In, J Rudmhm Onu,k~,w RioI Phr\.. Vol Prmted ,n the U S.A 411 nghts reserved.
24. pp.
$5.00 + .OO 0360.30 I6192 Copyright & 1992 Pergamon Press Ltd
463-468
??Clinical Original Contribution
COMBINED
PRE- AND POSTOPERATIVE ADJUVANT RADIATION THERAPY FOR BLADDER CANCER-A TEN YEAR EXPERIENCE SUSAN
A. REISINGER,
M.D.,* MOHAMMED
AND S. GRANT Departments
of *Radiation
MULHOLLAND,
MOHIUDDIN,
M.D.*
M.D.+
Oncology and +Urology. Thomas Jefferson University Hospital, Philadelphia, PA
From 1978 through 1987,78 patients with carcinoma of the bladder were treated with combined pre- and postoperative adjuvant radiation therapy. All were given a single dose of pre-operative radiation therapy, 500 cGy, either on the day of or the day before cystectomy. Histological staging on the cystectomy specimens according to the TNM classification system was performed. Forty patients with Stage P2 (high grade III and IV), P3A, P3B, P4A, or N+ underwent planned high dose postoperative radiation therapy (4000-4500 cGy) in 5 weeks. The whole pelvis was treated with conventional fractionation of 180 cGy 5 days per week. Median follow-up was 52 months, with 36 months minimum follow-up. There was a 67% overall 5-year survival, and those with PI and P2 (Grade I and II) had an 84% 5-year survival. Survival for patients with P2 tumor (Grade III and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Bowel obstructions developed in 8% of patients who received no postoperative radiation therapy and 37% in those who did. Genitourinary complication rates were similar in both groups, 13% in the group that received no postoperative radiation therapy and 10% in the group that did. Although the planned approach of combined pre- and postoperative radiation therapy for unfavorable stages of bladder cancer is associated with a better than 50% 5-year survival rate (except in Stage P3B cancer), the bowel toxicity was unacceptably high. Bladder carcinoma, Adjuvant radiation therapy, Bowel toxicity.
viable tumor cells at the time of surgery. However, the tumor architecture is not disturbed so that accurate histopathologic staging can be obtained from the cystectomy specimens. After assessment of histopathologic prognostic indicators in the cystectomy specimens, selected patients at high risk for local pelvic failure or distant dissemination of disease are treated with full dose postoperative radiation therapy. These patients include individuals with P2 (Grade III and IV), P3A, P3B, P4A, and N+ disease. In this report, we present an update of the previously reported experience with combined low dose pre-operative radiation therapy and high dose postoperative radiation therapy, together with survival rates and morbidity data.
INTRODUCTION Bladder cancer is the fourth most common solid tumor in men and seventh among women (3). In 199 1, it is estimated there will be 50,200 new cases of bladder cancer.
with approximately 9,500 deaths due to this disease (3). At initial clinical presentation, approximately 70% of bladder tumors are superficial, 25% have infiltrated muscle, and 5% are metastatic. Radical cystoprostatectomy with pelvic lymphadenectomy has become the standard of care for patients with carcinoma infiltrating the muscle. Extensive surgery for patients with carcinoma infiltrating the muscle has not prevented approximately 50% of them from dying of metastatic disease. This has led to the use of adjuvant treatment in these patients. An adjuvant protocol, using low dose pre-operative radiation therapy with selective postoperative radiation therapy, was developed at Thomas Jefferson Hospital in 1978. The results of this protocol have been previously reported in the literature ( 17, 18). The rationale for using low dose preoperative radiation therapy is to inhibit dissemination of
METHODS
AND
MATERIALS
From 1978- 1987,78 patients underwent pre-operative radiation therapy followed by cystectomy. Treatment was delivered in the manner described in the two prior RTOG/ Jefferson studies ( 17, 18). Forty patients included in this
Presented at the 33rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, DC, 48 November 199 1. Reprint requests to: Susan A. Reisinger, M.D., Thomas Jef-
ferson University Hospital, phia, PA 19107. Accepted for publication
463
I 1th and Sansom Streets, Philadel20 April 1992.
464
1. J. Radiation
Oncology 0 Biology 0 Physics
Table 1. Staging system: TNM Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: “flat tumor” Noninvasive papillary carcinoma Tumor invades subepithelial connective tissue Tumor invades superficial muscle (inner-half) Tumor invades deep muscle or perivesical fat Tumor invades deep muscle (outer-half) Tumor invades perivesical fat Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall
current
study
included
in the RTOG/
Jefferson studies (17, 18). Pre-operative radiation therapy was given to the whole pelvis with a parallel opposed I5 X 15 cm field. This was administered either on the day before, or immediately prior to surgery which consisted of simple cystectomy in 39 patients and a radical cystectomy in the remaining 39 patients. Thirty-two patients underwent a pelvic lymphadenectomy. Postoperatively, the surgical specimen was examined and patients were staged histopathologically according to the TNM system. (Table 1) Patients with a Stage P2 (Grade Ill and IV), P3A, P3B, P4A tumors or positive lymph nodes were selected for postoperative treatment. Those who were noted to have more extensive disease, such as intraabdominal involvement, were referred to palliative treatment and are not included in this protocol. (Fig. 1) Forty patients were eligible for postoperative radiation therapy. Table 2 illustrates the characteristics of the patients who received postoperative radiation therapy and those who did not. The two groups were similar with respect to median age, sex, and extent of surgery. Patients who received postoperative radiation therapy were treated with a four field box technique to the whole pelvis using supervoltage radiation therapy (Fig. 2). Field size was most
Treatment Study
period
Protocol 1978-1987
500 cGy preoperative
irradiation
Cystectomy Pathologidal / PO. Pis. Pa. PI. P2 (Gr l&Z) 1 No further treatment (38 patients)
staging
P.7 (Gr 3&4) P3A. P3B. P4A. N+ I Postoperative irradlation 4500 cGy/ 180 cGy per TX (40 patients)
Fig. 1. Treatment
protocol.
