Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: Preliminary results of a phase III study

ELSEVIER

l

Clinical Investigation COMBINED PROTON AND PHOTON CONFORMAL RADIATION THERAPY FOR LOCALLY ADVANCED CARCINOMA OF THE PROSTATE: PRELIMINARY RESULTS OF A PHASE I/II STUDY T. YONEMOTO, M.D., JERRY D. SLATER, M.D., CARL J. Ross, JR.. M.D., JOHN E. ANTOINE, M.D., F.A.C.R., LILIA LOREDO, M.D.. JOHN 0. ARCHAMBEAU, M.D., F.A.C.R., REINHARD W. M. SCHULTE, M.D.. W. MILLER, PH.D., SANDRA L. TEICHMAN, B.S.N. AND JAMES M. SLATER, M.D., F.A.C.R.

LESLIE

DANIEL

Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda. (‘:\ Purpose: A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related morbidity and tumor response. Methods and Materials: One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 25il-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median folIow-up time was 20.2 months (range: lo-30 months). Toxicity was scored according to the Radiation Therapy OncoIogy Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate speci& antigen (PSA) measurements. Results: Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade I or 2 late morbfdity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normaIization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients). ConcI~ons: The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing compIieations to serrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalizatiou with pretreatment PSA 5 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging. Copyright 0 1997 Elsevier Science Inc. Prostatic cancer, Conformal, Proton, Local control, Dose escalation, Radiation morbidity.

INTRODUCTION Adenocarcinoma of the prostate is the most common nonskin malignancy in the United States. The American Cancer Society estimated that 200,ooO new cases of prostatic carcinoma would be found in 1994, a 2 1% increase over the 1993 estimate. It is the second most common cause of cancer death in men (13). Approximately 70% of patients presenting with prostatic carcinoma have localized disease and are potential candidates for definitive radiation therapy (58). Several reports demonstrate the efficacy of radiation therapy in the definitive management of localized prostatic carcinoma (7,9,33,34,72). When patients with early stage (Tl2a, A2-Bl) disease and negative lymph node biopsies are Reprint requests to: Jerry D. Slater. M.D., Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson Street, P.O. Box 2000, Loma Linda, CA 92354. .4rknonlledXement.s-This work wassupportedin part by grants

treated with definitive radiation therapy. control rates are comparable to those of radical surgery (32.33). Forty to 50% of patients initially present with locally advanced disease (T2b-T3, B2-C) (14, 54). Historically, local recurrence rates following radiation for locally advanced prostatic carcinoma range from 20 to 50% (5. 8, 9. .12-34, 36. 39, 41, 46. 57, 61, 62. 66, 68. 72, 73, 77. 92). Previous studies have demonstrated improvements in local control rates as the dose to the prostate is increased (36, 60. 62). Because of the inability to selectively irradiate the cancer, however, the dose response of adjacent normal structures, including the bladder and rectum, becomes the dose-limiting factor. As a consequence, a suboptimal total tumor dose is frequently used to reduce the from The HearstFoundation.The authorsthank William Preston. Ed.D. for editorial contributions. Accepted for publication 10June I c)Y(,.

I. J. Radiation Oncology 0 Biology 0 Physics

22

incidence of unacceptable normal tissue damage (76). New techniques are being evaluated in an attempt to increase the rate of local disease control while reducing the dose delivered to surrounding normal tissues. Proton beams provide a promising method of accomplishing these objectives (72-74). Protons in a homogenous medium follow a predetermined track, have little side-scatter, and stop abruptly at any prescribed depth. Their pattern of energy deposition is characterized by the Bragg peak, wherein the dose is at its minimum upon entry and reaches a maximum at the stopping region located within the target volume (30, 53, 55,80,85,93). The proton beam can be shaped to deliver homogeneous doses of radiation to irregular three-dimensional volumes, such as those required for prostatic boost volumes. These capabilities make it possible to reduce the dose delivered to normal tissues by a factor of 2 to 5 (2, 3). Because of these features of the proton beam, a study was initiated at Loma Linda University Medical Center (LLUMC) to evaluate the toxicity and response of a proton boost combined with photons for the treatment of locally advanced prostatic carcinoma. This report is a preliminary evaluation of patients treated to a total prostate dose of 75 Cobalt Gray Equivalent (CGE). ’ METHODS

