31 Stereotactic Radiosurgery of

CHAPTER

31

Stereotactic Radiosurgery of Metastases from Colorectal Cancer

Mi Sook Kim Seong Yul Yoo Chul Koo Cho Kwang Mo Yang Hyung Jun You

Abstract

resection. It might also reduce the length of the hospital stay. The Korea Institute of Radiological & Medical Sciences installed a CyberKnife® system in June 2002. Through December 2004, we treated 68 sites from 53 patients with recurrent colorectal cancer. The treatment sites included the brain, bone (including spine), lung and chest wall, liver and lymph nodes. Fraction size and dose were dependent on the location of the metastasis, the history of prior radiation treatment and the size of the tumor. To reduce the tumor motion, a custom-made immobilization device, invented by our group, was used to reduce the diaphragm motion to an average of 45% of its initial range. For stereotactic extracranial radiosurgery, we implanted six gold fiducials in the vertebral body or in the sacrum adjacent to the tumor. For our 53 patients, the overall survival rates measured from the first day of radiosurgery were 70% and 39% at year one and year two, respectively, with a

The incidence of colorectal cancer has been increasing steadily in Korea. About one-third of all colorectal cancers have local recurrences and/or distant metastases after surgery with curative intent. Although metastases from primary tumors are usually considered to be fatal, but if patients have isolated metastases from colorectal cancers they can be expected to have a relatively long survival if treatment is performed adequately. Surgery, as an aggressive treatment for recurrence, produces the best chance for long-term survival. However, this treatment modality is accompanied by a relatively high complication rate and is typically associated with a long hospital stay. Also, surgery is only indicated for a highly select patient group. Because stereotactic radiosurgery provides the advantages of spatial accuracy, high conformality and an accelerated dose regimen in a non-invasive treatment, it might be a reasonable alternative to surgical

3 47

348

PA RT I V: Non-Central Nervous System Applications

median survival of 6 months (follow-up ranged from –29 months). A subgroup of 9/53 patients received stereotactic radiosurgery with a curative aim because they had isolated metastases and no history of prior radiation therapy. The survival rates for this curative group were 94% and 75% at one and two years, respectively. Disease responses evaluated by imaging and symptom assessment were complete in 2 sites, partial in 20 sites, stable in 20 sites and disease progressions in five sites. The sites that showed particularly excellent results were metastatic lymph nodes and chest tumors that had received no previous irradiation. A 00% response was observed in these sites. The palliative aim for brain and bone metastases was promptly achieved. We conclude that stereotactic radiosurgery can be a useful alternative treatment to surgery in metastatic lymph nodes and chest lesions from colorectal cancer. If, after longer follow-up, good results are obtained in terms of survival and late toxicity, stereotactic radiosurgery may replace conventional surgery. We also recommend the CyberKnife for patients with bone and brain metastases, especially in cases where the palliative aim is to quickly reduce pain.

Introduction Epidemiology Colorectal cancer in the USA ranked third in incidence in 2004 for both men and women, and represented 0% (7,820) of the total cancer burden in males and % (73,470) of the total cancer burden in females. The estimated annual percentages of deaths in 2005 from this malignancy in the USA are 0% in both men and women (28,540 and 27,750).1 In Korea, in 2002, colorectal cancer incidence ranked fourth for men (.6% of cancer cases) and third for women (0.7% of cancer cases).2

The risk factors for colorectal cancers, as summarized by the American Cancer Society, are as follows: “The primary risk factor for colorectal cancer is age, with more than 90% of cases diagnosed in individuals over the age of 50. A personal or family history of colorectal cancer or polyps or of inflammatory bowel disease increases colorectal cancer risk. Other risk factors include smoking, alcohol consumption, obesity, physical inactivity, a diet high in fat and/or red meat, as well as inadequate intake of fruits and vegetables. A recent study suggested that men and women who are overweight are more likely to die from colorectal cancer. Recent studies have also suggested that estrogen (with or without progestin) replacement therapy and non-steroidal anti-inflammatory drugs, such as aspirin, may reduce colorectal cancer risk.”1

Curative Resection Almost all patients with colorectal cancer (even in advanced stages) can receive curative resection. Local or distant metastases often occur after resection with curative intent. After potentially curative surgery, the incidence of local recurrences is approximately 20% and the incidence of distant metastases is 20–30% (both figures being independent of disease stage). Although metastases from a primary tumor are usually considered fatal, it is generally accepted that isolated recurrence from colorectal cancer should be treated aggressively. This is because patients with an isolated recurrent colorectal cancer can be expected to have longer survival rates than patients with nonisolated recurrences.

