In1 J Rudtufwn
Oncrh~v
Bwl. Phys.. IY77. Vol. 2. pp lO6Y-1074.
Pergamon Press
Printed in the lJ.S.A
l Original Contribution
POST-OPERATIVE RADIOTHERAPY FOR ADENOCARCINOMA OF THE RECTUM AND RECTOSIGMOIDt H. RODNEY WITHERS, M.D.,
Ph.D.?
and MARVIN M. ROMSDAHL, M.D.,
Ph.D.5
Local control of lrectosigmoid cancer in a series of 45 patients treated with post-operative radiotherapy is compared with tlhat achieved in 168 patients without such adjunctive therapy. There is about an 80% probability that lthe local recurrence rate was reduced significantly by irradiating patients in the early post-operative period. The local recurrence rate without radiotherapy varied between 20% and 50% depending upon the stage of the disease. Since a proportion of patients is cured by surgery alone, it is necessary that improved local control be achieved without an appreciable increase in complications, such as small bowel obstruction. Rectum, Radiotherapy,
Adenocarcinoma.
INTRlODUCTION
increments of 200rad); the result was a reduction from 40% to 29% in local recurrence rate in patients treated by abdomino-perineal resection, but no such improvement in patients treated by other methods of resection. No benefit was shown in a study in which doses of only 1500-2000 rad were given pre-operative1y.16 In April 1972 we began using radiotherapy postoperatively in those patients who were considered to be at high risk of local recurrence.
curative surgery for cancer of the rectum and lower sigmoid is common: published results vary between 10%15 and 72%,2’ but a common finding is that local recurrence is the cause of death in at least 50% of those who die from the improved local control disease. 3,4.~‘2~‘7-20Therefore, would, increase the curve rate in this disease. It also would improve the quality of life in those patients who die from distant metastases but with distressing symptoms from concurrent pelvic regrowth. recurrence develops from subclinical Local deposits of cancer left in the peivis at operation. Clinical experience in the treatment of cancer of the head and neck and of the breast has shown that small amounts of residual disease can be controlled by moderate doses of radia.tion (4500-5000 rad).7 There is suggestive evidence that pre-operative radiotherapy improves the results of treatement of recta1 cancer.‘.‘3,‘7,20 Stevens et (~1.~’ reported no local recurrences in 40 patients who were treated prior to curative resection with doses ranging from 5000 to 6000rad in 5-8 weeks. In a Veterans Administration study’3,‘7 lower doses were given (2000-2500rad in
Pelvic
regrowth
after
METHODS
tpresented at Annual Meeting of the American Society of Therapeutic Radiologists, Atlanta, Georgia, 14 October 1976. SDepartment of Radiotherapy. SDepartment of Surgery. The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, TX 77030, U.S.A. Acknowledgemenrs-Dr. G. H. Fletcher suggestions and guidance in developing
AND
MATERIALS
Patients This report deals only with patients whose adenocarcinoma was treated by curative resection. Patients with residual local disease or evidence of distant metastases at the time of surgery (although frequently radiotherapy) treated with post-operative are excluded from the present analysis. The patients forming a group for comparison were treated at the M. D. Anderson Hospital since 1969, mostly by surgery alone, although in some cases, with chemotherapy or chemoimmunotherapy.
approach and in preparing the manuscript. Drs. H. T. Barkley, Jr., C. McBride, M. McMurtrey and S. Simkin contributed significantly to the program. Dr. V. Guinee, Ms. Corky Wright, Linda Carroll, Linda Wallace and Eloise Schreiber helped in analyzing the data and Dr. L. J. Peters provided helpful discussion, particularly with respect to the staging system. The work was partially supported by NIH Research grant CA-06294 from the National Cancer Institute.
provided helpful the radiotherapy 1069
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Oncology
0
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0
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November-December
1977.
Volume 2, No. 1I and No. 12
Staging Staging is identical conceptually with Gunderson and Sosin’s modification’* of the Astler-Caller of Dukes’ original classification.6 modification’ However, for simplicity, the local extent of the primary is described numerically, and the absence or presence of lymph node involvement by A and B, respectively (Table 1, Fig. 1). For readers who prefer a Dukes’ type nomenclature, the Gunderson-Sosin modification is shown in parentheses. Only patients who had extension of tumor through the full thickness of the bowel wall and/or metastasis to lymph nodes were considered for radiotherapy. Table 2 shows the distribution by pathological staging of patients in both the control and study groups. Surgery Radiotherapy was used after various types of surgical resection (Table 3), and varied to some degree with the type of operation.
Fig. 1. Diagrammatic representation of the staging system. The dashed circumferential line represents the peritoneum. Note that a more advanced stage 2 lesion (as denoted by the dashed line) would be stage 3 if it were below the peritoneal reflection. The system is based on Gunderson and Sosin’s modification” of Astler and Caller’s modification* of Dukes’ classification:6 Table 1 shows the comparison of nomenclature.
