Int. J. Radiation Oncology Biol. Phys., Vol. 35, No. 2, pp. 259-166, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved

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l Clinical Original Contribution

CONFORMAL MIXED NEUTRON AND PHOTON IRRADIATION IN LOCALIZED AND LOCALLY ADVANCED PROSTATE CANCER:

PRELIMINARY ESTIMATES OF THE THERAPEUTIC RATIO

JEFFREY D. FORMAN, M.D., MARIE DUCLOS, M.D., RENU SHARMA, B.S., PAUL CHUBA, M.D., KIM HART, M.D., MARK YUDELEV, M.S., SYAMALA DEVI, M.D., WAYNE COURT, M.D.,

FALAH SHAMSA, PH.D., PETER LITTRUP, M.D., DAVID GFUGNON, M.D., ARTHUR PORTER, M.D. AND RICHARD MAUGHAN, PH.D.

Department of Radiation Oncology, Wayne State University, Detroit, MI 48201

Purpose: To determine the incidence of chronic toxicity and the probability of biochemical and histologic complete response among patients with nonmetastatic prostate cancer, treated with three dimensional (3D) conformal mixed neutron and photon irradiation. Methods and Materials: Between November 1991 and December 1994, 151 patients with prostate cancer were entered in three prospective dose-finding studies of conformal mixed neutron and photon irradiation. Patients with low stage, low to intermediate grade prostate cancer (Tl-ZNXMO, Gleason Score 57) received 38 Photon Gy (PhGy) plus 9 (51 patients) or 10 (53 patients) Neutron Gy (NGy) to the prostate and seminal vesicles. Forty-seven patients with locally advanced prostate cancer (T3-4 NO-l MO and/or Gleason Score 28) received 15 NGy + 18 PhGy to the prostate and seminal vesicles and 9 NGy + 18 PhGy to the pelvic lymph nodes. Results: The median follow-up was 16 months (range: 3-30 months). There was no Grade 3-5 GI or GU toxicity recorded. At 20 months, the actuarial rates of Grade 2 GI morbidity were 6 and 29% for the 9- 10 and 15 NGy protocols, respectively @ = 0.07). At 20 months, the incidences of Grade 2 GU morbidity were 4 and 16%, respectively (p = 0.08). Stiffness in flexing or abducting the hips was seen in 20 and 42% of patients receiving 9-10 and 15 NGy, respectively (p = 0.01). Potency was maintained in 65% of all patients. Among patients with an initial PSA 510, 100% had a 1Zmonth PSA <2 and 78% <l rig/ml. Negative postradiation biopsies were seen in 30% of patients at 6 months, 79% at 12 months, and 84% of patients at 18 months. Conclusion: The use of conformal mixed neutron and photon irradiation has been well tolerated with no severe bladder or rectal complications observed. However, because of the enhanced toxicity seen with 15 NGy, the current maximum dose levels of neutron irradiation have been limited to 11 NGy.

Prostate cancer, Conformal neutron irradiation

INTRODUCTION In 1986, this trial was retested using the newer neutron

In the management of locally advanced prostate cancer fast neutron irradiation has demonstrated a statistically significant improvement in local tumor control and dis- ease-free survival compared with conventional photon ra- diotherapy (5, 14). The first trial was the Radiation Ther- apy Oncology Group (RTOG ) Trial 77-04, which com- pared mixed neutron/photon vs. photon irradiation. At 10 years follow-up, there was a significant improvement in clinically assessed local control (70 vs. 58%) and survival (53 vs. 29%) in favor of the neutron arm (5). In addition, there was no statistical difference in the rate of severe chronic complications between the two treatments.

therapy facilities that had been sponsored by the National Cancer Institute. In that study, RTOG 85-23, fast neutron therapy alone was compared to conventional photon irra- diation. With a median follow-up time of 68 months, a significant improvement in clinically assessed local con- trol was seen in favor of the neutron arm. The 5-year actuarial clinically determined local control rates were 89 and 68%, for the neutron and photon arms, respectively (p < 0.0 1) . The rate of biochemical relapse, as measured by elevation of the serum prostate-specific antigen (PSA) levels, was also significantly lower in the neutron-treated patients ( 17 vs. 45%) ( 14). However, the rate of severe complications were significantly higher for the neutron-

Reprint requests to: Jeffrey D. Fortnan, M.D., Department of Radiation Oncology, Wayne State University, 3990 John R,

Detroit, MI 48201. E-mail: Jeff@rocdec.roc.wayne.edu. Accepted for publication 28 December 1995.

