- Email: [email protected]
Radiation therapy in the management of carcinoma of the prostate
2. R a d i a t i o n t h e r a p y is i n d i c a t e d w i t h a) I n a d e q u a t e surgical m a r g i n s in low-grade t u m o r s b) All h i g h - g r a d e t u m o r s c) All r e c u r r e n t m a l i g n a n t t u m o r s 3. I r r a d i a t i o n of n e r v e p a t h w a y s is indicated w i t h d e m o n s t r a t e d n e r v e a n d p e r i n e u r a l i n v a s i o n a n d / o r with a d e n o i d c y s t i c carcinoma. 4. I r r a d i a t i o n of the e n t i r e i p s i l a t e r a l neck is i n d i c a t e d a) W i t h h i g h - g r a d e t u m o r s u n l e s s radical n e c k dissection shows n e g a t i v e nodes b) In the place of radical neck dissection REFERENCES 1. Beahrs, O. H., Woolner, L. B., Carveth, S. W., and Devine, K. D.: Surgical management of parotid lesions, Arch. Surg. 80:890, 1960. 2. Blanck, C., Eneroth, C.-M., Jacobsson, F., and Jakobsson, P.: Adenoid cystic carcinoma of the parotid gland, Acta Radiol. 6:177, 1967. 3. Fletcher, G. H.: Textbook of Radiotherapy (2d ed.; Philadelphia: Lea & Febiger, 1973). 4. Fletcher, G. H., Tapley, N. duV., and Patricio, M. B.: Malignant Tumors of Salivary Glands, in Conley, J. (ed.): Salivary Glands and the Facial Nerve {Stuttgart, Germany: Georg Thieme Verlag, 1975). 5. Fletcher, G. H.: Indications for combination of irradiation and surgery, J. Radiol. Electrol. Med. Nucl. In press. 6. Guillamondegui, O. hi., Byers, R. hi., Luna, hi. A., Chiminazzo, H., Jesse, R. H., and Fletcher, G. H.: Aggressive surgery in treatment for parotid cancer: The role of adjunctive radiotherapy, Am. J. Roentgenol. Radium Ther. Nucl. Med. 123:49, 1975. 7. King, J. J., and Fletcher, G. H.: Malignant tumors of the major salivary glands, Radiology 100:381, 1971. 8. Smith, L. C., Lane, N., and Rankow, R. M.: Cylindroma {adenoid cystic carcinoma): A report of fifty-eight cases, Am. J. Surg. 110:519, 1965. 9. Stewart, J. G., Jackson, A. W., and Chew, M. K.: Role of radiotherapy in the management of malignant tumors of the salivary glands, Am. J. Roentgenol. Radium Ther. Nucl. Med. 102:100, 1968. 10. Tapley, N. duV.: Clinical Applications of the Electron Beam (New York: John Wiley & Sons, Inc., 1976).
Radiation Therapy in the Management of Carcinoma of the Prostate Carlos A. Perez, M.D. HISTORIC REVIEW T h e use of ionizing r a d i a t i o n s in t h e t r e a t m e n t of c a r c i n o m a of t h e prostate was first r e p o r t e d by P a s t e a u in 1911. TM I n 1934 W i d m a n n ~' n o t e d i m p r o v e m e n t in s u r v i v a l t i m e a n d relief of lower u r i n a r y t r a c t o b s t r u c t i o n in a g r o u p of p a t i e n t s w i t h a d v a n c e d c a r c i n o m a of the p r o s t a t e t r e a t e d w i t h 200-kv xThis project was supported by USPHS Cancer Center Grant No. 1 P02 CA13053-03, National Cancer Institute. 30
rays to doses probably not greater than 1,500 rad in 2 weeks (the actual exposures were measured in erythema dose). At the end of 6 weeks, when the physical condition of the patient permitted it, the series of treatment was repeated. In some patients, additional radium treatments were delivered with rectal tampons or packs. Starting in 1952, Flocks 12used interstitial colloidal gold injected into the prostate gland as an adjunct to surgery or as definitive therapy in an effort to eradicate the tumor. With the advent of supervoltage equipment, several authors began to report encouraging results with high-dose external beam irradiation. High local tumor control and survival rates comparable to those of patients with early lesions treated by a radical prostatectomy were noted2 s, 2o
PATIENT SELECTION Approximately 50% of patients presenting with lesions extending beyond the capsule of the gland have no evidence of distant dissemination (stage C or III). They have been traditionally treated by orchiectomy and estrogen therapy. A Veterans Administration Cooperative Urological Research Group prospective clinical trial 2° showed that no significant increase in survival followed treatment with 5 mg diethylstilbestrol (DES) daily compared to treatment by placebo. This was mostly due to an appreciable increase in cerebrovascular and cardiac complications in the patients receiving DES. Because of this, a resurgence of interest in radical radiation therapy for this particular group of patients has occurred in the past 10 years.