Table 1. The staging system used in this paper Pathology
Stage
IA
(At)
1B
(Cl)
2A
(Bt)
2B
(Cl)
3A
(B2)
3B
(C2)
4A
(B3)
4B
(C3)
Limited to mucosa and/or submucosa As for 1A but with metastasis in lymph node(s) Extension into muscle but not through the entire thickness of the wall As for 2A but with metastasis in lymph node(s) Extension through entire thickness of bowel wall As for 3A but with metastasis in lymph node(s) Invasion of (not just attachment to) adjacent organs, e.g. vagina, uterus, ureters, bladder, prostate, skin As for 4A but with metastasis in lymph node(s)
Table 3. The distribution of surgical procedures for which radiotherapy was used as an adjuvant
(B2) (C2) (B3) (C3) Total
14/45 24/45 6/45 l/45 45
(31) (53) (13)
and local failure
(2)
o/14 2/14 O/6 O/l
19
6 I 1
Radiotherapy A range of doses, fractionation patterns, and field arrangements and dimensions have been used in treating patients in this study. Of the 45 patients in the series, 33 had only the pelvis treated, 8 had fields extended to the middle or top of L4 and 4 were
Post-operative irradiation group (4/72-9/76) Survival Local failure Number (%) Number (%j
Stage 2A 3B 4A 4B
of patients
I8
Abdomino-perineal Anterior resection with re-anastomosis Anterior resection leaving rectal stump (Hartmann procedure) Local excision Exenteration
The nomenclature in parentheses is that proposed by as a modification of the AstlerGunderson and Sosin” Coller modification* of Dukes’ system.6 The system used here is that of Gunderson and Sosin but with simpler nomenclature. For staging purposes, discrete nodules of neoplastic tissue in mesentery or peri-rectal far are considered to be lymph nodes replaced by tumor. Table 2. Distribution
Number of patients
Technique
rates by stage of disease
Control group Survival Number (%)
(0) (8) (0) (0)
92/ 168 61/168 IO/168 5/168
2145 (4.4)
168
(55) (36) (6) (3)
(l/69-9/76) Local failure Number (%) 13/92 16/61 3/10 3/5
(14) (26) (30) (60)
35/168 (21)
Radiotherapy
for carcinoma of rectum l
treated with fields extending to the top of L2. Although treatments continue to be individualized, our basic approach is now to give 4500 rad central midline dose in 25 fractilons, 5 days per week, through opposed anterior and posterior pelvic portals using 25 MV X-rays. Thereafter, the dose to the volume considered to be at maximum risk is boosted. If a perineal field is used (e.g. after abdomino-perineal resection for low lesions), 1000 rad at D,,, is given in 4 fractions. If lateral fields are used, a midline dose of 600 rad is given in 4 fractions. If there is a perineal wound it is included in the lateral fields. After anterior resection, 600 rad midline dose may be given through a reduced posterior portal. It should be emphasized that this treatment is adapted to the machines we have available. If X-rays of greater energy than 20 MV are not available, the treatment techniques must be more complex. In large patients, it may not be possible to attain a satisfactory midline dose with lower energy beams. Radiotherapy is begun as soon as feasible, usually between 3-8 weeks after surgery. In patients who are not treated by primary closure of the perineum after abdomino-perineal resection, the perineal wound usually is incompletely healed at the start of radiotherapy, but continues healing during treatment. Local recurrence sometimes confirmed by surgical Although exploration, biopsy, or at autopsy, local recurrence was a clinical diagnosis, based primarily on some form of continuing pain, frequently with symptoms from pressure upon or invasion of adjacent viscera or tissues, and sometimes with palpable disease, especially in women. Radiological evidence (e.g. of ureteric obstruction) also was valuable in establishing the diagnosis. The frequency of clinically-diagnosed local recurrence is almost certainly less than the actual frequency because patients may die with distant metastases before symptoms from local recurrence are noticed. RESULTS Local control Table 2 and Figs. 2 and 3 show local control rates in the radiotherapy and comparison groups for stages 3A (B2) and 3B (C2), respectively. Figure 4 shows a similar comparison for the 4A (B3) and 4B (C3) groups combined. There was a reduced rate of local recurrence in the irradia.ted patients in all groups. In 45 patients who received adjuvant radiotherapy, there were 2 recurrences in the irradiated volume, both in stage 3B (C2) patients. One failure was in a patient who received .5200 rad midline dose in 29 fractions: the other was in a man who received 5275 rad midline dose in 30 fractions with some prolongation of overall treatment time (48 days)
H. R. WITHERS and M. M. ROMSDAHL
1071
c%Y%-Yr-
84
Months
Fig. 2. Kaplan-Meier14 plots of local control as a function of time since curative surgery for patients with stage 3A (B2) adenocarcinoma of rectum and lower sigmoid. The graduations on the curves represent survival duration at time patient was last seen. Fourteen patients were treated with radiotherapy (upper curve), 92 without (lower curve). The local recurrence rate without radiotherapy reaches 20%. Months
0 k,
k
E
’
24 I
I
40 I
I
72 I
t .3 L
Fig. 3. Curves similar to those in stage 3B (C2) disease. There were therapy group (upper curve) and 61 (lower curve). The local recurrence 45% in the control
Fig. 2 for patients with 24 patients in the radioin the unirradiated group rate plateaued at about group.
because of intercurrent hepatitis. At autopsy 12 months later, he had a carcinomatous lymphangitis throughout the abdomen and thorax. Both of these recurrences were assumed to reflect the random probability of failure of radiotherapy, although in the second case, pelvic infiltration by retrograde spread from the massive proximal lymphatic involvement cannot be excluded. Complications An analysis of complications is shown in Table 4. Four patients required surgery to relieve obstruction caused by adhesions between loops of irradiated small bowel. All were treated through extended fields-3 to the top of L4 and 1 to the top of L2. All received 4000-4600 rad to the extended fields followed by a boost dose to the pelvis through anterior-
1072
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Oncology
0
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0
Physics
November-December
1977, Volume
2, No.
