Stereotactic Body Radiation Therapy

Dr Umesh V

HistoryDeparting from the established traditions of conventionally fractionated external beam radiotherapy, in the late 1980s and early 1990s groups of investigators in Sweden and Japan began to explore the use of alternative hypofractionated radiation treatment regimens for lung, liver, and selected other malignant extracranial tumors.

Established in early 1990s at Karolinska Institute,Stockholm, Sweden

Stereotactic body radiation therapy (SBRT) is the term applied in the United States by the American Society of Therapeutic Radiology and Oncology (ASTRO) for the management and delivery of image-guided high-dose radiation therapy with tumor-ablative intent within a course of treatment that does not exceed 5 fractions .

Other terms have been variously applied in the past to describe what is now called SBRT (for example, extracranial radiosurgery and extracranial stereotactic radioablation)

SBRT Hypothesis• High-dose focused radiation may provide high probability of local tumor control when surgical approaches are not indicated– Medical inoperability

• Improved therapeutic ratio over fractionated RT courses

• High dose focused radiation promises similar tumor control where limited surgical approaches are standard of care

– Stage 1 NSCLC

– Lung metastases

– HCC

– Liver metastases

– Spinal tumors

Radiobiological RationaleThe appeal of SBRT is based upon the nonlinear relationship between radiation dose and cytotoxic effect, whereby one or a few large individual doses of radiation therapy have substantially more cell-killing effect than the same dose of radiation given in smaller individual doses

An experimental model of the effect of intrafraction radiation repair during cranial stereotactic radiosurgery supports the notion that significant repair can occur within the clinically realistic variations of time of an individual high-dose treatment

Conceptual theories of cancer growth and dissemination

(a) the phenomenological

(b) the patterns of failure concept

(c) the theory of oligometastases

(d) the Norton-Simon hypothesis

Phenomenological model Numerous reports of patients enjoying a high rate of 3- to 5-year survival following other forms of aggressive local treatment (surgical resection, radiofrequency ablation, cryotherapy, and so forth) for limited metastases in the liver or lung from an assortment of solid tumor types.

On one level, then, SBRT can be considered a noninvasive substitute for other local modalities if it can be demonstrated to provide similar efficacy and the same or less toxicity.

Patterns of failure conceptAn example of one application of this concept already commonplace in radiation oncology would be the practice patterns that have been employed for many years in the combined modality treatment of lymphomas.

Here, systemic treatment with chemotherapy is combined with involved field radiotherapy on the supposition that the sites of disease that were grossly evident at the time of diagnosis contain the highest number of clonogenic cells and are thus least likely to be completely eliminated by the chemotherapy.

Involved field radiotherapy is then given in an effort to eradicate tumor cells in the sites most likely to harbor residual disease.

SBRT given to sites of residual disease following some form of systemic therapy might be given with this goal in mind.

OligometastasesSubgroup of patients with metastatic disease that is intermediate between completely absent and widely metastatic.

For such patients the entire systemic disease burden is then entirely contained within the finite number of individual sites of gross disease recognized by the pertinent imaging studies.

This condition would reflect an intermediate point in the natural history of that individual's cancer; therefore, these patients might be cured if their limited numbers of metastatic sites are eradicated.

SBRT can be considered in such cases

Norton-Simon hypothesisBolstered by the success of dose-dense chemotherapy in the treatment of breast cancer, SBRT given according to the tenets of the Norton-Simon hypothesis would have two goals:

To reduce the patient's total burden of disease in such a way that the remaining cancer within the patient's body enters into a state of relatively higher growth fraction and is thus more susceptible to cytotoxic systemic agents; and, more importantly

To prevent or delay as long as possible the condition of lethal tumor burden that is fatal to the patient

Guidelines for SBRTQualified personnel:

Board-certified radiation oncologist

Qualified medical physicist

Licensed radiation therapist

Other support staff as indicated (dosimetrists, oncology nurses, and so forth);

Ongoing machine quality assurance program;

Documentation in accordance with the ACR Practice Guideline for Communication: Radiation Oncology;

Quality control of treatment accessories;

Quality control of planning and treatment images;

Quality control of treatment planning system;

Simulation and treatment systems that account for systematic and random errors associated with setup and target motion in a manner that is based on actual measurement of organ motion and setup uncertainty

Proper patient repositioning, target localization, and management of breathing-related motion are essential for SBRT.

A variety of patient immobilization devices are available, including several types of body frames with external fiducial markers. So-called frameless systems incorporate ultrasound, kilovolt, or near real-time computed tomography (CT) scanning to verify the location of internal targets relative to the beams to be used.

It should be appreciated that since SBRT treatment sessions are lengthier than conventional external beam treatments, patient comfort is an important issue.

Breathing-related motion control devices and systems fall into three general categories: (a) dampening, (b) gating, and (c) tracking

Respiratory dampening techniques include systems of abdominal compression intended to diminish one of the largest contributors to breathing-related motion, namely diaphragmatic excursion, by obliging the inspiratory expiratory lung motion pattern to involve more intracostal expansion and shallower breathing overall.

