Japanese Journal of Clinical Oncology 30:225-229 (2000)
© 2000 Foundation for Promotion of Cancer Research
The Relationship Between Technical Parameters of External Beam Radiation Therapy and Complications for Localized Prostate Cancer
Departments of 1Radiology and 3Urology, Hokkaido University School of Medicine, Sapporo, 2Department of Radiology, Obihiro Kosei Hospital, Obihiro, 4Takayama Urological Hospital, Obihiro and 5Department of Urology, Otaru Municipal Hospital, Otaru, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: This study was performed to review retrospectively the clinical course of chronic rectal bleeding as a complication of external beam radiation therapy for localized prostate cancer and to analyze the relationship between technical parameters of radiation therapy and the complications.
Methods: Seventy-one patients with stages A2, B and C were treated with local-field radiotherapy (total dose 52.5–66 Gy, daily dose 2.0–3.28 Gy, field area 30–81 cm2, number of fields 3–15 ports, planning simulations X-ray or CT-based) between 1989 and 1998 at three institutions. The protocols were consistent during this same period at these institutions.
Results: Multivariate analysis revealed pretreatment PSA and Gleason sum to be statistically significant predictors of 5 year prostatic specific antigen (PSA) relapse-free rates in a median follow-up period of 42 months (range 12–119 months). The significant risk factors for higher grading of acute morbidity were a biological equivalent dose, 
/ß = 10(BED10) 
65 Gy, dose per fraction 3.0 Gy, field area 42 cm2, fewer ports and X-ray planning simulation. However, no parameter was associated with higher grading of late morbidity. Eleven patients (15.4%) experienced a late GI complication: grade 1 (4.2%), grade 2 (9.8%), grade 3 (1.4%). The median time to occurrence of rectal bleeding was 12 months after radiotherapy and the mean duration of morbidity was 11 months.
Conclusions: Higher total dose and dose per fraction, larger field area, fewer ports and X-ray simulation increased the grades of acute morbidity. A majority of chronic rectal bleedings were transient and responded to conservative treatment.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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External beam irradiation is an established curative modality in the management of patients with localized or locally advanced prostate cancer (1,2). Because of the proximity of normal tissues, such as the bladder and rectum, to the prostate, increasing the radiation dose to the prostate could lead to severe complications. It is well known that radiation-induced chronic rectal bleeding is the most common sequela after radiotherapy for prostatic cancer (3). However, the actual clinical course of such bleeding and its severity are still debatable (4,5).
There has been an increase in the use of computed tomography (CT) for treatment planning of radiotherapy (6). This promoted the technical development of multi-portal and conformal radiotherapy for prostate cancer (7). However, it is not clear how much these technical factors affect complications. This study was performed to analyze retrospectively the clinical course of chronic rectal bleeding as a complication of external beam radiation therapy for prostate cancer and to see the relationship between technical parameters of radiation therapy and complications.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Each patient diagnosed with prostate cancer who was treated with external beam radiation therapy at our institution or either of its two affiliated hospitals between 1989 and 1998 was included in this study if the patient met the following entry criteria: the patient had a biopsy or transurethral resection of the prostate (TUR-P) that revealed adenocarcinoma; no history of prostatectomy; the patient was staged by a digital rectal examination (DRE), an abdominal CT scan and a bone scintigraphy, which showed no evidence of metastases; the clinical stage was A2, B or C; the patient had received radiotherapy of radical doses and a minimum 12 month follow-up period. The 71 patients who met these criteria were the subjects of this study. Ages ranged from 50 to 91 years, with a mean of 71 years. There were eight stage A2, 29 stage B and 34 stage C diseases. Histological grade was well differentiated in 21, moderately in 25 and poorly in 16 patients. Pretreatment PSA (ng/ml) was <4 in 13, 4–10 in 12, 10–20 in 14, 20–50 in 16 and
50 in 11 patients. Sixty of 63 patients who were stage B and C had hormonal manipulation prior to irradiation. Patients’ characteristics are summarized in Table 1.