DIAGNOSTIC WORK-UP Accurate staging is crucial to the selection of optimal therapeutic techniques. A high incidence of pelvic lymph node metastases was described by Flocks 11 in 1959. The pedal lymphangiogram has definite value in the staging of these patients. However, because not all of the potentially involved lymph nodes are opacifled by the contrast material and because small metastatic deposits (<5 mm in diameter) are extremely difficult to detect, the accuracy of lymphangiography is not better than 80%. Furthermore, some filling defects seen in the lymph nodes are not necessarily due to metastatic carcinoma; fibrosis, reactive hyperplasia, fatty infiltration or other causes may result in false positive interpretations in about 5% of the patients, a The therapeutic value of staging laparotomy and its prognostic implications is yet to be evaluated. Bagshaw e t a l . a reported that this surgical exploration combined with radiation therapy had a significant morbidity; four of seven patients treated in this manner (with 5,500 rad tumor dose) required a small bowel resection because of radiation 31
injury. Similar observations had been reported in patients with carcinoma of the uterine cervix. TECHNIQUES OF I R R A D I A T I O N
Basically two radiation therapy approaches, or combinations of the two, have been used in the treatment of carcinoma of the prostate. INTERSTITIAL IRRADIATION.-- Radium was applied by the implantation of needles in the gland through a perineal route, as described by Barringer. 6 Flocks,O, ,2 published several articles describing a technique for the interstitial injection of radioactive colloidal gold into the prostate gland by a variety of approaches, including the retropubic, transrectal and transperineal as well as through an open perineal incision. EXTERNAL BEAM THERAP¥.--A variety of techniques has been used for external irradiation in the treatment of patients with carcinoma of the prostate. Bagshaw e t al. 2 initially treated their patients with a small (6 × 6 cm or 8 × 8 cm), 360-degree rotational port using a 4.7-mev x-ray linear accelerator b e a m (Fig 13). Approximately 7,000- 7,500 rad was given to the prostate in 6 - 8
Fig 13.-360-degree rotation with a linear accelerator. (From Bagshaw et al?)
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15 x 18 cm 15x!8 ca 14x 14 cm 6 x 8 cm Fig 14.--Example of treatment portals used at the Mallinckrodt Institute of Radiology, using 22-mev x-rays.
weeks. The high incidence of pelvic and periaortic node involvement prompted a review of their t r e a t m e n t policies. These investigators now 4 advocate small-field irradiation for patients with tumor limited to the prostate, whereas in those patients with extracapsular extension the entire pelvis is given 5,500 rad with larger ports, followed by a supplemental dose of 1,500-2,000 rad to the prostatic bed. The periaortic lymph nodes may be treated concomitantly with combinations of opposed anterior and posterior ports and either 360-degree rotation or two posterior oblique fields to deliver 5,000 rad in 5 - 6 weeks. Perez e t al. '7 employed a decreasing field technique with anterior and posterior portals, using a 22-mev x-ray betatron beam to deliver a minimum 7,000-rad tumor dose to the prostate gland, 6,000 rad to the external iliac and hypogastric nodes and 5,000 rad to the common iliac lymph nodes (Fig 14). Patients with metastases to the periaortic nodes shown by lymphangiogram or exploratory laparotomy received irradiation to this area through anterior and posterior portals (5,000 rad tumor dose in 6 weeks), with a 2 : 1 loading favoring the posterior portal.
SENSITIVITY OF ADENOCARCINOMA TO IRRADIATION AND LOCAL TUMOR CONTROL A long-standing misconception has been that adenocarcinoma {breast, prostate) is not a radiosensitive tumor. This was based on the slow regression of the tumor observed following irradiation. However, newer concepts in cell kinetics have shown that rapidly growing tumors show the effects of irradiation more rapidly, whereas slow-growing tumors take longer to demonstrate a simi33
TABLE 1 0 . - L O C A L RECURRENCE FOLLOWING RADIATION THERAPY IN STAGE C ADENOCARCINOMA OF THE PROSTATE* RECURRENCE BY YROFFOLLOW-UP Y R OF
NO. OF
THERAPY
PATIENTS
1
2
3
4
5
1973 1972 1971 1970 1969 1968 1967 Totals
15 15 ll 8 10 14 10 83
1 0 1 1 0 0 1 4
0 2 4 1 0 3 0 10
1 0 0 0 0 1 2
0 0 0 0 0 0
0 0 0 0 0
*Mallinckrodt Institute of Radiology, 1967-1973.
Fig 15.-Correlation of biopsy results with postirradiation internal. Chart shows results of 68 needle biopsies on 30 patients treated with 7,000 rad for stage C carcinoma of the prostate. Note that the biopsies become negative in the majority of the patients 9 - 1 2 months following the radiation therapy. (From COX and Tijerina?) 30 Bio;s~ h ga!ive Bio;sy Positive
10
0
0
"
3
6
9
12 Months
34
|8
24
30
lar response to irradiation. A very low incidence of local tumor recurrence (15-20%) has been reported following high doses of radiation therapy. The local recurrence rate in patients with stage C disease is shown in Table 10 by year of appearance after treatment. Most recurrences appear within 2 years. Only 5 local recurrences have developed in 34 patients followed for 5 years. Local recurrence was seen in 1 of 12 patients with stage B disease. In 75% of the patients who were t r e a t m e n t failures, distant dissemination was noted; approximately 65% of these patients had evidence of distant metastasis only, without local recurrence. Biopsies of the prostate following radical irradiation have been performed by a number of investigators. The number of specimens positive for tumor have been correlated with the stage of the disease and the time at which the biopsies were performed after radiation therapy. Cox and Tijerina 9 evaluated 68 biopsies obtained at different periods of follow-up in 30 patients with stage C adenocarcinoma of the prostate treated with 7,000 rad. They found that it took 9 - 1 2 months following irradiation for the majority of the prostatic specimens to become negative for tumor (Fig 15).