AND MATERIALS

Patient eligibility and enrollment Between December 1991 and April 1993, 106 patients with locally advanced adenocarcinoma of the prostate were treated with curative intent using combined proton and photon therapy. Eligible patients included previously untreated men who had clinical stage T2b-T4 prostatic carcinoma with no evidence of disease outside the firstlevel pelvic lymph nodes. Patients ranged from 54 to 81 years of age (mean: 69). Exclusion criteria included previous prostatectomy, cryosurgery, pelvic irradiation, androgen deprivation therapy, chemotherapy, and inflammatory bowel disease. PSA level, Gleason score, and age were not used as exclusion criteria. Pretreatment evaluation Initial evaluation consisted of history and physical examination, including digital rectal examination (DRE), prostatic ultrasound, prostate specific antigen (PSA), acid and alkaline phosphatase, bone scan, chest x-ray examination, and pathologic review of the biopsy specimens with assignment of a Gleason score. One hundred and four patients were biopsied via transrectal needle; in two patients the diagnoses were made by transurethral resection of the prostate (TURP). Pelvic lymph nodes were assessed by computed tomography (CT) scans in all patients and by laparoscopic bilateral pelvic lymph node sampling in 53 (50%). Pathologic pelvic node involvement was found ‘Computed

using an RBE of 1.1 as compared to “OCo (86, 89).

Volume 37, Number 1, 1997 Table 1. Patient population Characteristic Stage Gleason score PSA*

Number T2b T2c T3 2-4 5-7 8-10 o-4 > 4-20 > 20-70 1 70

43 44 19 8 85 13 6 66 28 6

* Average = 22.4.

in eight patients (7.5%), all of whom had normal CT scans. The distribution of patients by stage, grade, and initial PSA is shown in Table 1. Treatment planning Prior to treatment, all patients were immobilized in a polyvinyl chloride (PVC) half cylinder using customshaped foam material to minimize patient movement and to maintain a constant distance from the patient’s skin surface to the distal edge of the tumor. A rectal balloon was inserted and filled with water to distend the rectum and remove its posterior portion from the field, as well as to minimize rectal air in the treatment field (Fig. 1). Patients were then placed in the immobilization device, where CT scans were taken at 3 mm intervals from L5Sl to below the pubic symphysis. This scanning process typically generated 90-125 CT slices. Three-dimensional (3D) treatment planning for the proton boost was accomplished using the Massachusetts General Hospital/Harvard Cyclotron Laboratory planning system (28, 29), as modified by LLUMC investigators. The tumor volume and surrounding critical structures, including bladder and rectum, were outlined on each applicable CT slice. The target volume for the proton portion of the treatment included the prostate and seminal vesicles plus a 0.7 cm margin at the 90% isodose line. Patients were treated with 250-MeV protons delivered by opposing lateral fields; all received 30 CGE in 15 fractions (Fig. 2). Digitally reconstructed radiographs (DRRs) generated by the treatment planning system were used to identify the tumor volume for simulation and photon planning. The target volume for the photon portals was a wholepelvis field, which included the primary tumor and pelvic lymph nodes; the positions of the latter were determined with reference to bony landmarks. The planned photon portion of the treatment regimen specified delivery of 18 23 MeV X-rays through four fields to a dose of 45 Gy in

Combined proton and photon conformal radiation therapy 0 L. T.

YCNEMOTO

or cd

7.3

Fig. 2. Dose distribution Fig. I. Computed tomogram image of patient in immobilization cylinder with rectal balloon in place.

to the 100% isodose line, for a total prostate dose of 75 CGE in 40 fractions.