Liver Metastases Hepatic resection of isolated metastasis from colorectal cancer showed a five-year survival rate of 30%, a 0-year survival rate of 20%, and a median survival range of 30–40 months.3 The natural history of the

C H A P T E R 3 1 : Stereotactic Radiosurgery of Metastases from Colorectal Cancer

untreated disease shows a three-year survival rate of 4–23% and a five-year survival rate of only 2–8%. Thus, hepatic resection has become well accepted as an effective and potentially curative treatment.

3 49

Table . Patient characteristics of 53 patients

with recurrent colorectal cancer, August 2002 to December 2003.

Pulmonary Metastases Aggressive treatment of pulmonary metastases from colorectal cancer has also been investigated. After the resection of an isolated pulmonary metastasis, approximately one-third of patients survive five years and about one-quarter survive 0 years.4 If it were possible to treat isolated metastatic lesions from colorectal cancer aggressively, survival rates might increase.

Characteristic

Operative Morbidity & Quality of Life

Initial disease stage

While surgery, as an aggressive treatment for recurrence, might provide the best chance for long-term survival or, in some cases, the best palliation, it is clear that an operative procedure is associated with a relatively high complication rate. After resection with curative intent, a significant proportion of patients will develop a subsequent recurrence either at the same or at a different site. Repeat surgery for a subsequent metastasis from colorectal cancer can increase operative morbidity and make quality of life worse.

Stereotactic Radiosurgery Stereotactic radiosurgery, therefore, offers an alternative treatment to surgical resection for metastatic lesions from colorectal cancer. Furthermore, radiosurgery may reduce treatment-related morbidity and increase quality of life. Stereotactic radiosurgery is a non-invasive technique compared to traditional surgery and delivers highly conformal dose distributions compared to conventional external beam radiotherapy. The lack of highly conformal dose

Number of Cases

Sex Male

28

Female

25

Post-operative or palliative chemotherapy

5

Post-operative adjuvant radiation therapy to whole pelvis

9

I

2

II

5

III

3

IV

5

Disease-free interval (DFI) post-curative resection (months) Range Median

0 to 6 7

Age (years) Range Median

2–83 56

delivery with conventional beam radiotherapy has limited this treatment modality to palliative intent. Clinical evidence shows that radiosurgery with high spatial accuracy, high conformality and accelerated dose regimens can achieve good tumor response rates and excellent clinical results.5–8 Furthermore,

350


radiosurgery provides the advantages of a short treatment duration and a brief hospital stay.

Patient Characteristics At the Korea Institute of Radiological & Medical Sciences (KIRAMS), we treated 53 patients with recurrent colorectal cancer by using CyberKnife image-guided radiosurgery from August 2002 to December 2004. Table  summarizes the patient characteristics. The primary tumor sites were 35/53 rectum and 8/53 colon.

using spiral CT in expiration and inspiration phases during decompression of the abdomen. Tumor contouring was identified from CT in the inspiration and expiration phases, and then image fusion was performed. The tumor volume of the fusion image should always be larger than that taken separately from CT in the inspiration and expiration phases.