SURVIVAL AFTER RADICAL IRRADIATION Evaluation of survival following irradiation in carcinoma of the prostate is difficult because of the insidious course of the disease and the fact that many patients survive for a number of years after palliative treatment with persistent local tumor or even with distant metastases. Furthermore, because of the advanced age of these patients and the high incidence of intercurFig 16.--Survival in 430 patients with prostatic carcinoma treated with irradiation to the prostatic region, using a linear accelerator. (From Bagshaw e t al. 4) TOTAL POPULATION 430PATIENTS 0 0 ~ 1
1
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EXTR__ACAPSULAR ~ EXTENSION / ~ 200 PATIENTS
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o
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I I ,I 4 5 6 SURVIVAL IN YEARS
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35
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DLp~O'Ox-ra9 olon~ (m~z7 a9~26f, ~ p f s ) [O'--Qx-n:~ + hormone I~.x (m~n o9# 65, 5Ipl'~) ECE[~..~x-r~y olon¢ (m¢on o9~ 65, 60pra) ! , ~ x-ro 9 ~ hormone R.x. (m~on o~e 65, ZTphs)
100
~ 60
-
40
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~ 20-
-
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-
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-
Actuorial ~urvivol I
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8
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Survivol in 9~ors
Fig 17.-Actuarial survival in patients with carcinoma of the prostate limited to the gland (DLP) or with extracapsular extension (ECE) treated by irradiation alone or with irradiation and hormonal therapy. There is no significant difference in survival with the addition of hormonal manipulation. (From Ray et al. TM)
rent disease, many of them die of other causes with no clinical evidence of tumor. A number of studies have shown that patients with disease limited to the prostate (stage B) have 5-year cure rates in the range of 55-75%. Patients with tumors exhibiting extracapsular extension have shown 5-year survival rates in the range of 40- 50% (Fig 16). Ray et al. ~ analyzed the results at Stanford Medical Center, comparing 156 patients treated by irradiation alone and 128 receiving preradiation hormonal manipulation. The survival curves showed that, although not statistically significant, there was a slightly higher survival for those patients treated by radiation alone (Fig 17). Bailar et a l 2 and Gleason et al. ~3 have pointed out the significance of tumor differentiation in prognosis. Although poorly differentiated or anaplastic tumors respond well to radiation therapy and have rapid regression rates, their prognosis is extremely poor because of distant dissemination. ~ COMPLICATIONS
OF T R E A T M E N T
As in any radical treatment, acute side effects during irradiation and the possibility of late complications cannot be completely avoided. Judicious administration of radiation therapy, choice of portals, accurate treatment planning and dose optimization, as well as the best supportive care, will significantly contribute to 36
better tolerance for t r e a t m e n t and will lessen the probability of severe complications. During the administration of radiation, acute symptoms such as diarrhea, abdominal cramping, rectal discomfort (tenesmus) and occasional rectal bleeding due to a transient enteroproctitis can usually be managed. Genitourinary symptoms secondary to a cystourethritis induced by the irradiation are not uncommon and are characterized by dysuria, frequency and nocturia. Persistent gastrointestinal or genitourinary symptoms are reported in 5 - 1 0 % of patients. 's Over 95% of the patients with persistent severe symptoms improved with conservative treatment within 1 year following therapy. More severe complications, such as proctosigmoiditis requiring a colostomy or cystitis necessitating a u r i n a r y diversion or cystectomy, are extremely r a r e Y Complications in 95 patients treated at the Mallinckrodt Institute of Radiology using betatron x-rays are shown in Table 11. Pubic bone necrosis developed in a markedly obese patient who received 7,800 rad to t h a t bone in 71/2 weeks. Colostomy was required in only one patient on whom a hemorrhoidectomy was performed while he was receiving radiation. H e m a t u r i a and severe cystitis were noted in 3 patients, but none required a cystectomy. Urinary incontinence, observed in 6 patients, was associated with transurethral resection, suggesting t h a t this surgical procedure may have weakened the internal bladder sphincter, with incontinence following the added intravesical pressure secondary to the postradiation fibrosis t h a t may develop in the bladder. U r e t h r a l stricture was reported in 14 of 310 patients treated by Ray et al., TM 2 of the patients showing persistent local neoplasm. In 10 of the patients, strictures were correlated with transurethral resections prior to or during the therapy and doses over 7,800 rad. TABLE ll.-COMPLICATIONS AFTER RADICAL IRRADIATION FOR ADENOCARCINOMA OF THE PROSTATE (95 PATIENTS)* COMPLICATION
NO, OF CASES
Minor Persistent diarrhea or rectal symptoms 5 Chronic symptomsof cystitis 3 Urinary incontinencet 6 Pubic subcutaneous fibrosis 3 Major Pubic bone necrosis 1 Proctitis treated with colostomy$ 1 Perirectal abscess (4 yr after treatment) 1 Impotence 8 *Mallinckrodt Institute of Radiology,1967-1973. tPatients had transurethral resection. ~tHemorrhoidectomywas done while patient was receiving irradiation. 37
Although difficult to assess, sexual activity of the patients has been a matter of great interest to the radiation therapists because this is one of the main arguments for proposing this therapy as opposed to hormonal manipulation. Ray et al. TM obtained reliable data on sexual activity before and after irradiation in 166 patients. Fifty-two patients were impotent and 114 potent prior to initiation of treatment. Potency was maintained in 70% of 96 patients in this latter group who were neither castrated nor given estrogens following irradiation.
