metastases.  The cumulative incidence of the initial skeletal adverse event (SAE) at 180 days was 23.6% for single fraction (SF) radiation versus 9.2% for multiple fraction (MF) treatment.  On multivariate analysis, SF treatment (hazard ratio [HR] 2.8, p=0.001) and baseline spine instability score (HR 2.5, p=0.007) were significant predictors of the incidence of first SAE.  To account for baseline variations, outcomes were compared using a propensity score matched analysis.  The researchers found that the 90 day incidence of SAEs was 22% for individuals treated with SF radiotherapy versus 6% for those treated with a MF regimen (HR 3.9, p=0.003).  Spinal adverse events were defined as a symptomatic fracture, hospitalization for site related pain, interventional procedure, salvage surgery, new neurologic symptoms or cord compression.

Oligometastatic Disease
Radiation therapy is commonly used for the treatment of metastatic spinal cord compression.  Fractionation schedules may vary with respect to the individual's prognosis for survival.  In general, individuals with metastatic spinal cord compression have a poor expected survival and typically receive a shorter course of radiation therapy such as 8 Gy in a single fraction or 20 Gy in 5 fractions.  Individuals with a relatively favorable survival prognosis have better outcomes when treated with a longer course of radiation therapy radiotherapy such as 30 Gy in 10 fractions.  A longer course of radiation therapy is associated with fewer in-field recurrences than a shorter course of radiation therapy.  Because individuals with oligometastatic disease have a better survival prognosis than those with more widespread metastatic disease, it has been suggested that these individuals are better suited to undergo a longer course of radiation therapy (Freundt, 2010; Rades, 2007; Singh, 2004).

The bone metastases criteria set forth in this Clinical UM Guideline are limited to the use of palliative radiation therapy for bone metastases in those individuals with complicated bone metastases that may require a longer fractionation schedule (more than a single fraction).

Lung Cancer
Lung cancer (LC) is the leading cause of cancer-related deaths in the United States.  It has been estimated that 222,500 new cases of LC will be diagnosed and 155,870 deaths secondary to LC will occur in the United States during 2017.  The 5-year relative survival rate for individuals with LC varies significantly depending on the stage at diagnosis.  Factors associated with adverse prognosis include but are not limited to: the presence of pulmonary symptoms, a large (greater than 3cm tumor), nonsquamous histology, metastases to multiple lymph nodes and vascular invasion.  For individuals with inoperable disease, prognosis is adversely affected by weight loss greater than 10% and poor PS ( American Cancer Society, 2017a).

There are two principal types of LC: Non-small cell lung cancer (NSCLC) cancer accounts for approximately 85-90% of LCs and the remaining 10-15% is comprised of small-cell lung (SCLC) cancer.  NSCLC tends to progress relatively slowly and takes longer to proliferate beyond the lung.  Treatment options for individuals with NSCLC may include surgery, chemotherapy or radiotherapy, with each of these being offered as a single modality or as a combination of therapies.  While surgery is the most potentially curative therapeutic option for individuals with NSCLC, postoperative chemotherapy may be used to provide additional benefit to individuals with resected disease.  Radiation therapy used in combination with chemotherapy can result in a cure in a small number of individuals and may result in the palliation of symptoms in most individuals.  Many factors are taken under consideration when determining if treatment with curative intent is appropriate.  These factors include but are not limited whether the treatment is likely to achieve a cure and the fitness of the individual (NCI, 2017b).  

SCLC, (also known as oat-cell cancer), is generally found in active or former cigarette smokers.  SCLC tends to be more aggressive tumor and more likely to metastasize beyond the lung.  While chemotherapy is the principal treatment for SCLC, radiation therapy may be used in combination with chemotherapy to treat lung tumors that have not metastasized beyond the chest or other organs. 

Chemotherapy has produced short-term improvement in disease-related symptoms in individuals with advanced NSCLC.  Several clinical trials have demonstrated that tumor-related symptoms may be constrained by chemotherapy.  However, because many individuals experience negative side-effects from chemotherapy, researchers are exploring means to mitigate the negative impact of chemotherapy on quality of life.  

Radiation Therapy for the Treatment of NSCLC
Radiotherapy may be employed as a treatment option for all stages of LC.  The goals of radiotherapy are to maximize tumor control while minimizing treatment related toxicity.  In individuals with NSCLC, radiotherapy uses include:

(1) Definitive therapy for locally advanced NSCLC which is typically combined with chemotherapy;
(2) Definitive therapy for early –stage NSCLC in individuals with contraindications for surgery;
(3) Preoperative or postoperative therapy for selected individuals treated with surgery;
(4) Treatment for limited recurrences and metastases; and
(5) Palliative therapy for individuals with incurable NSCLC (NCCN, 2017b).  

