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Preoperative use of 5-fluorouracil suppository for carcinoma of the rectum
Preoperative Use of 5Fluorouracil Suppository for Carcinoma of the Rectum
Toshio Takahashi, MD, Akita, Japan Kenichi Kohno, MD, Akita, Japan Toshiharu Yamaguchi, MD, Akita, Japan Tomlo Narisawa, MD, Akita, Japan
Local recurrence and metastasis are the major problems after surgery for carcinoma of the rectum [I]. Prompted by reports that use of preoperative irradiation and 5fluorouracil reduced local recurrence and metastasis of carcinoma of the rectum and improved 5 year survival [Z-4], we attempted to prepare a suppository of Sfluorouracil for the treatment of carcinoma of the rectum. The attempt was based on the knowledge that 5-fluorouracil has both cytocidal and radiosensitive .effects on cancer cells and that a suppository produces a higher drug concentration at the site of application than systemic administration. Furthermore, a suppository can be easily given preoperatively on an outpatient basis and might enhance the radiotherapeutic effect in combination with preoperative irradiation. We have so far treated 50 patients with the 5-fluorouracil suppository, and this experience constitutes the basis of this report. Material and Methods The suppository was made by dissolving 5-fluorouracil in a Witepsol suppository base, each suppository containing 200 mg of 5-fluorouracil [5]. Fifty patients with carcinoma of the rectum were given the suppository intrarectally once or twice a day for 5 to 30 days before operation. The suppository was inserted close to the tumor after bowel movement. The patients consisted of 26 men and 14 women with a mean age of 59.9 years (range 32 to 87). Selection of patients was not randomized; rather, the From the department of Sugary, Akita University school of Medicine, Akita, Japan. Requests for reprlnts shot&I be addressed to Toshio Takahashi, MD. Department of Surgery, Akita University School of Medicine, 1-1-l Hondo, Akita 010, Japan.
Volume 143, February 1992
5-fluorouracil suppository was given to those who had carcinoma of the rectum in advanced clinical stages. Thinly-two patients underwent Miles’ operation, 6 anterior resection and 2 pull-through operation. Ten patients with inoperable carcinoma of the rectum were colcstomized and given the 5-fluorouracil suppository as long as possible.
Results Concentration of 54luorouracil in tissues and draining blood: The concentration of 5-fluorouracil in the tumor, lymph nodes and blood withdrawn from the draining vein was measured by the method of zone inhibition technique of Clarkson et al [6]. The surgical specimens were obtained about 90 minutes after application of 400 mg of 5-fluorouracil in suppository. As shown in Table I, the mean concentration of 5-fluorouracil in tumor tissues was 18.2 pg/g (range 4.5 to 45). The mean drug level was 13.8 pg/g in normal rectal mucosa just proximal to the carcinoma and 2.0 pg/g in pararectal lymph nodes. Blood of the superior rectal vein contained 6.4 pglg of 5fluorouracil. Gross changes in carcinoma after treatment with 54uorouracil suppository: The antitumor effects of the suppository were evaluated by proctoscopically assessing the change in diameter of the tumor before and after treatment with the suppository. In surgical specimens the tumor size was actually measured. Eight of 50 carcinomas decreased in size after treatment with the suppository, more than 50 percent of the initial size in 4 cases and 30 to 50 percent in the other 4 cases. These eight patients were those who had been treated with the 5-fluorouracil suppository for more than 20 days (Table II).
183
Takahashiet al
TABLE I
Concentration of B-FluorouracllAtter Rectal Admlnistratlon as a Suppository Samples (n) . ,
Carcinoma Normal rectal mucosa Pararectal lymph node Superior rectal venous blood
10 10
4.5-45 3.5-36 Trace-2.7 2.7-13
18.2 f 13.8 f 2.0 f 6.4 f
3.2 1.5 0.3 1.9
Histologic changes in carcinoma by treatment with 54’luorouracil suppository: Various histologic changes occurred in carcinoma of the rectum after treatment with the suppository. The changes varied from slight to marked, including swelling of the cells, vacuolation of cytoplasm, individual cell lysis, destruction of glandular structures and extensive necrosis of cancer. Since these changes were seen in various degrees even in the same patient, we graded histologic changes arbitrarily into four categories as indicated in Table III. We judged grades 2 and 3 to represent effective treatment. Table IV shows the grading of histologic changes of carcinoma of the rectum treated with the suppository preoperatively. Thirteen of the 40 resected carcinomas showed grade 2 or 3 changes. The grade of histologic changes correlated well with the total dose of 5fluorouracil given in suppository preoperatively. Side effects of B-fluorouracil suppository: The type and incidence of adverse effects of the suppository were anal pain in 20 percent, tenesmus in 9 percent and anal bleeding in 7 percent. These side effects were not serious and disappeared immediately after administration of 5fluorouracil was stopped. Neither blood cell count nor liver function tests showed any abnormality. Redness of the rectal mucosa, which seemed to be due to topical irritation of 5fluorouraci1, was seen up to 20 cm proximal to the pectinate line in the resected rectum. Histologic examination of such mucosa revealed the features of acute colitis.