RADIATION THERAPY FOR PALLIATION A D V A N C E D T U M O R I N T H E P E L V I S . - - Patients with massive pelvic extensions of carcinoma of the prostate or lymph node involvement may complain of pelvic pain or hematuria or may develop urethral obstruction or leg edema due to lymphatic obstruction. Radiation therapy at doses in the range of 5,000 rad may be quite efficacious in the treatment of these symptoms. Carlton et a l : reported relief of bladder neck obstruction in 20 of 40 patients (50%) treated with radiation for palliation, improvement of hydronephrosis in 8 of 11 patients (73%) and disappearance of intractable hematuria in 7 patients (100%). These patients had either failed to respond to estrogen therapy or were treated with hormones following irradiation, so that the successful therapeutic results were clearly ascribable to radiation therapy alone. T R E A T M E N T OF DISTANT METASTASES. - - D i s s e m i n a t i o n t o the bones, particularly the vertebral column and pelvis and, to a lesser extent, the long bones, is common in advanced prostatic carcinoma. Marked symptomatic relief is noted in over 80% of patients treated with doses of 3,000 rad in 2 weeks. Large ports to include the entire bone, as in the extremities or the pelvis, must be used. Also portals encompassing the entire thoracic or lumbar spine, as the case may be, will decrease the need for retreatment. Brain metastases may be successfully treated with doses in the range of 3,000 rad in 2 or 3 weeks to the entire cranial contents (75% of the patients have multiple lesions). I R R A D I A T I O N OF THE B R E A S T PRIOR TO H O R M O N A L T H E R A P Y . - -
Gynecomastia is a common and unwanted side effect of estrogen therapy. Pain, discomfort and embarrassment frequently occur in these patients. Larsson and Sundbom," Corvalan et al. s and Rodriguez-Antunez et al. '9 have reported prevention of gynecomastia and related symptoms in approximately 80% of the patients treated with radiation in the range of 1,000 rad single dose. These authors used small appositional ports with superficial x-rays. We have preferred to use tangential ports with a 6°Co irradiator, delivering 1,200 rad midplane dose to each breast in 3 days. Except for minimal erythema, no other effects are noted. The breasts 38
must be irradiated before the orchiectomy or initiation of estrogen therapy because glandular hyperplasia, once initiated, is not reversible.
SUMMARY Radiation therapy is an effective method in the eradication of prostatic carcinoma at the primary site and in the regional pelvic lymph nodes. Radiation therapy is also effective in the relief of pain or other symptoms associated with extensive pelvic disease or distant metastases. REFERENCES 1. Arduino, L. J., et al.: Factors in the prognosis of carcinoma of the prostate: A cooperative study, J.Urol. i00:59, 1968. 2. Bagshaw, M. A., Kaplan, H. S., and Sagerman, R. H.: Linear accelerator supervoltage radiotherapy-VII. Carcinoma of the prostate, Radiology 85:121, 1965. 3. Bagshaw, hi. A., et al.: Extended-field radiation therapy for carcinoma of the prostate: A progress report, Cancer Chemother. Rep. 59:165, 1975. 4. Bagshaw, M. A., Ray, G. R., Pistenma, D. A., Castellino, R. A., and Meares, E. M., Jr.: External beam radiation therapy of primary carcinoma of the prostate, Cancer 36:723, 1975. 5. Bailar, J. D., III, Mellinger, G. T., and Gleason, D. F.: Survival rates of patients with prostatic cancer, tumor stage, and differentiation-preliminary report, Cancer Chemother. Rep. 50:129, 1966. 6. Barringer, B. S.: Radium in the treatment of prostatic carcinoma, Ann. Surg. 80:881, 1924. 7. Carlton, C. E., Jr., Dawoud, F., Judgins, P., and Scott, R., Jr.: Irradiation treatment of carcinoma of the prostate: A preliminary report based on 8 years ofexperience, J. Urol. 108:924, 1972. 8. Corvalan, J. G., Gill, W. M., Jr., Egleston, T. A., and Rodriguez-Antunez, A.: Irradiation of the male breast to prevent hormone produced gynecomastia, Am. J. Roentgenol. Radium Ther. Nucl. Med. 106:839, 1969. 9. Cox, J. D., and Tijerina, A.: Preliminary results of biopsies following irradiation for locally advanced adenocarcinoma of the prostate, Radiology 112:215, 1974. 10. Flocks, R. H.: Interstitial irradiation therapy with a solution of ~98Auas part of combination therapy for prostatic carcinoma, J. Nucl. Med. 5:691, 1964. I1. Flocks, R. H., Culp, D., and Porte, R.: Lymphatic spread from prostatic cancer, J. Urol. 81:194, 1959. 12. Flocks, R. H., Kerr, H. D., Elkins, H. V., and Culp, D. A.: Treatment of carcinoma of the prostate by interstitial radium with radioactive gold (~98Au): A preliminary report, J. Urol. 73:510, 1952. 13. Gleason, D. F., Mellinger, G. T., and Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J. Urol. 111:58, 1974. 14. Larsson, L. G., and Sundbom, C. M.: Roentgen irradiation of the male breast, Acta Radiol., 58:253, 1962. 15. Murphy, G. P., Saroff, J., Joiner, J., and Gaeta, J.: Prostatic carcinoma: Treated at a categorical center, 1960-1969, NY State J. Med. 75:1163, 1975. 16. Pasteau, O.: Traitement du cancer de la prostate par le radium, Rev. de Mal de la Nutrition, p. 363, 1911. 17. Perez, C. A., Ackerman, L. V., Silber, I., and Royce, R. K.: Radiation therapy 39
18. 19.
20. 21.
in the treatment of localized carcinoma of the prostate: Preliminary report using 22-MeV protons, Cancer 34:1059, 1974. Ray, G. R., Cassady, R., and Bagshaw, M. A.: Definitive radiation therapy of carcinoma of the prostate: A report on 15 years of experience, Radiology 106: 407, 1973. Rodriguez-Antunez, A., Cook, S. A., Jelden, G. L., Hunter, T. W., Straffon, R. A., and Stewart, B. H.: Management of primary and metastatic carcinoma of the prostate by the radiotherapist, Am. J. Roentgenol. Radium Ther. Nucl. Med. 118:876, 1973. Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate, Surg. Gynecol. Obstet. 124:1011, 1967. Widmann, B. P.: Cancer of the prostate: The results of radium and roentgenray treatment, Radiology 22:153, 1934.