I1 and No.
12
was followed by a boost dose of 1500 rad central midline dose given through a shrinking posterior portal using ?Zo y-rays. Although the total midline dose was 5100 rad, the dose in the area of proctitis was estimated to be 5800 rad in 28 fractions over 38 days. Since the time of follow-up for many patients is relatively short, the possibility of further complications is a deterrant to more aggressive radiotherapy, and demands that treatment, especially with beams less penetrating than 25 MV X-rays, be planned with a view to minimizing the dose outside the posterior half of the pelvis.
4A and 48
DISCUSSION 21
I 12
I
/ 36
I
1 60
1
1 04
Months
Fig. 4. Curves similar to those in Figures 2 and 3 for stages 4A (B3) and 4B (C3) combined. In the radiotherapy series (upper curve), the disease was stages 4A in 6 patients and 4B in 1 patient. In the no radiotherapy group (lower curve), 10 patients had a stage 4A lesion and 5 were staged 4B. The local recurrence rate without radiotherapy plateaued at 50%.
Table 4. Complications in patients receiving adjuvant postoperative radiotherapy, with relevant data on field size, central midline dose and interval between beginning radiotherapy and onset of complication
Type
Maximum midline Dose (rad)
Latent interval (months)
L2
5450
24
L4
5500
7
L4
5200
6
L4 L5
5600 5100
14 1
Superior margin Top of
Intestinal obstruction Intestinal obstruction Intestinal obstruction Intestinal obstruction Rectal necrosis
posterior or perineal portals. None of the patients had detectable residual disease at the time of the operation to relieve obstruction, but one subsequently developed a pelvic recurrence. The patient whose treatment field had extended to the top of L2 become obstructed by adhesions between relatively inelastic and friable loops of small bowel and died post-operatively with fecal peritonitis. One patient who had had an anterior resection developed necrosis of the posterior rectal wall which required a diverting colostomy. He had received 3600 rad midline pelvic dose given through opposed anterior-posterior portals using 25 MV X-rays. This
Staging Most staging systems for carcinoma of the rectum and rectosigmoid are based on that proposed initially by Dukes.6 The TNM system porposed by the American Joint Committee is probably avoided by most clinicians because it is unduly cumbersome.’ With the passage of time, Dukes’ classification has been found inadequate and has been refined so frequently that familiarity with the original system is a mark of erudition. Through trying to maintain a link with Dukes’ nomenclature, the modifications are easily confused with one another. One source of confusion is that Dukes’ A and B refer to local extent of tumor, while C denotes lymphatic metastases: when nodes are positive (Dukes’ C), the local extent of the tumor must then be described by numerals, up to 3. The staging system used in this analysis is simple, is based on a modification of Dukes’ but is unlikely to be confused with Dukes’ or other modifications. Radiotherapy techniques (a) Post-operative vs pre-operative radiotherapy. Although radiation was given post-operatively, there are certain advantages to pre-operative radiotherapy: in patients treated by abdomino-perineal resection, a smaller volume may be irradiated since there is no need to treat the perineum (as there is when radiotherapy is given after surgery): also, the probability of dissemination of viable tumor cells at surgery should be negligible. Furthermore, it is commonly believed that higher doses are needed post-operatively in order to produce the same result, perhaps because the residual tumor cells are less adequately vascularized, or are growing more rapidly than in the unperturbed tumor. The major advantages of postoperative radiotherapy are that the extent of the disease can be established by the pathologist, and the surgeon can indicate to the radiotherapist areas of poor margin or even incomplete excision which can receive additional doses. Determining the stage of the disease is important in deciding the patient’s need for
Radiotherapy
for carcinoma of rectum 0 H. R. WITHERS,and M. M. ROMSDAHL
elective radiotherapy (and/or chemotherapy), and in evaluating the results of, and potential role for such adjuvants. (b) Treatment uofume. Initially, treatment fields included the para-aortic nodes to the level of L2. After treating 4 of the patients reported upon here, it was decided that the potential benefit of extended fields was outweighed by the risk of radiation enteritis. Now only the pelvis is irradiated (to about the middle or bottom of LS). Local
tumor
control
Because the follow-up times in the radiotherapy group are relatively short, the imporved local control rates with post-operative radiotherapy shown in Figs. 2-4 have only about an 80% probability of being significant. Nevertheless, the trend strongly suggests that radiotherapy could assume an important role as an adjuvant to surgery in the management of rectosigmoid cancer. The dleath rate from local recurrence should be reduced 5- to lo-fold. Also, elective post-operative radiotherapy can imporve the quality of life in those pateints who will die with distant metastases but who now also have local recurrence. Dose
response
relationships
The dose that yeilds the maximal differential between tumor control an’d normal tissue complications has yet to be established. Two patients in this series developed recurrence in the treated volume after
1073
doeses of the order of 5200-5300 rad, and 5 developed complications. Two patients who developed local recurrence who were not included in the analysis are also of interest: I received only 4000 rad of a planned midline dose of 5000rad; the other had a small metastasis in the liver but was given 4500 rad midline pelvic dose in 25 fractions in an attempt to prevent a local recurrence. Both these patients developed recurrence in the treated volume. Results in these latter two patients represent anecdotal experience; but their results, coupled with the data from the 45 patients already reported upon, suggest that it may be necessary to deliver doses of not less than about 5000 rad in 25-30 fractions to ensure a high probability of local control of even subclinical deposits of colorectal adenocarcinoma. Unless the treatment volume is confined to the pelvis, the rate of late intestinal complications appears to increase substantially after midline doses greater than 4500-5000 rad in 25-30 fractions given Patients having only their pelvis post-operatively.22 treated have not been followed for as long as those treated with extended fields so that intestinal injury may still prove to be a problem even with smaller treatment volumes. Thus, the margin between doses leading to recurrence and those leading to complications may be narrow in this disease; accordingly, optimizing treatment equipment and techniques may be critical in determining the successful use of adjuvant radiotherapy in colorectal cancer.