CyberKnife Treatment Strategy Immobilization Device to Restrict Tumor Motion The motion of extracranial tumors has been a critical limitation in the precise beam delivery of radiotherapy such as radiosurgery and intensity-modulated radiotherapy (IMRT). Many approaches to reduce the tumor motion have been studied. The range of mobility of lung tumors in different regions—upper, middle and lower lobes—reaches a maximum of 2 cm in the cranio-caudal direction, and  cm in the medio-lateral and anterior-posterior direction.9 Liver tumors have ranges of motion similar to the lung.0 To reduce tumor motion in lung and liver, we developed a device to compress the chest and abdomen, as well as to immobilize the patient. Our immobilization device is composed of four belts to compress the abdomen, a large vacuum cradle to support the body and both arms, and small cradles placed on the abdomen to exert additional pressure, Figure . The device was studied for feasibility and usefulness. In seven patients, it reduced the motion of the diaphragm in the range 20–68% (mean of 45%), as compared to the previous range of motion.11 To compensate for the tumor motion during treatment, consecutive imaging studies were conducted

Figure . The immobilization device that we developed to reduce tumor motion by compressing the abdomen.


Fiducials We used gold fiducials 4 mm in length by  mm in diameter for markers. Two gold fiducials were fixed to the transverse processes of the vertebral segment. Six fiducials were placed into three segments of the vertebral body, or of the sacrum adjacent to the tumor. We percutaneously placed the fiducials using an 8 gauge spinal needle under fluoroscopy, Figure 2. We found that anesthesia was not always needed for this procedure.

35

Treatment Sites Table 2. Metastatic sites that were treated. A single

treatment site is defined as one planning target volume (PTV) treated using the CyberKnife.

Metastatic site

Number of sites treated

Brain

0

Bone

5

Spine

0

Sacrum

4

Pelvic



Lung & Chest wall

7

Liver

4

Lymph nodes

32

Mediastinal

3

Para-aortic

7

Pelvic



Pre-sacral



Total

68

Re-Treatment A total of eight patients received repeated stereotactic radiosurgery for subsequent recurrences: twice for three patients, three times for three patients and four times for two patients. However, only one patient received repeated radiosurgery for the same site, and this was due to progression of pain.

Results: Survival, Response & Prognostic Factors Figure 2. Simulation film showing six gold fiducials,

inserted at level L5 and in the sacrum for a pre-sacral

lymph node treatment using the CyberKnife.

Survival Rates The metastatic sites treated using CyberKnife radiosurgery were: brain, bone, lung and chest wall, liver and lymph nodes, with some of our 53 patients having more than a single metastasis. Figure 3 shows the overall actuarial survival rates, measured from the

352


100

Survival rate (%)

80 60 40 20 0

0

5

10

15 20 Time (months)

25

Figure 3. Actuarial survival rates for the curative

30

intent group, N=9, (red) and palliative intent group, N=34 (blue) .

date of radiosurgery, with the curative intent (N=19) versus the palliative intent (N=34) treatment groups. The curative intent group had only single isolated metastasis and no previous history of radiation therapy. The one-year and two-year survival rates for the curative intent group were 94% and 75%, respectively. However, it should be noted that this patient group was relatively small and contained several different metastatic sites; therefore, comparison with results from other centers was not meaningful. For the entire group of 53 patients, the one-year and two-year actuarial survival rates were 70% and 39%, respectively.

Response Rates & Complications The response rates, based on symptoms and imaging, are given in Table 3. Nausea was observed in almost all patients on the first day of treatment but had been spontaneously relieved on the second day. No grade III or grade IV complications were noted.

Multivariate Analysis for Prognostic Factors Table 3. Response rates for 57 treated sites. Data for

the remaining /68 sites are not included because of insufficient post-treatment follow-up.

Response

Number of sites

Complete response

2

Partial response

20

Stable disease

20

Disease progression

5

Table 4 summarizes the results of a Cox multivariate analysis for prognostic indicators using the logrank test statistic and choosing the level of significance as p = 0.05. The factors studied were age (≤ 60 years versus > 60 years), primary site (colon versus rectum), sex, stage (I+II versus III+IV), intent (curative versus palliative), disease-free interval (DFI) measured from the starting date of curative radiosurgery to the date of first recurrence (DFI ≤ 30 months versus DFI > 30 months) and carcinoembryonic antigen (CEA) level (≤ 50 ng/ml versus > 50 ng/ml). Only CEA and treatment intent were statistically significant (p < 0.05). However, we fully realized that subgroup numbers in this the multivariate analysis were relatively small and, for this reason alone, statistical significance might not be demonstrable. Additional patients must be accrued to increase the subgroup numbers.


