Chemoradiation for Bone Metastasis
Chemoradiation for Bone Metastasis
Pain from bone metastases of breast cancer origin is treated with localized radiation.
 Modulating doses and schedules has shown little efficacy in improving results. Given the
 synergistic therapeutic effect reported for combined systemic chemotherapy with local
 radiation in anal, rectal, and head and neck malignancies, the investigators sought to
 evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation
 of pain due to bone metastases from breast cancer Hypothesis: Given the hypothesis that
 regimens employing greater intensity radiation yield higher rates of pain relief,
 radiosensitization using a tumor targeted drug like Xeloda should improve the rate of
 complete pain relief as compared to radiosensitization with 5FU alone.

 Primary Objective:

 To determine the frequency and duration of pain relief and narcotic relief for the proposed
 regimen.

 Secondary Objective:

 To determine the toxicity of concurrent Capecitabine and radiotherapy in breast cancer
 patients with bone metastases.
BACKGROUND

 Much of the clinical practice of oncology involves palliative care. In this setting ,the
 emphasis is on alleviation of symptoms and preservation or improvement of quality of life. A
 large body of clinical evidence documents the effectiveness of local-field external beam
 radiotherapy in palliation of pain from osseous metastases (1). Despite this general
 agreement, controversy remains regarding the optimal dose and fractionation schedule.
 Prospective phase III clinical trials (2-6), today, have failed to demonstrate superiority of
 one schedule over another ,and as a result, the patterns of practice of remain diverse in
 duration and intensity.

 Between 1974 and 1980 the RTOG conducted a large national study to determine the
 effectiveness of five different dose fractionation schedules(2). A total of 1016 patients
 were entered ,266 into a "solitary metastasis" stratum, and 750 into a "multiple metastasis "
 stratum. The former were randomly assigned to treatment with 40,5Gy in 15 fractions or 20Gy
 in 5 fractions. The latter were assigned to 30Gy in 10 fractions, 15 Gy in5 fractions ,20 Gy
 in 5 fractions, or 25 Gy in 5 fractions. A quantitative measure of pain ,based on severity
 and frequency of pain, and the type and frequency of pain medications used, was devised to
 evaluate response. Overall, 89% of patients experienced minimal relief. There were no
 significant difference between the treatment arms in both strata. The initial pain score was
 found to be a useful predictor ; patients with high score were less likely to respond and
 were less likely to experience a complete response. Patients with breast and prostate cancer
 were significantly more likely to respond than patients with lung or other primary lesions.
 Patients completing their treatment as planned had significantly higher rates of complete
 response than those who did not .While some relief was experienced almost invariably within
 the first four weeks, complete relief was first reported later than four weeks after start of
 treatment in about 50 % of patients .The median duration of minimal and complete pain relief
 was 20 and 12 weeks ,respectively. There were no significant differences in duration of pain
 relief between the different arms It was concluded that all treatment dose schedules were
 equally effective.

 A reanalysis of the RTOG study was reported by Blitzer (7).Using a stepwise logistic
 regression, he examined the effect of the number of fractions, the dose per fraction, and
 solitary versus multiple metastases, on the probability of attaining complete pain relief and
 the need for retreatment. This multivariate technique allowed patients with solitary and
 multiple metastases to be analyzed together. By increasing the number of subjects and events
 the statistical power of the analysis was outcome. There was no correlation of the time dose
 factor with outcome (8). It was concluded that the more protracted schedules resulted in
 improved pain relief.

 Price et al. randomized 288 patients to receive either 8 Gy in one fraction or 30 Gy in 10
 daily fractions. Pain was assessed using a questionnaire completed by the patients at the
 home on a daily basis. No differences were found in the probability of attaining pain relief,
 the speed of onset or the duration of relief between the two arms(4). Hoskin et al.
 randomized 270 patients to receive either 4 Gy or 8 Gy in one fraction (3) Pain assessed by
 the patient) and analgesic usage were recorded before treatment and at 2,4,8 and 12 weeks. At
 4 weeks the response rates were 69% for 8 Gy and 44% for 4 Gy (p<0.001). The duration of the
 effect was independent of dose.

