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Prognostic evaluation of preoperative combined treatment for advanced cancer in the lower rectum with radiation, intraluminal hyperthermia, and 5-fluorouracil suppository
Prognostic Evaluation of Preoperative Combined Treatment for Advanced Cancer in the Lower Rectum With Radiation, Intraluminal Hyperthermia, and Wluorouracil Suppository Daisuke
Ichikawa, MD, Toshiharu Yamaguchi, Kiyoshi Sawai, MD, Toshio Takahashi,
BACKGROUND: Since 1977, we have studied preoperative treatments using Ii-fluorouracil (5FU) suppositories alone or in combination with radiation to reduce local recurrence and improve survival of patients with rectal cancer. PAnENTsAND METHODS: We developed a novel preoperative therapy combining radiation, intraluminal hyperthermia, and 5-FU suppositories. Thirty-five patients with rectal cancer underwent surgery after this treatment, and 41 patients underwent surgery without pretreatment. RESULTS: The patients who underwent preoperative combination treatment showed significant tumor reduction; 2 achieved microscopically complete regression. In comparison with the patients who underwent surgery without pretreatment, the preoperative treatment group had a 16.7% lower local recurrence rate (10.4% versus 27.1%) and an improved survival rate (61.6% versus 67.6%). CONCLUSIONS: Preoperative combination therapy is a promising modality for the patients with resectable advanced cancer in the lower rectum. Am J Surg. 1996;171:346-350.
D
espite remarkable progress in surgical techniques, survival among patients undergoing radical surgery for advanced rectal cancer has not improved during the last 20 years. Some 25% to 40% of patients die from uncontrolled local recurrences.1~4 A variety of adjuvant therapies have been attempted to inhibit these local recurrences?~‘7 At present, the most powerful adjuvant therapy for controlling local lesions is undoubtedly radiation, either alone or in combination with other therapies. Various protocols for radiation therapy have been developed, and the clinical outcomes examined carefully. The ma-
From the First Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Requests for reprints should be addressed to Toshio Takahashi, MD, Professor and Chairman, First Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachihirokoji, Kajiicho, Kamigyo-ku, Kyoto 602, Japan. Manuscript submitted September 26, 1994 and accepted in revised form April 14, 1995.
346
THE AMERICAN
JOURNAL
OF SURGERY”
VOLUME
171
MD, Yuji Yoshioka, MD, Kyoto, Japan
MD,
jority of these studies have suggested that a high or biologically intense dose of radiation is essential for a significant clinical response. 12-r7 However, such protocols often induce severe adverse effects, such as intractable radiation colitis, and hence result in high morbidity after surgery.‘2~‘3~15 To circumvent this problem, an additional treatment that enhances the efficacy of radiation without deleterious side effects must be developed. Hyperthermia and 5fluorouracil (5-FU) have been previously reported to enhance the clinical efficacy of radiation therapy.‘sdZ3 Since 1977, we have been seeking a preoperative treatment for rectal cancer that would prevent local recurrences and improve survival.24.26 We recently developed a novel combination therapy using intraluminal hyperthermia and 5-FU suppositcaies.27 In a preliminary clinical trial, this combination therapy showed a striking tumoricidal effect, even inducing complete remission in a few patients with advanced rectal cancer.27 However, the clinical utility of our treatment remained to be investigated in a follow-up study. We here report such a study, examining whether our treatment can improve the prognosis of patients with advanced cancer in the lowelr rectum.
PATIENTS AND METHODS Patients From 1986 to 1993, 91 patients with advanced cancer in the lower rectum were admitted to the First Department of Surgery at the Kyoto Prefectural University of Medicine and enrolled in this trial. Advanced rectal cancer,3 were defined as those fixed to the surrounding structures. AI1 cancers were located in the rectum < 10 cm proximal from the anal verge. Clinical evaluation of tumor extension consisted of physical examination, barium enema, endoscopy, computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasonography (EUS). Our present trial was directed toward patients with American Joint Committee on Cancer Stage T3 and T4 tumors that were surgically resectable. Patients with distant metastases were excluded from this analysis. Seventy-six patients with lesions that were thought to be clinically resectable (T3, NX, MO and T4, NIX, MO, except tumors preoperatively diagnosed as unresectable by pelvic CT and EUS) were divided into two groups. Group 1 consisted of 35 patients who underwent combination therapy with radiation, intraluminal hyperthermia, and 5-FU suppositories, and then underwent surgery 7 days later. Group 2 included 41 patients who underwent surgery without preMARCH
1996
1 COMBINED TREATMENT
FOR ADVANCED CANCER IN THE LOWER RECTUM/lCHlKAWA
treatment. The sex ratios of the two groups were different, but there were no significant differences in clinicopathologic characteristics (Table I). Methods Radiation. A 4-MeV linear accelerator or Co6@ was used for the radiation therapy. A bilateral irradiation technique through anteroposterior portals was used to deliver the radiation to an area of the pelvis approximately 12 cm in diameter surrounding the carcinoma in the lower rectum. The target volume included the whole dorsal part of the pelvic cavity from the anus up to promontorium. The inferior border was the bottom of the obturator foramen, and the lateral border was 1 cm lateral to the bony margin. Thirty Gy were delivered in 10 fractions, 3 times a week. Hyperthermia. To create hyperthermia in rectal cancer, an inn-alumina1 electrode was developed that consisted of a transmitter for radio frequency radiation and a cooling system.2s A radio frequency sy stem (OMRON, HEH-500, Kyoto, Japan) was then introduced for the hyperthermia. We confirmed that the electrode was safely placed and the intratumoral temperature maintained at 42”Cz9 Intraluminal hyperthermia was performed twice a week at 42°C to 43°C for 40 to 50 minutes within 1 hour after radiation. The details of the practical procedure used in intraluminal hyperthermia were described in a previous report.27 Briefly, the electrode was inserted into the rectum and a counter electrode applied to the lower back. In each case, the preoperative assessment of the degree of stenosis and the distance of the tumor anal verge directed the application of the intraluminal electrode. Whenever possible, the tip of the electrode was located and fixed 2 to 3 cm beyond the proximal margin of the tumor. 5-Fluorouracil suppositories. Studies in both advanced colorectal cancer in vivo and in the laboratory in vitro have suggested an advantage when 5-FU is delivered in conjunction with radiation therapy. Suppositories were made by dissolving 5-FU in a Witepsol suppository base; they contained 100 mg of 5&J. 24,25The patients were given one suppository via the anus every day for 20 days. Intraluminal administration of the suppositories was continued until 1 week prior to surgery. Protocol The protocols for the preoperative treatment in Group 1 are described above. During preoperative treatment, the patients were further examined by barium enemas, colonoscopy, CT, and EUS. Tumor shrinkage was evaluated by conventional digital examination and the examinations described above. One week after completion of the preoperative treatment, the patients underwent an abdominoperineal resection (n = 12) or a low anterior resection (n = 23), with regional lymph node dissection. The patients in Group 2 underwent surgery alone; 13 abdominoperineal resections and 28 low anterior resections.