Grade 0
1 2 3
184
Extent of Decrease In Tumor Size According to Total Dose of 5-Fluorouracll
Concentration &g/g) Ranae Mean f SE
SE = standard error.
TABLE Ill
TABLE II
Crlterla for Evaluatlon of Hlstologlc Changes Histologic Changes Showlno Predominant-Features -
No remarkable changes Swelling of cells, enlarged vesicular nuclei, pycnosls of nuclei and vacuolated cytoplasm Cell nests consisting of markedly damaged cells, often exhlbltlng moth-eaten appearance and slmpllfled alandular structures Ext;tnslve degenerative changes and fibrosis
Total Dose (mg)
Decrease in Diameter No Change or 30-50 >50 Percent Percent Unmeasurable
<2,000 2,000-4,000 4,000-6,000 6,000-8,000 8,000-10,000 bin nnn
...
6 13 14 0 2
1 1
... .. ... 1 1
1
2
1
...
1
Comments Carcinoma of the rectum can be treated with a rectally administered chemotherapeutic agent. Intrarectal administration of 5fluorouracil in suppository form allows the drug to make direct contact with cancer cells and produces a higher local concentration of the drug than does intravenous administration. In fact, the suppository, which was made of Witepsol base and 5-fluorouracil, yielded high drug concentrations in carcinoma and in adjacent tissues of the rectum. The drug was also detected at significant levels in draining blood and in regional lymph nodes. These findings indicate that 5-fluorouracil permeates easily into carcinoma or the mucosa of the rectum and that a considerable portion of the drug is taken up into the portal vein and lymphatic system. The clinical response to the suppository was evaluated by assessing the change in tumor size after treatment. A significant decrease in tumor size was noted in 8 of 50 carcinomas. However, no change in size could be detected in most cases. It seems difficult to assess accurately subtle changes in size of carcinomas of the rectum situated in the pelvis. Histologic changes induced by the 5fluorouracil suppository were characterized by vacuolated cytoplasm, destruction of glandular structure and extensive necrosis. We arbitrarily graded histologic changes into four categories as previously reported [7,8]. Thirteen of 40 carcinomas resected surgically
TABLE IV
Hlstologlc Changes In Surgically Resected Carcinoma of the Rectum After Admlnlstratlonot I-Fluorouracll Supposltory Grade
Total Dose
0
1
2
3
<2,000 2,000-4,000 4,000-6,000 6,000-8,000 >8,000
2 4 2
2 7 5 3 2
...
.,. ...
... ...
The
2 4 3
...