 Two other randomized trials have been reported (5,6). Given the small difference in the
 Biological Effective Dose ( BED) between the arms (6) and the small number of patients
 accrued (5,6), it is not surprising that no differences between the treatment arms were
 detected.

 RTOG have reported the results of a pooled data dose response analysis (11). A computerized
 literature search was conducted to identify prospectively randomized clinical studies which
 addressed this issue and the results of these studies (2 6) were pooled together to form a
 database for analysis. The endpoint selected for analysis was complete response (CR). It was
 felt that this endpoint was most likely to be evaluated in a consistent fashion by different
 investigators. One study (6) was excluded from the analysis because outcome was not reported
 using conventional definitions of complete and partial response. To allow comparison of the
 different study arms, the BED was calculated for each schedule. Odds ratios calculated for
 various dose levels showed a statistically significant increase from 1.00 to 3.32 as the BED
 increased from 14.4 Gy to 5 1.4 Gy.

 For the first time, RTOG analysis demonstrated a highly significant dose response
 relationship for palliation of pain from bone metastases with radiotherapy. Furthermore,
 there was no evidence of flattening of the dose¬-response curve within the dose range tested,
 suggesting that further gains can be realized at doses outside of the range tested. We
 propose a phase II clinical trial in which the biological effective dose will be increased by
 the concurrent use of a radiosensitizer. The main advantage of this approach over escalation
 of the physical dose is the avoidance of increase in the overall treatment time.

 Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally
 administered systemic prodrug of 5' deoxy 5 fluorouridine (5' DFUR) which is converted to 5
 Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60 kDa
 carboxyesterase hydrolyzes much of the compound to 5' deoxy 5 fluorocytidine (5' DFCR).
 Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts
 5' DFCR to 5' deoxy 5 fluorouridine (5' DFUR).. The enzyme, thymidine phosphorylase
 (dThdPase), then hydrolyzes 5' DFUR to the active drug 5 FU. Many tissues throughout the body
 express thymidine phosphorylase. Some human carcinomas express this enzyme in higher
 concentrations than surrounding normal tissues. Both normal and tumor cells metabolize 5 FU
 to 5¬fluoro 2 deoxyuridine monophosphate (FdUMP) and 5 fluorouridine triphosphate (FUTP).
 These metabolites cause cell injury by two different mechanisms. First, HUMP and the folate
 cofactor, N5 10¬methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a
 covalently bound ternary complex. This binding inhibits the formation of thymidylate from
 uracil. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential
 for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division.
 Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine
 triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA
 processing and protein synthesis. Capecitabine is already approved for use in patients with
 metastatic breast cancer resistant to both paclitaxel and an anthracycline containing
 chemotherapy regimen.

 Although 5FU is an established radiosensitizer, the exact mechanism by which it enhances cell
 kill is not well understood. Sensitization is schedule dependent and is maximal when a
 cytocidal concentration of 5FU is given after the radiation exposure (12). The effect does
 not result from increased sublethal damage or inhibition of sublethal damage repair (12,13).
 Current evidence suggests that radiosensitization by 5FU is mediated through its effects on
 DNA rather then RNA (14). In vivo (15) as well as clinical studies (16) have demonstrated the
 superiority of continuous over bolus infusion of 5FU.

 Over the last several decades, concurrent 5FU and radiation have been used successfully in a
 variety of malignancies. Several important lessons have been learned from clinical trials
 (16). Simultaneous delivery of large (IV bolus) doses of 5 fluorouracil with irradiation is
 associated with improved survival compared to treatment with radiation alone, but at a price
 of increased normal tissue toxicity. These side effects can be ameliorated by using
 protracted venous infusion. This is an efficacious approach, with a wide therapeutic index,
 which permits concurrent treatment of micrometastatic disease and radiation sensitization.