TABLE
ET AL
I Patients and Clinical Tumor Characteristics Combination Therapy Control Group Group. (n = 35) (n=41) . ~
Mean age (y) Range
56.3 29-75
64.5 39-81
29 6
20 21
21 14
25 16
30 5
39 2
19 14 2
26 12
Sex Men Women Distance from anal verge o-5 5-10 Tumor stage T3 T4 Histologic grade Well differentiated Moderately differentiated Others
TABLE
(cm)
1
II Postooerative Complications Combination Theraw Group (n’i 35)
Surgery LAR APR Curative resection Type of complication Wound or pelvic infection (12.2%) Anastomotic leakage (14.3%) Intestinal obstruction Neurogenic bladder LAR
= low anterior
resection;
23 12 32 (91.4%)
Control Grow (n-41) ’ 28 13 36 (87.8%)
8/35 (22.8%) 4/23 (17.4%)
4i28
2’35 (6.0%) l/35 (2.9%)
3/41 (7.3%) 3/41 (7.3%)
APR
= abdominoperineal
observed after the preoperative previously described. 25
treatment
resection.
were classified as
Prognosis After discharge, all patients were followed up in the outpatient clinic at our hospital. During regular visits to the clinic, they were followed up by conventional digital examination, chest roentegenography, ultrasonogtaphy, pelvic CT, and tumor markers, such as cardioembryonic antigen and CA19-9, etc. The analyses regarding local control and survival were based on follow-up data as of Ju1.y 1994. The follow-up period ranged from 8 to 100 months (median 45) in Group 1 and from 8 to 99 months (median !52) in Group 2. The cumulative survival and local control rates were calculated by the Kaplan-Meier method.
RESULTS Pathological Examination In order to evaluate the histologic changes induced by the preoperative treatment, the resected specimens were subjected to pathologic investigation. The histological changes THE AMERICAN
Surgery * Thirty-two (91%) of the 35 patients in Group 1 underwent curative operation; the remaining 3 underwent noncurative resections due to multiple liver metastases and a positive surJOURNAL
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“11.LJ.1, rl. ;t.....J.J...L.......LIJ..IJ.U.....I
4-s LL . ..__ l.l..J
-
Preoperative
----
Control
___.__.
Treatment Group
E E 00 50 -
JJI.lLJL....J
Group
(n = 31)
3
-
Praopsrative
----
Control
Treetment Group
2000
8
t
2000 Time
3000
3000
(days)
(days)
igure 2. Local control of recurrence. The rates of local control at 5 years were 89.6% after the combination treatment and surgery, and 72.9% after surgery alone. The difference of 16.7% was not statistically significant.
:..L.l..J.......Ill.ll~U.....I
toplasm (~25%); Grade 2-tell nests consisting of markedly damaged cells, often exhibiting a moth-eaten appearance and simplified glandular structures; and Grade 3-extensive degeneration changes and fibrosis (>75%). Excluding 4 patients with no material for histologic examination, 5, 12, and 11 patients were classified into Grades 1, 2, and 3, respectively. No patient was classified into Grade 0. Local recurrence was observed in 1 of 5 patients in Grade 1, and 2 of 12 in Grade 2. No local recurrence was observed in patients in Grade 3. The histologic grading of resected specimens also correlated with the incidence of local recurrence.
-
Preoperative
-.--
Control
Treatment Group
loo0
Group
(n = 31)
(n = 34)
2Wo Time
3000
(days)
Figure 1. A. Recurrence-free interval after B. Survival related to rectal cancer in patients
curative surgery who have under
gone curative surgery.