Combined Irradiation and Surgery for Rectal and Sigmoid Carcinoma Leonard L. Gunderson, M.D.* S u r v i v a l rates for colorectal carcinoma have improved slightly over the past 25 to 30 years. Such improvements, however, have b e e n the result of an increase in operability, with little improvem e n t b y stage of disease in those patients who have survived a "curative resection. 'ns Until recently, irradiation has played a very minor role in the t r e a t m e n t of colorectal carcinoma, having been used primarily for palliation of unresectable lesions. Irradiation alone is not a competitive alternative to surgery because the limited tolerance of the surrounding organs and initial tumor bulk prevents a suitTABLE 12.-STAGING SYSTEMS FOR COLORECTAL CARCINOMA SYSTEm[ DUKE'S 5
MODIFIED ASTLE R-COLLER 1
A
A B,
B
Bz*
C
C, C2"
DESCRIPTION
Nodes negative; lesion limited to mucosa Nodes negative; extension of lesion through mucosa but still within bowel wall Nodes negative; extension through the entire bowel wall Nodes positive; lesion limited to bowel wall Nodes positive; extension of lesion through the entire bowel wall
*Separate notation (not shown here) is made regarding degree of extension through the bowel wall: microscop.ie on!y (m); gross extension confirmed by microscopy (m&g); adherence to or invasion of surrounding organs or structures (B 3 & C3). F r o m Gunderson and Sosin.I°
*Present address: Department of Radiation Medicine, Massachusetts General Hospital, Boston 02114. 40
Radiation Therapy in the Management of Carcinoma of the Prostate Carlos A. Perez, M.D. HISTORIC REVIEW T h e use of ionizing r a d i a t i o n s in t h e t r e a t m e n t of c a r c i n o m a of t h e prostate was first r e p o r t e d by P a s t e a u in 1911. TM I n 1934 W i d m a n n ~' n o t e d i m p r o v e m e n t in s u r v i v a l t i m e a n d relief of lower u r i n a r y t r a c t o b s t r u c t i o n in a g r o u p of p a t i e n t s w i t h a d v a n c e d c a r c i n o m a of the p r o s t a t e t r e a t e d w i t h 200-kv xThis project was supported by USPHS Cancer Center Grant No. 1 P02 CA13053-03, National Cancer Institute. 30
rays to doses probably not greater than 1,500 rad in 2 weeks (the actual exposures were measured in erythema dose). At the end of 6 weeks, when the physical condition of the patient permitted it, the series of treatment was repeated. In some patients, additional radium treatments were delivered with rectal tampons or packs. Starting in 1952, Flocks 12used interstitial colloidal gold injected into the prostate gland as an adjunct to surgery or as definitive therapy in an effort to eradicate the tumor. With the advent of supervoltage equipment, several authors began to report encouraging results with high-dose external beam irradiation. High local tumor control and survival rates comparable to those of patients with early lesions treated by a radical prostatectomy were noted2 s, 2o
PATIENT SELECTION Approximately 50% of patients presenting with lesions extending beyond the capsule of the gland have no evidence of distant dissemination (stage C or III). They have been traditionally treated by orchiectomy and estrogen therapy. A Veterans Administration Cooperative Urological Research Group prospective clinical trial 2° showed that no significant increase in survival followed treatment with 5 mg diethylstilbestrol (DES) daily compared to treatment by placebo. This was mostly due to an appreciable increase in cerebrovascular and cardiac complications in the patients receiving DES. Because of this, a resurgence of interest in radical radiation therapy for this particular group of patients has occurred in the past 10 years.
DIAGNOSTIC WORK-UP Accurate staging is crucial to the selection of optimal therapeutic techniques. A high incidence of pelvic lymph node metastases was described by Flocks 11 in 1959. The pedal lymphangiogram has definite value in the staging of these patients. However, because not all of the potentially involved lymph nodes are opacifled by the contrast material and because small metastatic deposits (<5 mm in diameter) are extremely difficult to detect, the accuracy of lymphangiography is not better than 80%. Furthermore, some filling defects seen in the lymph nodes are not necessarily due to metastatic carcinoma; fibrosis, reactive hyperplasia, fatty infiltration or other causes may result in false positive interpretations in about 5% of the patients, a The therapeutic value of staging laparotomy and its prognostic implications is yet to be evaluated. Bagshaw e t a l . a reported that this surgical exploration combined with radiation therapy had a significant morbidity; four of seven patients treated in this manner (with 5,500 rad tumor dose) required a small bowel resection because of radiation 31
injury. Similar observations had been reported in patients with carcinoma of the uterine cervix. TECHNIQUES OF I R R A D I A T I O N
Basically two radiation therapy approaches, or combinations of the two, have been used in the treatment of carcinoma of the prostate. INTERSTITIAL IRRADIATION.-- Radium was applied by the implantation of needles in the gland through a perineal route, as described by Barringer. 6 Flocks,O, ,2 published several articles describing a technique for the interstitial injection of radioactive colloidal gold into the prostate gland by a variety of approaches, including the retropubic, transrectal and transperineal as well as through an open perineal incision. EXTERNAL BEAM THERAP¥.--A variety of techniques has been used for external irradiation in the treatment of patients with carcinoma of the prostate. Bagshaw e t al. 2 initially treated their patients with a small (6 × 6 cm or 8 × 8 cm), 360-degree rotational port using a 4.7-mev x-ray linear accelerator b e a m (Fig 13). Approximately 7,000- 7,500 rad was given to the prostate in 6 - 8
Fig 13.-360-degree rotation with a linear accelerator. (From Bagshaw et al?)
j
"%
f(
--
32
~
0
Z
4
¢
6
|
JO
tJ.
_J
:,-..; .,,.-" .;,, ;,] :; ...
• ...
.