24. Number
3, 1992
Table 2. Patient population
TX TO Tis Ta Tl T2 T3 T3a T3b T4
were previously
Volume
Median age Sex (no. of patients) Male Female Median follow-up Surgery (no. of patients) Total cystectomy Radical cystectomy Lymph node dissection (no. of patients) Yes No
No postoperative radiation
Postoperative radiation
65
65
28 10 75 months
29 10 40 months
20 18
19 21
12 16
20 20
often 15 X 15 cm. These patients were treated at 180 cGy per day, 5 fractions per week, to a total dose of 4500 cGy. Length of follow-up was calculated from the date of diagnosis. The median follow-up was 52 months and all cases have been followed for at least 36 months. The median follow-up in the postoperative radiation therapy patients was 40 months, while the median follow-up in patients who received no postoperative radiation therapy was 75 months. Complications were divided into genitourinary or gastrointestinal. Since the aim of this study was to present long-term morbidity, complications in the immediate postoperative period were not included. Actuarial survival rates were determined by the method of Kaplan and Meier ( 11). Patients dying of intercurrent disease were censored. The Logrank test was used for comparisons between subsets of patients. RESULTS
Survival The j-year Kaplan-Meier actuarial survival by stage is presented in Table 3. The j-year survival for the entire patient population was 67%. Patients with Stages Pl and P2 (Grade 1 and 11)had a j-year survival of 84%. Survival for P2 (Grade Ill and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Six patients were identified with N+ disease and had a j-year survival of 33%. The difference in survival between the low risk Pl/P2 (Grade 1 and 11)patients versus the high risk patients who required postoperative radiation therapy was statistically significant (t, < 0.001). However, there was no statistical significance when comparing P3A versus P3B patients.
Unresectable
Local recurrence 1 Other treatment
Three patients or 7.5% of the 40 who underwent adjuvant treatment, were classified as local treatment failures. Two patients had recurrence of the tumor in the urethra and one in the pelvis. Four patients or 10.5% of those with early stage disease who did not require post-
465
Bladder cancer and adjuvant radiation therapy 0 S. A. REISINGER et al.
Table 3. Actuarial 5-year survival by stage Stage
No. patients
Survival %
P 1, P2 (Grades 1 and 2) P2 (Grades 3 and 4) P3A P3B P4/N+ All stages
38 11 12 10 I 78
84 57 56 39 50 67
receiving no postoperative radiation therapy developed a bowel obstruction, as compared to 37% of patients who received postoperative radiation therapy (Table 5). This difference in bowel complication rates between the two groups was statistically significant (chi-square p < 0.05). Ten of the 15 intestinal obstructions occurred within the first year after treatment.
DISCUSSION
(a)
(b) Fig. 2. Four field technique. (a) Anterior and posterior field. (b) Lateral fields.
operative radiation therapy had local recurrence of the tumor. One of these treatment failures involved the ileal conduit, one in the cervix and parametrium, and two others in the pelvis. Complications We compared complications between those patients who received postoperative radiation therapy and those who did not. Complications were further divided between genitourinary complications and gastrointestinal complications. The incidence of genitourinary complications was similar in both groups: 13% in the patients without postoperative radiation therapy and 10% in the patients who received postoperative radiation therapy (Table 4). Postoperative radiation therapy was, however, associated with significant bowel toxicity. Eight percent of the patients
Surgical resection remains the current recommended treatment for invasive bladder carcinoma, with most patients requiring a cystectomy. However, muscle infiltration is associated with a 40% to 60% incidence of distant metastases. This high incidence of distant metastases has caused investigators to search for other adjuvant treatment modalities to be used after cystectomy. That search has so far failed to yield conclusive results and remains a subject of controversy, with some investigators recommending radiation therapy and others recommending chemotherapy. The purpose of this review was to give an updated report of our experience with preoperative and postoperative adjuvant radiation therapy, and compare survival and complication rates associated with adjuvant therapy and treatment by cystectomy alone. Unfortunately, reports on patients treated by cystectomy alone are not abundant in the literature, due to the popularity of preoperative radiotherapy since the early 1960’s. Table 6 compares our survival rates with those of various cystoprostatectomy series. All series presented in Table 6 represent pathological staging. It is quite evident that survival increased markedly in the last decade. Most urologic surgeons argue that improved surgical technique over the past few decades has resulted in a decrease in local recurrence (27, 32). In addition, Skinner argues that meticulous pelvic lymph node dissection has also contributed to improved survival (25).