gical margin. Thirty-six (88%) of the 41 patients in Groq 2 underwent curative operations; the remaining 5 underwent noncurative surgeries due to liver metastases and a positive surgical margin. The 3 patients in Group 1 and 5 patients ir Group 2 who received noncurative resections were exclude< from this study. No patients were lost during follow-up. Tumoricidal Effects The tumoricidal effects of the preoperative treatment wen evaluated macroscopically and microscopically in the re sected specimens. Of the 32 patients in Group 1, 24 (75%: demonstrated marked tumor shrinkage (reduction in lengtt by 30% or more on barium enema) after the preoperative treatment. Elevated lesions and the marginal elevation o cancerous craters, which were obvious before the preopera tive treatment, were flattened macroscopically after the treatment. This finding was further confirmed by histologic examination using the resected specimens. Microscopic ex amination of the resected specimens showed varying degree of transformation from cancerous mass to scar tissue Complete depletion of cancer cells occurred in 2 patients The degree of transformation was classified as follows: Grade O-no remarkable changes; Grade l-swelling of cells, en larged vesicular nuclei, pyknosis of nuclei and vacuolated cy 348
(n = 31)
3
(n = 34)
1000
Time
Group
(n = 34)
Postoperative Complications Postoperative complications occurred in 14 (1 patient had multiple complications) and 15 patients in Groups 1 and 2, respectively. Incision or pelvic infections, anastomotic leakage, intestinal obstruction, and neurogenic bladder complications were noted, but all the complications were resolved and no sepsis developed. There were no deaths within 30 days after the surgery in either group, and there was no sig nificant difference in the incidence of complications between the two groups (Table II). Survival One patient from Group 1 and 3 patients from Group 2, who died of intercurrent disease, were excbuded from this study. The disease-free survival and cause-specific survival rates are shown in Figure 1. The survival rate of patients in Group 1 was higher than that of Group 2 (81.8% versus 67.6%), although this difference was not statistically significant. The degree of local control is largely responsible for the prognosis of patients with advanced cancer in the lower rectum, and was compared between the two groups. The incidence of local recurrence in Group 1 was lower than in Group 2 (10.4% versus 27.1%), but not statlistically significant (Figure 2). Type of Recurrence As to the type of recurrence,
THE AMERICAN JOURNAL OF SURGERY@ VOLUME 171 MARCH 1996
Group
1 included
3 patients
-1
COMBINED
TREATMENT
FOR
ADVANCED
with local recurrence and 4 patients with distant metastases. Group 2 included 5 patients with local recurrences, 4 patients with distant metastases, and 2 patients with both local and distant metastases.
COMMENTS The local recurrence of rectal cancer after surgery is thought to result from regrowth of residual cancer cells surrounding the rectum. Since these remnant cancer cells are usually not visible during surgery, it is extremely difficult to remove every cancer cell by surgery alone. To efficiently eliminate all cancer cells in advanced lower rectal cancer, we have developed a preoperative combination therapy using radiation and 5-FU suppositories. A clinical trial of this combination treatment performed in our department from 1977 to 1985 resulted in insufficient local control, although the protocol was successful in some patients.24s26 These results suggested that additional treatments were required for a more effective local response and for improvement in the prognosis of these patients. A few studies reported excellent local control and subsequent prolonged survival with certain preoperative radiation treatments, even with low doses.5 Other studies have reported that low-dose preoperative radiation ~20 Gy was ineffective>* The current trend in radiation therapy is a high-dose treatment or a more biologically intense fractionation.12e17 However, the postoperative morbidity and mortality rates are usually high when preoperative treatment with high-dose radiation is performed. ‘*,13*15Therefore, to achieve adequate therapeutic efficacy with low-dose radiation, additional treatments must be developed. Hyperthermia is well known to enhance the cytotoxic effects of radiation.1a~21~30 This enhancement is more prominent in malignant than normal tissues, because heat loss is minimal in malignant tissues due to poor blood supply and return, and thus poor heat dissipation.‘8-21~30 In a preliminary study, we demonstrated that the device used in the present study achieved a high temperature inside the tumor, and thus provided a marked tumoricidal effect in combination with radiation.27 In addition, the combination of hyperthennia and radiation led to enhanced delivery of radioactivity to the malignant tissues and less damage to the normal tissues. Our present study confirmed that the addition of hyperthermia to combination therapy with radiation and 5-W suppository led to a more effective tumoricidal effect, without any serious postoperative complications. In this study, the incidence of local recurrence at 5 years after the surgery was 27.1% in patients who had undergone surgery without preoperative treatment, and 10.4% in patients who had undergone the treatment. The 16.7% reduction in local recurrence for the preoperative treatment group can be explained as follows: ( 1) a reduced number of cancer cells invading the surrounding tissues through the original tumor; (2) a reduced number of lymph nodes involved by the original cancer cells; and (3) reduced viability of the cancer cells. Surprisingly, the 16.7% reduction in local recurrence produced by our treatment was similar to data from other reliable reports that suggested a benefit of preoperative radiation therapy using high-dose or intense radiation.12-15 Postoperative survival was also prolonged by the preoperTHE AMERICAN
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ET AL
ative treatment, most likely due to the lower incidence of local recurrence. It is interesting to note that the addition of hyperthermia and 5-FU achieved a similar survival rate to other protocols using high-dose radiation, despite our relatively lower dose. Hyperthermia and 5-FU would undoubtedly be a further enhancement for radiation. One negative aspect of this study is that the number of patients is small and the survival difference was not statistically significant. Nevertheless, our treatment evidently succeeded in reducing the local recurrence rate for advanced1 rectal cancer. The effectiveness of this treatment paradigm will become more definite as the number of patients increases in the future. Another outstanding feature of this trial was a shorter therapeutic term. Conventional powerful preoperative treatments commonly require approximately 8 to 10 weeks from initiation to the day of surgery.16J7 Our treatmeent, in contrast, required only 29 days for completion. Several reports have described delaying the surgical treatmen): for 1 or 2 months whenever a high-dose preoperative radliation therapy was performed, lest unfavorable perioperative complications occur. However, long intervals from the end of the preoperative treatment to the surgery may increase the patient’s risk for further cancer growth and metastasis. In contrast, the moderate dose of radiation used in our trial induced no serious complications, and curative surgery could be performed just 1 week after the preoperative treatment. This shorter delay period is not likely to permit the growth or metastasis of cancer cells. In conclusion, preoperative combination treatment with moderate-dose radiation, intraluminal hyperthennia, and 5FU suppositories reduced the local recurrence ‘of advanced cancer in the lower rectum after surgery, and thereby improved the patients’ prognosis, without any serious postoperative complications. Tk administration of conventional 5-fhwrouracil in suppository form for rectalcancerhasbeen largely ignored by American chiciuns. Its theoretic value and confirmation in tk laboratory is impressive. This nonrandomized trial is another in a growing list of publicationsthat purswdesomeof us that thereis something special and additional about the su@ository method of administration. It may be that this, like the directed chemotherapy via tk obliterated umbilical vein for liver metawlses,will not stand up to a randomized trial. “Clinical alerts” have been distributed by theAJCI fur lessimpressive benefitsfor othercancers and other modali ties.