 Combined modality therapy, including irradiation and concurrently administered 5FU based
 chemotherapy, has become the mainstay of therapy for anal and rectal cancers. Protracted
 venous infusion chemoradiation is also used in the preoperative management of rectal cancer
 and in the nonoperative management of anal cancers. The Gastrointestinal Tumor Study Group
 (GITSG) has demonstrated a significant survival advantage for patients who receive adjuvant
 combined radiation and bolus 5FU following curative resection of pancreatic cancer (17,18).
 Similar advantages have been demonstrated in unresectable pancreatic cancers. Significant
 advantages have also been shown for concurrent chemotherapy regiments containing 5FU in
 esophageal cancer (19), squamous cell carcinoma of the Head and Neck (20,21), and carcinoma
 of the cervix (22).

 There is very limited experience with the use of capecitabine and radiation. Based on its
 relative selectivity and the increase in tumor cell 5FU levels, it should be expected that
 capecitabine will provide superior radiosensitization at equivalent or reduced systemic
 toxicity levels. Interestingly, it has been recently reported that radiation induces
 thymidine phosphorylase and enhances the efficacy of capecitabine in human cancer xenografts
 (23). This may further enhance the synergistic effects, and consequently the therapeutic
 ratio.

 In RTOG study a substantial number of patients with gastrointestinal malignancies treated
 with concurrent radiotherapy and capecitabine at a dose of 1600 mg/m2/day (5 days a week)
 with very little toxicity(24 ).In phase II study of chemoradiation for rectal cancer
 1650mg/m2/d of capecitabine for 14 days was safe and well-tolerated treatment(25).

 In this study we will investigate the feasibility of concurrent Capecitabine and external
 beam radiotherapy, as well as collect preliminary data regarding the efficacy of this
 regimen.

 OBJECTIVES

 Hypothesis: Given the hypothesis that regimens employing greater intensity radiation yield
 higher rates of pain relief, radiosensitization using a tumor targeted drug like Xeloda
 should improve the rate of complete pain relief as compared to radiosensitization with 5FU
 alone.

 Primary Objective:

 To determine the frequency and duration of pain relief and narcotic relief for the proposed
 regimen.

 Secondary Objective:

 To determine the toxicity of concurrent Capecitabine and radiotherapy in breast cancer
 patients with bone metastases.

 Eligibility Criteria

 Patients with metastatic breast will be allowed on the study regardless of their prior
 exposure to chemotherapy. Today, there is no evidence to suggest crossresistance between
 radiotherapy and prior chemotherapy, or that response to radiotherapy is related in any way
 to the number of lines of chemotherapy used in a particular patient. Good palliative
 responses can often be achieved in heavily pretreated patients.

 1. The patient must be 18 years of age or older.

 2. The patient must have histologically proven breast adenocarcinoma.

 3. Radiographic evidence of bone metastasis is required .Acceptable studies include plain
 radiographs, radionuclide bone scans, computed tomography scans and magnetic resonance
 imaging.

 4 .The patient must have pain that appears to be related to the radiographically documented
 metastasis.

 5. Patients receiving systemic therapy with Capecitabine to metastatic disease (according to
 health basket ).

 6. Patients must have an estimated life expectancy of 3 months or greater.

 7. Patients will be eligible for treatment of multiple metastases only if these can be
 included in no more than two treatment sites.

 8. Signed study specific informed consent.

 9 Karnofsky Performance Status > 40.

 10. Calculated Creatinine Clearance > 50 ml/min

 11.ALT and AST no greater than 3 5 times the institutional normal; bilirubin and serum
 creatinine no greater than 1.5 times normal; ANC greater than 1500, and platelets at least
 100,00.

 Exclusion Criteria

 1. Prior radiation therapy or prior palliative surgery to the painful site.

 2. Impending fracture of the treatment site or planned surgical fixation of the bone.

 3. Patients with clinical or radiographic evidence of spinal cord or cauda equina
 compression.

 4. Patients receiving systemic radionuclides (strontium, samarium, etc.) within 60 days
 prior to registration.

 PRETREATMENT EVALUATION

 1. Histologic diagnosis of the primary site. 2. Radiographic assessment, with must include
 plain x-ray of the index lesion (s) and a bone scane.

 3. Pain assessment score (BPI ). 4. Laboratory studis within 2 weeks of registration (CBC,
 serum ALT, AST ,total bilirubin and creatinine).