REFERENCES 1. Allen, C.V., Fletcher, W.S.: A pilot study on preoperative irradiation of rectosigmoid carcinoma. Am. J. Roentgenol. 114: 504-508, March 1972. 2. Astler, V.B., Caller, F.A.: The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann. Surg. 139: 846-851, 1954. 3. Bacon, H.E.: Present status of the pull-through sphincter-preserving procedure. Cancer 28: 183-189, Sept. 1971. 4. Cass, A.W., Million, R.R., Pfaff, W.W.: Patterns of recurrence following surgery alone for adenocarcinoma of colon and rectum. Cancer 37: 2861-2865, June 1976. 5. Classification and Staging for Cancer by Site: A Preliminary Handbook. Chicago, America1 Joint Committee for Cancer Staging and End-results Reporting, 1976. 6. Dukes, C.E.: The classification of cancer of the rectum. J. Path. and Bact. 35: 323-332, May 1932. 7. Fletcher, G.H.: Clinical dose-response curve of subclinical aggregates of epithelial cells. J. Radiol. Electrol. Med. Nucl. 53: 201-206, Mar. 1972. 8. Floyd, C.E., Cosley, R.G., Cohn, I.J.: Local recurrence of carcinoma of the colon and rectum. Am. J. Surg. 109: 153-159, Feb. 1965. 9. Gilbersten, V.A.: Improving the prognosis for patients with intestinal cancer. Surg. Gynecol. & Obstet. 124: 1253-1259, June 1967. 10. Gilchrist, R.K., David, V.C.: Lymphatic spread of car-
11.
12.
13.
14.
15.
16. 17.
18.
cinoma of the rectum. Ann. Surg. 108: 621-626, Oct. 1938. Glenn, F., McSherry, C.K.: Carcinoma of the distal large bowel: 32-year review of 1,026 cases. Ann. Surg. 163: 838-849, June 1966. Gunderson, L.L., Sosin, H.: Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma of the rectum. Cancer 34: 1278-1292, Oct. 1974. Higgins, G.A., Conn, J.A., Jordan, P.H., Humphrey, E.W., Roswit, B., Keehn, R.J.: Preoperative radiotherapy for colorectal cancer. Ann. Surg. 181: 624-631, May 1975. Kaplan, E., Meier, P.: Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457481, 1958. Morson, B.C., Bussey, H.J.R.: Surgical pathology of rectal cancer in relation to adjuvant radiotherapy. Br. J. Radiol. 40: 161-165, Mar. 1967. Quan, S.H.Q.: A surgeon looks at radiotherapy in cancer of the colon and rectum. Cancer 31: 1-5, Jan. 1973. Roswit, B., Higgins, G.A., Keehn, R.J.: Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: Report of a national Veterans Administration randomized study. Cancer 35: 1597-1602, June 1975. Shindo, K.: Recurrence of carcinoma of large intestine.
1074
Radiation Oncology 0 Biology 0 Physics
A statistical review. Am. J. Proctol. 25: 80-90, June 1974. 19. Slanetz, C.A., Herter, F.P., Grinnell, R.S.: Anterior resection versus absominoperineal resection for cancer of the rectum and rectosigmoid. Am. J. Surg. 123: 110-l 17, Jan. 1972. 20. Stevens, K.R., Jr., Allen, C.V., Fletcher, W.S.: Preoperative radiotherapy for adenocarcinoma of the rectosigmoid. Cancer 37: 2866-2874, June 1976.
November-December 1977, Volume 2, No. I1 and No. 12
21. Taylor, F.W.: Cancer of the colon and rectum: A study of the routes of metastases and death. Surgery 52: 305-308, Aug. 1962. 22. Wharton, J.T., Jones, H.W., III, Day, T.G., Jr., Rutledge, F.N., Fletcher, G.H.: Exploratory celiotomy and extended fiekd irradiation therapy for invasive squamous carcinoma of the cervix. Obstet. & Gynecol. 49: 333-338, March 1977.