REFERENCES 1. Malcolm AW, Perencevich NP, Olson RM, et al. ,4nalysis of recurrence patterns following curative resection for carcinoma of the colon and rectum. Surg Gynecol O&t. 1981;152:131--136. 2. Rich T, Gundetson LL, Lew R, et al. Patterns of recurrence of rectalcancerafterpotentiallycumtivesurgery.Cancer. 1983;52:1317-1329. 3. Pilipshen SJ, Heilweil M, Quan SH, et al. Pattern of pelvic recurrence following definitive resections of rectal cancer. Ctmcer. 1984;53: 1354-1362. 4. Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of rectosigmoid and rectum, I: patterns of failure and survival. Cuncer. 1988;61:1408-1416. 5. Steam MJ Jr., Weddish MR, Quan SH, Leaning RH. Pre-operative
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roentgen therapy for carcinoma of the rectum and rectosigmoid. Surg Gynecol Obstet. 1974;138:584-586. 6. Second Report of an M.R.C. Working Party. The evaluation of low dose preoperative xeray therapy in the management of operable rectal cancer: results of a randomly controlled trial. Br 1 Surg. 1984;71:21-25. 7. Higgins GA, Humphrey EW, Dwight RW, et al. Preoperative radiation and surgery for cancer of the rectum: Veterans Administration Surgical Oncological Group trial 2. Cancer. 1986;58:352-359. 8. Dahl 0, Horn A, Morild I, et al. Low-dose preoperative radiation postpone recurrences in operable rectal cancer. Cancer. 199Q66: 2286-2294. 9. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-1450. 10. ShumateCR, RichTA, SkibberJM, et al. Preoperative chemotherapy and radiation therapy for locally advanced primary and recurrent rectal carcinoma. Cancer. 1993;71:369C-3696. 11. Kitamura K, Takahashi T, Kotani T, et al. Local administration of monoclonal antibody-drug conjugate: a new strategy to reduce the local recurrence of colorectal cancer. Cancer Res. 1992;52:6323-6328. 12. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiation therapy as adjuvant treatment in rectal cancer: final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg. 1988;208:606614. 13. Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma: a prospective randomized trial. Cancer. 1990;66:49-55. 14. Neto JAR, Quilici FA, Reis JA. A comparison of non-operative versus preoperative radiotherapy in rectal carcinoma: a lo-year randomized trial. Dis Colon Rectum. 1989;32:702-710. 15. Pahhnan L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Ann Surg. 1990;211:187-195. 16. Mender&all WM, Bland KI, Copeland EM, et al. Does preoperative radiation therapy enhance the probability of local control and survival in high-risk distal rectal cancer? Ann Surg. 1992;215:696-706. 17. Marks G, Mouhiuddin M, Eitan A, et al. High-dose preoperative radiation and radical sphincterpreserving surgery for rectal cancer. Arch Surg. 1991;126:1534-1540.
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ET AL
I-
18. Suit H, Gerweck LE. Potential for hyperthennia and radiation therapy. Cancer Res. 1979;39:229&2298. 19. Noel1 UR, Woodward KT. Microwave-induc&l local hyperthermia in combination with radiotherapy of human malignant tumors. Cancer. 1980;45:638-646. 20. Gvergaard J. The current and potential role of hyperthermia in radiotherapy. IntJ Radiut Oncol Biol Phys. 1989;16:535-543. 21. Vaupel P, Kallinowski F. Physiological effects of hyperthermia. Recent Results Cancer Res. 1987;104:71-109. 22. Moertel CG, Childs DS, Reitemeier RJ, et al. ‘Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancer. 1969;2:865-867. 23. Byfield JE, Calabro-Jones P, Klisak 1, Kulhanian F. Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and x-rays. Inc J Radiut Oncol Bial Phys. 1982;8:1923-1933. 24. Takahashi T, Nakao E, Watanabe S, et al. 5-Fluorouracil suppository for carcinoma of the rectum. [in Japanese] J&n Sot Cancer Ther. 1976;11:558-560. 25. Takahashi T, Kohno K, Yamaguchi T, Narisav+a T. Preoperative use of 5-fluorouracil suppository for carcinoma of the rectum. Am J Surg. 1982;143:183-185. 26. Takahashi T, Mizusawa H, Kato T, Yamaguchi T. Preoperative irradiation and 5-fluorouracil suppository for carcinoma of the rectum. AmJ Surg. 1988;156:58-62. 27. Takahashi T, Horie H, Kojima 0, Itoh M. Preoperative combined treatment with radiation, intraluminal hyperthermia, and 5-fluorouracil suppositories for patients with rectal cancer. Surg Today. 1993;23:1043-1048. 28. Horie H, Takahashi T, Kojima 0, et al. Innovation and clinical trial of the applicator for local hyperthermia against rectal cancer. In: Sugawara T, Saitoh M, eds. Hype&en& Oncology. London: Talor and Francis; 1989:558-560. 29. Horie H, Takahashi T, Kojima 0, et al. Fundamental study of local hyperthermotherapy for rectal carcinoma. [in Japanese with English abstract] ]pn J Hymic 0~01. 1988;4:31-37. 30. Reinhold HS. Physiological effects of hypertherrnia. Recent Results Cancer Res. 1988;107:32+3.