1 2
1
AmerlcanJournal of Surgery
5-Fluorouracil
appeared to have responded to the suppository and the grade of the response correlated well with the total dose of 5-fluorouracil. The adverse effects of the 5-fluorouracil suppository were confined to anal pain, tenesmus and anal bleeding, which are common features in patients with carcinoma of the rectum. The gross and microscopic findings in resected specimens showed that the 5fluorouracil suppository possessed a topical effect that was followed by acute inflammatory change in the mucosa of the rectum and rectosigmoid. Thus, caution should be used when anastomosis is made within that area. Although a definitive conclusion must be postponed until long-term survival studies are performed, the experience described herein suggests that the 5-fluorouracil suppository provides an additional therapeutic method for the management of carcinoma of the rectum. Summary A total of 50 patients with carcinoma of the rectum were treated with 5-fluorouracil suppository before operation. The suppository, which was made of Witepsol suppository base containing 5-fluorouracil, yielded high drug concentrations in carcinoma, draining blood and regional lymph nodes. As a clinical response to the suppository, a significant decrease in the size of tumor mass was noted in 8 of 50 carcinomas, but in other cases the gross change was
Volume 143, February 1962
Suppository for Rectal Carcinoma
unmeasurable. Thirty-three percent of the surgically resected carcinomas were histologically judged to have responded to the suppository. In such cases, histologic changes correlated well with the total dose of 5-fluorouracil. The adverse effects of the suppository were confined to anal pain, tenesmus and anal bleeding, probably due to the topical effect of Mluorouracil on the rectal mucosa. References 1. Goligher JC. Surgery of the anus, rectum and colon. London: Bailliere Tindall, 1975:791. 2. Roswit R, Higgins GA, Keehn RJ. Preoperative irradiatlon for carcinoma of the rectum and rectosigmold colon: report of a national veterans administration randomized study. Cancer 1975;35:1597-602. 3. Stevens K Jr, Allen CV, Fletcher WS. Preoperative radiotherapy for adenocarclnoma of the rectoslgmold. Cancer 1976;37: 2666-74. 4. Higgins GA, Dwlght RW, Smith JV, Keen RJ. Fluorouracil as an adjuvant to surgery in carcinoma of the colon. Arch Surg 1971;102:339-43. 5. Takahashl T, Nakao E, Watanabe S, et al. 5-Fluorouracil supposltory for carcinoma of the rectum. J Jap Sot Cancer Ther 1976;11:558-60. 6. Clarkson B, D’Cornor A, Wlnston L, Hutchinson 0. The physiologic deposltlon of 5-fluorouracll and 5-fluoro-2’deoxyurldIne in man. Clln Pharmacol Ther 1965;5:581-610. 7. Majima S, Watanabe S, Nakao E, et al. Histologlcal evaluation of the effect of 5-FU emulsion on lymph node metastasls of stomach cancer. Jap J Surg 1978;8:111-8. 8. Takahashl T, Kohno K, Yamaguchi T. Enhancement of ths cancer chemotherapeutic effect by anticancer agents In the form of fat emulsion. Tohoku J Exp Med 1977;123:235-46.
Toshio Takahashi, MD, Akita, Japan Kenichi Kohno, MD, Akita, Japan Toshiharu Yamaguchi, MD, Akita, Japan Tomlo Narisawa, MD, Akita, Japan
Local recurrence and metastasis are the major problems after surgery for carcinoma of the rectum [I]. Prompted by reports that use of preoperative irradiation and 5fluorouracil reduced local recurrence and metastasis of carcinoma of the rectum and improved 5 year survival [Z-4], we attempted to prepare a suppository of Sfluorouracil for the treatment of carcinoma of the rectum. The attempt was based on the knowledge that 5-fluorouracil has both cytocidal and radiosensitive .effects on cancer cells and that a suppository produces a higher drug concentration at the site of application than systemic administration. Furthermore, a suppository can be easily given preoperatively on an outpatient basis and might enhance the radiotherapeutic effect in combination with preoperative irradiation. We have so far treated 50 patients with the 5-fluorouracil suppository, and this experience constitutes the basis of this report. Material and Methods The suppository was made by dissolving 5-fluorouracil in a Witepsol suppository base, each suppository containing 200 mg of 5-fluorouracil [5]. Fifty patients with carcinoma of the rectum were given the suppository intrarectally once or twice a day for 5 to 30 days before operation. The suppository was inserted close to the tumor after bowel movement. The patients consisted of 26 men and 14 women with a mean age of 59.9 years (range 32 to 87). Selection of patients was not randomized; rather, the From the department of Sugary, Akita University school of Medicine, Akita, Japan. Requests for reprlnts shot&I be addressed to Toshio Takahashi, MD. Department of Surgery, Akita University School of Medicine, 1-1-l Hondo, Akita 010, Japan.
Volume 143, February 1992
5-fluorouracil suppository was given to those who had carcinoma of the rectum in advanced clinical stages. Thinly-two patients underwent Miles’ operation, 6 anterior resection and 2 pull-through operation. Ten patients with inoperable carcinoma of the rectum were colcstomized and given the 5-fluorouracil suppository as long as possible.