In individuals with NSCLC, radiotherapy may be used as an adjunct to surgery or as definitive therapy in unresectable disease.  Radiotherapy administered concurrently with chemotherapy is considered standard of care, when the individual is able to tolerate it.  Definitive radiotherapy is generally recommended for individuals with early stage NSCLC (stage I to II, NO) who are not good surgical candidates or who refuse surgery.  Definitive chemoradiation is recommended for individuals with stage II to III disease who are not appropriate candidates for surgical treatment.  Individuals with advanced (stage IV) LC with extensive metastases may be treated with systemic therapy.  Palliative radiotherapy may be used for symptom relief and potentially for prophylaxis at primary and distant sites (NCCN 2017b).

Radiotherapy may be administered via a variety of means, including but not limited to Intensity Modulated Radiation Therapy (IMRT) and Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy (SBRT).  For more information, see:

Fractionation Schemes for the Treatment of NSCLC

Altered fractionation schemes explored in the medical literature include:

(1)   Hyperfractionation - lower dose per fraction over the standard treatment duration;
(2)   Accelerated fractionation - conventional fraction size and same total dose, given in a briefer period of time;
(3)   Accelerated hyperfractionation – a combination of #1 and #2 above, and
(4)   Hypofractionation - higher dose per fraction and fewer fractions) (Rodrigues, 2015).

Stinchcombe and colleagues (2008) reported the results of a phase I/II prospective study which evaluated 2 cycles of induction carboplatin and paciltaxel followed by dose-escalated radiotherapy.  The 3D-CRT dose was escalated from 60 to 74 Gy in 4 arms (60, 66, 70, and 74 Gy), and the 74 Gy arm was expanded into a phase II trial.  The 5-year progression-free survival (PFS) rate was 21% (12-32%) and OS rates were and 27% (17-39%), respectively.  The OS rate at 10 years was 14% (7-25%).

Sekine and colleagues (2012) investigated the maximum tolerated dose in 3D-CRT with concurrent chemotherapy (cisplatin and vinorelbine) for unresectable Stage III NSCLC.  The successive 3D-CRT doses evaluated in this study were 66 Gy, 72 Gy, and 78 Gy.  Stringent normal tissue dose constraints were used, keeping the lung V20 ≤ 30%, and excluding subjects with excessive dose to brachial plexus and esophagus.  The median and the 3-year and 4-year OS rates were 41.9 months, 72.3% and 49.2%, respectively. 

Bradley and colleagues (2015) reported the results of randomized trial (RTOG 0617) which was initially designed to explore whether outcomes are improved with high-dose (74 Gy) as opposed to standard-dose (60 Gy) thoracic radiation therapy.  The other study objective investigated the possible benefit of epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux) on radiation therapy.  The trial was developed as a two-by-two factorial phase 3 trial in which 544 participants with stage IIIA or IIIB NSCLC received weekly carboplatin and paclitaxel with chest radiotherapy followed by two additional cycles of carboplatin/paclitaxel every 3 weeks; participants were randomly assigned to receive a radiation dose of either 60 or 74 Gy, and with or without the cetuximab administered weekly.  The researchers compared radiation therapy doses of 60 and 74 Gy and arms receiving or not receiving cetuximab.  The trial closed early as a result of an interim review of data by the data safety monitoring committee which determined that the trial results crossed a futility boundary for high-dose radiation, after which participants continued to be randomly assigned to chemotherapy/radiation to 60 Gy with or without cetuximab.  The trial was then closed after a second interim analysis demonstrated that results specific to cetuximab also crossed a futility boundary.  The authors found that the addition of cetuximab did not result in a significant difference in median PFS or OS.  In contrast, there was a notable variance favoring the 60 Gy arm vs 74 Gy: median PFS was 11.8 vs 9.8 months (HR 1.19; p=0.120) and median OS was 28.7 vs 20.3 months (HR 1.38; p=0.004).  There were also more treatment-related deaths in the high-dose radiation concurrent with cetuximab groups: 8 vs 3 deaths in the high- vs low-dose radiation therapy arms, and 10 vs 5 deaths in the cetuximab vs no cetuximab arms.  Severe esophagitis was also seen more often in individuals who received high-dose radiation therapy (21% vs 7%, p< 0.0001).  Severe toxicity from a wide range of adverse events was more common in those individuals receiving cetuximab (86% vs 70%, p<0.0001).  The results of this study suggest that high-dose radiation therapy employing 74 Gy with concurrent chemotherapy does not improve survival and in fact, may be harmful when compared with the standard 60 Gy dose (Bradley 2015; NCCN 2017b).