MARCH
1996
Ichikawa, MD, Toshiharu Yamaguchi, Kiyoshi Sawai, MD, Toshio Takahashi,
BACKGROUND: Since 1977, we have studied preoperative treatments using Ii-fluorouracil (5FU) suppositories alone or in combination with radiation to reduce local recurrence and improve survival of patients with rectal cancer. PAnENTsAND METHODS: We developed a novel preoperative therapy combining radiation, intraluminal hyperthermia, and 5-FU suppositories. Thirty-five patients with rectal cancer underwent surgery after this treatment, and 41 patients underwent surgery without pretreatment. RESULTS: The patients who underwent preoperative combination treatment showed significant tumor reduction; 2 achieved microscopically complete regression. In comparison with the patients who underwent surgery without pretreatment, the preoperative treatment group had a 16.7% lower local recurrence rate (10.4% versus 27.1%) and an improved survival rate (61.6% versus 67.6%). CONCLUSIONS: Preoperative combination therapy is a promising modality for the patients with resectable advanced cancer in the lower rectum. Am J Surg. 1996;171:346-350.
D
espite remarkable progress in surgical techniques, survival among patients undergoing radical surgery for advanced rectal cancer has not improved during the last 20 years. Some 25% to 40% of patients die from uncontrolled local recurrences.1~4 A variety of adjuvant therapies have been attempted to inhibit these local recurrences?~‘7 At present, the most powerful adjuvant therapy for controlling local lesions is undoubtedly radiation, either alone or in combination with other therapies. Various protocols for radiation therapy have been developed, and the clinical outcomes examined carefully. The ma-
From the First Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Requests for reprints should be addressed to Toshio Takahashi, MD, Professor and Chairman, First Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachihirokoji, Kajiicho, Kamigyo-ku, Kyoto 602, Japan. Manuscript submitted September 26, 1994 and accepted in revised form April 14, 1995.
346
THE AMERICAN
JOURNAL
OF SURGERY”
VOLUME
171
MD, Yuji Yoshioka, MD, Kyoto, Japan
MD,
jority of these studies have suggested that a high or biologically intense dose of radiation is essential for a significant clinical response. 12-r7 However, such protocols often induce severe adverse effects, such as intractable radiation colitis, and hence result in high morbidity after surgery.‘2~‘3~15 To circumvent this problem, an additional treatment that enhances the efficacy of radiation without deleterious side effects must be developed. Hyperthermia and 5fluorouracil (5-FU) have been previously reported to enhance the clinical efficacy of radiation therapy.‘sdZ3 Since 1977, we have been seeking a preoperative treatment for rectal cancer that would prevent local recurrences and improve survival.24.26 We recently developed a novel combination therapy using intraluminal hyperthermia and 5-FU suppositcaies.27 In a preliminary clinical trial, this combination therapy showed a striking tumoricidal effect, even inducing complete remission in a few patients with advanced rectal cancer.27 However, the clinical utility of our treatment remained to be investigated in a follow-up study. We here report such a study, examining whether our treatment can improve the prognosis of patients with advanced cancer in the lowelr rectum.
PATIENTS AND METHODS Patients From 1986 to 1993, 91 patients with advanced cancer in the lower rectum were admitted to the First Department of Surgery at the Kyoto Prefectural University of Medicine and enrolled in this trial. Advanced rectal cancer,3 were defined as those fixed to the surrounding structures. AI1 cancers were located in the rectum < 10 cm proximal from the anal verge. Clinical evaluation of tumor extension consisted of physical examination, barium enema, endoscopy, computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasonography (EUS). Our present trial was directed toward patients with American Joint Committee on Cancer Stage T3 and T4 tumors that were surgically resectable. Patients with distant metastases were excluded from this analysis. Seventy-six patients with lesions that were thought to be clinically resectable (T3, NX, MO and T4, NIX, MO, except tumors preoperatively diagnosed as unresectable by pelvic CT and EUS) were divided into two groups. Group 1 consisted of 35 patients who underwent combination therapy with radiation, intraluminal hyperthermia, and 5-FU suppositories, and then underwent surgery 7 days later. Group 2 included 41 patients who underwent surgery without preMARCH
1996
1 COMBINED TREATMENT
FOR ADVANCED CANCER IN THE LOWER RECTUM/lCHlKAWA
treatment. The sex ratios of the two groups were different, but there were no significant differences in clinicopathologic characteristics (Table I). Methods Radiation. A 4-MeV linear accelerator or Co6@ was used for the radiation therapy. A bilateral irradiation technique through anteroposterior portals was used to deliver the radiation to an area of the pelvis approximately 12 cm in diameter surrounding the carcinoma in the lower rectum. The target volume included the whole dorsal part of the pelvic cavity from the anus up to promontorium. The inferior border was the bottom of the obturator foramen, and the lateral border was 1 cm lateral to the bony margin. Thirty Gy were delivered in 10 fractions, 3 times a week. Hyperthermia. To create hyperthermia in rectal cancer, an inn-alumina1 electrode was developed that consisted of a transmitter for radio frequency radiation and a cooling system.2s A radio frequency sy stem (OMRON, HEH-500, Kyoto, Japan) was then introduced for the hyperthermia. We confirmed that the electrode was safely placed and the intratumoral temperature maintained at 42”Cz9 Intraluminal hyperthermia was performed twice a week at 42°C to 43°C for 40 to 50 minutes within 1 hour after radiation. The details of the practical procedure used in intraluminal hyperthermia were described in a previous report.27 Briefly, the electrode was inserted into the rectum and a counter electrode applied to the lower back. In each case, the preoperative assessment of the degree of stenosis and the distance of the tumor anal verge directed the application of the intraluminal electrode. Whenever possible, the tip of the electrode was located and fixed 2 to 3 cm beyond the proximal margin of the tumor. 5-Fluorouracil suppositories. Studies in both advanced colorectal cancer in vivo and in the laboratory in vitro have suggested an advantage when 5-FU is delivered in conjunction with radiation therapy. Suppositories were made by dissolving 5-FU in a Witepsol suppository base; they contained 100 mg of 5&J. 24,25The patients were given one suppository via the anus every day for 20 days. Intraluminal administration of the suppositories was continued until 1 week prior to surgery. Protocol The protocols for the preoperative treatment in Group 1 are described above. During preoperative treatment, the patients were further examined by barium enemas, colonoscopy, CT, and EUS. Tumor shrinkage was evaluated by conventional digital examination and the examinations described above. One week after completion of the preoperative treatment, the patients underwent an abdominoperineal resection (n = 12) or a low anterior resection (n = 23), with regional lymph node dissection. The patients in Group 2 underwent surgery alone; 13 abdominoperineal resections and 28 low anterior resections.