.~ ; =-.:
¢~::" :i :!; ''~'~' / - - - , ~ .- > .--.,,
AP
PA
15 x 18 cm 15x!8 ca 14x 14 cm 6 x 8 cm Fig 14.--Example of treatment portals used at the Mallinckrodt Institute of Radiology, using 22-mev x-rays.
weeks. The high incidence of pelvic and periaortic node involvement prompted a review of their t r e a t m e n t policies. These investigators now 4 advocate small-field irradiation for patients with tumor limited to the prostate, whereas in those patients with extracapsular extension the entire pelvis is given 5,500 rad with larger ports, followed by a supplemental dose of 1,500-2,000 rad to the prostatic bed. The periaortic lymph nodes may be treated concomitantly with combinations of opposed anterior and posterior ports and either 360-degree rotation or two posterior oblique fields to deliver 5,000 rad in 5 - 6 weeks. Perez e t al. '7 employed a decreasing field technique with anterior and posterior portals, using a 22-mev x-ray betatron beam to deliver a minimum 7,000-rad tumor dose to the prostate gland, 6,000 rad to the external iliac and hypogastric nodes and 5,000 rad to the common iliac lymph nodes (Fig 14). Patients with metastases to the periaortic nodes shown by lymphangiogram or exploratory laparotomy received irradiation to this area through anterior and posterior portals (5,000 rad tumor dose in 6 weeks), with a 2 : 1 loading favoring the posterior portal.
SENSITIVITY OF ADENOCARCINOMA TO IRRADIATION AND LOCAL TUMOR CONTROL A long-standing misconception has been that adenocarcinoma {breast, prostate) is not a radiosensitive tumor. This was based on the slow regression of the tumor observed following irradiation. However, newer concepts in cell kinetics have shown that rapidly growing tumors show the effects of irradiation more rapidly, whereas slow-growing tumors take longer to demonstrate a simi33
TABLE 1 0 . - L O C A L RECURRENCE FOLLOWING RADIATION THERAPY IN STAGE C ADENOCARCINOMA OF THE PROSTATE* RECURRENCE BY YROFFOLLOW-UP Y R OF
NO. OF
THERAPY
PATIENTS
1
2
3
4
5
1973 1972 1971 1970 1969 1968 1967 Totals
15 15 ll 8 10 14 10 83
1 0 1 1 0 0 1 4
0 2 4 1 0 3 0 10
1 0 0 0 0 1 2
0 0 0 0 0 0
0 0 0 0 0
*Mallinckrodt Institute of Radiology, 1967-1973.
Fig 15.-Correlation of biopsy results with postirradiation internal. Chart shows results of 68 needle biopsies on 30 patients treated with 7,000 rad for stage C carcinoma of the prostate. Note that the biopsies become negative in the majority of the patients 9 - 1 2 months following the radiation therapy. (From COX and Tijerina?) 30 Bio;s~ h ga!ive Bio;sy Positive
10
0
0
"
3
6
9
12 Months
34
|8
24
30
lar response to irradiation. A very low incidence of local tumor recurrence (15-20%) has been reported following high doses of radiation therapy. The local recurrence rate in patients with stage C disease is shown in Table 10 by year of appearance after treatment. Most recurrences appear within 2 years. Only 5 local recurrences have developed in 34 patients followed for 5 years. Local recurrence was seen in 1 of 12 patients with stage B disease. In 75% of the patients who were t r e a t m e n t failures, distant dissemination was noted; approximately 65% of these patients had evidence of distant metastasis only, without local recurrence. Biopsies of the prostate following radical irradiation have been performed by a number of investigators. The number of specimens positive for tumor have been correlated with the stage of the disease and the time at which the biopsies were performed after radiation therapy. Cox and Tijerina 9 evaluated 68 biopsies obtained at different periods of follow-up in 30 patients with stage C adenocarcinoma of the prostate treated with 7,000 rad. They found that it took 9 - 1 2 months following irradiation for the majority of the prostatic specimens to become negative for tumor (Fig 15).
SURVIVAL AFTER RADICAL IRRADIATION Evaluation of survival following irradiation in carcinoma of the prostate is difficult because of the insidious course of the disease and the fact that many patients survive for a number of years after palliative treatment with persistent local tumor or even with distant metastases. Furthermore, because of the advanced age of these patients and the high incidence of intercurFig 16.--Survival in 430 patients with prostatic carcinoma treated with irradiation to the prostatic region, using a linear accelerator. (From Bagshaw e t al. 4) TOTAL POPULATION 430PATIENTS 0 0 ~ 1
1
I
I
'
I
I
~O
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>
5 6o e~
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EXTR__ACAPSULAR ~ EXTENSION / ~ 200 PATIENTS
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~
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==.=°
o
I 1
I 2
I 3
I I ,I 4 5 6 SURVIVAL IN YEARS
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35
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DLp~O'Ox-ra9 olon~ (m~z7 a9~26f, ~ p f s ) [O'--Qx-n:~ + hormone I~.x (m~n o9# 65, 5Ipl'~) ECE[~..~x-r~y olon¢ (m¢on o9~ 65, 60pra) ! , ~ x-ro 9 ~ hormone R.x. (m~on o~e 65, ZTphs)
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~ 60
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-
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-
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-
Actuorial ~urvivol I
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8
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Fig 17.-Actuarial survival in patients with carcinoma of the prostate limited to the gland (DLP) or with extracapsular extension (ECE) treated by irradiation alone or with irradiation and hormonal therapy. There is no significant difference in survival with the addition of hormonal manipulation. (From Ray et al. TM)
rent disease, many of them die of other causes with no clinical evidence of tumor. A number of studies have shown that patients with disease limited to the prostate (stage B) have 5-year cure rates in the range of 55-75%. Patients with tumors exhibiting extracapsular extension have shown 5-year survival rates in the range of 40- 50% (Fig 16). Ray et al. ~ analyzed the results at Stanford Medical Center, comparing 156 patients treated by irradiation alone and 128 receiving preradiation hormonal manipulation. The survival curves showed that, although not statistically significant, there was a slightly higher survival for those patients treated by radiation alone (Fig 17). Bailar et a l 2 and Gleason et al. ~3 have pointed out the significance of tumor differentiation in prognosis. Although poorly differentiated or anaplastic tumors respond well to radiation therapy and have rapid regression rates, their prognosis is extremely poor because of distant dissemination. ~ COMPLICATIONS