 RADIATION THERAPY

 1. Treatment must be given using 6-15MV photons or 6-18 MeV electrons .

 2. All fields must be treated each day. Treatment volume will include the radiographic
 abnormality with at least a 2 cm margin. Treatment of the entire bone is not required.

 3. Anterior and posterior parallel opposed fields will be used for lumbar spine, sacrum,
 and extremity sites. Equal weighting is recommended, although unequal weighting may be
 used for the lumbar or sacral spine with a ratio of doses of 1:2 AP:PA. Dose will be
 prescribed at mid depth at the central axis, or at the center of target volume if
 unequal weighting is used.

 Alternatively, the lumbar spine may be treated with a single PA field, with the dose
 prescribed to the mid vertebral body as defined by a lateral simulator film.

 4. Single posterior fields will be used for the thoracic spine and scapula .The treatment
 depth is set at the middle of the vertebral body, as determined by a lateral simulation
 film.

 5. The cervical spine may be treated with either parallel opposed lateral fields or with a
 single posterior field. When lateral fields are used, the isocenter should be at mid
 thickness, with the dose prescribed to the mid vertebral body.

 6. Pubic. bone lesions will be treated with a single anterior field at a depth determined
 by lateral radiograph or CT scan.

 7. Clavicular lesions will be treated with a single anterior field at a depth of 3 cm. The
 dose will be prescribed to the 3 cm depth. An alternative depth may be used as
 determined by CT scan or other radiographs.

 8. Rib metastases may be treated with electrons or with photons. When electrons are used,
 the appropriate energy should be chosen such that the entire lesion is covered by the
 90% (or higher) isodose curve. The dose will be prescribed to the 100% isodose line.
 When photons are used, parallel opposed fields may be used, with the depth prescribed to
 the mid thickness. Tangential fields are strongly encouraged to avoid treatment of
 underlying structures. A single field may be used to cover the lesion, with the depth
 set at the estimated depth of the rib lesion, and the dose prescribed to that level.

 9. When more than one osseous site is to be included into a treatment field, the treating
 radiation oncologist may use different field arrangements at herlhis discretion, with
 the goal of providing relatively uniform coverage of the target sites and minimum
 inclusion of uninvolved tissues.

 Radiation Dose

 All patients will receive radiotherapy to a dose 30 Gy in 10fractions (3 Gy per fraction)
 over two weeks.

 CHEMOTHERAPY

 Chemotherapy with capecitabine tablets will be given concurrently with radiotherapy in the
 dose 1400 mg/m2 orally, in two daily divided doses.

 Total daily dose rounded to the nearest 500 mg and divided into morning and evening

 Doses, as per the following table:

 Number of 500 mg tablets to be taken Surface Area Total Daily Dose morning evening (m2) (mg)*
 <= 1.08 1000 1 1 1.09 1.4 1500 2 1 1.41 1.71 2000 2 2 1.72 2.02 2500 3 2

 *Total Daily Dose rounded to the nearest 500 mg and divided into morning and evening doses.

 Dose Limiting Toxicity

 i) >grade 3 non hematologic toxicity, except for diarrhea, nausea, vomiting, fatigue,
 anorexia, alopecia, fever and/or local reactions.

 ii) grade 4 diarrhea lasting >3 days which is not controllable with loperamide or other such
 medications. Or grade 4 diarrhea that requires IV hydration.

 iii) grade 4 neutropenia lasting >3 days

 iv) grade 4 thrombocytopenia

 v) grade 2 hand foot syndrome. Dose adjustments will be as per the following table:

 Toxicity NCI Grades During a Course of Therapy Grade 1 Maintain dose Grade 2 1st appearance
 (non HFS) Interrupt until resolved to grade 0 1

 1st appearance of HFS Interrupt until resolved to grade 0 1, then continue at 75 % of
 original dose.

 2nd appearance Interrupt until resolved to grade 0 1, then continue at 75 % of original dose.

 3rd appearance Interrupt until resolved to grade 0 1, then continue at 50 % of original dose.