Oncrh~v
Bwl. Phys.. IY77. Vol. 2. pp lO6Y-1074.
Pergamon Press
Printed in the lJ.S.A
l Original Contribution
POST-OPERATIVE RADIOTHERAPY FOR ADENOCARCINOMA OF THE RECTUM AND RECTOSIGMOIDt H. RODNEY WITHERS, M.D.,
Ph.D.?
and MARVIN M. ROMSDAHL, M.D.,
Ph.D.5
Local control of lrectosigmoid cancer in a series of 45 patients treated with post-operative radiotherapy is compared with tlhat achieved in 168 patients without such adjunctive therapy. There is about an 80% probability that lthe local recurrence rate was reduced significantly by irradiating patients in the early post-operative period. The local recurrence rate without radiotherapy varied between 20% and 50% depending upon the stage of the disease. Since a proportion of patients is cured by surgery alone, it is necessary that improved local control be achieved without an appreciable increase in complications, such as small bowel obstruction. Rectum, Radiotherapy,
Adenocarcinoma.
INTRlODUCTION
increments of 200rad); the result was a reduction from 40% to 29% in local recurrence rate in patients treated by abdomino-perineal resection, but no such improvement in patients treated by other methods of resection. No benefit was shown in a study in which doses of only 1500-2000 rad were given pre-operative1y.16 In April 1972 we began using radiotherapy postoperatively in those patients who were considered to be at high risk of local recurrence.
curative surgery for cancer of the rectum and lower sigmoid is common: published results vary between 10%15 and 72%,2’ but a common finding is that local recurrence is the cause of death in at least 50% of those who die from the improved local control disease. 3,4.~‘2~‘7-20Therefore, would, increase the curve rate in this disease. It also would improve the quality of life in those patients who die from distant metastases but with distressing symptoms from concurrent pelvic regrowth. recurrence develops from subclinical Local deposits of cancer left in the peivis at operation. Clinical experience in the treatment of cancer of the head and neck and of the breast has shown that small amounts of residual disease can be controlled by moderate doses of radia.tion (4500-5000 rad).7 There is suggestive evidence that pre-operative radiotherapy improves the results of treatement of recta1 cancer.‘.‘3,‘7,20 Stevens et (~1.~’ reported no local recurrences in 40 patients who were treated prior to curative resection with doses ranging from 5000 to 6000rad in 5-8 weeks. In a Veterans Administration study’3,‘7 lower doses were given (2000-2500rad in
Pelvic
regrowth
after
METHODS
tpresented at Annual Meeting of the American Society of Therapeutic Radiologists, Atlanta, Georgia, 14 October 1976. SDepartment of Radiotherapy. SDepartment of Surgery. The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, TX 77030, U.S.A. Acknowledgemenrs-Dr. G. H. Fletcher suggestions and guidance in developing
AND
MATERIALS
Patients This report deals only with patients whose adenocarcinoma was treated by curative resection. Patients with residual local disease or evidence of distant metastases at the time of surgery (although frequently radiotherapy) treated with post-operative are excluded from the present analysis. The patients forming a group for comparison were treated at the M. D. Anderson Hospital since 1969, mostly by surgery alone, although in some cases, with chemotherapy or chemoimmunotherapy.
approach and in preparing the manuscript. Drs. H. T. Barkley, Jr., C. McBride, M. McMurtrey and S. Simkin contributed significantly to the program. Dr. V. Guinee, Ms. Corky Wright, Linda Carroll, Linda Wallace and Eloise Schreiber helped in analyzing the data and Dr. L. J. Peters provided helpful discussion, particularly with respect to the staging system. The work was partially supported by NIH Research grant CA-06294 from the National Cancer Institute.
provided helpful the radiotherapy 1069
1070
Radiation
Oncology
0
Biology
0
Physics
November-December
1977.
Volume 2, No. 1I and No. 12
Staging Staging is identical conceptually with Gunderson and Sosin’s modification’* of the Astler-Caller of Dukes’ original classification.6 modification’ However, for simplicity, the local extent of the primary is described numerically, and the absence or presence of lymph node involvement by A and B, respectively (Table 1, Fig. 1). For readers who prefer a Dukes’ type nomenclature, the Gunderson-Sosin modification is shown in parentheses. Only patients who had extension of tumor through the full thickness of the bowel wall and/or metastasis to lymph nodes were considered for radiotherapy. Table 2 shows the distribution by pathological staging of patients in both the control and study groups. Surgery Radiotherapy was used after various types of surgical resection (Table 3), and varied to some degree with the type of operation.
Fig. 1. Diagrammatic representation of the staging system. The dashed circumferential line represents the peritoneum. Note that a more advanced stage 2 lesion (as denoted by the dashed line) would be stage 3 if it were below the peritoneal reflection. The system is based on Gunderson and Sosin’s modification” of Astler and Caller’s modification* of Dukes’ classification:6 Table 1 shows the comparison of nomenclature.