Table 4. Long-term genitourinary
Stoma1 stenosis Pyelonephritis requiring nephrectomy Ureteral stricture Total
complications
No post-op RT (no. of patients)
Post-Op RT (no. of patients)
3
2
2 0 5/38 (13%)
0 2 4/40 ( 10%)
466
1. J. Radiation Oncology 0 Biology 0 Physics Table 5. Incidence
of intestinal
No post-op RT (no. of patients) Requiring surgery Not requiring surgery Deaths
obstruction Post-Op RT (no. of patients)
2
9 3
1 0 3/38 (8%)
15,46:37%)
Further scrutiny of Table 6, however, reveals the scarcity of modern cystoprostatectomy series where no adjuvant therapy was used. Brendler et al. (2), Montie et al. (19), and Skinner et al. (27) combine survival results for Stages T3A and T3B. This practice may not be legitimate because Table 6 also indicates that survival results in these two groups are very different. Exclusion of these studies leaves merely two studies for comparison. For T3B disease, our results are no different from Mathur’s ( 14) results, but are considerably better than Pagano’s (20) results. Therefore, due to the scarcity of studies in which patients were treated with cystectomy alone, it is difficult to make any statement about the value of adjuvant radiation therapy. Historically, positive pelvic nodes in patients with bladder carcinoma have connoted a dismal prognosis. Smith and Whitmore (28) reported a 7% (9/134) 5-year survival rate in patients presenting with positive pelvic lymph nodes. Laplante and Brice (I 2) reported a j-year survival of 13%, while Dretler et al. (6) reported a 17% 5year survival. Pagan0 et al. (20) later confirmed this dismal figure, finding that no patients other than those with PT2 disease survived for five years. The report of Skinner et al. (25) was more optimistic, with a 5-year survival of 36% for patients with nodal disease. Skinner did, however, emphasize the need for a thorough pelvic lymph node dissection and some of his patients did receive pre-operative radiation therapy. We were able to identify six pa-
Table 6. 5-year survival rates in radical cystoprostatectomy series 5-year survival rates (%) Series Historical Riches (1960) (22) Bowles (1963) ( 1) Jewett (1964) (9) Whitmore (1977) (31) Pearse (1977) (2 1) Contemporary Mathur (1981) (14) Montie ( 1984) ( 19) Skinner and Lieskowsky Pagan0 ( 1988) (20) Brendler ( 1990) (2) Current series
P3A
P3B
9 50 16 26 42
4 20 12 16 13
Volume 24. Number 3, 1992
tients with positive lymph nodes and found a 33% 5-year survival rate with adjuvant radiation therapy in this group. It was extremely disturbing that 37% of our patients who received postoperative radiation therapy developed a small bowel obstruction. Our series is unique in that we were able to compare the complication rates in patients who did and did not receive postoperative pelvic radiation therapy. It is readily apparent in Table 4 that the genitourinary complication rates of the two groups are the same. The incidence of gastrointestinal complications is considerably higher for the group of patients who received postoperative radiation therapy, however. Table 7 outlines the reported rate of intestinal obstruction from other cystoprostatectomy series. This is quite similar to that in patients who only received 500 cGy pre-operatively. It is quite evident that postoperative radiation therapy markedly increases the bowel complication rate. Of interest, in patients receiving high dose preoperative radiation therapy (4800 cGy to 5000 cGy), the bowel obstruction rate reported in the literature ranges from 2.5% to 8% (5, 16, 24). Hyperfractionation may be a way to reduce the incidence of bowel obstruction in those patients requiring postoperative radiation therapy. It is known that the late toxicity of radiation may be decreased by reducing the dose per fraction. Reviews of the literature reveal scant information about post-cystectomy hyperfractionated pelvic radiation. Zaghloul et al. (33) administered postoperative pelvic radiation therapy to post-cystectomy patients. One group received conventional fractionation to a dose of 5000 cGy in 5 weeks, while a second group was given three daily fractions of 125 cGy with a 3-hr interval between each fraction to a dose of 3750 cGy. It was found that the hyperfractionated regimen led to considerably fewer late complications. The authors did not offer specific details on the type of complications or the complication rate. Other techniques for reducing small bowel injury include decreasing the field size, omental slings, and retroperitonealizing the pelvis (7). Absorbable mesh can be used to exclude the small bowel from the pelvis (4, 23). Sugarbaker (30) has described the use of a silicon implant as another alternative for removing the small bowel from the pelvis. Table 7. Intestinal
(1984) (27)
57 40 48 (P3A-P3B) 44 (P3A-P3B) 66 10 52 (P3A-P3B) 56 39
complications-review
of the literature
Cystectomy alone (no. of patients) Johnson* (1977) (10) Mathur (1981) (14) Current series (199 1) (no post-op RT) Current series ( 199 1) (postoperative RT) * Some patients therapy.
received
Percent
13/158 4158
8.2 7.0
3138
8.0
15140 high dose preoperative
37 radiation
Bladder cancer and adjuvant radiation therapy 0 S. A. REISINGER et a/.
Some investigators have suggested the use of chemotherapy as an adjuvant modality after cystectomy. Unfortunately, current literature contains no 5-year survival data for this treatment. There are, however, published trials of adjuvant chemotherapy with limited numbers of patients and short follow-up. Menin et al. (15) reported on the use of adjuvant doxorubicin and cyclophosphamide and Socquet et al. (29) reported on the use of adjuvant high dose methotrexate with folinic acid rescue. Both of these studies showed that adjuvant chemotherapy leads to some clinical benefit, while Hall et al. (8) reported no benefit due to adjuvant chemotherapy with adriamycin. bleomycin, 5-FU, and methotrexate. More recently, however, adjuvant chemotherapy trials have been using cisplatinum. Logothesis et al. (13) reported in 1988 that high-risk patients benefited from a regimen using cyclophosphamide, doxorubicin, and cisplatinum. These high risk patients had vascular invasion in their primary tumor, nodal metastases, extra-vesicular tumor involvement, or direct invasion into pelvic viscera. They survived longer than similar high-risk patients who did not receive chemotherapy because of overall poor medical condition, refusal of treatment, or physician decision to withhold chemotherapy. Logothesis et al. (13) found that adjuvant chemotherapy led to improved survival, but his results must be viewed with caution because of the small number of patients, lack of randomization. and extremely high chance for introducing bias into the study. It was also unclear why certain patients had treatment withheld by their physicians. Perhaps the medically unfit patients were a poor prognostic subgroup whose exclusion introduced additional bias into the study. A second study of cisplatinum-based chemotherapy was reported by Skinner et al. (26) in 1991. In this trial, patients with pathological stage P3, P4, or N+ and MO carcinoma of the bladder were assigned at random to either observation or chemotherapy consisting of four cycles of cisplatinum, doxorubicin, and cyclophosphamide. The authors claim a significant increase in the time to progression and survival in the adjuvant chemotherapy group.