TABLE
ET AL
I Patients and Clinical Tumor Characteristics Combination Therapy Control Group Group. (n = 35) (n=41) . ~
Mean age (y) Range
56.3 29-75
64.5 39-81
29 6
20 21
21 14
25 16
30 5
39 2
19 14 2
26 12
Sex Men Women Distance from anal verge o-5 5-10 Tumor stage T3 T4 Histologic grade Well differentiated Moderately differentiated Others
TABLE
(cm)
1
II Postooerative Complications Combination Theraw Group (n’i 35)
Surgery LAR APR Curative resection Type of complication Wound or pelvic infection (12.2%) Anastomotic leakage (14.3%) Intestinal obstruction Neurogenic bladder LAR
= low anterior
resection;
23 12 32 (91.4%)
Control Grow (n-41) ’ 28 13 36 (87.8%)
8/35 (22.8%) 4/23 (17.4%)
4i28
2’35 (6.0%) l/35 (2.9%)
3/41 (7.3%) 3/41 (7.3%)
APR
= abdominoperineal
observed after the preoperative previously described. 25
treatment
resection.
were classified as
Prognosis After discharge, all patients were followed up in the outpatient clinic at our hospital. During regular visits to the clinic, they were followed up by conventional digital examination, chest roentegenography, ultrasonogtaphy, pelvic CT, and tumor markers, such as cardioembryonic antigen and CA19-9, etc. The analyses regarding local control and survival were based on follow-up data as of Ju1.y 1994. The follow-up period ranged from 8 to 100 months (median 45) in Group 1 and from 8 to 99 months (median !52) in Group 2. The cumulative survival and local control rates were calculated by the Kaplan-Meier method.
RESULTS Pathological Examination In order to evaluate the histologic changes induced by the preoperative treatment, the resected specimens were subjected to pathologic investigation. The histological changes THE AMERICAN
Surgery * Thirty-two (91%) of the 35 patients in Group 1 underwent curative operation; the remaining 3 underwent noncurative resections due to multiple liver metastases and a positive surJOURNAL
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“11.LJ.1, rl. ;t.....J.J...L.......LIJ..IJ.U.....I
4-s LL . ..__ l.l..J
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Preoperative
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E E 00 50 -
JJI.lLJL....J
Group
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3
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2000
8
t
2000 Time
3000
3000
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igure 2. Local control of recurrence. The rates of local control at 5 years were 89.6% after the combination treatment and surgery, and 72.9% after surgery alone. The difference of 16.7% was not statistically significant.
:..L.l..J.......Ill.ll~U.....I
toplasm (~25%); Grade 2-tell nests consisting of markedly damaged cells, often exhibiting a moth-eaten appearance and simplified glandular structures; and Grade 3-extensive degeneration changes and fibrosis (>75%). Excluding 4 patients with no material for histologic examination, 5, 12, and 11 patients were classified into Grades 1, 2, and 3, respectively. No patient was classified into Grade 0. Local recurrence was observed in 1 of 5 patients in Grade 1, and 2 of 12 in Grade 2. No local recurrence was observed in patients in Grade 3. The histologic grading of resected specimens also correlated with the incidence of local recurrence.
-
Preoperative
-.--
Control
Treatment Group
loo0
Group
(n = 31)
(n = 34)
2Wo Time
3000
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Figure 1. A. Recurrence-free interval after B. Survival related to rectal cancer in patients
curative surgery who have under
gone curative surgery.