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External beam radiotherapy was delivered to the prostate using 4 or 10 MV photons. Treatment volumes (planning target volume, PTV), determined according to clinical stage, were the prostate only for stages A2 and B and the prostate plus seminal vesicles for stage C. CT simulation or conventional X-ray simulation was used for treatment planning. The field area of irradiation ranged from 30 (5 x 6 cm) to 81 (9 x 9 cm) cm2. Four different total doses, fractionations and portal numbers were used at different institutions and in different time periods. The irradiation protocol used did not change within the same institution in the same period. Multi-portal static fields were used, giving 52.5 Gy in 16 fractions within 4 weeks between 1989 and 1992 in 19 patients and 65 Gy in 28 fractions within 7 weeks between 1993 and 1998 in 20 patients in hospital A (7); conformal radiotherapy using seven ports of 60–66 Gy in 24–33 fractions within 6–8 weeks in 17 patients in hospital B; and conventional radiotherapy using 3–4 ports of 60–65 Gy in 24–26 fractions within 6–6.5 weeks in 15 patients in hospital C. CT simulation was used in hospitals A and B and X-ray simulation was used in hospital C. A four-times-a-week schedule was used in each hospital. A biologically equivalent dose (BED) in 2 Gy fractions was calculated for various treatment regimens using a linear quadratic equation (8). The BED10 of
/ß = 10 was assumed for tumor control and acute complications; on the other hand, the BED2 of /ß = 2 was assumed for late complications (8). The treatment regimen at each hospital and its corresponding BED are summarized in Table 2.
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Complications were scored using our own grading scale and treatments used for them are shown in Table 3. The grading criteria were as follows: grade 1, required no treatment or minor medication (<3 months); grade 2, required prolonged medication (
3 months) or minor intervention; grade 3, required major surgical intervention.
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Survival rates were calculated using Kaplan–Meier methods. A duration of rectal bleeding was shown using Kaplan–Meier type illustration. Univariate analysis of potential prognostic factors for a prostate-specific antigen (PSA) relapse was performed using Kaplan–Meier survival methodology with tests of significant differences in survival distributions based on the log-rank statistic. Independent covariates that affected the PSA relapse were determined multivariately using a stepwise Cox proportional hazards model. The analysis of relationships between technical parameters of radiation therapy and complication grades was performed using the Mann–Whitney U-test. A p value of <0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Table 4 shows the 5 year overall, cause-specific survival and PSA relapse-free rates in a median follow-up period of 42 months (range 12–119 months). PSA relapse was defined as a PSA rise of over 2.0 ng/ml if the nadir PSA was <2.0 ng/ml or two consecutive rises in PSA over the nadir PSA if the nadir was >2.0 ng/ml. Seven patients (9.8%) experienced a PSA relapse at a mean follow-up of 27 months after radiotherapy. Of the seven patients, two with stage C experienced a local recurrence by a DRE, two with stage C and one with stage A2 experienced distant metastases and the other two patients had a biochemical failure.
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The results of univariate and multivariate analysis, with several prognostic variables using PSA relapse-free as the end point, are shown in Table 5. Multivariate analysis revealed pretreatment PSA and Gleason sum to be statistically significant predictors of being PSA relapse-free after 5 years.
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Table 6 shows genitourinary (GU) and gastrointestinal (GI) complication rates with time to occurrence and duration of morbidities for late complications. Eleven patients (15.4%) experienced late GI complication: 4.2% grade 1, 9.8% grade 2 and 1.4% grade 3. One patient who received 52.5 Gy in 16 fractions experienced a proctitis requiring surgical intervention (grade 3). One rectal bleeding required a blood transfusion and two patients were treated with hyperbaric oxygen (grade 2). The other seven out of 11 patients who had proctitis did not require any medication or responded to the following medication shown in Table 3: stool softener, iron therapy, hemostatics, steroids enema, endoscopic coagulation. The median time to occurrence of late GI complication was 12 months (range 8–33 months) after radiotherapy and the median duration of morbidity was 11 months (range 3–37 months). The median time to occurrence of late GU complication was 11 months (range 8–17 months) after radiotherapy and the median duration of morbidity was 3 months (range 1–6 months). A rectal bleeding curve is shown in Fig. 1. It illustrates that the 1 and 2 year bleeding rates were 37.5 and 12.5%, respectively, suggesting recovery from bleeding during the second year.