25 fractions

Twatment The proton treatment center at LLUMC is the first proton-beam facility designed specifically for patient treatments and based in a hospital environment (76). This facility is also the first to use rotating gantries (Fig. 3) for delivering proton treatment beams from any angle (3). The accelerator is a synchrotron; its energy can be varied continuously from 70 to 250 MeV and it supplies proton beams to four treatment rooms. All prostate treatment fields were shaped with apertures to conform to the projected shape of the target volume. The Bragg peak was spread out sufficiently to provide a uniform dose over the range of target volume depth; shaped tissue compensators were used to stop the proton beam in conformity with the distal shape of the target. Patients were treated initially with protons to the prostate gland and seminal vesicles. They were placed in an immobilization cylinder and the rectal balloon was inserted and tilled with water to distend the rectum. Orthogonal X-ray films were taken prior to each patient’s daily treatment: measurements were made using bony landmarks as reference points. These X-ray films were compared to the DRRs; any patient misalignment was corrected prior to each treatment. The total treatment, including alignment, was completed in 20 to 30 min; actual beam time was less than 2 min. Following completion of the proton portion of the planned regimen, each patient received photon irradiation to the pelvis: there was no break in the treatment schedule. All patients received within 5% of their prescribed total dose of 75 CGE.

Patients were evaluated weekly throughout the course of therapy for the occurrence of signs and symptoms related to the treatment. The follow-up interval was calcu-

of proton boost using opposed lateral fields. isodose lines are shown in color. from 30% (blue) to 100% (pink).

lated from the last day of irradiation. Follow-up evaluations were performed at 2 weeks and 2 months after treatment, with subsequent examinations every 3 to 4 months. Evaluation included history, physical examination with DRE, and serum PSA level (done prior to DRE). Patients who developed symptoms suggestive of metastatic disease, or who had PSA levels that were rising. were evaluated with other diagnostic tests including biochemical screening profile. imaging of the abdomen and pelvis, bone scan, chest and skeletal radiographs. and prostatic biopsies as indicated. Morbidity was defined as acute if the reactions arose during treatment or within the first 90 days after completion of treatment. Late morbidity was defined as either acute symptoms that persisted, or symptoms arising more than 90 days after the completion of treatment. Morbidities were graded according to the Radiation Therapy Oncology Group (RTOG) system (44. 64) (Table 2). Serum PSA concentration was measured using the Hybritech method (17,156): the normal range was defined to be O-4.0 rig/ml. Normalizing PSA was defined as an initially elevated PSA that demonstrated a continuous dr-

Fig. 3. One of three isocentric facility.

gantries at the LLUMC

proton

24

I. J. Radiation Oncology 0 Biology 0 Physics

Table 2. RTOG morbidity grading system Grade 1 Grade 2 Grade 3

Grade 4 Grade 5

Minor symptoms requiring no treatment Symptoms responding to simple outpatient management, life style (performance status) not affected Distressing symptoms altering patient’s life style (performance status) Hospitalization for diagnosis or minor surgical intervention (such as urethral dilatation) may be required Major surgical intervention (such as laparotomy, colostomy, cystectomy) or prolonged hospitalization Fatal complications

