What Is Stereotactic Body Radiotherapy Biology Essay

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Stereotactic Body Radiotherapy is a novel treatment method in which very high doses of radiation are delivered to extracranial tumours in single or fractionated doses with high precision. The prinicple of SBRT comes from intracranial stereotactic radiosurgery (SRS) developed by Leksell in the 1960's and was taken further by Lax and Blomgren. In Japan Uematsu et al conducted a trial in which patients were treated with 30-75 Gy in 5-15 fractions. The results were were promising and this was followed up by other institues around the world.

Before the development of SBRT, inoperable patients with Stage 1 non-small cell lung cancer (NSCLC) used to undergo radiotherapy, however this was more palliative than curative and survival rates were as low as 10%. This was mainly due to low raditation doses and long treatment periods allowing repopulation of tumour cells. In 1997 the CHART trial demonstrated that patients who were treated with 54Gy in 12 days compared to 60Gy in 6 weeks has markedly improved survival rates, as well as a decrease in local progression and distant metastases.

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SBRT is mainly used for medically inoperable patients who have co-morbidities such as cardiovascular and repiratory diseases with pulmonary function tests 40-60% of the predicted value and are too frail to undergo resection. A few studies have compared SBRT with surgery but they are retrospective. Although the Japanese trial conducted by Onishi et al has very promising results for SBRT, it is difficult to say how accurate these results are and whether SBRT really delivers the same outcomes as surgery.

Several trials are being conducted whose main outcomes are to find the maximum tolerated dose of SBRT and estimate local control rates. The RTOG 0236 trial in which patients were treated with 60Gy had OS of 55.3% and local tumour control rates of 87.2% which is double that of conventional radiotherapy. SBRT provides a very promising outlook for both operable and inoparable patients with T1-2N0M0 and along with VATS, should lead to much higher sucess rates in NSCLC patients. .........ANYTHING ELSE??

SBRT INTRO

Stereotactic Body Radiation Therapy (SBRT) is a novel treatment method in which very high doses of radiation are delivered to extracranial tumours with high precision. The radiation is delivered in single or fractionated doses, while minimizing radiation exposure to the surrounding tissue. The concept of SBRT is very similar to intracranial stereotactic radiosurgery (SRS) which was developed in the 1960's by Leksell at the Karolinska Institute in Sweeden. The first stereotactic Gamma Unit used beams of Cobalt-60 which were focused onto the tumour from different directions, allowing a higher degree of control whilst minimizing the cytotoxic effects of radiation to the surrounding tumour. This led to the development of the Linear Accelerator (LINAC), in which delivery of radiation is in fractionated doses which is advantageous as it allows larger tumours to be treated. (Leksell, Lo et al)

The pioneering work of Leksell was taken one step further by Lax and Blomgren who developed SBRT at the Karolinska Institute in 1995. A stereotactic body frame was built which reduced respiratory motion to 1cm or less. 4-8 noncoplanar low dose beams were directed at a large angle at the target, therefore at the point of convergence, the dose was much higher. The average tumour regression rate was 50% which was higher than expected. (blogren, lax)

In the late 1990's Uematsu et al treated 45 patients with lung carcinoma with 30-75Gy in 5-15 fractions. Of the 66 lesions, only 2 showed local progression on the follow-up CT after a median follow-up time of 11 months. The major problem with treating lung carcinoma is displacement of the tumour due to respiratory motion. To minimize this, they asked patient to take shallow breaths while having an oxygen mask and positioning was monitored with CT. Irradation was performed immediately with margins less than 2cm. These results were very promising and was followed up in other institutes around the world. (Uematsu et al)

INDICATORS FOR SBRT

The eligibility criteria for SBRT in patients with primary lung cancer are:

1. Tumour size less than 5cm diameter without metastases (T14N0M0)

2. Surgery was refused or contraindicated

3. The patient remained stable in the body frame for 30mins or more (WHO performance status <=2)

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4. No active interstitial pneumonitis

SBRT criteria for patients with secondary lung cancer:

1. Tumour size <5cm in diameter

2. 3 or less tumours

3. No other metastases

4. Local tumour is controlled

In patients with nonmetatstatic cancer, SBRT allows a non-invasive ablative treatment option while in oligometastases it can potentially cause shrinkage of the primary tumour so tumour cells are more sensitive to systemic therapy. The main advantage of SBRT over radiation therapy is that high doses of radiation in a small number of fractions can be safely delivered to a tumour <5cm. SBRT has a more ablative affect on the tumour, however, it is also more toxic to the surrounding tissue (in a late phase) if it is exposed to radiation. (Nagata, lo and hiraoka)

However, the advantage with the lung is that it is made up of small functional subunits so there is a capacity for organ reserve whereas organs such as the spinal cord and oesophageous are made up of structurally undefined subunits so if there is damage to tissue at any point, all function is lost downstream from that point.