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Table 7 shows the relationship between technical parameters of radiation therapy and complication grades. Higher grading of acute morbidity was significantly correlated with BED2 (
/ß = 2) 65 Gy, dose per fraction 3.0 Gy, field area 42 cm2, fewer ports and X-ray planning simulation. However, no parameter was associated with a higher grading of late morbidity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our multivariate analysis demonstrated that pretreatment PSA and Gleason sum were significant predictors of the 5 year PSA relapse-free rate. This result was identical with those of previous, larger studies (9). Recently, PSA nadir level after radiation therapy, time to PSA nadir and prostate carcinoma volume have become increasingly recognized as prognostically significant (10–12).
In our study, the significant risk factors for higher grading of acute morbidity were higher total dose, higher daily dose, larger field area, fewer ports and X-ray simulation. Patients receiving high total doses and dose per fraction irradiation to larger areas had more complications than those who received lower doses to smaller fields, as expected. It was not possible to distinguish the contribution of CT from the other treatment parameters because the analysis was retrospective. Although two previous randomized studies (13,14) failed to find a statistically significant difference in acute complications between conventional and conformal radiotherapy, Koper et al. (15) reported that a reduction in acute gastrointestinal toxicity was observed by the reduction of field area by three-dimensional conformal radiotherapy in a randomized trial. Recently, Schultheiss et al. (16) showed late gastrointestinal and genitourinary injuries correlated with their corresponding acute side effects.
We observed no correlation between the treatment factors and grade of late complications. However, because of the small number of patients, these results will need to be validated with longer follow-up periods. Occasionally, patients treated with radiation therapy to the pelvis, as in carcinoma of the prostate, even more than 5 years later complications of the small intestine including obstruction and fatal ileitis will occur, but it is inconceivable in our small localized field irradiation. Cho et al. (17) and Beard et al.(18) reported that irradiated volume and total dose to central axis were not associated with a higher prevalence of late proctitis. Cho et al. (17) indicated that a high posterior rectal dose (>50 Gy) was associated with increased prevalence of proctitis. Perez et al. (19) reported that the volume treated was an important factor influencing significant late morbidity. Dearnaley et al. (20) have shown that conformal techniques significantly lowered the risk of late radiation-induced proctitis by a randomized trial. Among the 225 men treated, significantly fewer developed radiation-induced proctitis and bleeding in the conformal group than in the conventional group, without tumor control being compromised.
Radiation-induced chronic rectal bleeding has been recognized to be refractory to treatment (21). In our study, except for one patient (1.4%) who required a colostomy, the mean time to occurrence of rectal bleeding was 15.9 months after radiotherapy and the mean duration of morbidity was 13.5 months for proctitis of grades 1 and 2. Teshima et al. (22) demonstrated a similar analysis that the median times to occurrence for our grades 1 and 2 late rectal bleeding were 13 and 18 months, respectively, whereas the corresponding median durations of symptom were 1 and 10 months, respectively. These data indicate that the actual clinical course of rectal bleeding does not result in a long refractory course associated with a poor quality of life and the majority of cases of this complication do not need a major surgical intervention.
In conclusion, pretreatment PSA and Gleason sum were the potential predictors of PSA relapse after radiotherapy. Higher total dose and dose per fraction, larger field area, fewer ports and X-ray simulation increased the grades of acute morbidity. However, no parameter of radiation therapy was found to be associated with higher grading of late morbidity in the moderate dose range. A majority of chronic rectal bleedings responded well to conservative treatment.
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FOOTNOTES |
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+ For reprints and all correspondence: Kei Kitamura, Department of Radiology, Hokkaido University School of Medicine, North-15, West-7, Kita-ku, Sapporo 060-8638, Japan. E-mail: ktmr@radi.med.hokudai.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1 Bagshaw MA, Cox RS, Ray GR. Status of radiation therapy of prostate cancer at Stanford University. Monogr Natl Cancer Inst 1988;7:47–60.
2 Perez CA, Lee HK, Georgiou A, Lockett MA. Technical and tumor-related factors affecting outcome of definitive irradiation for localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1993;26:565–81.