OF T R E A T M E N T
As in any radical treatment, acute side effects during irradiation and the possibility of late complications cannot be completely avoided. Judicious administration of radiation therapy, choice of portals, accurate treatment planning and dose optimization, as well as the best supportive care, will significantly contribute to 36
better tolerance for t r e a t m e n t and will lessen the probability of severe complications. During the administration of radiation, acute symptoms such as diarrhea, abdominal cramping, rectal discomfort (tenesmus) and occasional rectal bleeding due to a transient enteroproctitis can usually be managed. Genitourinary symptoms secondary to a cystourethritis induced by the irradiation are not uncommon and are characterized by dysuria, frequency and nocturia. Persistent gastrointestinal or genitourinary symptoms are reported in 5 - 1 0 % of patients. 's Over 95% of the patients with persistent severe symptoms improved with conservative treatment within 1 year following therapy. More severe complications, such as proctosigmoiditis requiring a colostomy or cystitis necessitating a u r i n a r y diversion or cystectomy, are extremely r a r e Y Complications in 95 patients treated at the Mallinckrodt Institute of Radiology using betatron x-rays are shown in Table 11. Pubic bone necrosis developed in a markedly obese patient who received 7,800 rad to t h a t bone in 71/2 weeks. Colostomy was required in only one patient on whom a hemorrhoidectomy was performed while he was receiving radiation. H e m a t u r i a and severe cystitis were noted in 3 patients, but none required a cystectomy. Urinary incontinence, observed in 6 patients, was associated with transurethral resection, suggesting t h a t this surgical procedure may have weakened the internal bladder sphincter, with incontinence following the added intravesical pressure secondary to the postradiation fibrosis t h a t may develop in the bladder. U r e t h r a l stricture was reported in 14 of 310 patients treated by Ray et al., TM 2 of the patients showing persistent local neoplasm. In 10 of the patients, strictures were correlated with transurethral resections prior to or during the therapy and doses over 7,800 rad. TABLE ll.-COMPLICATIONS AFTER RADICAL IRRADIATION FOR ADENOCARCINOMA OF THE PROSTATE (95 PATIENTS)* COMPLICATION
NO, OF CASES
Minor Persistent diarrhea or rectal symptoms 5 Chronic symptomsof cystitis 3 Urinary incontinencet 6 Pubic subcutaneous fibrosis 3 Major Pubic bone necrosis 1 Proctitis treated with colostomy$ 1 Perirectal abscess (4 yr after treatment) 1 Impotence 8 *Mallinckrodt Institute of Radiology,1967-1973. tPatients had transurethral resection. ~tHemorrhoidectomywas done while patient was receiving irradiation. 37
Although difficult to assess, sexual activity of the patients has been a matter of great interest to the radiation therapists because this is one of the main arguments for proposing this therapy as opposed to hormonal manipulation. Ray et al. TM obtained reliable data on sexual activity before and after irradiation in 166 patients. Fifty-two patients were impotent and 114 potent prior to initiation of treatment. Potency was maintained in 70% of 96 patients in this latter group who were neither castrated nor given estrogens following irradiation.
RADIATION THERAPY FOR PALLIATION A D V A N C E D T U M O R I N T H E P E L V I S . - - Patients with massive pelvic extensions of carcinoma of the prostate or lymph node involvement may complain of pelvic pain or hematuria or may develop urethral obstruction or leg edema due to lymphatic obstruction. Radiation therapy at doses in the range of 5,000 rad may be quite efficacious in the treatment of these symptoms. Carlton et a l : reported relief of bladder neck obstruction in 20 of 40 patients (50%) treated with radiation for palliation, improvement of hydronephrosis in 8 of 11 patients (73%) and disappearance of intractable hematuria in 7 patients (100%). These patients had either failed to respond to estrogen therapy or were treated with hormones following irradiation, so that the successful therapeutic results were clearly ascribable to radiation therapy alone. T R E A T M E N T OF DISTANT METASTASES. - - D i s s e m i n a t i o n t o the bones, particularly the vertebral column and pelvis and, to a lesser extent, the long bones, is common in advanced prostatic carcinoma. Marked symptomatic relief is noted in over 80% of patients treated with doses of 3,000 rad in 2 weeks. Large ports to include the entire bone, as in the extremities or the pelvis, must be used. Also portals encompassing the entire thoracic or lumbar spine, as the case may be, will decrease the need for retreatment. Brain metastases may be successfully treated with doses in the range of 3,000 rad in 2 or 3 weeks to the entire cranial contents (75% of the patients have multiple lesions). I R R A D I A T I O N OF THE B R E A S T PRIOR TO H O R M O N A L T H E R A P Y . - -
Gynecomastia is a common and unwanted side effect of estrogen therapy. Pain, discomfort and embarrassment frequently occur in these patients. Larsson and Sundbom," Corvalan et al. s and Rodriguez-Antunez et al. '9 have reported prevention of gynecomastia and related symptoms in approximately 80% of the patients treated with radiation in the range of 1,000 rad single dose. These authors used small appositional ports with superficial x-rays. We have preferred to use tangential ports with a 6°Co irradiator, delivering 1,200 rad midplane dose to each breast in 3 days. Except for minimal erythema, no other effects are noted. The breasts 38
must be irradiated before the orchiectomy or initiation of estrogen therapy because glandular hyperplasia, once initiated, is not reversible.