Table 1. The staging system used in this paper Pathology
Stage
IA
(At)
1B
(Cl)
2A
(Bt)
2B
(Cl)
3A
(B2)
3B
(C2)
4A
(B3)
4B
(C3)
Limited to mucosa and/or submucosa As for 1A but with metastasis in lymph node(s) Extension into muscle but not through the entire thickness of the wall As for 2A but with metastasis in lymph node(s) Extension through entire thickness of bowel wall As for 3A but with metastasis in lymph node(s) Invasion of (not just attachment to) adjacent organs, e.g. vagina, uterus, ureters, bladder, prostate, skin As for 4A but with metastasis in lymph node(s)
Table 3. The distribution of surgical procedures for which radiotherapy was used as an adjuvant
(B2) (C2) (B3) (C3) Total
14/45 24/45 6/45 l/45 45
(31) (53) (13)
and local failure
(2)
o/14 2/14 O/6 O/l
19
6 I 1
Radiotherapy A range of doses, fractionation patterns, and field arrangements and dimensions have been used in treating patients in this study. Of the 45 patients in the series, 33 had only the pelvis treated, 8 had fields extended to the middle or top of L4 and 4 were
Post-operative irradiation group (4/72-9/76) Survival Local failure Number (%) Number (%j
Stage 2A 3B 4A 4B
of patients
I8
Abdomino-perineal Anterior resection with re-anastomosis Anterior resection leaving rectal stump (Hartmann procedure) Local excision Exenteration
The nomenclature in parentheses is that proposed by as a modification of the AstlerGunderson and Sosin” Coller modification* of Dukes’ system.6 The system used here is that of Gunderson and Sosin but with simpler nomenclature. For staging purposes, discrete nodules of neoplastic tissue in mesentery or peri-rectal far are considered to be lymph nodes replaced by tumor. Table 2. Distribution
Number of patients
Technique
rates by stage of disease
Control group Survival Number (%)
(0) (8) (0) (0)
92/ 168 61/168 IO/168 5/168
2145 (4.4)
168
(55) (36) (6) (3)
(l/69-9/76) Local failure Number (%) 13/92 16/61 3/10 3/5
(14) (26) (30) (60)
35/168 (21)
Radiotherapy
for carcinoma of rectum l
treated with fields extending to the top of L2. Although treatments continue to be individualized, our basic approach is now to give 4500 rad central midline dose in 25 fractilons, 5 days per week, through opposed anterior and posterior pelvic portals using 25 MV X-rays. Thereafter, the dose to the volume considered to be at maximum risk is boosted. If a perineal field is used (e.g. after abdomino-perineal resection for low lesions), 1000 rad at D,,, is given in 4 fractions. If lateral fields are used, a midline dose of 600 rad is given in 4 fractions. If there is a perineal wound it is included in the lateral fields. After anterior resection, 600 rad midline dose may be given through a reduced posterior portal. It should be emphasized that this treatment is adapted to the machines we have available. If X-rays of greater energy than 20 MV are not available, the treatment techniques must be more complex. In large patients, it may not be possible to attain a satisfactory midline dose with lower energy beams. Radiotherapy is begun as soon as feasible, usually between 3-8 weeks after surgery. In patients who are not treated by primary closure of the perineum after abdomino-perineal resection, the perineal wound usually is incompletely healed at the start of radiotherapy, but continues healing during treatment. Local recurrence sometimes confirmed by surgical Although exploration, biopsy, or at autopsy, local recurrence was a clinical diagnosis, based primarily on some form of continuing pain, frequently with symptoms from pressure upon or invasion of adjacent viscera or tissues, and sometimes with palpable disease, especially in women. Radiological evidence (e.g. of ureteric obstruction) also was valuable in establishing the diagnosis. The frequency of clinically-diagnosed local recurrence is almost certainly less than the actual frequency because patients may die with distant metastases before symptoms from local recurrence are noticed. RESULTS Local control Table 2 and Figs. 2 and 3 show local control rates in the radiotherapy and comparison groups for stages 3A (B2) and 3B (C2), respectively. Figure 4 shows a similar comparison for the 4A (B3) and 4B (C3) groups combined. There was a reduced rate of local recurrence in the irradia.ted patients in all groups. In 45 patients who received adjuvant radiotherapy, there were 2 recurrences in the irradiated volume, both in stage 3B (C2) patients. One failure was in a patient who received .5200 rad midline dose in 29 fractions: the other was in a man who received 5275 rad midline dose in 30 fractions with some prolongation of overall treatment time (48 days)
H. R. WITHERS and M. M. ROMSDAHL
1071
c%Y%-Yr-
84
Months
Fig. 2. Kaplan-Meier14 plots of local control as a function of time since curative surgery for patients with stage 3A (B2) adenocarcinoma of rectum and lower sigmoid. The graduations on the curves represent survival duration at time patient was last seen. Fourteen patients were treated with radiotherapy (upper curve), 92 without (lower curve). The local recurrence rate without radiotherapy reaches 20%. Months
0 k,
k
E
’
24 I
I
40 I
I
72 I
t .3 L
Fig. 3. Curves similar to those in stage 3B (C2) disease. There were therapy group (upper curve) and 61 (lower curve). The local recurrence 45% in the control
Fig. 2 for patients with 24 patients in the radioin the unirradiated group rate plateaued at about group.