cline but had not reached 5 4.0 rig/ml. Normalized PSA was defined as any level that was initially elevated but had declined to 5 4.0 rig/ml following therapy. Primary tumor response was measured during the follow-up examination with DRE. A finding of no evidence of disease (NED) required complete disappearance of palpable abnormalities in the prostate and periprostatic tissues, and a normalized PSA. Local failure was defined as progression in the primary tumor, as evidenced by reappearance or increasing size of the tumor mass or nodule with respect to pretreatment examination, or a continued abnormal prostate with rising PSA; regional failure, as progression of disease in the regional lymph nodes on follow-up; and distant failure, as any evidence of metastasis outside the primary site and regional lymph nodes. RESULTS The median follow-up time was 20.2 months (range: lo-30 months). Follow-up information was obtained on all patients. Three patients died of intercurrent disease at 4, 5, and 10 months after completion of treatment; PSA information was not obtained on one patient prior to his death. At the time of analysis, surviving patients had been followed for at least 10 months since completion of therapy. Actuarial analysis was based on the life table method (15, 16). Treatment morbidity Two patients died from intercurrent disease I 6 months after completion of therapy. Of the remaining 104 patients, 12 (11.5%) demonstrated Grade 1 or 2 tissue reaction (one patient had both urinary and rectal late morbidity); no patients developed Grade 3 or 4 sequelae (Table 3). These late complications occurred within 8 to 17 months of completion of therapy (median: 12 months). Four patients (3.8%) experienced episodes of gross hematuria, attributable to radiation cystitis and occurring 8 to 17 months after completion of treatment; all resolved without intervention. Nine patients (8.7%) had intermittent rectal bleeding, occurring 9- 13 months following completion of treatment and requiring symptomatic care only. Colonoscopy was performed in four of these pa-

Volume 37, Number 1, 1997

tients; the findings were consistent with radiation proctitis. The actuarial 2-year rate of minor morbidity was 12% (rectal morbidity, 8%; urinary morbidity, 4%) (Fig. 4). Treatment response Six patients, who had normal pretreatment PSA levels, were excluded from PSA response analysis (all remained normal). One hundred patients were available for PSA response evaluation (Fig. 5). The actuarial l-and 2-year rates of PSA normalization were 92 and 96%, respectively, in patients whose pretreatment PSAs were 5 10 rig/ml; these patients continued to have normal PSA measurements in subsequent follow-up examinations. In patients whose pretreatment PSA levels ranged from > 10 to 20 rig/ml, the l- and 2-year actuarial rates of PSA normalization were 84 and 97%, respectively; two patients had rising PSA levels after normalization. Among patients whose pretreatment PSA levels were > 20 mg/ml, the actuarial l- and 2-year rates of PSA normalization were 44 and 63%, respectively; three patients whose PSA levels had normalized subsequently developed rising PSA levels. One patient was found to have distant metastases. Disease status At the time of analysis, 102 patients were alive and 4 had died, 3 of intercurrent disease at 4, 5, and 10 months after completion of treatment, and 1 of metastatic carcinoma of the prostate, 22 months after completion of treatment. Local failure was found in three patients (2.8%); distant failure was found in eight patients (7.5%), all of whom evidenced local disease control, while two with increasing PSA levels had no clinically identifiable evidence of disease (Table 4). After treatment, PSA levels increased in 13 patients (Table 5). The three patients with local failure all had rising PSA with DRE demonstrating local relapse. One patient with stage T2b disease, a Gleason score of 9, and an initial PSA level of 27, underwent salvage prostatectomy and was also found to have a histologically positive lymph node. The second patient had stage T3 disease, a Gleason score of 9, and an initial PSA level of 13.3. This man had a positive biopsy after treatment and is receiving hormonal therapy. The third patient, who had stage T2b disease, a Gleason score of 7, and an initial PSA level of 25, was found to have an increasing mass on DRE. His elevated

Table 3. Incidence of late morbidity by grade Grade None 1 2 3 4

Rectal C%) 95 5 (4.8>* 4 (3.8) 0 0

Urinary 100 4 (3.:)* 0 0

* One patient had both rectal and urinary late morbidity.

(%)

Combined

0

3

proton

6

and photon

9

conformal

12

radiation

15

18

therapy

21

0 L. T. ~ONEMOTO

24

27

CT t/'

30

Months After Completion Of Treatment Fig. 4. Actuarial analyses of the time to Grade 1 or 3 (minor) morbidit!,.

PSA has stabilized and he presently shows no clinical symptoms of disease without androgen deprivation therapy. In these patients, the average Gleason score was 8.3 and the average pretreatment PSA level was 21.7. None of these patients had demonstrated evidence of distant metastasis at the time of this report. None of the eight patients with distant metastasis had evidence of local failure on DRE. Of these patients, three had been evaluated by staging bilateral pelvic lymphadenectomy; one of them had been found to have evidence of lymph node disease.