260 1. J. Radiation Oncology 0 Biology 0 Physics Volume 35. Number 2. 1906

treated patients. These complications primarily consisted of rectal toxicity resulting in surgery or bladder complica- tions resulting in contracted bladders. In total, 24% of neutron-treated patients experience Grade 3 or 4 chronic toxicity compared to 8% of photon-treated patients ( 14). Analysis of these complications suggested that differ- ences in beam collimation capabilities between different neutron facilities were responsible for the observed differ- ences in late rectal and bladder complication rates. The rates of complications were found to be inversely corre- lated with the degree of neutron beam shaping that was available ( 1).

In view of the benefits of neutron irradiation for local control in prostate cancer, a series of three Phase II studies were conducted at Wayne State University to study whether the use of three dimensional (3D) conformal neutron irradiation would allow for the safe delivery of fast-neutron irradiation in patients with localized and lo- cally advanced adenocarcinoma of the prostate. In this paper, we present the preliminary results of the first 15 1 patients treated on these studies to evaluate the efficacy and chronic toxicity of various conformal neutron-photon combinations.

METHODS AND MATERIALS

Patient population From November 1991 to December 1994, 151 patients

with Stages TI-T4 NX NO-l MO adenocarcinoma of the prostate were entered on three prospective, Internal Review Board approved, dose-finding studies of 3D con- formal mixed neutron and photon irradiation. Informed consent was obtained from all patients prior to treatment. The average age of all patients was 66.7 years (range: 45 to 82). Forty-three patients (28%) were African Ameri- can and 108 (72%) Caucasian. Seventy-eight patients (53%) received neoadjuvant hormonal therapy. Major prognostic factors (stage, grade, PSA) were balanced be- tween the patients who did or did not receive neoadjuvant hormones. The distribution of patient pretreatment char- acteristics are shown in Table 1. Forty-seven patients with locally advanced disease (Stage 2 T3 and/or Gleason Score 2 8) received 15 NGy + 18 PhGy. One hundred and four patients with localized prostate cancer (Stage 5 T2C and Gleason Score zz 7) received either 9 N Gy + 38 PhGy (51 patients) or 10 NGy + 38 PhGy (53 patients).

Pretreatment evaluation included a complete history, physical examination, complete blood count, blood chem- istries, serum prostatic acid phosphatase (PAP), and PSA in all patients. Radiographic evaluation included transrec- tal ultrasound, pelvic and abdominal computed tomogra- phy (CT), and radionuclide bone scan with plain radio- graphs to confirm bone scan abnormalities, Pretreatment gastrointestinal (GI) and genitourinary (GU) symptoms were recorded for all patients.

RADIATION DESIGN, FIELDS, AND DOSES

Prior to treatment, patients either underwent conven- tional x-ray simulation followed by a treatment-planning CT or virtual CT simulation alone. All patients were im- mobilized in the supine position with a custom-made alpha cradle cast. Simulation included oral. intravesicle, and urethral contrast according to a previously reported technique ( 16). Rectal contrast was not used because of concerns relating to iatrogenic prostate motion induced by the contrast as well as the ease of identifying the rectum on CT. The outline of the prostate, seminal vesi- cles, pelvic lymph nodes, pelvic bones, femoral heads. urethra, bladder, rectum, and skin were digitized into the 3D planning system. The tumor volume, normal tissues, and block outline were displayed with the beam’s eye view (BEV) technique. The BEVs were registered to the simulation films by aligning the bony pelvic anatomy. These films served as templates for the cerrobend block fabrication and port film verification for the photon treat- ment. For neutron field shaping or patients undergoing virtual simulation, block fabrication was directly accom- plished using the BEV and digitally reconstructed radio- graphs (DRR ) .