The clinical target volume (CTV) is the total tumour volume which needs to removed. An additional area surrounding the tumour is added to the CTV called the Planning Treatment Volume (PTV). Therefore, when performing SBRT, it is crucial to limit the Planning Treatment Volume to the high dose zone and reduce the exposure to the immediately surrounding normal parenchymal tissue which will be permanently damaged. (Lo, nature glossary, Wolbart)

In order to achieve precise treatment and reduce exposure to the surrounding tissues, a fixation device is needed which will keep the patient in precisely the same position. Lax and Blomgren were the first to introduce a stereotactic body frame with a vaccum pillow for support. The main difference between the head frame and SBRT frame is the large contact area between the soft tissue and frame which allows reproducible patient positioning. Verification of the tumour location was done using CT which was initially repeated after each treatment to find the reproducibility of tumour location. Once sufficient knowledge had been gained of this technique only one CT scan was done before the first treatment. (lax, blomgren, n and ?) Other body fixing techniques include vacuum sheets and thermoplastic devices which if used properly should not affect the clinical outcome.

Respiratory monitoring:

There are 3 ways in which respiration and organ motion can be controlled:

1. Respiratory dampening: The patient holds their breath for 10s to freeze the tumour in a specific phase of the respiratory cycle and treatment is given intermittently 4-10 times.

2. Respiratory regulation: pressure is exerted on the abdomen using an abdominal belt of diaphragm control

3. Respiratory gating: The movement of the tumour is tracked during the respiratory cycle and the treatment is only delivered at certain phases of the cycle. This method was invented in Japan and uses gold fiducial markers to correlate to the different phases of the respiratory cycle. The radiation beam is initially stationary and then activated at certain phases (Chang, Lo, Nagata)

Target Definition

As the dose of radiation used is very high with a rapid fall off, it is crucial that the tumour is clearly identified and delineated so the Internal target Volume (ITV) and Planning Target Volume (PTV) can be determined. A 4-D CT or 3 sets of CT scans are done: during free breathing, deep inspiration and expiration and this generates an ITV which includes respiratory motion. The margins vary for the PTV but 5mm AP and 8-10mm craniocaudally are approximately added to account for setup error and ensure the tumour is within the margins. (Nagata et al) Organs at Risk (OAR) include stomach, lung, spinal cord, trachea, intestines, oesophagus bronchus and pulmonary artery and a 5mm margin is added to determine the planning organ-at-risk volumes (PRV). (Hiraoka)

18F-flurodeoxyglucose PET (FDG-PET) is important in staging and for finding mediastinal and hilar lymph nodes and distant metastases. It has been found that PET is much more accurate than CT in differentiating between begnin and malignant tumours as small as 1cm in diameter, as well as determining the extent of metastasis. However, sensitivity of PET drops to 80% from 92% in tumours which are less than 1.5cm and only significant FDG uptake by those cells is of clinical relevance. (Lo, Nagata, Schriven, Lowe) FDG-PET is also useful in the follow-up of lung cancer when trying to differentiate between therapy-induced fibrosis and re-growth of the tumour.

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Radiotherapy and movement to fractionated therapy

The two major types of lung cancer are Small Cell Lung cancer (SCLC) which accounts for 10-15% of all cancers and Non-Small Cell Lung (NSCLC) cancer which accounts for 85-90% of all cancers.

The standard therapy for patients who have Stage 1 or 2 NSCLC (T1N0M0/ T2N0M0) is lobectomy or pneumonectomy and resection of systemic lymph nodes. For these patients the 5 year overall survival (OS) rate for 1A is 60-75% and 1B is 40-60%. For certain reason, mainly due to co-morbidities or the extent of the disease, patients are not always a candidate for surgery. The main alternative for these patients is radiotherapy, however, the overall 5 year survival rate for patients treated with radiotherapy alone is between 10-34%. The main reason for very low OS rates are that the biological radiation dose is not high enough and treatment period is to long allowing cells to repopulate. As treatment time exceeds 6 weeks, there is a decrease in survival time of 1.6% each day due to repopulation of tumour cells. (Fowler et al., 2000)