DISCUSSION Local recurrence rates of locally advanced prostatic carcinomas range from 20 to 50% when conventional external-beam radiation therapy is employed. Most studies have defined local control as the absence of a palpable abnormality, rather than determining control by systematic prostatic biopsy (19, 24, 38) or serial PSA determinations. Local recurrences were associated with a threeto fourfold increase in risk of metastatic disease across a spectrum of stage and grade permutations, suggesting that early and complete eradication of the primary tumor is required if a cure is to be achieved (25). Patterns of failure in patients undergoing locoregional therapy with curative intent demonstrate an increase in metastatic dissemination after failure to control the primary tumor (1, 18, 40, 4 1, 45, 50, 59, 60). Factors influencing local recurrence of prostatic carcinoma include tumor biology and treatment technique (63,

71). The radiosensitivity of human tumors varies considerably with type (20, 21, 78, 80). Some carcinomas of the prostate may have an oncogene. which may confer a relative radiation insensitivity (7.5. 87). Other well-known biological factors include tumor hypoxia, sublethal and potentially lethal damage repair, and tumor cell kinetics. These factors are under active investigation; however, no biological agents are available presently to manipulate them. The two treatment-related factors, tumor volume determination and total radiation dose, are significantly more controllable than biological factors and are strongly correlated with the incidence of morbidity and local control (9. 23, 35, 42. 5 1, 68, 91). In the pre-CT era, tumor target volumes were usually defined based on anatomic assumptions of prostate position relative to other pelvic structures as seen on simulation films (27, 37. 54). Much of the long-term data are based on the early experience from Stanford University. where the design of standard prostatic boost fields was based on information garnered from simulator films (6, 10). When the tumor volume later was defined by CT. it was seen that the 8 X 8 cm boost field often underestimated the true tumor volume. especially in locally advanced disease where the seminal vesicles were at risk or involved with tumor (4, 67, 7 1, 83). Three-dimensional computerized treatment planning, based on computed tomography (CT) data with reconstruction of the beam’s eye views of the target volume, allows for precise definition of the target volume and dose distribution (47. 69, 71). The other controllable treatment-related factor is the tumor dose delivered. The dose-response curve for human

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Volume 37, Number 1, 1997

Pretreatment PSA t*10

rl++~lWO

0

3

6

9

12

15

18

21

24

27

30

Months After Completion Of Treatment Fig. 5. Actuarial

Table 4. Clinical Stage

Disease free

T2b T2c T3 Total

38 43 14* 95

analyses of the time to normalization (< 4 rig/ml) of the posttreatment PSA.

status at last follow-up Local failure 2 0 1 3

Distant failure 3 it 8

* Includes three patients who died of intercurrent disease. +Includes one patient who died of prostatic carcinoma.

tumor appears to have a sigmoidal shape (12, 14, 22, 52, 60, 81, 84, 90). The Patterns of Care outcome study strongly suggests a dose response for in-field control of stage B and C (T2b-T3) prostatic carcinoma (34). In that study, patients with stage C carcinoma demonstrated an actuarial 5-year in-field recurrence rate of 37% when receiving total doses of less than 60 Gy. The rate declined slightly, to 36%, for patients receiving doses of 60-65 Gy; to 28% if the total dose was 70 Gy; and to 19% for those receiving > 70 Gy. However, the rate of serious late complications doubled with doses beyond 70 Gy. Rectal complications appear to have a strong dose dependence: there is a 60% 2-year incidence of moderate or severe proctitis when doses exceed 75 Gy, compared to 22% for less than 75 Gy (11, 77). With conventional approaches to tumor localization and treatment planning, a tumor volume dose of less than 70 Gy appears to be suboptimal for local disease control, albeit dictated by the tolerances of critical normal structures. If these controllable factors are optimized, it is reasonable to expect that improvements in local control could be

