STEREOTACTIC BODY RADIATION THERAPY

IN EARLY STAGE NON-SMALL CELL LUNG CANCER

Figure 1

Figure 2

Figure 3

Radiation therapy is the medical discipline that treats malignant diseases with ionizing radiation. The practice of treating cancer with radiation has been around for more than a century. Shortly following Willhelm Conrad Roentgen’s discovery of x-rays in late 1895, the very first (breast) cancer patient was treated with x-rays in early 1896.

Radiation, as a therapeutic modality, is a local treatment. Its efficacy in killing tumour cells depends, amongst others, on dose. However, higher doses also incidentally damage the normal surrounding tissue, increasing treatment toxicity. Empirically, less radiation toxicity was observed if the total dose was divided into smaller doses (i.e. fractions) over multiple days. Fractionation exploits radiobiological differences in cellular repair mechanism between the tumour and normal tissue and is an important means of reducing toxicity and sparing normal tissue.

Further normal tissue sparing can be achieved by conforming the radiation dose around the tumour target, reducing the dose to adjacent normal tissue. The degree of conformality is, in part, limited by the technical constraints and associated treatment uncertainty (such as random positioning errors, patient motion, etc.). Radiation oncology is a technical discipline. In the last decade, the field has witnessed tremendous advances both in treatment planning and treatment delivery. This is largely due to more powerful computers and better imaging devices. These advances allow targeting of tumours in a precise and accurate manner and, consequently, make possible the sparing of adjacent normal tissue.

WHAT IS SBRT?

SBRT stands for stereotactic body radiotherapy (also known as SABR, stereotactic ablative radiotherapy). SBRT is a method of delivering ablative doses of radiation safely. Typically, very large doses per fraction (i.e. 7.5-20 Gy) are given over a few fractions (i.e. 1 to 8 fractions over 1 to 2 weeks). Fractionation effects to spare normal tissue become less important with larger fraction sizes. By necessity, the dose gradients must be very sharp and tightly conformed around the tumour target in order to limit the dose spilling into the surrounding normal tissue (Figure 1). SBRT represents the culmination of several important technological developments in radiation therapy. These technologies constitute essential components of a SBRT treatment and allow clinicians the ability to target the tumour precisely and accurately so that each treat-

SBRT stands for stereotactic body radiotherapy (also known as SABR, stereotactic ablative radiotherapy). SBRT is a method of delivering ablative doses of radiation safely. Typically, very large doses per fraction (i.e. 7.5-20 Gy) are given over a few fractions (i.e. 1 to 8 fractions over 1 to 2 weeks).

ment fraction will be delivered as per the intended treatment plan. Major technological developments which allow lung SBRT to become possible include: 4DCT in treatment planning and image guidance radiotherapy (IGRT) during treatment delivery. Adoption of IMRT (intensity modulated radiotherapy, Figure 2) and more recently VMAT (volumetric modulated arc therapy) in treatment planning have also allowed improved treatment conformity and reduction in treatment times.

4DCT

One of the challenges in targeting a tumour in the lung is tumour motion. Under normal conditions, the tumour moves with respiration and the exact amount and direction varies between each individual. In the past, clinicians account for this by setting a generous empiric safety margin to avoid missing the tumour (in the majority of patients). However, this result in overtreatment of tumours with minimal motion while other tumours with significantly more respiratory motion than expected could result in a geographic miss. 4D CT imaging captures dataset in all phases of respiration and can visualize the respiratory excursion of a tumour for an individual patient. An individualized treatment plan can be designed with tailored target margins, taking into account the individual’s tumour motion. This reduces the risk of missing the tumour with significant motion as well as minimizes the irradiated volume of normal tissue such as lung.

IGRT

Imaging allows precise and accurate localization of tumour and critical normal structures both at treatment planning and also during treatment delivery. Imaging devices such as cone beam CT co-mounted on the treatment unit’s gantry allow imaging of the tumour at the time of treatment, usually just before (and/or during) the treatment (Figure 3). Thus, the position can be verified prior to each fraction and any misalignments are corrected. Greater confidence in correctly targeting the tumour allows tighter margins and minimizes irradiation of normal tissue such as lung.

WHAT ARE THE BENFITS OF SBRT?

Currently, the standard treatment for early stage non-small cell lung cancer (NSCLC) is surgical resection. Surgery offers 80-90 per cent local tumour control rates and five year overall survival rate of approximately 70 per cent.¹ However, some patients with resectable early stage NSCLC are elderly with significant co-morbid illness, particularly lung disease from smoking, and are deemed “medically inoperable” due to unacceptably high operative risk.

In the past, these medically inoperable patients are either: treated with conventional radiotherapy or observed without any treatment. Given sufficient time, all else being equal, untreated tumours will progress and, eventually, become incurable. Conventional radiotherapy offers lower local tumour control rates in the order of 30-40 per cent² Tumour control rates reported in SBRT series are comparable to those reported in the surgical series with local control rate in the order of 80-90 per cent.³ Inoperable patients with potentially curable, resectable disease can now be offered this potent, non-surgical treatment alternative.