because of intercurrent hepatitis. At autopsy 12 months later, he had a carcinomatous lymphangitis throughout the abdomen and thorax. Both of these recurrences were assumed to reflect the random probability of failure of radiotherapy, although in the second case, pelvic infiltration by retrograde spread from the massive proximal lymphatic involvement cannot be excluded. Complications An analysis of complications is shown in Table 4. Four patients required surgery to relieve obstruction caused by adhesions between loops of irradiated small bowel. All were treated through extended fields-3 to the top of L4 and 1 to the top of L2. All received 4000-4600 rad to the extended fields followed by a boost dose to the pelvis through anterior-
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was followed by a boost dose of 1500 rad central midline dose given through a shrinking posterior portal using ?Zo y-rays. Although the total midline dose was 5100 rad, the dose in the area of proctitis was estimated to be 5800 rad in 28 fractions over 38 days. Since the time of follow-up for many patients is relatively short, the possibility of further complications is a deterrant to more aggressive radiotherapy, and demands that treatment, especially with beams less penetrating than 25 MV X-rays, be planned with a view to minimizing the dose outside the posterior half of the pelvis.
4A and 48
DISCUSSION 21
I 12
I
/ 36
I
1 60
1
1 04
Months
Fig. 4. Curves similar to those in Figures 2 and 3 for stages 4A (B3) and 4B (C3) combined. In the radiotherapy series (upper curve), the disease was stages 4A in 6 patients and 4B in 1 patient. In the no radiotherapy group (lower curve), 10 patients had a stage 4A lesion and 5 were staged 4B. The local recurrence rate without radiotherapy plateaued at 50%.
Table 4. Complications in patients receiving adjuvant postoperative radiotherapy, with relevant data on field size, central midline dose and interval between beginning radiotherapy and onset of complication
Type
Maximum midline Dose (rad)
Latent interval (months)
L2
5450
24
L4
5500
7
L4
5200
6
L4 L5
5600 5100
14 1
Superior margin Top of
Intestinal obstruction Intestinal obstruction Intestinal obstruction Intestinal obstruction Rectal necrosis
posterior or perineal portals. None of the patients had detectable residual disease at the time of the operation to relieve obstruction, but one subsequently developed a pelvic recurrence. The patient whose treatment field had extended to the top of L2 become obstructed by adhesions between relatively inelastic and friable loops of small bowel and died post-operatively with fecal peritonitis. One patient who had had an anterior resection developed necrosis of the posterior rectal wall which required a diverting colostomy. He had received 3600 rad midline pelvic dose given through opposed anterior-posterior portals using 25 MV X-rays. This
Staging Most staging systems for carcinoma of the rectum and rectosigmoid are based on that proposed initially by Dukes.6 The TNM system porposed by the American Joint Committee is probably avoided by most clinicians because it is unduly cumbersome.’ With the passage of time, Dukes’ classification has been found inadequate and has been refined so frequently that familiarity with the original system is a mark of erudition. Through trying to maintain a link with Dukes’ nomenclature, the modifications are easily confused with one another. One source of confusion is that Dukes’ A and B refer to local extent of tumor, while C denotes lymphatic metastases: when nodes are positive (Dukes’ C), the local extent of the tumor must then be described by numerals, up to 3. The staging system used in this analysis is simple, is based on a modification of Dukes’ but is unlikely to be confused with Dukes’ or other modifications. Radiotherapy techniques (a) Post-operative vs pre-operative radiotherapy. Although radiation was given post-operatively, there are certain advantages to pre-operative radiotherapy: in patients treated by abdomino-perineal resection, a smaller volume may be irradiated since there is no need to treat the perineum (as there is when radiotherapy is given after surgery): also, the probability of dissemination of viable tumor cells at surgery should be negligible. Furthermore, it is commonly believed that higher doses are needed post-operatively in order to produce the same result, perhaps because the residual tumor cells are less adequately vascularized, or are growing more rapidly than in the unperturbed tumor. The major advantages of postoperative radiotherapy are that the extent of the disease can be established by the pathologist, and the surgeon can indicate to the radiotherapist areas of poor margin or even incomplete excision which can receive additional doses. Determining the stage of the disease is important in deciding the patient’s need for
Radiotherapy
for carcinoma of rectum 0 H. R. WITHERS,and M. M. ROMSDAHL
elective radiotherapy (and/or chemotherapy), and in evaluating the results of, and potential role for such adjuvants. (b) Treatment uofume. Initially, treatment fields included the para-aortic nodes to the level of L2. After treating 4 of the patients reported upon here, it was decided that the potential benefit of extended fields was outweighed by the risk of radiation enteritis. Now only the pelvis is irradiated (to about the middle or bottom of LS). Local
tumor
control
Because the follow-up times in the radiotherapy group are relatively short, the imporved local control rates with post-operative radiotherapy shown in Figs. 2-4 have only about an 80% probability of being significant. Nevertheless, the trend strongly suggests that radiotherapy could assume an important role as an adjuvant to surgery in the management of rectosigmoid cancer. The dleath rate from local recurrence should be reduced 5- to lo-fold. Also, elective post-operative radiotherapy can imporve the quality of life in those pateints who will die with distant metastases but who now also have local recurrence. Dose
response
relationships
The dose that yeilds the maximal differential between tumor control an’d normal tissue complications has yet to be established. Two patients in this series developed recurrence in the treated volume after
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doeses of the order of 5200-5300 rad, and 5 developed complications. Two patients who developed local recurrence who were not included in the analysis are also of interest: I received only 4000 rad of a planned midline dose of 5000rad; the other had a small metastasis in the liver but was given 4500 rad midline pelvic dose in 25 fractions in an attempt to prevent a local recurrence. Both these patients developed recurrence in the treated volume. Results in these latter two patients represent anecdotal experience; but their results, coupled with the data from the 45 patients already reported upon, suggest that it may be necessary to deliver doses of not less than about 5000 rad in 25-30 fractions to ensure a high probability of local control of even subclinical deposits of colorectal adenocarcinoma. Unless the treatment volume is confined to the pelvis, the rate of late intestinal complications appears to increase substantially after midline doses greater than 4500-5000 rad in 25-30 fractions given Patients having only their pelvis post-operatively.22 treated have not been followed for as long as those treated with extended fields so that intestinal injury may still prove to be a problem even with smaller treatment volumes. Thus, the margin between doses leading to recurrence and those leading to complications may be narrow in this disease; accordingly, optimizing treatment equipment and techniques may be critical in determining the successful use of adjuvant radiotherapy in colorectal cancer.