The neutrons were produced by using a superconduct- ing cyclotron with a 48.5 MeV deuteron beam incident on an internal beryllium target (7 ) . The resulting neutron beam has a depth of maximum dose at 9 mm, with depth dose characteristics similar to that of a 4 MV photon beam (9). The superconducting technology resulted in a compact treatment unit (30 tons) that is isocentric and capable of full 360” rotation at a source-axis distance of 182.9 cm. The megavoltage photon irradiation consisted of a 10 or 15 MV beam. The multirod collimating system (X,10) of the cyclotron produced irregularly shaped and partial transmission fields by means of 12,000 indepen- dently moving tungsten rods, 3.17 mm in diameter, ar- ranged in four arrays, of 21 layers. The rods are moved pneumatically to form the required portal shape defined by two Styrofoam templates. For both the photon and neutron components of treatment, a minimum margin of 15 mm from the gross tumor volume (GTV) of the pros- tate and seminal vesicles (PSV) was used. A summary of the doses, fields, and volumes irradiated is shown in Table 2.

Patients with locally advanced prostate cancer received elective (42 patients) or therapeutic pelvic lymph node irradiation (5 patients). Standard 4-field (AP/PA/RL/ LL arrangements were used for all portals. The pelvic lymph nodes (PLN) received 9 NGy + 18 PhGy. The prostate and seminal vesicles received 15 NGy + 18 PhGy. The beam apertures were designed with a 15 mm margin around the GTV,,, and 10 mm for the GTV,,. Doses were defined as the minimum tumor dose to a structure and prescribed to the highest isodose level en- compassing the volume. Dose-volume histograms com- paring the neutron and photon dose distribution to the

Conformal mixed neutron and photon irradiation 0 J. D. FORMAN et al. 261

Table 1. Patient characteristics

9-10 NGy + 38 Ph Gy

1.5 NGy + 18 Ph Gy Total

Average age Pretreatment hormones

No Yes

Avg. pretreatment PSA

Stage T1a.b Tic T2a T2b T2c T3,4 Nl

Gleason Score 3 4 5 6 7 8 9 10

Race African-American Caucasian

PSA: prostate-specific antigen.

67.2 (k7.0 yrs)

49 (47%) 55 (53%)

11.3 rig/ml

2 (2%) 16 (15%) 42 (40%) 33 (32%) 11 (11%) 0 (0%) 0 (0%)

2 (2%) 2 (2%)

15 (14%) 41 (39%) 44 (42%)

0 (0%) 0 (0%) 0 (0%)

27 (26%) 77 (74%)

65.8 (27.5 yrs)

24 (51%) 23 (49%)

46.1 rig/ml

0 (0%) 1 (2%) 0 (0%) 3 (6%) 6 (13%)

32 (68%) 5 (11%)

0 (0%) 0 (0%) 1 (2%) 8 (17%)

19 (40%) 10 (21%) 7 (15%) 2 (4%)

16 (34%) 31 (66%)

66.7 years

73 (48%) 78 (52%)

22.2 rig/ml

2 (1%) 17 (11%) 42 (28%) 36 (24%‘) 17 (11%) 32 (22%) 5 (3%)

2 (1%) 2 (1%)

16 (11%) 49 (32%) 63 (42%) 10 (7%) 7 (5%) 2 (1%)

43 (28%) 108 (72%)

prostate, seminal vesicles, rectum, and bladder demon- strated no significant differences (3, 16).

Patients with localized prostate cancer received 9 or 10 NGy through conformal noncoplanar fields ( 12) either following or followed by 4 weeks of conformal photon irradiation (38 Gy ) . The 100% isodose curve covered the PSV with the photon plans. The noncoplanar neutron

plans were prescribed to the highest isodose curve encom- passing the prostate (range: 89-97%). A typical isodose distribution for the 15 NGy treatment has been previously published ( 16). An isodose curve for the noncoplanar neutron plan is shown in Fig. 1. Treatment ports for all patients were verified on a weekly basis for both neutron and photon components.