467
But once again there is the potential for bias due to patient exclusion. Eleven of the 44 patients randomized to receive chemotherapy refused the treatment. The vast majority of the patients who received chemotherapy did not actually undergo four cycles as mandated by the protocol. Treatment efficacy therefore cannot be fully evaluated. Other treatment options for bladder cancer include bladder preservation with neoadjuvant chemotherapy and radiation therapy, radiation therapy alone to the bladder, and preoperative radiation therapy or preoperative chemotherapy followed by a cystectomy. Using these treatment modalities requires a clinical staging system as opposed to our surgically staged patients. Treatment results are impossible to compare due to the inaccuracy of the clinical staging system. The cystectomy alone series presented in this discussion report results on surgically staged patients which allows a valid comparison with the surgically staged patients presented in this study. In conclusion, the survival data from studies of different adjuvant therapies are difficult to evaluate. It is difficult to compare our results with historical surgical series because surgical technique has improved over the past few decades. The literature contains few modern reports on cystoprostatectomy series where the patients did not receive preoperative radiation therapy. Comparison of our results with these series suggest there may be an advantage to postoperative radiation, especially in patients with Stage T3B and P4A/N+ bladder cancer. However, it is clear that bowel toxicity associated with postoperative radiation is unacceptably high. Hyperfractionation, decreasing the field size. omental slings, absorbable mesh, and silicon implants reperitonealizing the pelvis may reduce the complication rate. Adjuvant chemotherapy could also be an alternative for these patients, although there is no solid evidence that any of the currently available drugs markedly improve survival over that achieved with contemporary surgery. In any case. methods of delivering postoperative pelvic radiation therapy need to be improved upon due to bowel toxicity.
REFERENCES Cordonnier, J. J. Total cystectomy for carcinema of the bladder. J. Ural. 90:731-735;1963.
1. Bowles, W. T.;
7. Gunderson,
2. Brendler, C. B.; Steinberg, G. D.; Marshal, F. F.; Mostwin,
3. 4.
5. 6.
J. L.; Walsh, P. C. Local recurrence and survival following nerve-sparing radical cystoprostatectomy. J. Urol. 144: I I371140;1990. Boring, C. C.; Squires, T. S.; Tong, T. Cancer statistics I99 I. Ca41(1):28-29;1991. Devereus. D. F.; Chandler, J. J.; Eisenstat, T. Efficacy of an absorbable mesh in keeping the small bowel out of the human pelvis following surgery. Dis. Col. Rectum 3 I : 1721;1988. Deweerd, J. H.; Colby, M. Y. Bladder carcinoma treated by irradiation and surgery: Internal report. J. Ural. 109: 409-413;1973. Dretler, S. P.; Ragsdale, B. D.; Leadbetter, W. F. The value of pelvic lymphadenectomy in the surgical treatment of bladder cancer. J. Urol. 109:414-2 16;1973.
8.
9.
IO.
1I.
12.
L. L.; Russel, A. H.: Llewellyn, H. J.; Doppke, K. P.; Tepper, J. E. Treatment planning for colorectal cancer: Radiation and surgical techniques and value of small bowel films. Int. J. Radiat. Oncol. Biol. Phys. 11:1379-l 393; 1985. Hail, R. R.; Evans, R. G. B.; Pritchett. C. J.; Price, D. A. Combination chemotherapy for advanced bladder cancer. Br. J. Urol. 54:16-19:1982. Jewett, H. J.; King, L. R.; Shelley, W. M. A study of 365 cases of infiltrating bladder cancer: Relation of certain pathological characteristics to prognosis after extirpation. J. Urol. 92:668-678;1964. Johnson, D. E.; Lamy, S. M. Complications of a single stage radical cystectomy and ileal conduit diversion. Review of 214 cases. J. Ural. 117:171-173;1977. Kaplan, E. W.; Meier, P. Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457481;1958. Laplante, M.; Brice, M. The upper limits of hopeful appli-
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14. 15.
16.
17.
18.
19.
20.
21.
22. 23.