Also included in this category are the systems employing breath-holding maneuvers to stabilize the tumor in a reproducible stage of the respiratory cycle (e.g., deep inspiration).

Gating systems for SBRT, as for any radiotherapy application, follow the respiratory cycle using a surrogate indicator for respiratory motion, for example, chest wall motion, and employ an electronic beam activation trigger allowing irradiation to occur only during a specified range of expected tumor locations.

Tracking systems move the radiation beam or patient to follow the movement of the tumor.

Delivery system

ITV

SBRT critical considerationsDose

Dose prescription

Dose planning

Dose schedule

Target and PTV concept

Normal organ tolerances

Criteria for dose delivery

Dose considerationComparison of different radiation delivery schedules and estimates of their biologic equivalent dose (BED)

Standard RT (2 Gy x 30-33) 72-79 Gy

Radiosurgery– 24 Gy x 1 81 Gy

– 30 Gy x 1 120 Gy

• Hypo fx (SBRT) – 12 Gy x 4 ,106 Gy

– 12 Gy x 5 ,144 Gy

– 20 Gy x 3 ,180 Gy

Indications

Liver

Lung

Spine

Other sites

LiverThe two major reasons for considering SBRT for hepatocellular cancer (HCC) is that underlying severe liver disease often renders patients medically inoperable and that other nonsurgical therapies have generally achieved at best rather modest success in that setting

Blomgren et al.- Twenty discrete tumors were treated in these patients, and a widely variable dose schedule was employed (minimum total doses, 14 to 45 Gy in 1 to 3 fractions). Partial or complete response was observed in 70% of the lesions

The estimate for liver that at least 700 cm3 should receive <15 Gy during a three-fraction SBRT course

One feature of the normal tissue effect of liver SBRT consistently observed within the first few months after SBRT is a zone of hypodensity observed on follow-up CT scans corresponding to the volume that received approximately 30 Gy

3 studies have been conducted in Liver Carcinomas

In 2001 Wulf et al.from WÃrzburg reported outcomes for the treatment of 24 liver tumors 23 metastases and one cholangiocarcinoma, the 18-month actuarial control rate was 61%.

In 2005 Herfarth and Debus et al. The 70 patients were treated with a single fraction of liver SBRT, sometimes termed liver radiosurgery. After a median dose of 22 Gy, the 18-month actuarial control rate was 66%

In 2006 investigators from the University of Colorado and collaborating institutions reported an interim analysis of a phase I or II trial of liver SBRT For 28 discrete lesions evaluable for analysis (median GTV 14 cm3, range 1 to 98), the 18-month actuarial local control estimate was 93%. Toxicity was generally mild, with only one instance of grade 3 toxicity in subcutaneous tissue that resulted from an unintentional dose hot spot.

Case StudyA 45-year-old female had been diagnosed with stage IV breast cancer 2 years previously.

Biopsy-proven liver metastases were present at the time of diagnosis. Numerous systemic agents had been given, most recently gemcitabine and trastuzumab.

Although all other measurable or assessable sites of disease were stable or regressing, a mass in the liver had progressed from 2.5 by 2.9 cm to 6.0 by 4.2 cm within the past 3 months.

Because the patient was tolerating the regimen well and apparently having a response in most sites, she was offered SBRT in an effort to eradicate tumor in the liver.

The 53 cm3 GTV was expanded by 5 mm radially and 10 mm in the superior-inferior direction to generate the PTV. The dose distribution shown was administered in three fractions within 1 week using multiple dynamic conformal arcs and a controlled breath-holding device. The nominal prescription dose was 45 Gy. The maximum point dose was 59 Gy, and the equivalent uniform dose was 54 Gy. The volume of normal liver receiving <15 Gy was 273 cm3. The portion of the right kidney receiving above 15 Gy was 13%.

Follow-up scans at 6 months and 10 months show a Herfarth type 2 reaction with hyperdensity in the treated normal liver. There is also the development of atrophy in the ablated normal liver parenchyma surrounding the lesion, a phenomenon that has also been reported.

Outcomes

LungProspective studies of SBRT in Primary Lung Cancer

Institution N SBRT dose and Fractionation

Results

Indiana University 47 60Gy/3# Phase I study; MTD not reached for T1 lesions; MTD 66 Gy for T2 lesions

Indiana University 70 60 – 66Gy /3# 1-y local control 98%

Aarhus University 40 45 Gy/3 # 2-y local control 85%

Kyoto University 45 48Gy / 4# 2-y local control 95%

Air Force General hospital, Beijing

43 50Gy/ 10 # 1-y local control 95%

University of Marburg

33 30 Gy/1 # 1-y local control 94%

One important observation from the Indiana University studies was that although the treatment was generally well tolerated, tumor location near large airways in the vicinity of the pulmonary hilum (called the zone of the proximal bronchial tree) was associated with a markedly higher risk of toxicity. The maximum tumor diameter was 5 cm.

Typically, a brisk fibrotic response will develop in the vicinity of the treated lesion.