Table 2. Summary of radiation fields and doses

Localized prostate cancer Locally advanced prostate cancer

Photon component Daily Dose PSV* 2 Gy 2 GY

Total Dose Fk? 38 Gy 38 Gy PLN

Field Arrangements AP/PA/RLlLL APIPAIRLILL Neutron Component

Daily Dose PSV 0.9 N Gy 1.0 N Gy PLN

Total Dose PSV 9 N Gy 10 N Gy PLN

Fields RL/LL RL/LL RAISO/LAISO RAISO/LAISO

Neutron Schedule 10 consecutive days (M-F) 10 consecutive days (M-F) Total Dose 9 N + 38 Ph Gy 10 N + 38 Ph Gy

* PSV prostate and seminal vesicles. + PSA + PLN Prostate, seminal vesicles and pelvic lymph nodes. * Using partial transmission through multirod collimator.

1.8 Gy 1.8 Gy 18 Gy 9 Gy* APIPAIRLILL

1.0 N Gy 0.6 N Gy 15 N Gy 9 N Gy AP/PA RL/LL Every other day alternate with photon 15 N + 18 Ph Gy

262 1. J. Radiation Oncology l Biology 0 Physics Volume 35. Number 2, 1996

Fig. 1. Axial computed tomography view at the level of the prostate gland showing the isodose distribution of the nonaxial neutron beams (RL/LL/RAISO/LAISO).

FOLLOW-UP AND STATISTICS

Patients were evaluated weekly during treatment. The first follow-up visit was 1 month following treatment and then at Months 3, 6, 9, 12, 16, 20, and 24. Patients were seen twice yearly, thereafter. At each visit, there was a symptom assessment, physical exam including digital rec- tal examination (DRE), complete blood count, blood chemistries, serum PAP, and PSA levels. Posttreatment biopsies were obtained at 6 and 18, or 12 and 24 months posttreatment. Toxicity was graded according to the RTOG morbidity grading system (Table 3) (6). Chronic complications were defined as those occurring more than 3 months after the completion of treatment.

A clinical local failure was scored if the patients had a palpable regrowth or progression on DRE. Distant me- tastasis was scored when a radiographic study demon- strated spread. Bone and CT scanning were not routinely done unless indicated by symptoms or an elevation in the PSA level. Biochemical failure was based on the serum

Table 3. RTOG Chronic morbidity grading scale

Grade 0 None. Grade 1 Minor symptoms, no treatment required. Grade 2 Symptoms responding to outpatient treatment. No

change in performance status. Grade 3 Distressing symptoms altering a patient’s lifestyle

and/or requiring hospitalization for minor surgical intervention.

Grade 4 Major surgical intervention or prolonged hospitalization.

Grade 5 Fatal complications.

PSA levels following treatment. A biochemical complete response was scored if a patient without hormone therapy reached a PSA level 5 1 rig/ml. We considered a bio- chemical failure if the PSA level rose on two successive follow-up visits. Postradiation biopsies were performed with transrectal ultrasound guidance. Six 1 g-gauge cores were obtained from the dominant hypoechoic or color doppler regions of suspicion in each sextant. All postradi- ation biopsies were reviewed by a single pathologist (DG) . Biopsies were scored as negative, marked, moder- ate, minimal therapeutic effect, or positive.

The times to last follow-up, to recurrence to developing a radiation complication, or to death were calculated from the date of last treatment. Estimates of survival probabili- ties were derived by the Kaplan-Meier method (4, 15). Estimates of cumulative incidence probabilities were done for biochemical complete response and complica- tions, and comparisons for these endpoints were done with a two-tailed log-rank test ( 13). Treatment compari- sons for categorical variables used the Fisher’s exact test ( 11). The median follow-up was 16 months (range: 3- 30 months).