3 Borghede G, Hedelin H. Radiotherapy of localized prostate cancer. Analysis of late treatment complications. A prospective study. Radiother Oncol 1997;43:139–46.[Web of Science][Medline]
4 Hanlon AL, Schultheiss TE, Hunt MA, Movsas B, Peter RS, Hanks GE. Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 1997;38:59–63.[Web of Science][Medline]
5 Denham JW, O’Brien PC, Dunstan RH, Johansen J, See A, Hamilton CS, et al. Is there more than one late radiation proctitis syndrome? Radiother Oncol 1999;51:43–53.[Web of Science][Medline]
6 Nagata Y, Okajima K, Murata R, Mizowaki T, Yamamoto S, Mitsumori M, et al. Development of the CT simulator and evaluation of its clinical efficacy. Nippon Hoshasen Shuyo Gakkai Zasshi 1995;7:65–76.
7 Suzuki K, Shirato H, Takayama N, Sutoh S, Irie G. Treatment of prostatic cancer using daily intermittent multiportal therapy (DIMT) technique. Nippon Hoshasen Shuyo Gakkai Zasshi 1992;4:85–93.
8 Barton M. Tables of equivalent dose in 2 Gy fractions: a simple application of the linear quadratic formula. Int J Radiat Oncol Biol Phys 1995;31:371–8.[Web of Science][Medline]
9 Preston DM, Bauer JJ, Connelly RR, Sawyer T, Halligan J, Leifer ES, et al. Prostate-specific antigen to predict outcome of external beam radiation for prostate cancer: Walter Reed Army Medical Center experience 1988–1995. Urology 1999;53:131–8.[Web of Science][Medline]
10 Lee WB, Hanlon AL, Hanks GE. Prostate specific antigen nadir following external beam radiation therapy for clinically localized prostate cancer: the relationship between nadir level and disease-free survival. J Urol 1996;156:450–3.[Web of Science][Medline]
11 Aref I, Eapen L, Agboola O, Cross P. The relationship between biological failure and time to nadir in patients treated with external beam therapy for T1–T3 prostate carcinoma. Radiother Oncol 1998;48:203–7.[Web of Science][Medline]
12 D’Amico AV, Whittington R, Kaplan I, Beard C, Schultz D, Malkowicz SB, et al. Calculated prostate carcinoma volume: the optimal predictor of 3-year prostate specific antigen (PSA) failure free survival after surgery or radiation therapy of patients with pretreatment PSA level of 4–20 nanograms per milliliter. Cancer 1998;82:334–41.[Web of Science][Medline]
13 Pollack A, Zagars GK, Starkschall G, Childress CH, Kopplin S, Boyer AL, et al. Conventional vs conformal radiotherapy for prostate cancer: preliminary results of dosimetry and acute toxicity. Int J Radiat Oncol Biol Phys 1996;34:555–64.[Web of Science][Medline]
14 Tait DM, Nahum AE, Meyer LC, Law M, Dearnaley DP, Horwich A, et al. Acute toxicity in pelvic radiotherapy: a randomized trial of conformal versus conventional treatment. Radiother Oncol 1997;42:121–36.[Web of Science][Medline]
15 Koper PCM, Stroom JC, van Putten WLJ, Korevaar GA, Heijmen BJM, Wijnmaalen A, et al. Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study. Int J Radiat Oncol Biol Phys 1999;43:727–34.[Web of Science][Medline]
16 Schultheiss TE, Lee WR, Hunt MA, Hanlon AL, Peter RS, Hanks GE. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:3–11.[Web of Science][Medline]
17 Cho KH, Lee CKK, Levitt SH. Proctitis after conventional external radiation therapy for prostate cancer: importance of minimizing posterior rectal dose. Radiology 1995;195:699–703.
18 Beard CJ, Lamb C, Buswell L, Schneider L, Propert KJ, Gladstone D, et al. Radiation-associated morbidity in patients undergoing small-field external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:257–62.[Web of Science][Medline]
19 Perez CA, Lee HK, Georgiou A, Lockett MA. Technical factors affecting morbidity in definitive irradiation for localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1994;28:811–9.[Web of Science][Medline]
20 Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahum A, Tait D, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 1999;353:267–72.[Web of Science][Medline]
21 Buchi K. Radiation proctitis: therapy and prognosis. J Am Med Assoc 1991;265:1180.[Web of Science][Medline]
22 Teshima T, Hanks GE, Hanlon AL, Peter RS, Schultheiss TE. Rectal bleeding after conformal 3D treatment of prostate cancer: time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 1997;39:77–83.[Web of Science][Medline]
Received December 16, 1999; accepted March 9, 2000.
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