Results by Metastatic Sites Brain Metastases Colorectal cancer accounts for only 5% of all brain metastases.12 Isolated metastases to the brain from colorectal cancer are rarely reported and are usually combined with liver or lung metastasis. Colorectal cancer typically produces only a single metastasis in the brain, and not multiple metastases.13-15 Therefore, our goals for radiosurgery of brain metastases from colorectal cancer are palliation of symptoms and a modest prolongation of survival, both of which are thought to be reasonable goals.

Ten sites from eight patients were treated by radiosurgery using the CyberKnife, shown in Table 2. Of these, 6/8 patients had only a single metastasis. Five sites were prescribed with doses in the range 6–26 Gy delivered as a single fraction, two sites were treated to 20 Gy and 26 Gy in two fractions, and three sites were treated to 33 Gy, 36 Gy and 38 Gy in three fractions. The median tumor volume was 8 cc (range 2–22 cc). The radiation dose was prescribed to a median 8% isodose line (range 78–89%). Whole brain radiation therapy with 33 Gy or 36 Gy in a standard fraction regimen was given before radiosurgery in 2/0 patients.

Table 4. Multivariate analysis study for possible prognostic factors.

Prognostic factor under study

353

Number of patients

- year survival rate (%)

2-year survival rate (%)

Median survival (months)

P-value

Age ≤ 60

40

68

33

5

0.24

Age > 60

3

76

52

Sex: male

28

68

29

5

0.49

Sex: female

25

74

57

25

Stage I + II

7

76

48

6

Stage III + IV

36

67

32

5

Primary site: colon

8

55

29

3

Primary site: rectum

35

77

43

6

Curative intent

9

94

75

Palliative intent

34

59

20

3

DFI ≤ 30 months

37

60

33

5

DFI > 3 months

6

92

6

CEA ≤50 ng/ml

36

75

36

6

CEA > 50 ng/ml

8

3

3

8

0.26 0.40 0.003

0.4 0.0’

354


A complete response was achieved 6/0 sites. However, two sites had local progression of the disease at six months and 0 months, respectively, after an initial complete response and an initial partial response. Disease progression of another cerebral lesion was also detected in two patients who received repeat radiosurgery.

Bone Metastases with Emphasis on Spinal Cord A total of 5 bone metastatic sites were treated, shown in Table 2. The radiosurgery was performed promptly for palliation to relieve the pain or to prevent cord compression. We also believed that recurrence after prior radiation therapy was an indication for radiosurgery. The radiation doses prescribed to the pelvis and sacrum were 39 Gy in three fractions or a single fraction of 20 Gy in cases without prior radiation treatment. Single fractions of 5–20 Gy were used for recurrent cases after fractionated external beam radiation therapy. In cases of spinal metastases, the spinal cord is a critical organ and the dose must be limited to the cord. However, difficulties arise because the true tolerance of the spinal cord to radiation is not known. The tolerable dose 5/5 (the dose at which there is a 5% probability of myelitis necrosis at five years post-treatment) for 5 cm, 0 cm, 20 cm lengths of the spinal cord in standard fractionation has been estimated by Ema et al 16 as 50 Gy, 50 Gy and 47 Gy, respectively. However, these dose levels are estimated based on extrapolations of much earlier data sets from 948.17 Yamada et al at Memorial Sloan Kettering Cancer Center (MSKCC) 18 have stated that these doses have been widely adopted in clinical practice despite the fact that there was no exact cause underlying these tolerances. Therefore, MSKCC sets the maximum spinal cord dose at 54 Gy for a standard fractionation