The ACR Appropriateness Criteria for Nonsurgical Treatment for Non-small Cell Lung Cancer: Poor Performance Status or Palliative Intent maintains that:

For patients with locally advanced disease (stage IIIA and IIIB) who are unable to tolerate surgery, concurrent chemoradiation therapy is the standard of care.  If patients are unable to tolerate this treatment, either sequential chemoradiation or radiation therapy alone can be used.  The dose of radiation therapy should be approximately 60 Gy for locally advanced disease (Rosenzweig, 2012).

Similarly, the ACR Appropriateness Criteria for Nonsurgical Treatment for Locally Advanced Non-small Cell Lung Cancer: Good Performance Status/Definitive Intent affirms that concurrent chemotherapy and RT remains the standard care for nonsurgical treatment of stage III NSCLC in individuals with good PS.  This guideline also indicates that 60 to 66 Gy with concurrent chemotherapy remains the standard regimen in the community setting (Chang, 2014).

According to the NCCN clinical practice guideline on NSCLC (V5.2017), when used as definitive radiation therapy to treat NSCLC, 60 to70 Gy given in 2 Gy fractions over a period of 6 to7 weeks is commonly prescribed.  Doses up to 74 Gy may be administered provided normal tissue constraints are respected.  Doses exceeding 74 Gy are not currently recommended for routine use.  

The ASTRO consensus and evidence-based clinical practice guideline on definitive and adjuvant radiotherapy in locally advanced NSCLC was developed to provide guidance to both physicians and patients with regard to the use of EBRT in individuals with locally advanced NSCLC.  According to the ASTRO recommendations:

For patients managed by RT alone, a minimum dose of 60 Gy of radiotherapy is recommended.  Dose escalation beyond 60 Gy in the context of combined modality concurrent chemoradiation has not been found to be associated with any clinical benefits.  In the context of combined modality therapy, chemotherapy and radiation should ideally be given concurrently in order to maximize survival, local control, and disease response rate (Rodrigues, 2015).

The American Society of Clinical Oncology (ASCO) endorsed the ASTRO recommendations (Rodrigues, 2015) and stated the following with regards to the appropriate dose of radiotherapy for individuals with unresectable LA NSCLC.

Radiation Therapy for the Palliative Treatment of NSCLC
In individuals with locally advanced or metastatic NSCLC, palliative thoracic radiotherapy plays an important role in relieving symptoms such as cough, shortness of breath, hemoptysis and chest pain and improving the quality of life.  Many of the peer-reviewed randomized controlled trials and meta-analyses/systematic reviews have focused on the use of external-beam radiation therapy (EBRT) dose fractionation in the initial or salvage palliative management (either alone or in conjunction with other treatment modalities) of LC (Rodrigues, 2011). 

The use of concurrent chemotherapy (CC) with palliative radiotherapy has been explored by various researchers.  Currently, the standard of care in the medical community for the palliation of LC is chemotherapy alone and/or thoracic radiotherapy alone without concurrent chemotherapy.  In an evidence and consensus-based guideline developed by ASTRO, the authors analyzed the peer-reviewed published literature addressing the integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy.  The ASTRO Task Force concluded that the integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature and its use should primarily be reserved for clinical trials.  With regards to this particular indication, ASTRO provided the following summary:

Overall, studies to date have suggested that the benefit/risk ratio does not support the addition of chemotherapy concomitantly with radiation for the palliation of LC, primarily because of concerns regarding toxicity and no clear evidence that symptom palliation is improved.  It is possible, though, that optimization of the radiation technique and attention to the nature and schedule of systemic therapy may, in the future, improve the therapeutic benefit (Rodrigues, 2011).

Fractionation Schemes for Radiation Therapy for Palliative Treatment of NSCLC
Researchers continue to explore the optimal palliative radiation dose-fractionation scheme in order to strike a balance between symptom relief, local control, toxicity and patient convenience.  Some studies have suggested that longer regimens may modestly improve overall survival but at the cost of increased treatment-related morbidity. 

Numerous prospective randomized trials of various dose/fractionation schemes have demonstrated that thoracic palliative EBRT can alleviate thoracic symptoms in individuals with locally advanced or metastatic NSCLC who are not eligible for curative therapy.  Practice guidelines, consensus statements and systematic reviews have been published to provide practitioners and patients with guidance regarding treatment options.