gical margin. Thirty-six (88%) of the 41 patients in Groq 2 underwent curative operations; the remaining 5 underwent noncurative surgeries due to liver metastases and a positive surgical margin. The 3 patients in Group 1 and 5 patients ir Group 2 who received noncurative resections were exclude< from this study. No patients were lost during follow-up. Tumoricidal Effects The tumoricidal effects of the preoperative treatment wen evaluated macroscopically and microscopically in the re sected specimens. Of the 32 patients in Group 1, 24 (75%: demonstrated marked tumor shrinkage (reduction in lengtt by 30% or more on barium enema) after the preoperative treatment. Elevated lesions and the marginal elevation o cancerous craters, which were obvious before the preopera tive treatment, were flattened macroscopically after the treatment. This finding was further confirmed by histologic examination using the resected specimens. Microscopic ex amination of the resected specimens showed varying degree of transformation from cancerous mass to scar tissue Complete depletion of cancer cells occurred in 2 patients The degree of transformation was classified as follows: Grade O-no remarkable changes; Grade l-swelling of cells, en larged vesicular nuclei, pyknosis of nuclei and vacuolated cy 348
(n = 31)
3
(n = 34)
1000
Time
Group
(n = 34)
Postoperative Complications Postoperative complications occurred in 14 (1 patient had multiple complications) and 15 patients in Groups 1 and 2, respectively. Incision or pelvic infections, anastomotic leakage, intestinal obstruction, and neurogenic bladder complications were noted, but all the complications were resolved and no sepsis developed. There were no deaths within 30 days after the surgery in either group, and there was no sig nificant difference in the incidence of complications between the two groups (Table II). Survival One patient from Group 1 and 3 patients from Group 2, who died of intercurrent disease, were excbuded from this study. The disease-free survival and cause-specific survival rates are shown in Figure 1. The survival rate of patients in Group 1 was higher than that of Group 2 (81.8% versus 67.6%), although this difference was not statistically significant. The degree of local control is largely responsible for the prognosis of patients with advanced cancer in the lower rectum, and was compared between the two groups. The incidence of local recurrence in Group 1 was lower than in Group 2 (10.4% versus 27.1%), but not statlistically significant (Figure 2). Type of Recurrence As to the type of recurrence,
THE AMERICAN JOURNAL OF SURGERY@ VOLUME 171 MARCH 1996
Group
1 included
3 patients
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with local recurrence and 4 patients with distant metastases. Group 2 included 5 patients with local recurrences, 4 patients with distant metastases, and 2 patients with both local and distant metastases.
COMMENTS The local recurrence of rectal cancer after surgery is thought to result from regrowth of residual cancer cells surrounding the rectum. Since these remnant cancer cells are usually not visible during surgery, it is extremely difficult to remove every cancer cell by surgery alone. To efficiently eliminate all cancer cells in advanced lower rectal cancer, we have developed a preoperative combination therapy using radiation and 5-FU suppositories. A clinical trial of this combination treatment performed in our department from 1977 to 1985 resulted in insufficient local control, although the protocol was successful in some patients.24s26 These results suggested that additional treatments were required for a more effective local response and for improvement in the prognosis of these patients. A few studies reported excellent local control and subsequent prolonged survival with certain preoperative radiation treatments, even with low doses.5 Other studies have reported that low-dose preoperative radiation ~20 Gy was ineffective>* The current trend in radiation therapy is a high-dose treatment or a more biologically intense fractionation.12e17 However, the postoperative morbidity and mortality rates are usually high when preoperative treatment with high-dose radiation is performed. ‘*,13*15Therefore, to achieve adequate therapeutic efficacy with low-dose radiation, additional treatments must be developed. Hyperthermia is well known to enhance the cytotoxic effects of radiation.1a~21~30 This enhancement is more prominent in malignant than normal tissues, because heat loss is minimal in malignant tissues due to poor blood supply and return, and thus poor heat dissipation.‘8-21~30 In a preliminary study, we demonstrated that the device used in the present study achieved a high temperature inside the tumor, and thus provided a marked tumoricidal effect in combination with radiation.27 In addition, the combination of hyperthennia and radiation led to enhanced delivery of radioactivity to the malignant tissues and less damage to the normal tissues. Our present study confirmed that the addition of hyperthermia to combination therapy with radiation and 5-W suppository led to a more effective tumoricidal effect, without any serious postoperative complications. In this study, the incidence of local recurrence at 5 years after the surgery was 27.1% in patients who had undergone surgery without preoperative treatment, and 10.4% in patients who had undergone the treatment. The 16.7% reduction in local recurrence for the preoperative treatment group can be explained as follows: ( 1) a reduced number of cancer cells invading the surrounding tissues through the original tumor; (2) a reduced number of lymph nodes involved by the original cancer cells; and (3) reduced viability of the cancer cells. Surprisingly, the 16.7% reduction in local recurrence produced by our treatment was similar to data from other reliable reports that suggested a benefit of preoperative radiation therapy using high-dose or intense radiation.12-15 Postoperative survival was also prolonged by the preoperTHE AMERICAN
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ative treatment, most likely due to the lower incidence of local recurrence. It is interesting to note that the addition of hyperthermia and 5-FU achieved a similar survival rate to other protocols using high-dose radiation, despite our relatively lower dose. Hyperthermia and 5-FU would undoubtedly be a further enhancement for radiation. One negative aspect of this study is that the number of patients is small and the survival difference was not statistically significant. Nevertheless, our treatment evidently succeeded in reducing the local recurrence rate for advanced1 rectal cancer. The effectiveness of this treatment paradigm will become more definite as the number of patients increases in the future. Another outstanding feature of this trial was a shorter therapeutic term. Conventional powerful preoperative treatments commonly require approximately 8 to 10 weeks from initiation to the day of surgery.16J7 Our treatmeent, in contrast, required only 29 days for completion. Several reports have described delaying the surgical treatmen): for 1 or 2 months whenever a high-dose preoperative radliation therapy was performed, lest unfavorable perioperative complications occur. However, long intervals from the end of the preoperative treatment to the surgery may increase the patient’s risk for further cancer growth and metastasis. In contrast, the moderate dose of radiation used in our trial induced no serious complications, and curative surgery could be performed just 1 week after the preoperative treatment. This shorter delay period is not likely to permit the growth or metastasis of cancer cells. In conclusion, preoperative combination treatment with moderate-dose radiation, intraluminal hyperthennia, and 5FU suppositories reduced the local recurrence ‘of advanced cancer in the lower rectum after surgery, and thereby improved the patients’ prognosis, without any serious postoperative complications. Tk administration of conventional 5-fhwrouracil in suppository form for rectalcancerhasbeen largely ignored by American chiciuns. Its theoretic value and confirmation in tk laboratory is impressive. This nonrandomized trial is another in a growing list of publicationsthat purswdesomeof us that thereis something special and additional about the su@ository method of administration. It may be that this, like the directed chemotherapy via tk obliterated umbilical vein for liver metawlses,will not stand up to a randomized trial. “Clinical alerts” have been distributed by theAJCI fur lessimpressive benefitsfor othercancers and other modali ties.