 4th appearance Discontinue treatment permanently Grade 3

 1. st appearance Interrupt until resolved to grade 0 1, then continue at 75 % of original
 dose with prophylaxis where possible.

 2. nd appearance Interrupt until resolved to grade 0 1, then continue at 50 % of original
 dose.

 3. rd appearance Discontinue treatment permanently Grade 4

 1st appearance Discontinue permanently or If physician deems it to be in the patient's best
 interest to continue, interrupt until resolved to grade 0 1, then continue at 50 % of
 original dose .

 Dosage modifications are not recommended for grade 1 events. Therapy with capecitabine should
 be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse
 event has resolved or decreased in intensity to grade 1, then therapy may be restarted at
 full dose or as adjusted according to the above table. If a grade 4 experience occurs,
 therapy should be discontinued or interrupted until resolved or decreased to grade 1, and
 therapy should be restarted at 50% of the original dose. Doses of capecitabine omitted for
 toxicity are not replaced or restored; instead the patient should resume the planned
 treatment cycles. Once the dose has been reduced it should not be increased at a later time.

 Toxicity

 CAPECITABINE can induce diarrhea, sometimes severe. Patients with severe diarrhea should be
 carefully monitored and given fluid and electrolyte replacement if they become dehydrated.
 National Cancer Institute of Canada (NCIC grade 2 diarrhea is defined as an increase of 4 to
 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or
 incontinence and malabsorption, and grade 4 diarrhea as an increase of >10 stools/day or
 grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea
 occurs, administration of capecitabine should be immediately interrupted until the diarrhea
 resolves or decreases in intensity to grade 1. Following grade 3 or 4 diarrhea, subsequent
 doses of capecitabine should be decreased. Standard antidiarrheal treatments (eg, loperamide)
 are recommended. Necrotizing enterocolitis (typhlitis) has also been reported.

 Hand and foot syndrome (palmar plantar erythrodysesthesia or chemotherapy induced acral
 erythema) is characterized by the following: numbness, dysesthesia/paresthesia, tingling,
 painless or painful swelling, erythema, desquamation, blistering and severe pain. Grade 2
 hand and foot syndrome is defined as painful erythema and swelling of the hands and/or feet
 and/or discomfort affecting the patient's activities of daily living. Grade 3 hand and¬foot
 syndrome is defined as moist desquamation, ulceration, blistering and severe pain of the
 hands and/or feet and/or severe discomfort that causes the patient to be unable to work or
 perform activities of daily living. If grade 2 or 3 hand and foot syndrome occurs,
 administration of capecitabine should be interrupted until the event resolves or decreases in
 intensity to grade 1. Following the occurrence of grade 2 handand foot syndrome, subsequent
 doses of capecitabine should be decreased.

 There has been cardiotoxicity associated with fluorinated pyrimidine therapy, including
 myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and
 electrocardiograph changes. These adverse events may be more common in patients with a prior
 history of coronary artery disease.

 Patients with mild to moderate hepatic dysfunction due to liver metastases should be
 carefully monitored when capecitabine is administered. The effect of severe hepatic
 dysfunction on the disposition of capecitabine is not known. If drug related grade 2 4
 elevations in bilirubin occur, administration of capecitabine should be immediately
 interrupted until the hyperbilirubinernia resolves or decreases in intensity to grade 1. NCIC
 grade 2 hyperbilirubinernia is defined as 1.5 x normal, grade 3 hyperbilirubinemia as 1.5 3 x
 normal and grade 4 hyperbilirubinemia as >3 x normal.

 Increases in adverse events have been noted in patients with reduced renal function.
 Therefore, patients will be excluded for a calculated creatinine clearance of less than 50
 ml/min.

 Myelosuppression was rare.