The question of the optimal EBRT dose schedule to palliate symptomatic advanced LC was addressed in a comprehensive, updated review by the Cochrane Collaboration.  The researchers found that the doses of RT investigated ranged from 10 Gy in 1 fraction to 60 Gy in 30 fractions over a period of 6 weeks, with a total of 19 different dose/fractionation regimens.  The Cochrane review determined that although significant heterogeneity of symptom assessment and toxicity endpoints were observed; in general, all studies demonstrated a beneficial effect of the palliative radiotherapy, without any specific schedule being favored.  This review found that "there is no strong evidence that any regimen gives greater palliation.  Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis" (Stevens, 2015).

The American College of Radiology (Rosenzweig, 2012) guidelines indicate that "for patients with metastatic (Stage IV) disease, chemotherapy is the standard of care limited with palliative radiation therapy to a dose of approximately 30 Gy limited to symptomatic sites".

The NCCN guidelines on Non-Small Cell Lung Cancer (V5.2017) recommend that for individuals with stage IV NSCLC, palliative radiotherapy can be used for symptom relief and potentially for prophylaxis at primary or distant sites.  Briefer courses of palliative RT are preferred for individuals with symptomatic chest disease who have poor PS and/or shorter life expectancy (for example, 17 Gy in 8.5 Gy fractions).  Higher dose and longer course thoracic RT (for example, greater than or equal to 30 Gy in 10 fractions) are associated with modestly improved survival and symptoms, especially in individuals with good performance score. 

Given the heterogeneity of therapeutic approaches using radiotherapy for the thoracic palliation of LC, the ASTRO Clinical Affairs and Quality Committee convened a Task Force of experts in the field of radiation oncology to develop a guideline on the use of radiotherapy in the thoracic palliation of LC.  The Task Force's recommendations were based on the results of a systematic review of the literature and supplemented by the expert opinion from the members of the Task Force.  One of the key issues addressed by the Task Force was the optimal dose/fractional schedule for thoracic palliative EBRT in patients with LC.  The results of the ASTRO review revealed the following:

Studies suggest that higher dose/fractionation palliative EBRT regimens (for example, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status.  As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (for example, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status… The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature (Rodrigues, 2011).

Fractionation Schemes for Radiation Therapy for the Treatment of Prostate Cancer
Several randomized trials have evaluated the potential role of hypofractionation regimens in the treatment of prostate cancer.  The RTOG 0415 trial (Lee, 2016) was designed to evaluate non-inferiority of hypofractionated based upon the 5-year disease-free survival with hypofractionation being no more than 7.65 percent worse than conventional fractionation.  A total of 1115 subjects with low-risk prostate cancer were randomly assigned 1:1 to receive conventional radiation therapy (73.8 Gy in 41 fractions over 8.2 weeks) or hypofractionated radiotherapy (70.8 Gy in 28 fractions over 5.6 weeks).  Of the 1092 participants that were protocol eligible and had follow-up information, 542 subjects received conventional radiotherapy and 550 received hypofractionated radiotherapy.  At a median follow-up of 5.9 years, the estimated 5-year disease-free survival rate was 85.3% (95% confidence interval [CI], 81.9 to 88.1) in the conventional radiotherapy arm and 86.3% (95% CI, 83.1 to 89.0) in the hypofractionated radiotherapy arm.  The hypofractionated arm was associated with a significant increase in late grade 2 and 3 gastrointestinal and genitourinary adverse events.  The authors concluded that although there was an increase in the risk of late toxicity, the hypofractionated radiotherapy regimen was non-inferior to conventional radiotherapy.

The HYPRO trial (Incrocci, 2016) explored whether dose escalated hypofractionated therapy can be used to improve disease control rates without increasing side effects.  A total of 820 participants with intermediate- or high-risk localized prostate cancer were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses.  A total of 397 were assigned conventionally fractionated radiotherapy (39 fractions of 2 Gy over 8 weeks and 407 participants were assigned hypofractionated radiotherapy (19 fractions of 3.4 Gy in 6.5 weeks).  A total of 537 (67%) of 804 subjects also received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44).  At a median follow-up of 60 months, treatment failure was reported in 169 (21%) of 804 subjects, 89 (22%) in the conventional fractionation group and 80 (20%) in the hypofractionation group.  There was no statistically significant difference in the 5-year relapse-free survival rate (77.1 in the conventional fractionation group and 80.5 percent in the hypofractionated group (adjusted HR 0.86, 95% CI, 0.63-1.16).  The authors concluded that hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival, and hypofractionated radiotherapy cannot be regarded as the new standard of care for individuals with intermediate-risk or high-risk prostate cancer.