I. J. Radiation Oncology 0 Biology 0 Physics
cation of radical cystectorny for vesical carcinoma: Does nodal metastasis always indicate incurability? J. Ural. 109: 261-264;1973. Logothesis, C. J.; Johnson, D. E.; Chong, C.; Dexeus, F. H.; Sella, A.; Ogden, S.; Smith, T.; Swanson, D. A.; Babaian, R. J.; Wishnow, K. I.; VonEschenbach, A. Adjuvant cyclophosphamide, doxorubicin, and cisplatin chemotherapy for bladder cancer: An update. J. Clin. Oncol. 6:15901596;1988. Mathur, V. K.; Krahn, H. P.; Ramsey, E. W. Total cystectomy for bladder cancer. J. Urol. 125:784-786; 198 1. Merrin, C.; Beckley, S. Adjuvant chemotherapy for bladder cancer with doxorubicin hydrochloride and cyclophosphamide: Pre-liminary report. J. Ural. 119:62-63;1978. Miller, L. S. Bladder cancer. Superiority of preoperative irradiation and cystectomy in clinical stages B2 and C. Cancer 39:973-980;1977. Mohiuddin, M.; Kramer, S.; Newall, J.; Parson, J.; Wiley, A. Combined pre- and postoperative adjuvant radiotherapy for bladder cancer: Results of RTOG/Jefferson study. Cancer 47:2840-2843; 198 1. Mohiuddin, M.; Kramer, S.; Wiley, A.; Strong, G.; Newall, J.; Parsons, J.; Mulholland, S. G. Combined preoperative and postoperative radiation for bladder cancer. Results of RTOG/Jefferson study. Cancer 55:963-966;1985. Montie, J. E.; Straffon, R. A.; Stewart, B. H. Radical cystectomy without radiation therapy for carcinoma of the bladder. J. Ural. 13 1:477-482; 1984. Pagano, F.; Guazzieri, S.; Artibani, W.; Prayer-Galetti, T.; Milani, C.; Bassi, P.; Garbeglio, A. Prognosis of bladder cancer. III. The value of radical cystectomy in the management of invasive bladder cancer. Eur. Ural. 15: 166170;1988. Pearse, H. D.; Pappas, J. T.; Hodges, C. V. Radical cystectomy for bladder cancer: 10 year survival. J. Ural. 109:623624;1973. Riches, E. Choice of treatment in carcinoma of the bladder. J. Urol. 84:474-480; 1960. Rodier, J. F.; Janser, J. C.; Rodier, D.; Dauplat, J.; Kauff-
Volume 24. Number 3, 1992
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
man, P.; LeBouedec, G.; Giraud, B.; Lorimier, G. Prevention of radiation enteritis by an absorbable polyglycolic acid mesh sling. Cancer 68:2545-2549; 199 1. Scanlon, P. W.; Scott, M.; Segura, J. W. A comparison of short-course, low-dose and long-course high-dose preoperative radiation for carcinoma of the bladder. Cancer 52: 1153-l 159;1983. Skinner, D. G. Management of invasive bladder cancer. A meticulous pelvic lymph node dissection can make a difference. J. Ural. 128:34-36; 1982. Skinner, D. G.; Daniels, J. R.; Russell, C. A.; Lieskovsky, G.; Boyd, S. D.; Nichols, P.; Kern, W.; Sakamoto, J.; Krailo, M.; Groshen, S. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J. Ural. 145:459-467;1991. Skinner, D. G.; Lieskovsky, G. Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J. Ural. 131:1069-1072;1984. Smith, J. A.; Whitmore, W. F., Jr. Regional lymph node metastasis from bladder cancer. J. Ural. 126:59 1; 1988. Socquet, Y. Surgery and adjuvant chemotherapy with highdose methotrexate and fohnic acid rescue for infiltrating tumors of the bladder. Cancer Treat. Rep. 65: 187- 189; 198 1. Sugarbaker, P. H. Intrapelvic prosthesis to prevent injury of the small intestine with high dose pelvic radiation. Surg. Gynecol. Obstet. 157:269-27 1;1983. Whitmore, W. F., Jr.; Batata, M. A.; Ghoneim, M. A.; Grabstald, H.; Vhal, A. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Ural. I18:184-187;1977. Wishnow, K. I.; Dmochoiwski, R. Pelvic recurrence after radical cystectomy without preoperative radiation. J. Ural. 140:42-43; 1988. Zaghloul, M. S.; Awwad, H. K.; Akoush, H.; Omar, S.; Sohman, 0.; El Attar, I. Postoperative radiotherapy of carcinoma in bilharcial bladder. Improved disease-free survival through improving local control. Int. J. Radiat. Oncol. Biol. Phys. 19(Suppl 1):200; 1990.
24. pp.
$5.00 + .OO 0360.30 I6192 Copyright & 1992 Pergamon Press Ltd
463-468
??Clinical Original Contribution
COMBINED
PRE- AND POSTOPERATIVE ADJUVANT RADIATION THERAPY FOR BLADDER CANCER-A TEN YEAR EXPERIENCE SUSAN
A. REISINGER,
M.D.,* MOHAMMED
AND S. GRANT Departments
of *Radiation
MULHOLLAND,
MOHIUDDIN,
M.D.*
M.D.+
Oncology and +Urology. Thomas Jefferson University Hospital, Philadelphia, PA
From 1978 through 1987,78 patients with carcinoma of the bladder were treated with combined pre- and postoperative adjuvant radiation therapy. All were given a single dose of pre-operative radiation therapy, 500 cGy, either on the day of or the day before cystectomy. Histological staging on the cystectomy specimens according to the TNM classification system was performed. Forty patients with Stage P2 (high grade III and IV), P3A, P3B, P4A, or N+ underwent planned high dose postoperative radiation therapy (4000-4500 cGy) in 5 weeks. The whole pelvis was treated with conventional fractionation of 180 cGy 5 days per week. Median follow-up was 52 months, with 36 months minimum follow-up. There was a 67% overall 5-year survival, and those with PI and P2 (Grade I and II) had an 84% 5-year survival. Survival for patients with P2 tumor (Grade III and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Bowel obstructions developed in 8% of patients who received no postoperative radiation therapy and 37% in those who did. Genitourinary complication rates were similar in both groups, 13% in the group that received no postoperative radiation therapy and 10% in the group that did. Although the planned approach of combined pre- and postoperative radiation therapy for unfavorable stages of bladder cancer is associated with a better than 50% 5-year survival rate (except in Stage P3B cancer), the bowel toxicity was unacceptably high. Bladder carcinoma, Adjuvant radiation therapy, Bowel toxicity.
viable tumor cells at the time of surgery. However, the tumor architecture is not disturbed so that accurate histopathologic staging can be obtained from the cystectomy specimens. After assessment of histopathologic prognostic indicators in the cystectomy specimens, selected patients at high risk for local pelvic failure or distant dissemination of disease are treated with full dose postoperative radiation therapy. These patients include individuals with P2 (Grade III and IV), P3A, P3B, P4A, and N+ disease. In this report, we present an update of the previously reported experience with combined low dose pre-operative radiation therapy and high dose postoperative radiation therapy, together with survival rates and morbidity data.