regimen in the absence of chemotherapy or a history of previous radiation. In terms of single-fraction therapy, MSKCC recommends that the maximum cord dose be kept below 0 Gy. The exhaustive literature review undertaken by Schultheiss et al 19 suggested that the true 5% risk of myelopathy is likely to be in the range 57–60 Gy for standard fractionation. At our Institute, the prescribed tumor dose was escalated from 24 Gy to 36 Gy in three fractions. Currently, though, 30–36 Gy in three fractions is usually used in our dose protocol for cases of spinal metastasis without any history of prior radiotherapy. A dose of 22 Gy in two fractions was used for patients who had received prior fractionated radiation treatment. The constraint dose for a partial volume of the spinal cord was defined to be a maximum of 24 Gy in three fractions. This dose was higher than the recommended dose of MSKCC 18 and of the University of Pittsburgh School of Medicine.20 However, we considered this treatment schedule in extreme cases where the cord is threatened by tumor growth. Even though our follow-up period was short, there were no complications related to spinal cord damage in our 0 patients. All showed an immediate response and there was also no subsequent worsening of symptoms during the available follow-up period.

Lung & Chest Wall Metastases Considerable research has been undertaken on aggressive surgical treatments of lung metastases from colorectal cancer. Pulmonary resection is well accepted as a method to increase survival.4, 8 Five-year survival rates greater than 50% have been reported after pulmonary resection.21, 22 However, there is a high incidence of recurrence following surgery; this remains a problem to be resolved.


Stereotactic body radiotherapy for metastatic lung tumors has also been investigated. Local control rates of 66–00% with grade III toxicity of 0–5.4% have been reported.8, 23–28 At our Institute a total of five patients with isolated lung metastases were treated by stereotactic radiosurgery. Four patients had a single metastasis and one patient had two nodules. Another patient had multiple nodules in the lung and chest wall and received radiosurgery only for palliation. For metastatic lung patients, the dose prescription range was 42–48 Gy delivered in three fractions. Of 6/7 sites treated, as seen in Table 2, either a complete response or a partial response was obtained in four and two sites, respectively. Tumor progression was not observed during the available follow-up period of 3–20 months. There were also no grade II or III complications. We therefore consider that 48 Gy in three fractions is a safe dose-fractionation scheme and now intend to escalate the dose to 5 Gy in three fractions to try to obtain much better responses in all patients.

Liver Metastases It is estimated that 20–50% of patients with stage II and III colorectal cancer will develop liver metastases within five years of treatment of their primary tumor.29 Surgery has been an effective treatment modality for a select group defined by the criteria listed in Table 5. However, in patients who were treated by resection, some significant risk factors for recurrence were reported,30 as shown in Table 6. Compared to surgical resection, stereotactic radiosurgery has the advantage of being a non-invasive modality for almost all patients who do not meet all the criteria for surgical resection, as seen in Table 5. It could also be a useful modality for those patients with high probability of recurrence, who would otherwise have received a surgical resection.

355

Table 5. Selection criteria for patients with liver metastases to be treated by surgical resection.

• Patients are medically fit for general anesthesia and recuperation after laparotomy

• The disease is limited to the liver • There is an adequate reserve of normal liver parenchyma for full recovery

• The disease is technically resectable such that the resection safely encompasses all clinically apparent liver disease

Table 6. Risk factors associated with post-resection

recurrence of liver metastases.

• Positive margin • Extrahepatic disease • Node-positive primary colorectal tumor • Disease-free interval from primary to metastases of < 2 months

• More than one hepatic tumor • Largest hepatic tumor of size > 5 cm • CEA level > 200 ng/ml

To date, we have treated four patients by CyberKnife radiosurgery to the liver, as seen in Table 2. The treatment aim was palliation with tumor mass reduction. The cases were not eligible for curative resection because they had two large nodules spreading over left and right lobes or three or more nodules. Three of these patients showed partial

356


response or stable disease and one patient showed disease progression.

Lymph Node Metastases Patients with lymph node metastases from colorectal cancer were the largest group of metastatic cases

that we treated using the CyberKnife: 32 patients, Figure 4. However, although the treatment of lung and liver metastases from colorectal cancer have been well reported,3–8 there are relatively few publications on optimal treatments and results for metastatic lymph nodes from colorectal cancer.