The tumor itself becomes less well defined.

Ultimately, residual fibrosis in a configuration that recapitulates the region of lung that received approximately 20 Gy or more can develop, and faint residual metabolic activity can sometimes be observed in this volume for many months on positron emission tomography scan.

Traditional CT scan-based tumor response criteria are not easily applied.

Lung SBRTA 74-year-old female had undergone wedge resection for a pT1N0M0 non small-cell cancer of the right lung 7 years previously. She had a right pneumonectomy 3 years later as salvage treatment for a locoregional recurrence. She was later observed to have developed a left lung nodule on a surveillance chest x-ray, and needle biopsy proved it to be a non small-cell lung cancer, presumed to be a second primary. Staging studies revealed no other sites of disease. She was given systemic therapy and enjoyed a transient minor response and then regrowth of the lesion .

The patient used supplemental oxygen, 2 L per minute at bedtime and occasionally during the day. She was offered SBRT as potentially curative therapy for a new T1N0M0 lung cancer. The 4 cm3 GTV was expanded by 5 mm radially and 10 mm in the superior-inferior direction to generate the 29 cm3 PTV. The dose distribution shown was administered in three fractions within 1 week using multiple dynamic conformal arcs. The patient did not comfortably tolerate a breath-holding technique because of her supplemental oxygen requirements; therefore, an abdominal compression technique was used during simulation and treatment. The nominal prescription dose was 60 Gy. The maximum point dose was 79 Gy, and the equivalent uniform dose was 72 Gy. The portion of normal lung receiving <15 Gy was 12.7%.

Outcome

SpineSpinal SBRT has also been labeled spinal radiosurgery when treatment is given in a single fraction.

The earliest investigation into this area was that of Hamilton et al. , who used a rigid immobilization with a device surgically attached to the spinal column.

Conservative doses in the range of 8 to 10 Gy were given in one fraction to nine patients with recurrent lesions in the spine following prior conventional radiotherapy.

Spinal cord doses were very low using this technique (0.5 to 3.2 Gy).

Limited follow-up suggested a favorable clinical effect in some patients, and no complications were observed. More recently, less invasive techniques have been investigated.

Ryu et al. (30) at the Henry Ford Hospital initially studied the treatment of spine metastases with initial fractionated radiotherapy followed by a spinal radiosurgery boost (6 to 8 Gy), observing prompt relief of pain in nearly all 10 treated patients. In a subsequent study of single fraction spinal radiosurgery alone (10 to 16 Gy), this group observed complete or partial pain relief in 85% of the 49 patients treated . Perhaps even more importantly, pain relief was rapid after SBRT, sometimes within hours of treatment

Chang et al. at the M.D. Anderson Cancer Center performed a prospective phase I dose escalation study in treating spinal metastases. The equipment used included a CT on rail that allowed for imaging immediately to guide patient �repositioning.

Thirteen patients received 30 Gy total dose (6 Gy per fraction). Two patients received 20 Gy in order to limit the maximum dose to the spinal cord to 10 Gy. The maximum spinal cord point dose was limited to 2 Gy per fraction. Five patients had received prior external beam radiation therapy. No neurological toxicity was detected with median follow-up of 9 months.

Dodd et al. (6) from Stanford is noteworthy in this regard. Among 51 patients treated with spinal radiosurgery for benign spinal tumors (30 schwannomas, nine neurofibromas, 16 meningiomas), there was one case of radiation myelopathy observed.

The patient had a recurrent C7-T1 spinal meningioma and developed new onset posterior column dysfunction 8 months after receiving a peripheral tumor dose of 24 Gy in three fractions to a 7.6 cm3 lesion.

The dose volume histogram revealed that approximately 1.7 cm3 of the spinal cord received >8 Gy per fraction.

Other SitesSBRT has also been investigated for prostate cancer, renal cell carcinoma (RCC), and pancreatic cancer, among other sites

Because prostate cancer tumor control outcomes are slow to mature, extended follow-up will be needed to evaluate the clinical efficacy

The largest single institutional experience of SBRT applied for RCC has been achieved at the Karolinska Institute, where 50 patients with metastatic and eight patients with inoperable primary tumor were treated with SBRT between 1997 and 2003 .A very high rate of in-field control was observed

Koong et al. have reported a phase II study of single fraction SBRT in patients with locally advanced pancreatic to determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by single fraction SBRT.

Stereotactic Body Frame

ConclusionsSBRT is an emerging technology with the potential to benefit cancer patients in many ways.

As SBRT is implemented more widely throughout the field, radiation oncologists are encouraged to participate in formal clinical trials whenever possible so that the knowledge base concerning the strengths and limitations of SBRT can continue to broaden.

Outside of formal clinical trials, the same level of discipline and quality assurance measures should be applied so that patients may receive this novel, technically complex treatment as safely and effectively as possible.

Hospitals in India Offering SBRTDharamshila hospital Delhi

Apollo Hospitals India

HCG group of Hospitals Bangalore

THANK U