RESULTS

Toxicity Two patients ( 1% ) reported acute Grade 3 GU toxicity

during radiation treatment. Both experienced bladder spasms requiring brief hospitalization for narcotics and antispasmodic medication. One patient was in the 9 NGy

Conformal mixed neutron and photon irradiation 0 J. D. FORMAN et al. 263

arm and 1 received 15 NGy. No other Grade 3-5 acute toxicity was recorded.

No chronic Grade 3-5 GI or GU complications have been reported. The actuarial rates of Grade 2 GI morbidity at 20 months were 6% for the low dose and 29% for the high neutron dose arm (p = 0.07, Fig. 2). The actuarial rate of Grade 2 GU morbidity were 4 and 16% for the low and high neutron dose arms, respectively (p = 0.08, Fig. 3).

Stiffness in flexing or abducting the hips was seen in 20 and 42% of the patients receiving 9- 10 NGy and 15 NGy, respectively (p = 0.01). Severe Grade 3 or 4 hip stiffness was seen in 0% and 26% of patients, respectively (p < 0.05). Three high dose (15 NGy) patients have painful pelvic bone necrosis identified on magnetic reso- nance imaging. Potency was maintained in 65% of pa- tients with no significant effect secondary to neutron dose or the use of neoadjuvant hormones. Chronic complica- tions as a function of dose are listed in Table 4. No Grade 3-5 skin or SC tissue toxicity has been reported.

Eficacy At 12 months, 91% of all patients had a serum PSA

<4, 78% <2, and 57% <l rig/ml. Among patients with an initial pretreatment PSA level < 10 nglml, 100% had a 12-month PSA 52 rig/ml, and 80% 51 rig/ml. By 18 months, the cumulative probability of achieving a PSA

<4 rig/ml was 95% for the low-dose, localized patients and 93% for the high-dose, locally advanced patients (p = 0.8 1) . The actuarial probability of reaching a PSA I 1 rig/ml was 81 and 57%, for localized and locally advanced patients, respectively (p = 0.001).

Histological local control has been assessed by postra- diation biopsies in 73 patients. Overall, 63% (46 patients) were negative, 3% (2 patients) showed a marked thera- peutic response, 4% (3 patients) a moderate response, and 30% (22 patients) were positive. At 6 months, 29% of biopsies were negative, 79% at 12 months, and 85% at 18 months (Fig. 4). The negative biopsy rate was not effected by clinical stage, Gleason score, pretreatment PSA volume, or neutron dose.

DISCUSSION

The data from these three prospective studies of differ- ent neutron-photon dose combinations confirm that con- formally designed fast-neutron irradiation can be deliv- ered with acceptable levels of chronic toxicity. The rates of biochemical and histologic complete response also sug- gest that the previously demonstrated superiority of neu- tron irradiation has been maintained with these mixtures of neutron and photon irradiation (5, 14). However, there was a neutron dose-response relationship seen in chronic rectal and bladder toxicity, as well as hip stiffness.

ACTUARIAL GI COMPLICATIONS (GRADE = 2)

I - 9-10N Gy+36Ph 0-Q-O 15N+lBPh (

P-.07

10 15 20 25 30

Months Aftef Treatment

Fig. 2. Actuarial probability of Grade 2 gastrointestinal morbidity for the low neutron dose (9- 10 NGy + 38 Gy) and high neutron dose treatments (15 NGy + 18 Gy).

264 I. .I. Radiation Oncology 0 Biology 0 Physics Volume 35. Number ?, 1996

ACTUARIAL GU COMPLICATIONS (GRADE = 2) P=.O8

- 9-10N Gy+36Ph 8-e-3 lSN+18Ph

pJ=-T:-:- @ ------- 8 -----__ f, -----__--- -+J

= B 0.6: 1 0 2 0.5 :

3 = 0.4:

0 5 10 15 20 25 30

Months After T-t

Fig. 3. Acturial probability of Grade 2 genitourinary morbidity for the low (9-10 NGy + 38 Gy) and high neutron dose treatments ( 15 NGy + 18 Gy).