REFERENCES 1. Malcolm AW, Perencevich NP, Olson RM, et al. ,4nalysis of recurrence patterns following curative resection for carcinoma of the colon and rectum. Surg Gynecol O&t. 1981;152:131--136. 2. Rich T, Gundetson LL, Lew R, et al. Patterns of recurrence of rectalcancerafterpotentiallycumtivesurgery.Cancer. 1983;52:1317-1329. 3. Pilipshen SJ, Heilweil M, Quan SH, et al. Pattern of pelvic recurrence following definitive resections of rectal cancer. Ctmcer. 1984;53: 1354-1362. 4. Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of rectosigmoid and rectum, I: patterns of failure and survival. Cuncer. 1988;61:1408-1416. 5. Steam MJ Jr., Weddish MR, Quan SH, Leaning RH. Pre-operative
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roentgen therapy for carcinoma of the rectum and rectosigmoid. Surg Gynecol Obstet. 1974;138:584-586. 6. Second Report of an M.R.C. Working Party. The evaluation of low dose preoperative xeray therapy in the management of operable rectal cancer: results of a randomly controlled trial. Br 1 Surg. 1984;71:21-25. 7. Higgins GA, Humphrey EW, Dwight RW, et al. Preoperative radiation and surgery for cancer of the rectum: Veterans Administration Surgical Oncological Group trial 2. Cancer. 1986;58:352-359. 8. Dahl 0, Horn A, Morild I, et al. Low-dose preoperative radiation postpone recurrences in operable rectal cancer. Cancer. 199Q66: 2286-2294. 9. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-1450. 10. ShumateCR, RichTA, SkibberJM, et al. Preoperative chemotherapy and radiation therapy for locally advanced primary and recurrent rectal carcinoma. Cancer. 1993;71:369C-3696. 11. Kitamura K, Takahashi T, Kotani T, et al. Local administration of monoclonal antibody-drug conjugate: a new strategy to reduce the local recurrence of colorectal cancer. Cancer Res. 1992;52:6323-6328. 12. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiation therapy as adjuvant treatment in rectal cancer: final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg. 1988;208:606614. 13. Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma: a prospective randomized trial. Cancer. 1990;66:49-55. 14. Neto JAR, Quilici FA, Reis JA. A comparison of non-operative versus preoperative radiotherapy in rectal carcinoma: a lo-year randomized trial. Dis Colon Rectum. 1989;32:702-710. 15. Pahhnan L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Ann Surg. 1990;211:187-195. 16. Mender&all WM, Bland KI, Copeland EM, et al. Does preoperative radiation therapy enhance the probability of local control and survival in high-risk distal rectal cancer? Ann Surg. 1992;215:696-706. 17. Marks G, Mouhiuddin M, Eitan A, et al. High-dose preoperative radiation and radical sphincterpreserving surgery for rectal cancer. Arch Surg. 1991;126:1534-1540.
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18. Suit H, Gerweck LE. Potential for hyperthennia and radiation therapy. Cancer Res. 1979;39:229&2298. 19. Noel1 UR, Woodward KT. Microwave-induc&l local hyperthermia in combination with radiotherapy of human malignant tumors. Cancer. 1980;45:638-646. 20. Gvergaard J. The current and potential role of hyperthermia in radiotherapy. IntJ Radiut Oncol Biol Phys. 1989;16:535-543. 21. Vaupel P, Kallinowski F. Physiological effects of hyperthermia. Recent Results Cancer Res. 1987;104:71-109. 22. Moertel CG, Childs DS, Reitemeier RJ, et al. ‘Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancer. 1969;2:865-867. 23. Byfield JE, Calabro-Jones P, Klisak 1, Kulhanian F. Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and x-rays. Inc J Radiut Oncol Bial Phys. 1982;8:1923-1933. 24. Takahashi T, Nakao E, Watanabe S, et al. 5-Fluorouracil suppository for carcinoma of the rectum. [in Japanese] J&n Sot Cancer Ther. 1976;11:558-560. 25. Takahashi T, Kohno K, Yamaguchi T, Narisav+a T. Preoperative use of 5-fluorouracil suppository for carcinoma of the rectum. Am J Surg. 1982;143:183-185. 26. Takahashi T, Mizusawa H, Kato T, Yamaguchi T. Preoperative irradiation and 5-fluorouracil suppository for carcinoma of the rectum. AmJ Surg. 1988;156:58-62. 27. Takahashi T, Horie H, Kojima 0, Itoh M. Preoperative combined treatment with radiation, intraluminal hyperthermia, and 5-fluorouracil suppositories for patients with rectal cancer. Surg Today. 1993;23:1043-1048. 28. Horie H, Takahashi T, Kojima 0, et al. Innovation and clinical trial of the applicator for local hyperthermia against rectal cancer. In: Sugawara T, Saitoh M, eds. Hype&en& Oncology. London: Talor and Francis; 1989:558-560. 29. Horie H, Takahashi T, Kojima 0, et al. Fundamental study of local hyperthermotherapy for rectal carcinoma. [in Japanese with English abstract] ]pn J Hymic 0~01. 1988;4:31-37. 30. Reinhold HS. Physiological effects of hypertherrnia. Recent Results Cancer Res. 1988;107:32+3.
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