SBRT is non invasive and very well tolerated. Very frail patients with poor pulmonary function have been safely treated. Since very little normal lung tissue is treated, the treatment is safe with a very modest side effect profile and major complications are extremely uncommon. Treatment is given as an outpatient and therefore no hospital stay is required.

Furthermore, the treatment course for SBRT is also much shorter (compared to conventional RT). A typical SBRT treatment takes only one to two weeks where as conventional radiotherapy generally takes six to seven weeks. This has a significant impact on patient compliance and convenience, especially in this frail, elderly patient population. In addition, they may live a long way away from the treating hospital and transport may be an issue.

From a health economics perspective, the lack of hospital stay and the much shorter treatment course also translates into a more cost effective treatment which reduces the burden on an already heavily stretched health system. Studies have shown that SBRT is more cost effective than conventional lung radiotherapy.4

EFFECTIVENESS AND SAFETY OF SBRT

Numerous single and multi-institutional studies have shown that SBRT for early stage non-small cell lung cancer is safe and effective. These studies have consistently shown long term tumour local control rates of 80-90 per cent and low rates of toxicity.

The excellent local control rates reported for SBRT is extremely encouraging as this represents significant improvement when compared to historical conventional radiotherapy series and are comparable with control rates reported in the surgical series. Princess Margaret Hospital reported a series of 108 patients with early stage non-small cell lung cancer treated with SBRT and the four year local control rate was 89 per cent. The most common side effects which occur during treatment include fatigue (50 per cent) and shortness of breath/cough (36 per cent) and vast majority of these were mild and manageable. Significant acute or late toxicities were rare (grade 3 early toxicities =4, grade 3 late toxicities =6, no grade 4 or 5 toxicities observed). 5

WHAT ABOUT SBRT FOR OTHER TYPES OF CANCER?

and challenges which need to be overcome but as clinicians gain more experience and confidence in using this technique there will be more widespread adoption of SBRT in treating other cancers.

WHAT CAN WE EXPECT IN THE FUTURE?

There is great interest in expanding the indications for lung SBRT. SBRT has not been rigorously compared, head to head, with surgery in a study but there is currently an on-going prospective randomized study comparing SBRT and surgical resection for borderline operable early stage NSCLC patients (ACOSOG Z4099/RTOG 1021). Other areas of active research include: defining the dose limiting toxicity in more centrally located tumours (as early experience have suggested increase risk in treating centrally

located tumours with the current dose fractionation), exploring the safety of treating larger tumours beyond the current size limits (>5cm) . There are also studies seeking to improve the accuracy of treatment response assessment.

In summary, SBRT is an effective, non-invasive, safe treatment alternative for medically inoperable patients with early stage nonsmall cell lung cancer. For operable patients, the available data suggest that SBRT may offer comparable tumour control rates but this remains to be proven in a randomized trial. SBRT represents a major advance in radiotherapeutic technique and a new paradigm in the treatment of cancer. SBRT has become a potent tool in the radiation oncologist’s armamentarium and we are likely to see the application of SBRT to many different types of cancer in the very near future.

REFERENCES

1. Narsule CK, Ebright MI, Fernando HC. Sublobar versus lobar resection.The Cancer

Journal .2011;17:23-27. 2. Rowell NP, Williams CJ. Radical radio-

therapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review. Thorax 2001;56:628-38. 3. Dahele M, Brade A, Pearson S, et al. Stereotactic radiation therapy for inoperable, early-stage non-small-cell lung. cancer

CMAJ 2009;180:1326-28. 4. Lanni TB Jr, Grills IS, Kestin LL, et al. Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer.Am J Clin

Oncol.2011;34:494-8. 5. Taremi M, Hope A, Dahele M, et al. Stereotactic body radiotherapy for medically inoperable lung cancer: prospective, single-center study of 108 consecutive patients. Int J Radiati Oncol Biol Phys 2011

Mar 4 [Epub ahead of print].

The concept of SBRT was first developed in Europe in the 1990s, modeled on stereotactic radiosurgery of brain tumours. Early stage non-small cell lung cancer was the first extracranial tumour site treated with SBRT and, thus, most of the experience and evidence supporting SBRT is for this site. With early success in treating primary lung cancer, SBRT is now also used to treat metastatic deposits in the lung from other cancers (such as colorectal, sarcoma, and breast).

There are also emerging data treating other disease sites using SBRT. Currently most of the experience in using SBRT is in the area of lung, liver, spine and prostate. Different organ sites present different considerations There is great interest in expanding the indications for lung SBRT. SBRT has not been rigorously compared, head to head, with surgery in a study but there is currently an on-going prospective randomized study comparing SBRT and surgical resection for borderline operable early stage NSCLC patients (ACOSOG Z4099/RTOG 1021).

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