The superiority of fast-neutron irradiation in the man- agement of locally advanced prostate cancer has been shown in two Phase II randomized trials performed by a neutron working group. At 10 years, there was a signifi- cant improvement in local control (70 vs. 58%) and sur- vival (53 vs. 29%) demonstrated in RTOG 77-04 (5). These results were confirmed in RTOG 8523, in which fast-neutron therapy alone was compared to photon irradi- ation (14). However, unlike RTOG 77-04, where mixed beam treatment was used, the rate of severe complications was significantly higher for the neutron-treated patients. Twenty-four percent of neutron-treated patients reported Grade 3 or 4 toxicity compared to 8% of photon-treated patients. The observation that the patients treated at the

Table 4. Grade 2 late treatment complications following conformal mixed neutron and photon irradiation

9-10 NGy 15 NGy + + 38 PhGy 18 PhGy p-Value

Rectal Bladder Potency Hip Stiffness

(Moderate & Severe)

6% 4%

67%

20%

29% 16% 60%

42%

p = 0.07 p = 0.08

NS

p = 0.01

NS: not significant, >O.OS.

University of Washington’s cyclotron with a multileaf collimator had a statistically significantly reduced rate of complications supplied the rationale for the current series of neutron dose-finding studies ( 1).

Because both RTOG 77-04 ( 40% neutrons) and RTOG 8523 (100% neutrons) were shown to be significantly better than photon irradiation for control of disease, it was hypothesized that the benefit of fast-neutron irradia- tion might be maintained with a lower percentage of neu- trons. In addition, because RTOG 7704 showed no in- crease in morbidity, it was hypothesized that a lower complication rate may be achieved using less than 100% neutrons. Finally, the optimal fractionation of neutron dose is not known, nor is the possible benefit of using noncoplanar conformal beams. For these reasons, dose combinations of 9 NGy + 38 PhGy (45% of RTOG 8523), 10 NGy + 38 PhGy (50% of RTOG 8523), and 15 NGy + 18 PhGy (75% of RTOG 8523) were tested. Methods of reducing toxicity shown to be effective in photon treatment were applied to fast-neutron irradiation. These included daily treatment, treating all fields each day, smaller daily doses ( 1.0 NGy ), and conformal field design.

The use of neutron irradiation in patients with localized prostate cancer (low stage, low to intermediate grade) was justified based on lower than expected rates of histo-

Conformal mixed neutron and photon irradiation 0 J. D. FORMAN et al. 265

Fig. 4. Probability of negative postradiation biopsy as a function of time.

logic and biochemical complete response reported in pa- tients with Stage Tl or T2 disease treated with photons alone ( 18). In this group of patients, high rates of chronic morbidity would not be acceptable and often therapeutic decisions are based on quality of life considerations ( 17 ) . The rates of chronic GI and GU morbidity seen in the low neutron dose arms are not statistically different than we have achieved using 3D conformal photon irradiation alone (2). Because of the enhanced rate of chronic toxic- ity seen with 15 NGy, the current dose level for locally advanced prostate cancer is 11 NGy + 46 PhGy twice daily with equates to a 2 Gy/fraction photon equivalent dose of 87 Gy.

Based on the preliminary observations that neoadjuvant hormonal therapy increased the histologic complete re-

sponse rate, the role of neoadjuvant hormonal therapy in conjunction with conformal neutron-photon irradiaton is being assessed. In addition, the optimal sequence of mixed neutron-photon irradiation is unknown and this is being assessed in an ongoing randomized trial at Wayne State University. It appears that a 50% mixture of neutron and photon irradiation has resulted in the greatest thera- peutic ratio between chronic complications and tumor control, as evidenced by histologic and biochemical com- plete response rates of 81%. Once the optimal combina- tion of hormones and neutrons is found, as well as the best sequence, best dose, and field arrangements are deter- mined, a randomized comparison with the best contempo- rary photon arm ( e.g., hormones and photons or escalated dose photons) could again be contemplated.

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