Results Concentration of 54luorouracil in tissues and draining blood: The concentration of 5-fluorouracil in the tumor, lymph nodes and blood withdrawn from the draining vein was measured by the method of zone inhibition technique of Clarkson et al [6]. The surgical specimens were obtained about 90 minutes after application of 400 mg of 5-fluorouracil in suppository. As shown in Table I, the mean concentration of 5-fluorouracil in tumor tissues was 18.2 pg/g (range 4.5 to 45). The mean drug level was 13.8 pg/g in normal rectal mucosa just proximal to the carcinoma and 2.0 pg/g in pararectal lymph nodes. Blood of the superior rectal vein contained 6.4 pglg of 5fluorouracil. Gross changes in carcinoma after treatment with 54uorouracil suppository: The antitumor effects of the suppository were evaluated by proctoscopically assessing the change in diameter of the tumor before and after treatment with the suppository. In surgical specimens the tumor size was actually measured. Eight of 50 carcinomas decreased in size after treatment with the suppository, more than 50 percent of the initial size in 4 cases and 30 to 50 percent in the other 4 cases. These eight patients were those who had been treated with the 5-fluorouracil suppository for more than 20 days (Table II).
183
Takahashiet al
TABLE I
Concentration of B-FluorouracllAtter Rectal Admlnistratlon as a Suppository Samples (n) . ,
Carcinoma Normal rectal mucosa Pararectal lymph node Superior rectal venous blood
10 10
4.5-45 3.5-36 Trace-2.7 2.7-13
18.2 f 13.8 f 2.0 f 6.4 f
3.2 1.5 0.3 1.9
Histologic changes in carcinoma by treatment with 54’luorouracil suppository: Various histologic changes occurred in carcinoma of the rectum after treatment with the suppository. The changes varied from slight to marked, including swelling of the cells, vacuolation of cytoplasm, individual cell lysis, destruction of glandular structures and extensive necrosis of cancer. Since these changes were seen in various degrees even in the same patient, we graded histologic changes arbitrarily into four categories as indicated in Table III. We judged grades 2 and 3 to represent effective treatment. Table IV shows the grading of histologic changes of carcinoma of the rectum treated with the suppository preoperatively. Thirteen of the 40 resected carcinomas showed grade 2 or 3 changes. The grade of histologic changes correlated well with the total dose of 5fluorouracil given in suppository preoperatively. Side effects of B-fluorouracil suppository: The type and incidence of adverse effects of the suppository were anal pain in 20 percent, tenesmus in 9 percent and anal bleeding in 7 percent. These side effects were not serious and disappeared immediately after administration of 5fluorouracil was stopped. Neither blood cell count nor liver function tests showed any abnormality. Redness of the rectal mucosa, which seemed to be due to topical irritation of 5fluorouraci1, was seen up to 20 cm proximal to the pectinate line in the resected rectum. Histologic examination of such mucosa revealed the features of acute colitis.
Grade 0
1 2 3
184
Extent of Decrease In Tumor Size According to Total Dose of 5-Fluorouracll
Concentration &g/g) Ranae Mean f SE
SE = standard error.
TABLE Ill
TABLE II
Crlterla for Evaluatlon of Hlstologlc Changes Histologic Changes Showlno Predominant-Features -
No remarkable changes Swelling of cells, enlarged vesicular nuclei, pycnosls of nuclei and vacuolated cytoplasm Cell nests consisting of markedly damaged cells, often exhlbltlng moth-eaten appearance and slmpllfled alandular structures Ext;tnslve degenerative changes and fibrosis
Total Dose (mg)
Decrease in Diameter No Change or 30-50 >50 Percent Percent Unmeasurable
<2,000 2,000-4,000 4,000-6,000 6,000-8,000 8,000-10,000 bin nnn
...
6 13 14 0 2
1 1
... .. ... 1 1
1
2
1
...