In the randomized (PROFIT) trial, researchers assessed the effectiveness of hypofractionated radiation as a means to improve radiation therapy for men with intermediate-risk prostate cancer.  The researchers hypothesized that a hypofractionated course of radiation therapy delivered in 20 fractions over 4 weeks would be as effective and less toxic as standard radiation therapy that is delivered in 39 fractions over a period of 8 weeks.  Study participants were followed for a median of 6 years.  A total of 109 of the 608 participants in the hypofractionated arm and 117 of the 598 participants in the standard arm experienced biochemical-clinical failure (defined as prostate-specific antigen failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death due to prostate cancer).  The authors indicated that no significant differences were identified between arms for grade ≥ 3 late genitourinary and gastrointestinal toxicity (Catton, 2017).

Dearnaley and colleagues (2016) reported the 5 year follow-up results of the CHHip trial; an open-label, randomized, phase III noninferiority study examining the efficacy and side effects of conventional and hypofractionated radiotherapy in men with prostate cancer.  A total of 3216 men with localized prostate cancer (T1b–T3aN0M0) were randomized to receive conventional radiotherapy at 74 Gy in 37 fractions over a period of 7.4 weeks (n=1065) or hypofractionated radiotherapy at 60 Gy in 20 fractions over a period of 4 weeks (n=1074) or 57 Gy in 19 fractions over a period of 3.8 weeks (n=1077).  All radiotherapy was given by intensity-modulated techniques.  Most participants received radiotherapy with 3 to 6 months of neoadjuvant and concurrent androgen suppression.  The primary endpoint was time to biochemical or clinical failure in the intent-to-treat population.  The median follow-up period was 62.4 months.  At the 5 year follow-up, biochemical or clinical failure-free rates were 88.3% (95% CI, 86.0%-90.2%) in the conventional 74-Gy group, 90.6% (95% CI, 88.5%-92.3%) in the hypofractionated 60-Gy group, and 85.9% (95% CI, 83.4%-88.0%) in the hypofractionated 57-Gy group.  While bladder and bowel symptoms peaked sooner in the hypofractionated groups (4-5 vs 7-8 weeks), at 18 weeks, rates were similar for all groups.  Long-term adverse effects were similar among the treatment groups.  The estimated cumulative 5-year rates of RTOG grade 2 or worse bowel and bladder adverse events were 13.7% (111 events) and 9.1% (66 events) in the 74 Gy arm, 11.9% (105 events) and 11.7% (88 events) in the 60 Gy arm, and 11.3% (95 events) and 6.6% (57 events) in the 57 Gy arm.  There were no treatment-related deaths reported.  The authors concluded that the hypofractionated approach using 60 Gy in 20 fractions was noninferior to standard fractionation using 74 Gy in 37 fractions. 

According to the NCCN (V2.2017), hypofractionated radiation regimens are being investigated as an alternative to conventionally fractionated radiation therapy in individuals with prostate cancer.  Long-term follow-up of large randomized clinical trials are needed to determine if hypofractionated radiation therapy for prostate cancer offers similar efficacy without increased toxicity as conventionally fractionated radiation therapy.  The long-term outcomes are particularly important in this population because late genitourinary toxicity may not become apparent until years after radiation therapy is completed.

Research on hypofractionated radiation therapy for prostate cancer is still ongoing, and there is uncertainty about late toxicity; therefore it is not considered a standard of care at this time.

Definitions

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone or biological therapy.

Brachytherapy (also known as internal radiation): A type of radiation treatment used to stop the growth of cancer cells by implanting radioactive material directly into the tumor or into the surrounding tissues.

ECOG Performance Status:

Breast-conserving surgery: A treatment alternative to mastectomy for early stage breast cancer consisting of tumor removal (lumpectomy) followed by external radiation to the whole breast.

Boost: An additional dose of radiation to a reduced size radiation field.

External beam radiation therapy (EBRT): A form of radiation therapy (such as, three dimensional conformal radiation therapy [3D-CRT], intensity modulated radiation therapy [IMRT], and image guided radiation therapy [IGRT]) used to stop the growth of cancer cells. A linear accelerator directs a photon or electron beam from outside the body through normal or healthy body tissue to reach the cancer.

Gray (Gy): The unit used to measure the total amount of radiation an individual is exposed to.

Intraoperative radiation therapy (IORT): Treating a cancerous tumor site with radiation in the operating room immediately following surgery to destroy the tumor.

Karnofsky performance status scale:

Metastasis: The spread of cancer from one part of the body to another.

Tumor node metastasis (TNM) system: One of the most widely used cancer staging systems accepted by the American Joint Committee on Cancer (AJCC). The TNM system is based on the size and/or extent (reach) of the primary tumor (T), the amount of spread to nearby lymph nodes (N), and the presence of metastasis (M) or secondary tumors formed by the spread of cancer cells to other parts of the body. A number is added to each letter to indicate the size and/or extent of the primary tumor and the degree of cancer spread.