Previously radiotherapy treatment was given at 2Gy per fraction for 6 weeks, totalling at 60Gy but strong evidence suggested that higher radiation doses combined with reduced treatment time lead to better overall survival rate. (Mehta et al) The CHART trial reported that of the 563 patients with NSCLC, those who received 54Gy in 12 days compared to 60Gy in 6 weeks had markedly improved survival rates at 1, 2 and 3 years. (63% vs. 55% - 1 year, 29% vs. 20% - 2 years, 20% vs. 13% - 3 years). The CHART trial also demonstrated that there was a 23% decrease in local progression and 24% reduction in distant metastases. Problems within 3 months of treatment included dsyphagia and radiation pneumonitis, Lhermittes sign was reported between 3-16 months and 16% reported symptoms of pulmonary fibrosis at 2 years. (Saunders et al., 1997)

This leads to the development of SBRT which is based on treating tumours with much higher radiation doses per fraction in a small number of fractions, without increasing the adverse effects of higher doses to the surrounding tissue. Reducing treatment time is not only important in terms of tumour cell repopulation, but also in reducing treatment costs and stress involved for the patient.

Factors affecting success rate of SBRT

There are six major factors which affect the outcome: age, sex, tumour size (<2cm), (pathological) p-T status, p-N status and nodal dissection.

It seems that female patients who have been diagnosed with an adenocarcinoma have a better OS rate with both surgery and SBRT compared to men and that an adenocarcinoma is a favourable factor. Women who have had complete resection of the tumour have a 5 and 10 year survival rate of 69% and 51% vs. 50% and 40%. Also, women who had been treated with SBRT had higher survival rates than men at 3 years- 80.3% vs 51.3%. (Matsuo et al., Minami et al) McGovern et al also concluded that women have better OS, disease free survival (DFS) and distant metastasis free survival (DMFS) but this is due to the origin of the NSCLC as women are more likely to be diagnosed with adenocarcinoma rather than large cell carcinoma. However they said that gender is an independent factor and is not linked to the histology of the tumour cells. (McGovern et al)

This leads to the question whether it is the female gender or the adenocarcinoma histology which is the more favourable prognostic factor. There seems to be less conclusive evidence that histology is more important for overall outcome as patients who were diagnosed with an adenocarcinoma had the same OS as those with squamous cell cancer if the tumour was less than 20mm. However if the tumour was greater than 20mm, patients with adenocarcinomas had higher lung cancer related mortality, therefore, adenocarcinomas are only favourable if they belong to the T1a subgroup. This was supported by Matsuo et al who concluded that sex is a very important factor affecting outcome after SBRT and histology is of less consequence.

Tumour size is one of the most important prognosis deciding factors after treatment with SBRT. The new TNM classification system divides T1 and T2 in subgroups: T1a -20mm, T1b -21-30mm, T2a- 31-50mm and T2b- 51-70mm. (Rami-Porta et al) Patients with tumours less than 20mm have a better prognosis than patients with tumours which are in the T1b category; 82.6% vs 73.3% at 5 years respectively. (Kameyama et al) The JJCLCR collected data on 7408 patients, 2085 patients who were T1a and 1230 who were T1b. The survival rates were 74.7% and 52.5% respectively as well as the survival curve being higher for T1a patients. Koieke et al concluded that for T1, tumours less than 20mm conveyed a better prognosis for the patient and for T2, tumours less than 50mm resulted in greater OS for the patients than tumours greater than 50mm.

Another factor which determines overall survival is delays between treatments. Fowler reported that patients with NSCLC whose treatment was delayed by 5 days or more had reduced survival rates at 1 and 3 years compared to treatment that was not delayed (37% and 1% vs 56% and 17%.) (Fowler 2000) This was also shown in the RTOG trial in which 8311 patients were randomly assigned to groups with total radiation doses of 60.0 Gy, 64.8 Gy, 69.6 Gy, 74.4 Gy or 79.2 Gy, 1.2 Gy twice daily, 5 days per week. Completion 'per protocol' was defined as <5 days and major deviation-unacceptable was defined as a delay of ≥14 days. It was found that patients who were receiving 69.9Gy or higher were more likely to have delays in completing planned therapy and survival time in hyperfractionation patients was shorter than 'per protocol' patients: 2 and 5 year rates were 24% and 10% vs. 13% and 3%. It should also be noted that patients who had a better outcome were more unfavourably affected by time delays than those who had a pooper prognosis. (Cox et al., 1993)

SBRT vs Surgery

Surgery is the standard treatment for early stage NSCLC, but for medically inoperable patients who have co-morbidities such as cardiovascular diseases or emphysema, surgery is not feasible. Pulmonary function tests are approximately 35% in such patients and they are too frail to undergo a lobectomy. For such patients, radiotherapy is used, however it is more palliative than curative, as survival rates are approximately 10-34% and mortality is usually the outcome. (Fowler et al., Timmerman 2010)