SUMMARY Radiation therapy is an effective method in the eradication of prostatic carcinoma at the primary site and in the regional pelvic lymph nodes. Radiation therapy is also effective in the relief of pain or other symptoms associated with extensive pelvic disease or distant metastases. REFERENCES 1. Arduino, L. J., et al.: Factors in the prognosis of carcinoma of the prostate: A cooperative study, J.Urol. i00:59, 1968. 2. Bagshaw, M. A., Kaplan, H. S., and Sagerman, R. H.: Linear accelerator supervoltage radiotherapy-VII. Carcinoma of the prostate, Radiology 85:121, 1965. 3. Bagshaw, hi. A., et al.: Extended-field radiation therapy for carcinoma of the prostate: A progress report, Cancer Chemother. Rep. 59:165, 1975. 4. Bagshaw, M. A., Ray, G. R., Pistenma, D. A., Castellino, R. A., and Meares, E. M., Jr.: External beam radiation therapy of primary carcinoma of the prostate, Cancer 36:723, 1975. 5. Bailar, J. D., III, Mellinger, G. T., and Gleason, D. F.: Survival rates of patients with prostatic cancer, tumor stage, and differentiation-preliminary report, Cancer Chemother. Rep. 50:129, 1966. 6. Barringer, B. S.: Radium in the treatment of prostatic carcinoma, Ann. Surg. 80:881, 1924. 7. Carlton, C. E., Jr., Dawoud, F., Judgins, P., and Scott, R., Jr.: Irradiation treatment of carcinoma of the prostate: A preliminary report based on 8 years ofexperience, J. Urol. 108:924, 1972. 8. Corvalan, J. G., Gill, W. M., Jr., Egleston, T. A., and Rodriguez-Antunez, A.: Irradiation of the male breast to prevent hormone produced gynecomastia, Am. J. Roentgenol. Radium Ther. Nucl. Med. 106:839, 1969. 9. Cox, J. D., and Tijerina, A.: Preliminary results of biopsies following irradiation for locally advanced adenocarcinoma of the prostate, Radiology 112:215, 1974. 10. Flocks, R. H.: Interstitial irradiation therapy with a solution of ~98Auas part of combination therapy for prostatic carcinoma, J. Nucl. Med. 5:691, 1964. I1. Flocks, R. H., Culp, D., and Porte, R.: Lymphatic spread from prostatic cancer, J. Urol. 81:194, 1959. 12. Flocks, R. H., Kerr, H. D., Elkins, H. V., and Culp, D. A.: Treatment of carcinoma of the prostate by interstitial radium with radioactive gold (~98Au): A preliminary report, J. Urol. 73:510, 1952. 13. Gleason, D. F., Mellinger, G. T., and Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J. Urol. 111:58, 1974. 14. Larsson, L. G., and Sundbom, C. M.: Roentgen irradiation of the male breast, Acta Radiol., 58:253, 1962. 15. Murphy, G. P., Saroff, J., Joiner, J., and Gaeta, J.: Prostatic carcinoma: Treated at a categorical center, 1960-1969, NY State J. Med. 75:1163, 1975. 16. Pasteau, O.: Traitement du cancer de la prostate par le radium, Rev. de Mal de la Nutrition, p. 363, 1911. 17. Perez, C. A., Ackerman, L. V., Silber, I., and Royce, R. K.: Radiation therapy 39
18. 19.
20. 21.
in the treatment of localized carcinoma of the prostate: Preliminary report using 22-MeV protons, Cancer 34:1059, 1974. Ray, G. R., Cassady, R., and Bagshaw, M. A.: Definitive radiation therapy of carcinoma of the prostate: A report on 15 years of experience, Radiology 106: 407, 1973. Rodriguez-Antunez, A., Cook, S. A., Jelden, G. L., Hunter, T. W., Straffon, R. A., and Stewart, B. H.: Management of primary and metastatic carcinoma of the prostate by the radiotherapist, Am. J. Roentgenol. Radium Ther. Nucl. Med. 118:876, 1973. Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate, Surg. Gynecol. Obstet. 124:1011, 1967. Widmann, B. P.: Cancer of the prostate: The results of radium and roentgenray treatment, Radiology 22:153, 1934.
Combined Irradiation and Surgery for Rectal and Sigmoid Carcinoma Leonard L. Gunderson, M.D.* S u r v i v a l rates for colorectal carcinoma have improved slightly over the past 25 to 30 years. Such improvements, however, have b e e n the result of an increase in operability, with little improvem e n t b y stage of disease in those patients who have survived a "curative resection. 'ns Until recently, irradiation has played a very minor role in the t r e a t m e n t of colorectal carcinoma, having been used primarily for palliation of unresectable lesions. Irradiation alone is not a competitive alternative to surgery because the limited tolerance of the surrounding organs and initial tumor bulk prevents a suitTABLE 12.-STAGING SYSTEMS FOR COLORECTAL CARCINOMA SYSTEm[ DUKE'S 5
MODIFIED ASTLE R-COLLER 1
A
A B,
B
Bz*
C
C, C2"
DESCRIPTION
Nodes negative; lesion limited to mucosa Nodes negative; extension of lesion through mucosa but still within bowel wall Nodes negative; extension through the entire bowel wall Nodes positive; lesion limited to bowel wall Nodes positive; extension of lesion through the entire bowel wall
*Separate notation (not shown here) is made regarding degree of extension through the bowel wall: microscop.ie on!y (m); gross extension confirmed by microscopy (m&g); adherence to or invasion of surrounding organs or structures (B 3 & C3). F r o m Gunderson and Sosin.I°
*Present address: Department of Radiation Medicine, Massachusetts General Hospital, Boston 02114. 40