INTRODUCTION Bladder cancer is the fourth most common solid tumor in men and seventh among women (3). In 199 1, it is estimated there will be 50,200 new cases of bladder cancer.
with approximately 9,500 deaths due to this disease (3). At initial clinical presentation, approximately 70% of bladder tumors are superficial, 25% have infiltrated muscle, and 5% are metastatic. Radical cystoprostatectomy with pelvic lymphadenectomy has become the standard of care for patients with carcinoma infiltrating the muscle. Extensive surgery for patients with carcinoma infiltrating the muscle has not prevented approximately 50% of them from dying of metastatic disease. This has led to the use of adjuvant treatment in these patients. An adjuvant protocol, using low dose pre-operative radiation therapy with selective postoperative radiation therapy, was developed at Thomas Jefferson Hospital in 1978. The results of this protocol have been previously reported in the literature ( 17, 18). The rationale for using low dose preoperative radiation therapy is to inhibit dissemination of
METHODS
AND
MATERIALS
From 1978- 1987,78 patients underwent pre-operative radiation therapy followed by cystectomy. Treatment was delivered in the manner described in the two prior RTOG/ Jefferson studies ( 17, 18). Forty patients included in this
Presented at the 33rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, DC, 48 November 199 1. Reprint requests to: Susan A. Reisinger, M.D., Thomas Jef-
ferson University Hospital, phia, PA 19107. Accepted for publication
463
I 1th and Sansom Streets, Philadel20 April 1992.
464
1. J. Radiation
Oncology 0 Biology 0 Physics
Table 1. Staging system: TNM Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: “flat tumor” Noninvasive papillary carcinoma Tumor invades subepithelial connective tissue Tumor invades superficial muscle (inner-half) Tumor invades deep muscle or perivesical fat Tumor invades deep muscle (outer-half) Tumor invades perivesical fat Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall
current
study
included
in the RTOG/
Jefferson studies (17, 18). Pre-operative radiation therapy was given to the whole pelvis with a parallel opposed I5 X 15 cm field. This was administered either on the day before, or immediately prior to surgery which consisted of simple cystectomy in 39 patients and a radical cystectomy in the remaining 39 patients. Thirty-two patients underwent a pelvic lymphadenectomy. Postoperatively, the surgical specimen was examined and patients were staged histopathologically according to the TNM system. (Table 1) Patients with a Stage P2 (Grade Ill and IV), P3A, P3B, P4A tumors or positive lymph nodes were selected for postoperative treatment. Those who were noted to have more extensive disease, such as intraabdominal involvement, were referred to palliative treatment and are not included in this protocol. (Fig. 1) Forty patients were eligible for postoperative radiation therapy. Table 2 illustrates the characteristics of the patients who received postoperative radiation therapy and those who did not. The two groups were similar with respect to median age, sex, and extent of surgery. Patients who received postoperative radiation therapy were treated with a four field box technique to the whole pelvis using supervoltage radiation therapy (Fig. 2). Field size was most
Treatment Study
period
Protocol 1978-1987
500 cGy preoperative
irradiation
Cystectomy Pathologidal / PO. Pis. Pa. PI. P2 (Gr l&Z) 1 No further treatment (38 patients)
staging
P.7 (Gr 3&4) P3A. P3B. P4A. N+ I Postoperative irradlation 4500 cGy/ 180 cGy per TX (40 patients)
Fig. 1. Treatment
protocol.
24. Number
3, 1992
Table 2. Patient population
TX TO Tis Ta Tl T2 T3 T3a T3b T4
were previously
Volume
Median age Sex (no. of patients) Male Female Median follow-up Surgery (no. of patients) Total cystectomy Radical cystectomy Lymph node dissection (no. of patients) Yes No
No postoperative radiation
Postoperative radiation
65
65
28 10 75 months
29 10 40 months
20 18
19 21
12 16
20 20
often 15 X 15 cm. These patients were treated at 180 cGy per day, 5 fractions per week, to a total dose of 4500 cGy. Length of follow-up was calculated from the date of diagnosis. The median follow-up was 52 months and all cases have been followed for at least 36 months. The median follow-up in the postoperative radiation therapy patients was 40 months, while the median follow-up in patients who received no postoperative radiation therapy was 75 months. Complications were divided into genitourinary or gastrointestinal. Since the aim of this study was to present long-term morbidity, complications in the immediate postoperative period were not included. Actuarial survival rates were determined by the method of Kaplan and Meier ( 11). Patients dying of intercurrent disease were censored. The Logrank test was used for comparisons between subsets of patients. RESULTS
Survival The j-year Kaplan-Meier actuarial survival by stage is presented in Table 3. The j-year survival for the entire patient population was 67%. Patients with Stages Pl and P2 (Grade 1 and 11)had a j-year survival of 84%. Survival for P2 (Grade Ill and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Six patients were identified with N+ disease and had a j-year survival of 33%. The difference in survival between the low risk Pl/P2 (Grade 1 and 11)patients versus the high risk patients who required postoperative radiation therapy was statistically significant (t, < 0.001). However, there was no statistical significance when comparing P3A versus P3B patients.