Figure 4. Male patient 63 years of age treated with the CyberKnife for a para-aortic lymph

node metastasis. Axial (top left), sagittal (top right) and coronal (bottom left) dose distributions are shown. Multiple para-aortic lymph nodes are delineated. The prescribed treatment was 36 Gy to the 83% isodose line in three fractions. Pre-treatment PET-CT fusion had shown hypermetabolism in the para-aortic lesion. At three months after CyberKnife treatment follow-up with PET-CT, no active tumor was revealed. To date, 2 months after treatment, there is no evidence of disease.


In most of our patients, lymph node recurrence was combined with multifocal metastases and treated with systemic chemotherapy. Nevertheless, a highly select patient group with isolated lymph node metastasis could be considered eligible for operative therapy. However, potential invasion to adjacent organs, even in small and well encapsulated tumors, would prevent radical surgery. Modern evaluation methods using 18F-fluoro-2-deoxy-glucose positron emission tomography (18F-FDG PET) or PET-CT can detect unexpected distant metastases more sensitively and effectively in a single investigative procedure. This results in avoidance of unnecessary aggressive treatment. Also, metastatic lymph nodes are not usually affected by respiratory or peristaltic motion. These facts mean that radiosurgery for the treatment of metastatic lymph nodes has significant benefits as an alternative to invasive surgery, Figure 4. Our results support this opinion. The number of patients treated by the CyberKnife was 29 cases with a total of 32 metastatic lymph nodes. Survival rates were 86% and 48% at 2 and 24 months, respectively. The median survival was 6 months. Among this group, 3/29 patients had isolated lymph node metastases when they were evaluated

Table 7. Treatment responses for 29 patients with lymph

node metastases. Response

Number of cases

Complete

8

Partial



Stable disease

9

Disease progression



3 57

by CT, MRI and/or PET-CT. Their survival rates were 00% and 78% at 2 and 24 months, respectively. No patients showed loco-regional progression during follow-up. Response rates are given in Table 7. In terms of response for different metastatic lymph node sites, the results appeared to be better for paraoaortic nodes than for pelvic or pre-sacral nodes, but the numbers in each group were very small, and therefore no statistically significant conclusions could be drawn. As a boost treatment after radiation therapy of 45 Gy, a single fraction of 5 Gy was prescribed for two patients. However, when radiosurgery was delivered as a sole modality, without prior radiation therapy, we escalated our dose from 30 Gy in three fractions to 45 Gy in three fractions. Severe grade III–IV complications were not observed during follow-up.

Conclusions Lung, Chest Wall & Lymph Nodes We conclude that for tumors from colorectal cancer metastasizing to lung, chest wall and lymph nodes, radiosurgery produced a response rate of almost 00%. Therefore, radiosurgery with the CyberKnife can certainly be an alternative treatment to invasive surgery. Indeed, it might eventually replace surgery if follow-up is long enough to fully assess any risks of late toxicity and to establish survival rates.

Brain & Bone The palliative aim of treating brain and bone metastasis from colorectal cancer can be promptly achieved. The CyberKnife was recommended for patients with metastases at these sites, especially in cases where it was essential to quickly reduce pain and also to prevent cord compression.

358


Liver To properly define stereotactic radiosurgery as an alternative to surgery for liver metastases, more studies are necessary. This is because several studies 5–8, 30 for liver metastases have failed to show response rates as high as those achieved for the treatment of lung metastases. One reason for these results might be that dose escalation could be better achieved without severe complications for the lung. Further studies on the optimal radiation dose, fraction number, method of immobilization, tumor delineation, and treatment indication criteria are required to improve the treatment response for liver metastases.

References . American Cancer Society. Cancer Facts and Figures 2004, & Cancer Facts and Figures 2005. Atlanta: American Cancer Society, 2004 & 2005. 2. Korea Central Cancer Registry Ministry of Health and Welfare Republic of Korea. 2002 Annual Report of the Korea Central Cancer Registry, 2003, 29–32. 3. Fong Y, Surgical therapy of hepatic colorectal metastasis. Ca Cancer J Clin 999;49:23–255. 4. Ogata Y, Matono K, Hayashi A et al. Repeat pulmonary resection for isolated recurrent lung metastases yields results comparable to those after first pulmonary resection in colorectal cancer. World J Surg 2005, In press. 5. Blomgren J, Lax I, Nüslund I et al. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Acta Oncol 995;34:86–870. 6. Blomgren J, Lax I, Goranson H et al. Radiosurgery for tumors in the body: clinical experience using a new method. J Radiosurg 998;:63–74. 7. Herfarth KK, Debus J, Lohr F et al. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 200;9:64–70.