Neuropathic pain: Pain due to dysfunction or injury to the nervous system.

Oligometastatic disease: A state in which an individual has 1–5 distant metastases that can be treated by local therapy in order to achieve long-term survival or cure.

Partial breast irradiation: Radiation focused at the tumor bed of the breast, after prior breast conserving surgery. An alternative to whole breast irradiation, breast brachytherapy is one technique of delivering partial breast irradiation.

Radiation: Energy carried by waves or a stream of particles; visible light, X-rays, and protons are all examples of radiation.

Radiation therapy:  Treatment with high energy radiation from X-rays or other sources of radiation.

Resectable locally advanced NSCLC: Stage II-III NSCLC that can be removed by definitive resection after an assessment is done to ensure adequate pulmonary reserve, appropriate surgical resectability and acceptable medical operability risk.

Stereotactic: Refers to the precise positioning of tumors and other lesions in three-dimensional space which allows for increased accuracy of treatment; for example, radiation therapy can be done stereotactically, as a number of precisely aimed beams of ionizing radiation are aimed from several directions to converge on a tumor.

Stereotactic body radiotherapy (SBRT): A type of external radiation therapy that uses special equipment to position an individual and precisely deliver radiation to tumors in the body.

Stereotactic radiosurgery (SRS): A radiation therapy technique that uses a large number of narrow, precisely aimed, highly focused beams of ionizing radiation. The beams are aimed from many directions and meet at a specific point.

Unresectable locally advanced NSCLC: Stage II-III lung cancer that cannot be removed by definitive resection (either due to medical operability factors and/or surgical resectability).

References

Peer Reviewed Publications:

  1. Appelt A, Vogelius I, Bentzen S, et al. Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart. Clin Oncol (R Coll Radiol) 2013; 25(3):147-152.
  2. Bartelink H, Maingon P, Poortmans P, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.  Lancet Oncol 2015; 16:47-56.
  3. Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: Randomized comparison with a multifraction schedule over 12 months of patient follow-up. Radiother Oncol. 1999; 52:111–121.
  4. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015; 16(2):187-199.
  5. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol 2017; ():JCO2016717397. [Epub ahead of print].
  6. Chan E, Woods R, Virani S, et al. Long-term mortality from cardiac causes after adjuvant hypofractionated vs. conventional radiotherapy for localized left-sided breast cancer. Radiother Oncol 2015; 114(1):73-78.
  7. Chan NK, Abdulluh KG, Lubelski D, et al.  Stereotactic radiosurgery for metastatic spinal tumors.  J Neurosurg Sci. 2014; 58:37-44.
  8. Chow E, Meyer RM, et al. Impact of reirradiation of painful osseous metastases on quality of life and function: A secondary analysis of the NCIC CTG SC.20 randomized trial. J Clin Oncol. 2014; 32:3867-3873.
  9. Chow E, Zeng L, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012; 24:112-124.
  10. 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 randomized trials. Lancet 2011; 378: 1707-1716.
  11. Dearnaley D, Syndikus I, Mossop H, et al. 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.
  12. Dennis K, Makhani L. Single fraction conventional external beam radiation therapy for bone metastases: a systematic review of randomised controlled trials. Radiother Oncol. 2013; 106:5-14.
  13. EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014; 383:2127-2135.
  14. Fisher B, Anderson, S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347:1233-1241.
  15. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med. 1993; 328:1581-1586.
  16. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999; 353:1993-2000.
  17. Foro A, Fontanals A, Galceran J, et al. Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in a single fraction. Radiother Oncol. 2008; 89:150-155.
  18. Freundt K, Meyners T, Bajrovic A, et al. Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol. 2010; 186(4):218-223.
  19. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010; 76(3 Suppl):S77-S85.
  20. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-term cardiac mortality after radiotherapy of breast cancer-application of the relative seriality model. Br J Radiol. 1996; 69(825):839-846.
  21. Gaze MN, Kelly CG, Kerr GR, et al. Pain relief and quality of life following radiotherapy for bone metastases: a randomized trial of two fractionation schedules. Radiother Oncol. 1997; 45:109-116.
  22. Hartsell W, Konski A, Scott C, et al. Randomized trial of short versus ling-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005; 97:798-804.
  23. 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(11):1086-1094.
  24. Hoskin P, Grover A, Bhana R. Metastatic spinal cord compression: radiotherapy outcome and dose fractionation. Radiother Oncol. 2003; 68:175-180.
  25. Huang O, Wang L, Shen K, et al. Breast cancer subpopulation with high risk of internal mammary lymph nodes metastasis: analysis of 2,269 Chinese breast cancer patients treated with extended radical mastectomy. Breast Cancer Res Treat. 2008; 107(3):379-387.
  26. 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.
  27. Jeremic B, Shibamoto Y, Acimovic L, et al. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys. 1998; 42:161-167.
  28. Kaasa S, Brenne E, Lund J-A, et al. Prospective randomized multicenter trial on single fraction radiotherapy (8Gy x 1) versus multiple fractions (3Gy x 10) in the treatment of painful bone metastases. Radiother Oncol. 2006; 79:278-284.
  29. Koshy M, Malik R, Mahmood U, et al. Prevalence and Predictors of Inappropriate Delivery of Palliative Thoracic Radiotherapy for Metastatic Lung Cancer. J Natl Cancer Inst. 2015; 107(12):djv278.
  30. Lam T-C, Uno H, Krishnan M, Lutz S, et al. Adverse Outcomes after Palliative Radiation Therapy for Uncomplicated Spine Metastases: Role of Spinal Instability and Single Fraction Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015; 93(2):373-378.
  31. Landau D, Adams JA, Webb S, Ross G. Cardiac avoidance in breast radiotherapy: a comparison of simple shielding techniques with intensity modulated radiation therapy. Radioth Oncol. 2001; 60:247-255.
  32. 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.
  33. Li S, Peng Y, et al. Estimated number of prevalent cases of metastatic disease in the US adult population. Clin Epidem. 2012; 4:87-93.
  34. Loblaw DA, Mitera G, Ford M and Laperriere NJ. A 2011 updated systematic review and clinical practice guideline for the management of malignant extradural spinal cord compression. Int J Radiat Oncol Biol Phys. 2012; 84:312-317.
  35. Nielsen OS, Bentzen SM, Sandberg E, et al. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Radiother Oncol. 1998; 47:233-240.
  36. Nielsen OS. Palliative radiotherapy of bone metastases: there is now evidence for the use of single fractions. Radiother Oncol 1999; 52:95.
  37. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006; 7(6):467-471.
  38. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005; 366:643–648.
  39. Rades D, Veninga T, Stalpers LJ, et al. Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol. 2007; 25(1):50-56.
  40. Roos D, Turner S, O'Brian P, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol. 2005; 75:54-63.
  41. Schulman K, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007; 109:2334-2342.
  42. Sekine I, Sumi M, Ito Y, et al. Phase I study of concurrent high-dose three-dimensional conformal radiotherapy with chemotherapy using cisplatin and vinorelbine for unresectable stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2012; 82(2):953-959.
  43. Singh D, Yi WS, Brasacchio RA, et al. Is there a favorable subset of patients with prostate cancer who develop oligometastases? Int J Radiat Oncol Biol Phys. 2004; 58(1):3-10.
  44. START Trialists' Group, Bentzen SM, Agrawal RK, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008; 9(4):331-341.
  45. START Trialists' Group, Bentzen SM, Agrawal RK, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008; 371(9618):1098-1107.
  46. Steenland E, Leer J, van Houwelingen, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: A global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 1999; 52:101-109.