Unresectable
Local recurrence 1 Other treatment
Three patients or 7.5% of the 40 who underwent adjuvant treatment, were classified as local treatment failures. Two patients had recurrence of the tumor in the urethra and one in the pelvis. Four patients or 10.5% of those with early stage disease who did not require post-
465
Bladder cancer and adjuvant radiation therapy 0 S. A. REISINGER et al.
Table 3. Actuarial 5-year survival by stage Stage
No. patients
Survival %
P 1, P2 (Grades 1 and 2) P2 (Grades 3 and 4) P3A P3B P4/N+ All stages
38 11 12 10 I 78
84 57 56 39 50 67
receiving no postoperative radiation therapy developed a bowel obstruction, as compared to 37% of patients who received postoperative radiation therapy (Table 5). This difference in bowel complication rates between the two groups was statistically significant (chi-square p < 0.05). Ten of the 15 intestinal obstructions occurred within the first year after treatment.
DISCUSSION
(a)
(b) Fig. 2. Four field technique. (a) Anterior and posterior field. (b) Lateral fields.
operative radiation therapy had local recurrence of the tumor. One of these treatment failures involved the ileal conduit, one in the cervix and parametrium, and two others in the pelvis. Complications We compared complications between those patients who received postoperative radiation therapy and those who did not. Complications were further divided between genitourinary complications and gastrointestinal complications. The incidence of genitourinary complications was similar in both groups: 13% in the patients without postoperative radiation therapy and 10% in the patients who received postoperative radiation therapy (Table 4). Postoperative radiation therapy was, however, associated with significant bowel toxicity. Eight percent of the patients
Surgical resection remains the current recommended treatment for invasive bladder carcinoma, with most patients requiring a cystectomy. However, muscle infiltration is associated with a 40% to 60% incidence of distant metastases. This high incidence of distant metastases has caused investigators to search for other adjuvant treatment modalities to be used after cystectomy. That search has so far failed to yield conclusive results and remains a subject of controversy, with some investigators recommending radiation therapy and others recommending chemotherapy. The purpose of this review was to give an updated report of our experience with preoperative and postoperative adjuvant radiation therapy, and compare survival and complication rates associated with adjuvant therapy and treatment by cystectomy alone. Unfortunately, reports on patients treated by cystectomy alone are not abundant in the literature, due to the popularity of preoperative radiotherapy since the early 1960’s. Table 6 compares our survival rates with those of various cystoprostatectomy series. All series presented in Table 6 represent pathological staging. It is quite evident that survival increased markedly in the last decade. Most urologic surgeons argue that improved surgical technique over the past few decades has resulted in a decrease in local recurrence (27, 32). In addition, Skinner argues that meticulous pelvic lymph node dissection has also contributed to improved survival (25).
Table 4. Long-term genitourinary
Stoma1 stenosis Pyelonephritis requiring nephrectomy Ureteral stricture Total
complications
No post-op RT (no. of patients)
Post-Op RT (no. of patients)
3
2
2 0 5/38 (13%)
0 2 4/40 ( 10%)
466
1. J. Radiation Oncology 0 Biology 0 Physics Table 5. Incidence
of intestinal
No post-op RT (no. of patients) Requiring surgery Not requiring surgery Deaths
obstruction Post-Op RT (no. of patients)
2
9 3
1 0 3/38 (8%)
15,46:37%)
Further scrutiny of Table 6, however, reveals the scarcity of modern cystoprostatectomy series where no adjuvant therapy was used. Brendler et al. (2), Montie et al. (19), and Skinner et al. (27) combine survival results for Stages T3A and T3B. This practice may not be legitimate because Table 6 also indicates that survival results in these two groups are very different. Exclusion of these studies leaves merely two studies for comparison. For T3B disease, our results are no different from Mathur’s ( 14) results, but are considerably better than Pagano’s (20) results. Therefore, due to the scarcity of studies in which patients were treated with cystectomy alone, it is difficult to make any statement about the value of adjuvant radiation therapy. Historically, positive pelvic nodes in patients with bladder carcinoma have connoted a dismal prognosis. Smith and Whitmore (28) reported a 7% (9/134) 5-year survival rate in patients presenting with positive pelvic lymph nodes. Laplante and Brice (I 2) reported a j-year survival of 13%, while Dretler et al. (6) reported a 17% 5year survival. Pagan0 et al. (20) later confirmed this dismal figure, finding that no patients other than those with PT2 disease survived for five years. The report of Skinner et al. (25) was more optimistic, with a 5-year survival of 36% for patients with nodal disease. Skinner did, however, emphasize the need for a thorough pelvic lymph node dissection and some of his patients did receive pre-operative radiation therapy. We were able to identify six pa-
Table 6. 5-year survival rates in radical cystoprostatectomy series 5-year survival rates (%) Series Historical Riches (1960) (22) Bowles (1963) ( 1) Jewett (1964) (9) Whitmore (1977) (31) Pearse (1977) (2 1) Contemporary Mathur (1981) (14) Montie ( 1984) ( 19) Skinner and Lieskowsky Pagan0 ( 1988) (20) Brendler ( 1990) (2) Current series
P3A
P3B
9 50 16 26 42
4 20 12 16 13
Volume 24. Number 3, 1992