achieved while minimizing unacceptable damage to normal tissue. This expected improvement is based upon improving the radiation dose distribution between the cancer and the normal tissues that surround it (49, 76). Several techniques are currently employed to improve the radiation dose distribution, including: interstitial brachytherapy (26, 71); 3D conformal photon radiation therapy (47, 48, 72, 82); androgen deprivation therapy to reduce the number of cells in the tumor prior to radiation therapy (65); fast neutron therapy (40, 43, 70); and proton-beam radiation therapy (13, 74, 76, 79). Because it can reduce the radiation dose delivered to surrounding normal tissues while increasing the dose to the tumor, proton-beam therapy should improve the inciTable 5. Pretreatment Recurrence

site

Local Distant

None * pN1. + Moderately

status of patients with rising PSA

Stage

Initial PSA

T2b T2c T3 T2b T2b T2b T2c T3 T3 T3* T3 T2b* T2b

21 25 13 30 39 110 101 29 70 55 19 90 22

differentiated.

Gleason score 9 7 Is 7 10 6 4 7 9 8 5 3

Combined proton and photon conformal radiation therapy 0 L. T.

dence of local control for patients with locally advanced adenocarcinoma of the prostate. The incidence of side effects can be used to assess the effect of the reduced dose delivered to the normal tissue. This preliminary report demonstrates that combined proton and photon therapy has delivered a high radiotherapeutic dose of 75 CGE to the prostate, with a low incidence of late morbidity. Despite the high dose, only 12 of our patients (11.5%) demonstrated Grade I or 2 late morbidity and none developed Grade 3 or 4 sequelae. The side effects that did occur required symptomatic care only; the four patients having hematuria al1 resolved without intervention. This outcome is comparable to results reported with the use of traditional and conformal photon radiation modalities (23, 31, 47). Other factors that may contribute to the low incidence of

YONEMOTO

(jr 0;

17

late morbidity observed in the present experience are the technique of employing lateral proton-beam boost fields and the use of a rectal balloon, both of which permit delivery of essentially no radiation to the posterior rectal wall. These initial data are highly encouraging, with only three recurrences arising within the treatment field. In addition, the initial tumor response. as assessed by the high actuarial 2-year rate of PSA normalization with pretreatment PSA < 20, suggests the likelihood of local tumor control. Because of the long doubling time of most prostatic carcinomas, however. tumor response data such as reported in this article are very preliminary: many years of follow-up are required for complete assessment.

REFERENCES I. Anderson. P.; Dische, S. Local tumor control and subsequent incidence of distant metastatic disease. Int. J. Radiat. Oncol. Biol. Phys. 7:1645-1648; 1981. 2. Archambeau, J. 0.; Bennett, G. W. Potentialities of proton radiotherapy. Report of Symposium Aug. 9-10, 1972. Brookhaven National Laboratory report #BNL-50365; 1972. 3. Archambeau, J. 0.; Slater, J. M.; Coutrakon, G. B. ; et al. Proton-beam irradiation for the cancer patient: An approach to optimal therapy and normal-tissue sparing. Adv. Radiat. Biol. 1853-89; 1994. 4. Asbell, S. 0.; Schlager, B. A.: Baker, A. S.; et al. Revision of treatment planning for carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 6:861-865; 1980. 5. Bagshaw, M. A. Current conflicts in the management of prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 12:17211727; 1986. 6. Bagshaw, M. A. External radiation in carcinoma of the prostate. Cancer 45:1912-1922; 1980. 7. Bagshaw, M. A. Potential for radiotherapy alone in prostate cancer. Cancer 55:2079-2085; 1985. 8. Bagshaw. M. A.; Cox, R. S.; Ramback, J. E. Radiation therapy for localized prostate cancer. Justification by long-term follow-up. Urol. Clin. North Am. 17:787-802; 1990. 9. Bagshaw. M. A.; Cox, R. S.; Ray, G. R. Status of radiation treatment of prostate cancer at Stanford University. NC1 Monogr. 7:47-60; 1988. 10. Bagshaw. M. A.; Kaplan, H. S.; Sagerman, R. H. ; et al. Linear accelerator supervoltage radiotherapy: Carcinoma of the prostate. Radiology 85:121-129; 1965. 1I. Benk, V. A.; Adams, J. A.; Shipley, W. U.; et al. Late rectal bleeding following combined x-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. lnt. J. Radial. Oncol. Biol. Phys. 26:551-557; 1993. 12. Bentzen, S. M.; Thames, H. D.; Overgaard, J. Does variation in the in idtro cellular radiosensitivity explain the shallow clinical dose-control curve for malignant melanoma? Int. J. Radiat. Biol. 57:117-126; 1990. 13. Boring, C. C.; Squires, T. S.; Tong, T.; et al. Cancer Statistics. 1994. CA-Cancer J. Clin. 44:7-26; 1994. 14. Carter, H. G.; Coffey, D. S. Prostate cancer: The magnitude of the problem in the United States. In: Coffey, D. S.; Resnick, M. I.; Dorr, F. A.; Karr. J. P., eds. A multidisciplinary analysis of controversies in the management of prostate cancer. Proceedings of the second prouts neck conference on prostate cancer, October 17- 19, 1986. New York: Plenum Press; 1986: l-7.