 Assessment of Response

 Pain scores and narcotic scores will be determined using the guidelines in following table:

 PAIN AND NARCOTIC CATEGORIES AND SCORES PAIN ANALGESIA Severity 0 No pain 0 None I Mild I
 Analgesics (ASA, Bufferin, Tylenol, Anacin, etc.) 2 Moderate 2 Mild Narcotic, (< 112 gr.
 codeine, Darvon, etc.) 3 Severe 3 Moderate Narcotic (> 112 < gr. codeine, Percoan, etc) 4
 Strong 4 Narcotic, (> 1 gr. codeine, demerol, morphine, etc) Frequency 0 None 0 None I
 Occasional (< daily) I p.r.n. (< daily) 2 Intermittent (at least daily) 2 q.d. (I tab. or
 cap./day) 3 Frequent (>. I < 3 daily) 3 b.i.d. t.i.d. (> I < 4 tab. or cap./day) 4 Constant
 (most of the time) 4 > t.i.d. (> 4 tab. or cap./day)

 Pain Score = Pain Severity Grade x Pain Frequency Grade Narcotic Score = Analgesia Severity
 Grade x Analgesic Frequency Grade

 Response will be evaluated by questionnaires at follow up visit at 2, 4 and 8 weeks after
 completion of radiotherapy and by phone call interviews (when necessary for completeness) in
 poor compliance patients.

 The "worst pain score" will be used as response endpoint. The time to maximal pain relief is
 the time from the first day of irradiation to the time of the lowest pain score for average
 pain.

 Response Definitions

 Complete response is defined as an average pain score of 0 for two consecutive analysis
 periods. Narcotic consumption must not be increased. Partial response. A decrease of at least
 2 points in the worst pain score for two consecutive analysis periods. Narcotic consumption
 must not be increased. No response (any of the following): A pain score that does not change
 within 8 weeks from the start of radiation therapy.

 A 2 point increase in worst pain score that is sustained at a higher level in the month
 following the first day of radiation therapy.

 A pain score that drops by at least 2 points and subsequent sustained rise (on 2 successive
 questionnaires) of pain score by at least 2 points. Any patient with progressive pain in the
 treated area should have plain radiographs of the area to assess for bone stability and
 pathologic fracture.

 References.

 1.

 Hoskin PJ. Scientific and clinical aspects of radiotherapy in the relief of bone pain. Cancer
 Surv. 7:69, 1988.

 2. Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases: the

 results of the Radiation Therapy Oncology Group. Cancer 1982; 50: 893.

 3. Hoskin PJ, Price P, Easton D, et a]. A prospective randomized trial of 4 Gy or 8 Gy single
 doses

 in the treatment of metastatic bone pain. Radiotherapy and Oncology 23:74 78, 1992.

 4. Price P, Hoskin PJ, Easton D, et al. Prospective randomized trial of single and
 multifraction

 radiotherapy schedules in the treatment of painful bony metastases. Radiotherapy and Oncology
 6: 247 255, 1986.

 Okawa T, Kita M, Goto M, et al. Randomized prospective clinical study of small, large and
 twice a day fraction radiotherapy for painful bone metastases. Radiotherapy and Oncology 13:
 99 104, 1988.

 6. Madsen EL, Painful bone metastases: Efficacy of radiotherapy assessed by the patients: A

 randomized trial comparing 4 Gy x 6 versus 10 Gy x 2. Int. J. Radiat. Oncol. Biol. Phys.
 9:1775¬ 1779, 1983.

 7. Blitzer PH. Reanalysis of the RTOG study of the palliation of symptomatic osseous
 metastasis.

 Cancer 1985; 55: 1468 1472.

 8. Orton CG, Ellis F, A simplification in the use of the NSD concept in practical
 radiotherapy. Br.

 J. Radiol. 1973; 46:529 537.

 9. Daut R, Cleeland C, Flanery R: Development of the Wisconsin Brief Pain questionnaire to
 assess

 pain in cancer and other diseases. Pain 17:197 210, 1983.

 10.

 11.

 12.

 13.

 14.

 Cella DF, Tulsky DS, Gray G, et al.: The Functional Assessment of Cancer Therapy Scale:
 Development and validation of the general measure. J Clin Oncol 11:570 579, 1993.

 Ben Josef E, Shamsa F, Youssef E, Porter AT. External beam radiotherapy for painful osseous
 metastases: pooled data dose response analysis. Int J Radiat Oncol Biol Phys 45(3):715 719,
 1999.