In 1995 The Lung Cancer Study Group conducted a trial comparing the outcomes after lobectomy vs partial resection (either wedge or segmental) for T1-2 N0 NSCLC. The advantages of limited resection include increased preservation of pulmonary function, lower perioperative mortality and the ability to undergo future surgeries if a second primary cancer should develop. Of the 247 patients, 122 received limited resection and 125 received lobectomy. Eligibility criteria included T1 N0 tumour <3cm with no evidence of metastasis and patients were segregated into each arm of the trial on the surgeon's assessment. The authors reported that there was an overall increase of 30% in death rate with limited resection and death rate with cancer increased by 50% in the 86 patients who died. However, if the total group is considered, these values reduce to 20% and 30% and are less significant. Local recurrence rates were also higher for limited resection (17% vs 7%) Ginsberg et al concluded that due to the higher mortality and local recurrence rates, as well as no improvement in postoperative pulmonary function, surgery should still be considered as the first choice of treatment for patients with early stage NSCLC. (Ginsberg et al)SURGERY OR LOBECTOMY?? CHECK!

Onishi et al carried out a retrospective study comparing toxicity, local control rate and survival rate in SBRT and surgery. Final outcome was separated into two categories: complete response occurred if the tumour was completely eradicated or was replaced by fibrotic tissue or partial response if there was a decrease of >30% in diameter. The authors noted that it was difficult differentiating between radiation fibrosis and residual tumour tissue after radiotherapy treatment was given. Any remaining mass was considered as a tumour that had partially responded however there is no histological confirmation so true results could be lower than those reported, as any residual tumour tissue may not have responded to radiotherapy. There was also discrepancy in some patients being treated every day while others received treatment on alternate days. BED was not altered depending on the location of the tumour (central or peripheral), nor was it corrected for tumour doubling time or treatment term. The 5yr OS for stage 1a are 60-75% and 40-60% for stage 1b, however as this is a prospective study with a small sample size, survival rates for SBRT cannot be accurately compared to surgery. The authors say that as the patients treated using SBRT were 10 years older than surgical candidates and some had worse prognostic factors therefore survival rates for SBRT and surgery are comparable. However, some of the patients in this trial were medically operable and not all factors were controlled, so the results are not sufficiently conclusive to accurately compare SBRT to surgery.

William Beaumont Hospital also conducted a similar trial in which 124 patients with stage 1 NSCLC were treated with SBRT or wedge resection. Patients are described as "borderline surgical candidates" with pulmonary function tests between 40% and 60% of the normal predicted value and had more co-morbidities or were older than the surgical candidates. Results showed that there is no difference in terms of regional recurrence, locoregional recurrence, distant metastasis or freedom from any failure. However, chances of local recurrence were reduced (4% compared to 20%) with SBRT, but overall survival was higher for wedge resection.

However, it should be noted that patients were followed up for a median of 30 months, which is firstly less than in other studies, but also that patients who underwent wedge resection started treatment earlier so were followed up for a longer period of time. The difference in follow up time (SBRT-9 months, Resection-25 months) could account for the lower recurrence rates rather than the superiority of treatment. 11/69 patients in the wedge resection group had T4 (multifocal) disease and once they were removed from the data, results were significantly in favour of SBRT.

Being a retrospective study, it is much harder for Grills et al to control many factors and gather accurate data on co-morbidities and clinical staging, thereby ensuring two equal populations are being compared. Although the study shows SBRT is superior in certain areas, there isn't sufficient evidence to say final outcome with SBRT is as good or superior to surgery.

What is the future of SBRT?

There has been a lot of development in lung cancer therapy over the past decade, from VATS to SBRT almost replacing conventional radiotherapy. (Altorki) The RTOG 0236 trial in the United States which recently finished showed that medically inoperable patients with T1-T2N0 treated with 60 Gy had OS of 55.3% and primary tumour control rate of 87.2% at 3 years. 16% of patients suffered from grade 3/4 toxicity but no treatment related deaths were reported. The primary tumour control rates shown in this trial are double that of conventional radiotherapy, and is a significant step for better tumour control in medically inoperable patients. (Timmerman et al., 2010)

RTOG 0813 http://clinicaltrials.gov/ct2/show/NCT00750269

Like the RTOF 0236 trial, the primary outcome of RTOG 0813 is also to find out the maximum tolerated dose of SBRT and estimate the local control rates in medically inoperable patients with T1-2, N0, M0 NSCLC.