15. Chiang, C. L. A stochastic study of the life table and its apphcatlons. I. Probability distributions of the biometric functions. Biometrics 16:618-635: 1960. 16. Chiang, C. L. The life table and its applications. Malabar. FL: Robert E. Kriger Publications; 1984:316. 17. Chu, T. M.; Murphy, G. P. What’s new in tumor marker:, for prostate cancer’? Urology 27:487-490; 1986. 18. Chung, C. K.: Stryker, J. A.; O’Neill, M.: ef ul. Evaluation of adjuvant postoperative radiotherapy for lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 8: 1877-I 880: 1982. 19. Cox. J. D.: Stoffel, T. J. The significance of needle biopsy after irradiation for stage C adenocarcinoma of the prostate. Cancer 40: 156-160; 1977. 20. Deacon. J. M.; Peckham, M. J.; Steel, G. G. The radioresponsiveness of human tumours and the initial slope of the cell survival curve. Radiat. Oncol. 1:317-323; 1984. 2 1. Fertil, B.; Malaise, E. P. Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 7:62 I-629; 1981. 22. Fischer, J. J.: Moulder, J. E. The steepness of the doseresponse curve in radiation therapy. Radiology I 17: 179184; 1975. 23. Forman, J. D.; Zinreich, E.; Lee. D. J.; 6’~~1. Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. Int. J. Radiat. Oncol. Riol. Phys. II :2073: 1985. 24. Freiha, F. S.; Bagshaw. M. A. Carcinoma of the prostate: Results of postirradiation biopsy. Prostate 5: 19.-25; 1984. 25. Fuks, Z.: Leibel, S. A.; Kutcher, G. E.: rt ctl.Three-dimensional conformal treatment: A new frontier in radiation therapy. In: DeVita, V. T., Jr.; Hellman. S.: Rosenberg, S. A.. eds. Important advances in oncology. Philadelphia, PA: J. B. Lippincott: 1991:151-172. 26. Fuks, Z.: Leibei, S. A.; Wallner, K. E.; et cri. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with ‘I’? implantation. Int. J. Radiat. Oncol. Biol. Phys. 21537-547; 1991. 27. Goitein. M. The utility of computed tomography in radiation therapy: An estimate of outcome. Int. J. Radiat. Oncol. Biol. Phys. 5: 1799-1807; 1979. 28. Goitein, M.; Abrams. M. Multi-dimensional treatment planning: I. Delineation of anatomy. Int. J. Rndiat. Oncol. Riol. Phys. 91777-787; 1983. 29. Goitein. M.; Abrams, M.; Rowe% D.: it al. Multi-dimensional treatment planning: II. Beam’s eye view. back projection, and projection through CT sections. Int. J. Radiat. Oncd. Biol. Phys. 9:789-797: 1983.

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