  47. Stinchcombe TE, Lee CB, Moore DT, et al. Long-term follow-up of a phase I/II trial of dose escalating three-dimensional conformal thoracic radiation therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer. J Thorac Oncol. 2008; 3(11):1279-1285.
  48. Sze W, Shelly M, et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev. 2004; CD004721.
  49. van den Hout WB, van der Linden YM, Steenland E, et al. Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: cost-utility analysis based on a randomized trial. J Natl Cancer Inst. 2003; 95(3):222-229.
  50. van der Linden YM, Steenland E, van Houwelingen HC, et al. Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch bone metastasis study. Radother Oncol. 2006; 78:245-253.
  51. Wang W, Purdie TG, Rahman M, Marshall A, et al. Rapid automated treatment planning process to select breast cancer patients for active breathing control to achieve cardiac dose reduction. Int J Radiat Oncol Biol Phys. 2012; 82:386-393.
  52. Whelan T, MacKenzie R, Julian J, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002; 94(15):1143-1150.
  53. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010; 362(6):513-520.
  54. Wu J, Wong R, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003; 55:594-605.
  55. Yarnold J, Ashton A, Bliss J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol. 2005; 75(1):9-17.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Radiology Appropriateness Criteria® conservative surgery and radiation: stages I and II breast cancer. Last reviewed 2015. Available at: https://acsearch.acr.org/docs/69351/Narrative/ . Accessed on March 16, 2017.
  2. American Society of Breast Surgeons. Consensus Statement for Accelerated Partial Breast Irradiation. Revised August 15, 2011. Available at: https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/APBI.pdf . Accessed on March 17, 2017
  3. American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol. 1997; 15(8):2996-3018.
  4. Bellon JR, Harris EE, Arthur DW, et al. ACR Appropriateness Criteria® conservative surgery and radiation--stage I and II breast carcinoma: expert panel on radiation oncology: breast. Breast J. 2011; 17(5):448-455.
  5. Bezjak A, Temin S, Franklin G, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2015; 33(18):2100-2105.
  6. Chang JY, Kestin LL, Barriger RB, et al. ACR Appropriateness Criteria® nonsurgical treatment for locally advanced non-small-cell lung cancer: good performance status/definitive intent. Oncology (Williston Park). 2014; 28(8):706-710.
  7. Expert Panel on Radiation Oncology Bone Metastases. Lo SS, Lutz ST, et al. ACR Appropriateness Criteria® spinal bone metastases. J Palliat Med. 2013; 16(1):9-19.
  8. Graham MV, Byhardt RW, Sause WT, et al. Non-aggressive, non-surgical treatment of inoperable non-small cell lung cancer (NSCLC). American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000; 215 Suppl: 1347-1362.
  9. Janjan N, Lutz ST, Bedwinek JM, et al. Therapeutic guidelines for the treatment of bone metastasis: a report from the American College of Radiology Appropriateness Criteria Expert Panel on Radiation Oncology. J Palliat Med. 2009; 12(5):417-426.
  10. Kim EY, Chapman TR, Ryu S, et al. ACR Appropriateness Criteria (®) non-spine bone metastases. J Palliat Med. 2015; 18(1):11-17.
  11. Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011; 79:965-976.
  12. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2017 National Comprehensive Cancer Network, INC. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 17, 2017.
    • Breast Cancer (V1.2017). Revised March 10, 2017. NCCN, 2017(a).
    • Non-small Cell Lung Cancer (V5.2017). Revised March 16, 2017. NCCN, 2017(b).
    • Prostate Cancer (V2.2017). Revised February 21, 2017. NCCN, 2017(c).
  13. Rodrigues G, Choy H, Bradley J, et al. Definitive and adjuvant radiotherapy in locally advanced non-small cell lung cancer: An American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. 2015. Available at: www.asco.org. Accessed on March 17, 2017.
  14. Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol. 2011; 1(2):60-71.
  15. Rosenzweig KE, Chang JY, Chetty IJ, et al. ACR appropriateness criteria nonsurgical treatment for non-small-cell lung cancer: poor performance status or palliative intent. J Am Coll Radiol. 2012. Available at: https://www.guideline.gov/content.aspx?id=43890 . Accessed on March 17, 2017.
  16. 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(4):987-1001.
  17. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011; 81(1):59-68.
  18. Souchon R, Feyer P, Thomssen C, et al. Clinical recommendations of DEGRO and AGO on preferred standard palliative radiotherapy of bone and cerebral metastases, metastatic spinal cord compression, and leptomeningeal carcinomatosis in breast cancer. Breast Care. 2010; 5:401-407.
  19. Stevens R; Macbeth F, Toy E, et al. Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer. Cochrane Database Syst Rev 2015; 1:CD002143.
Websites for Additional Information
  1. American Cancer Society (ACS).
  2. National Cancer Institute (NCI). Non-Small Cell Lung Cancer Treatment –Health Professional Version (PDQ® ). Updated January 20, 2017. Available at: http://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed on March 17, 2017.
  3. National Cancer Institute (NCI). Radiation therapy for cancer. Reviewed June 30, 2010. Available at: http://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/radiation-fact-sheet. Accessed on March 17, 2017.
Index

Bone metastases
Breast cancer treatment following breast-conserving surgery
Fractionation therapy
Lung cancer
Non-small cell lung cancer
Radiation therapy
Small cell lung cancer

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed 06/13/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 06/07/2017 Hematology/Oncology Subcommittee review. Updated Discussion/General Information, References, Websites for Additional Information and History sections.
Revised 05/04/2017 MPTAC review.
Revised 05/03/2017 Hematology/Oncology Subcommittee review.
Revised 05/05/2016 MPTAC review.
Revised 05/04/2016 Hematology/Oncology Subcommittee review. Title changed to "Fractionation and Radiation Therapy in the Treatment of Specified Cancers". Scope of the document expanded to address radiation fractionation for non-small cell lung cancer. In the Medically Necessary section for Whole Breast Irradiation Following Breast-Conserving Surgery, change the phrase "irradiation therapy" to "radiation therapy". Updated Coding, Discussion/General Information, Definitions, References and History sections.
New 11/05/2015 MPTAC review.
New 11/04/2015 Hematology/Oncology Subcommittee review. Initial document development