8. Wulf J, Handinger U, Oppits U et al. Stereotactic radiotherapy of targets in lung and liver. Strahlenther Onkol 200;77:645–655. 9.Plathow C, Ley S, Fink C et al. Analysis of intrathoracic tumor mobility during whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol Phys 2004;59:952–959. 0. Rohlfing T, Maurer CR, O,Dell WG et al. Modeling liver motion and deformation during the respiratory cycle using intensity-based registration of gated MR images. Med Phys 2004;3:427–432 . Kim JG, Lee DH, Kim MS et al. A study on the reduction of organ motion from respiration. Korean J Med Phys 2004;5:79–85. 2. Wen PY, Black PM, Loeffler JS. Treatment of metastatic cancer. In: DeVita VT, Hellman S, Rosenberg S eds. 6th edn. Cancer Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 200, 2655–2670. 3. Patchell R. Brain metastases. Handbook Neurol 997;25:35–50. 4. Wen PY, Loeffler JS, Management of brain metastases. Oncology 999;3:94–96. 5. Delattre JY, Krol G, Thaler HT et al. Distribution of brain metastases. Arch Neurol 988;45:74–744. 6. Emami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 99;2:09–22. 7. Boden G. Radiation myelitis of cervical spinal cord. Br J Radiol 948;2:464–469. 8. Yamada Y, Lovelock M. Stereotactic body radiation therapy for paraspinal tumors. In: Kavanagh BD, Timmerman RD eds. Stereotactic Body Radiation Therapy. Philadelphia: Lippincott Williams & Wilkins, 2005, 43–5. 9. Schultheiss TE, Kun LE, Ang KK et al. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 995;3:093–2.


3 59

20. Gerszten PC, Welch WC. CyberKnife radiosurgery for the spine. In: Heibrun MP, ed. CyberKnife Radiosurgery: a Practical Guide. Sunnyvale: The CyberKnife Society, 2003, 20–30.

26. Lee SW, Choi EK, Park HJ et al. Stereotactic body frame based fractionated radiosurgery on consecutive days for primary or metastatic tumors in the lung. Lung Cancer 2003;40:309–35.

2. Ike H, Shimada H, Ohki S et al. Results of aggressive resection of lung metastases from colorectal carcinoma detected by intensive follow-up. Dis Colon Rectum 2002;45:468–473.

27. Nakagawa K, Aoki Y, Tago M et al. Megavoltage CT assisted stereotactic radiosurgery for thoracic tumors: original research in the treatment of thoracic neoplasms. Int J Radiat Oncol Biol Phys 2000;48:449–457.

22. Watanabe I, Arai T, Ono M et al. Prognostic factors in resection of pulmonary metastasis from colorectal cancer. Br J Surg 2003;90:436–440.

28. Nagata Y, Negoro Y, Aoki T et al. Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2002;52:04–046.

23. Song DY, Blomgren H. Stereotactic body radiation therapy for lung tumors. In: Kavanagh BD, Timmerman RD eds. Stereotactic Body Radiation Therapy. Philadelphia: Lippincott Williams & Wilkins, 2005, 99–4. 24. Uematsu M, Shioda A, Suda A et al. Computed tomography-guided cancer: a five-year experience. Int J Radiat Oncol Biol Phys 200;5:666–670. 25. Hara R, Itami J, Kondo T et al. Stereotactic single high dose irradiation of lung tumors under respiratory gating. Radiother Oncol 2002;63:59–63.

29. Scheele J, Stangl R, Atendorf-Hofmann A et al. Resection of colorectal metastases. World J Surg 995;9:59–7. 30. Fong Y, Fortner J, Sun RL et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Ann Surg 999; 230:309–32.