 Byfield JE, calabro Jones P, Klisak 1, et al. Pharmacologic requirements for obtaining
 sensitization of human tumor cells in vitro to combined r fluorouracil or ftorafur and x
 rays. Int J Radiat Oncol Biol Phys 1982, 8:1923 33.

 Nakajima V, Miyamoto Y, Tanabe M, et al. Enhancement of mammalian cell killing by
 5fluorouracil in combination with x rays. Cancer Res 39:3763 3767, 1979.

 Lawrence TS, Davis MA, Maybaum I Dependence of 5 fluorouracil mediated radiosensitization on
 DNA directed effects. Int J Radiat Oncol Biol Phys 1994, 29(3):519 23.

 15. Weinberg MJ, Rauth AM. 5 fluorouracil infusion and fractionated doses of radiation:
 Studies with a murine sqamous cell carcinoma. Int J Radiat Oncol Biol Phys 13: 1691 1699,
 1987.

 Rich TA. Infusional chemoradiation for rectal and anal cancers. Oncology (Huntingt) 1999,
 13(10 Suppl 5):131 4.

 17. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined
 radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987,
 59(12):2006¬ 10.

 18. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy
 following curative resection. Arch Surg 1985, 120(8):899 903.

 19. al Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J,
 Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus
 radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol
 1997, 15(l):277 84.

 20. Wendt TG, Grabenbauer GG, Rodel CM, Thiel HJ, Aydin H, Rohloff R, Wustrow TP, Iro H,
 Popella C, Schalhorn A. Simultaneous radiochemotherapy versus radiotherapy alone in advanced
 head and neck cancer: a randomized multicenter study. J Clin Oncol 1998, 16(4):1318 24.

 21. Al Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr
 WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced
 nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998,
 16(4):1310 7.

 22. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM,
 Mutch DG. Pelvic radiation with concurrent chemotherapy compared with pelvic and para aortic
 radiation for high risk cervical cancer. N Engl J Med 1999, 340(15):1137 43.

 23. Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X ray irradiation induces
 thymidine phosphorylase and enhances the efficacy of capecitabine in human cancer xenografts.
 Clin Cancer Res 1999, 5(10):2948 53.

 24. U.N.Vaishampayan, E. Ben-Josef, P.A. Philip, V.K. Vaitkevicius, K.J. Levin and A.F.
 Shields. A single- institution experience with concurrent capecitabine and radiation therapy
 in gastrointestinal malignancies . Int J Radiat Oncol Biol Phys ,2002, 53,675-679.

 25. Jun-Sang Kim, Jae-Sung Kim, Moon-June Cho and Wan-Hee Yoon .Preoperative chemoradiation
 using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys
 ,2002,54,403-408.
Inclusion Criteria:

 1. The patient must be 18 years of age or older

 2. The patient must have histologically proven breast adenocarcinoma

 3. Radiographic evidence of bone metastasis is required .Acceptable studies include plain
 radiographs, radionuclide bone scans, computed tomography scans and magnetic resonance
 imaging

 4. The patient must have pain that appears to be related to the radiographically
 documented metastasis

 5. Patients receiving systemic therapy with Capecitabine to metastatic disease (according
 to health basket)

 6. Patients must have an estimated life expectancy of 3 months or greater

 7. Patients will be eligible for treatment of multiple metastases only if these can be
 included in no more than two treatment sites

 8. Signed study specific informed consent

 9. Karnofsky Performance Status > 40

 10. Calculated Creatinine Clearance > 50 ml/min

 11. ALT and AST no greater than 3 5 times the institutional normal; bilirubin and serum
 creatinine no greater than 1.5 times normal; ANC greater than 1500, and platelets at
 least 100,00

 Exclusion Criteria:

 1. Prior radiation therapy or prior palliative surgery to the painful site

 2. Impending fracture of the treatment site or planned surgical fixation of the bone

 3. Patients with clinical or radiographic evidence of spinal cord or cauda equina
 compression

 4. Patients receiving systemic radionuclides (strontium, samarium, etc.) within 60 days
 prior to registration