tients with positive lymph nodes and found a 33% 5-year survival rate with adjuvant radiation therapy in this group. It was extremely disturbing that 37% of our patients who received postoperative radiation therapy developed a small bowel obstruction. Our series is unique in that we were able to compare the complication rates in patients who did and did not receive postoperative pelvic radiation therapy. It is readily apparent in Table 4 that the genitourinary complication rates of the two groups are the same. The incidence of gastrointestinal complications is considerably higher for the group of patients who received postoperative radiation therapy, however. Table 7 outlines the reported rate of intestinal obstruction from other cystoprostatectomy series. This is quite similar to that in patients who only received 500 cGy pre-operatively. It is quite evident that postoperative radiation therapy markedly increases the bowel complication rate. Of interest, in patients receiving high dose preoperative radiation therapy (4800 cGy to 5000 cGy), the bowel obstruction rate reported in the literature ranges from 2.5% to 8% (5, 16, 24). Hyperfractionation may be a way to reduce the incidence of bowel obstruction in those patients requiring postoperative radiation therapy. It is known that the late toxicity of radiation may be decreased by reducing the dose per fraction. Reviews of the literature reveal scant information about post-cystectomy hyperfractionated pelvic radiation. Zaghloul et al. (33) administered postoperative pelvic radiation therapy to post-cystectomy patients. One group received conventional fractionation to a dose of 5000 cGy in 5 weeks, while a second group was given three daily fractions of 125 cGy with a 3-hr interval between each fraction to a dose of 3750 cGy. It was found that the hyperfractionated regimen led to considerably fewer late complications. The authors did not offer specific details on the type of complications or the complication rate. Other techniques for reducing small bowel injury include decreasing the field size, omental slings, and retroperitonealizing the pelvis (7). Absorbable mesh can be used to exclude the small bowel from the pelvis (4, 23). Sugarbaker (30) has described the use of a silicon implant as another alternative for removing the small bowel from the pelvis. Table 7. Intestinal
(1984) (27)
57 40 48 (P3A-P3B) 44 (P3A-P3B) 66 10 52 (P3A-P3B) 56 39
complications-review
of the literature
Cystectomy alone (no. of patients) Johnson* (1977) (10) Mathur (1981) (14) Current series (199 1) (no post-op RT) Current series ( 199 1) (postoperative RT) * Some patients therapy.
received
Percent
13/158 4158
8.2 7.0
3138
8.0
15140 high dose preoperative
37 radiation
Bladder cancer and adjuvant radiation therapy 0 S. A. REISINGER et a/.
Some investigators have suggested the use of chemotherapy as an adjuvant modality after cystectomy. Unfortunately, current literature contains no 5-year survival data for this treatment. There are, however, published trials of adjuvant chemotherapy with limited numbers of patients and short follow-up. Menin et al. (15) reported on the use of adjuvant doxorubicin and cyclophosphamide and Socquet et al. (29) reported on the use of adjuvant high dose methotrexate with folinic acid rescue. Both of these studies showed that adjuvant chemotherapy leads to some clinical benefit, while Hall et al. (8) reported no benefit due to adjuvant chemotherapy with adriamycin. bleomycin, 5-FU, and methotrexate. More recently, however, adjuvant chemotherapy trials have been using cisplatinum. Logothesis et al. (13) reported in 1988 that high-risk patients benefited from a regimen using cyclophosphamide, doxorubicin, and cisplatinum. These high risk patients had vascular invasion in their primary tumor, nodal metastases, extra-vesicular tumor involvement, or direct invasion into pelvic viscera. They survived longer than similar high-risk patients who did not receive chemotherapy because of overall poor medical condition, refusal of treatment, or physician decision to withhold chemotherapy. Logothesis et al. (13) found that adjuvant chemotherapy led to improved survival, but his results must be viewed with caution because of the small number of patients, lack of randomization. and extremely high chance for introducing bias into the study. It was also unclear why certain patients had treatment withheld by their physicians. Perhaps the medically unfit patients were a poor prognostic subgroup whose exclusion introduced additional bias into the study. A second study of cisplatinum-based chemotherapy was reported by Skinner et al. (26) in 1991. In this trial, patients with pathological stage P3, P4, or N+ and MO carcinoma of the bladder were assigned at random to either observation or chemotherapy consisting of four cycles of cisplatinum, doxorubicin, and cyclophosphamide. The authors claim a significant increase in the time to progression and survival in the adjuvant chemotherapy group.
467
But once again there is the potential for bias due to patient exclusion. Eleven of the 44 patients randomized to receive chemotherapy refused the treatment. The vast majority of the patients who received chemotherapy did not actually undergo four cycles as mandated by the protocol. Treatment efficacy therefore cannot be fully evaluated. Other treatment options for bladder cancer include bladder preservation with neoadjuvant chemotherapy and radiation therapy, radiation therapy alone to the bladder, and preoperative radiation therapy or preoperative chemotherapy followed by a cystectomy. Using these treatment modalities requires a clinical staging system as opposed to our surgically staged patients. Treatment results are impossible to compare due to the inaccuracy of the clinical staging system. The cystectomy alone series presented in this discussion report results on surgically staged patients which allows a valid comparison with the surgically staged patients presented in this study. In conclusion, the survival data from studies of different adjuvant therapies are difficult to evaluate. It is difficult to compare our results with historical surgical series because surgical technique has improved over the past few decades. The literature contains few modern reports on cystoprostatectomy series where the patients did not receive preoperative radiation therapy. Comparison of our results with these series suggest there may be an advantage to postoperative radiation, especially in patients with Stage T3B and P4A/N+ bladder cancer. However, it is clear that bowel toxicity associated with postoperative radiation is unacceptably high. Hyperfractionation, decreasing the field size. omental slings, absorbable mesh, and silicon implants reperitonealizing the pelvis may reduce the complication rate. Adjuvant chemotherapy could also be an alternative for these patients, although there is no solid evidence that any of the currently available drugs markedly improve survival over that achieved with contemporary surgery. In any case. methods of delivering postoperative pelvic radiation therapy need to be improved upon due to bowel toxicity.
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