1
Comments Carcinoma of the rectum can be treated with a rectally administered chemotherapeutic agent. Intrarectal administration of 5fluorouracil in suppository form allows the drug to make direct contact with cancer cells and produces a higher local concentration of the drug than does intravenous administration. In fact, the suppository, which was made of Witepsol base and 5-fluorouracil, yielded high drug concentrations in carcinoma and in adjacent tissues of the rectum. The drug was also detected at significant levels in draining blood and in regional lymph nodes. These findings indicate that 5-fluorouracil permeates easily into carcinoma or the mucosa of the rectum and that a considerable portion of the drug is taken up into the portal vein and lymphatic system. The clinical response to the suppository was evaluated by assessing the change in tumor size after treatment. A significant decrease in tumor size was noted in 8 of 50 carcinomas. However, no change in size could be detected in most cases. It seems difficult to assess accurately subtle changes in size of carcinomas of the rectum situated in the pelvis. Histologic changes induced by the 5fluorouracil suppository were characterized by vacuolated cytoplasm, destruction of glandular structure and extensive necrosis. We arbitrarily graded histologic changes into four categories as previously reported [7,8]. Thirteen of 40 carcinomas resected surgically
TABLE IV
Hlstologlc Changes In Surgically Resected Carcinoma of the Rectum After Admlnlstratlonot I-Fluorouracll Supposltory Grade
Total Dose
0
1
2
3
<2,000 2,000-4,000 4,000-6,000 6,000-8,000 >8,000
2 4 2
2 7 5 3 2
...
.,. ...
... ...
The
2 4 3
...
1 2
1
AmerlcanJournal of Surgery
5-Fluorouracil
appeared to have responded to the suppository and the grade of the response correlated well with the total dose of 5-fluorouracil. The adverse effects of the 5-fluorouracil suppository were confined to anal pain, tenesmus and anal bleeding, which are common features in patients with carcinoma of the rectum. The gross and microscopic findings in resected specimens showed that the 5fluorouracil suppository possessed a topical effect that was followed by acute inflammatory change in the mucosa of the rectum and rectosigmoid. Thus, caution should be used when anastomosis is made within that area. Although a definitive conclusion must be postponed until long-term survival studies are performed, the experience described herein suggests that the 5-fluorouracil suppository provides an additional therapeutic method for the management of carcinoma of the rectum. Summary A total of 50 patients with carcinoma of the rectum were treated with 5-fluorouracil suppository before operation. The suppository, which was made of Witepsol suppository base containing 5-fluorouracil, yielded high drug concentrations in carcinoma, draining blood and regional lymph nodes. As a clinical response to the suppository, a significant decrease in the size of tumor mass was noted in 8 of 50 carcinomas, but in other cases the gross change was
Volume 143, February 1962
Suppository for Rectal Carcinoma
unmeasurable. Thirty-three percent of the surgically resected carcinomas were histologically judged to have responded to the suppository. In such cases, histologic changes correlated well with the total dose of 5-fluorouracil. The adverse effects of the suppository were confined to anal pain, tenesmus and anal bleeding, probably due to the topical effect of Mluorouracil on the rectal mucosa. References 1. Goligher JC. Surgery of the anus, rectum and colon. London: Bailliere Tindall, 1975:791. 2. Roswit R, Higgins GA, Keehn RJ. Preoperative irradiatlon for carcinoma of the rectum and rectosigmold colon: report of a national veterans administration randomized study. Cancer 1975;35:1597-602. 3. Stevens K Jr, Allen CV, Fletcher WS. Preoperative radiotherapy for adenocarclnoma of the rectoslgmold. Cancer 1976;37: 2666-74. 4. Higgins GA, Dwlght RW, Smith JV, Keen RJ. Fluorouracil as an adjuvant to surgery in carcinoma of the colon. Arch Surg 1971;102:339-43. 5. Takahashl T, Nakao E, Watanabe S, et al. 5-Fluorouracil supposltory for carcinoma of the rectum. J Jap Sot Cancer Ther 1976;11:558-60. 6. Clarkson B, D’Cornor A, Wlnston L, Hutchinson 0. The physiologic deposltlon of 5-fluorouracll and 5-fluoro-2’deoxyurldIne in man. Clln Pharmacol Ther 1965;5:581-610. 7. Majima S, Watanabe S, Nakao E, et al. Histologlcal evaluation of the effect of 5-FU emulsion on lymph node metastasls of stomach cancer. Jap J Surg 1978;8:111-8. 8. Takahashl T, Kohno K, Yamaguchi T. Enhancement of ths cancer chemotherapeutic effect by anticancer agents In the form of fat emulsion. Tohoku J Exp Med 1977;123:235-46.