REFERENCES 1. Allen, C.V., Fletcher, W.S.: A pilot study on preoperative irradiation of rectosigmoid carcinoma. Am. J. Roentgenol. 114: 504-508, March 1972. 2. Astler, V.B., Caller, F.A.: The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann. Surg. 139: 846-851, 1954. 3. Bacon, H.E.: Present status of the pull-through sphincter-preserving procedure. Cancer 28: 183-189, Sept. 1971. 4. Cass, A.W., Million, R.R., Pfaff, W.W.: Patterns of recurrence following surgery alone for adenocarcinoma of colon and rectum. Cancer 37: 2861-2865, June 1976. 5. Classification and Staging for Cancer by Site: A Preliminary Handbook. Chicago, America1 Joint Committee for Cancer Staging and End-results Reporting, 1976. 6. Dukes, C.E.: The classification of cancer of the rectum. J. Path. and Bact. 35: 323-332, May 1932. 7. Fletcher, G.H.: Clinical dose-response curve of subclinical aggregates of epithelial cells. J. Radiol. Electrol. Med. Nucl. 53: 201-206, Mar. 1972. 8. Floyd, C.E., Cosley, R.G., Cohn, I.J.: Local recurrence of carcinoma of the colon and rectum. Am. J. Surg. 109: 153-159, Feb. 1965. 9. Gilbersten, V.A.: Improving the prognosis for patients with intestinal cancer. Surg. Gynecol. & Obstet. 124: 1253-1259, June 1967. 10. Gilchrist, R.K., David, V.C.: Lymphatic spread of car-
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cinoma of the rectum. Ann. Surg. 108: 621-626, Oct. 1938. Glenn, F., McSherry, C.K.: Carcinoma of the distal large bowel: 32-year review of 1,026 cases. Ann. Surg. 163: 838-849, June 1966. Gunderson, L.L., Sosin, H.: Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma of the rectum. Cancer 34: 1278-1292, Oct. 1974. Higgins, G.A., Conn, J.A., Jordan, P.H., Humphrey, E.W., Roswit, B., Keehn, R.J.: Preoperative radiotherapy for colorectal cancer. Ann. Surg. 181: 624-631, May 1975. Kaplan, E., Meier, P.: Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457481, 1958. Morson, B.C., Bussey, H.J.R.: Surgical pathology of rectal cancer in relation to adjuvant radiotherapy. Br. J. Radiol. 40: 161-165, Mar. 1967. Quan, S.H.Q.: A surgeon looks at radiotherapy in cancer of the colon and rectum. Cancer 31: 1-5, Jan. 1973. Roswit, B., Higgins, G.A., Keehn, R.J.: Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: Report of a national Veterans Administration randomized study. Cancer 35: 1597-1602, June 1975. Shindo, K.: Recurrence of carcinoma of large intestine.
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A statistical review. Am. J. Proctol. 25: 80-90, June 1974. 19. Slanetz, C.A., Herter, F.P., Grinnell, R.S.: Anterior resection versus absominoperineal resection for cancer of the rectum and rectosigmoid. Am. J. Surg. 123: 110-l 17, Jan. 1972. 20. Stevens, K.R., Jr., Allen, C.V., Fletcher, W.S.: Preoperative radiotherapy for adenocarcinoma of the rectosigmoid. Cancer 37: 2866-2874, June 1976.
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21. Taylor, F.W.: Cancer of the colon and rectum: A study of the routes of metastases and death. Surgery 52: 305-308, Aug. 1962. 22. Wharton, J.T., Jones, H.W., III, Day, T.G., Jr., Rutledge, F.N., Fletcher, G.H.: Exploratory celiotomy and extended fiekd irradiation therapy for invasive squamous carcinoma of the cervix. Obstet. & Gynecol. 49: 333-338, March 1977.
