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Endocavitary irradiation for early rectal carcinomas T1 (T2). A series of 101 patients treated with the Papillon's technique
0360~3016(95)02109-4
ELSEVIER
0 Clinical Original Contribution ENDOCAVITARY IRRADIATION FOR EARLY RECTAL CARCINOM Tl (T2). A SERIES OF 101 PATIENTS TREATED WITH THE PAPILLON’S TECHNEQUE JEAN-PIERRE GI%ARD, M.D.,* LOUIS AYZAC, M.D.,* RI~GIS COQUARD, M.D.,* PASCALE ROMESTAING, M.D.,* JEAN-MICHJZL ARDIET, M.D., * FRANCOIS-PIERRE ROCHER, M.D.,* NICOLAS BARESETM.D.,* JEAN-LOUIS CENNI, M.D.* AND JEAN-CHRISTOPHE SOUQUET, M.D.+ *University
Hospital Lyon-Sud and the ‘University
Hospital Croix Rousse, Lyon
Pu-: This work is a retrospective analysis of a series of patients treated with endocavitary irr&ation stressmg the role of transrectal ultrasound (TRUS), which has been used routinely in the staging since 1987. : Between was 65 Tl . Contact x was 92 Gy (60-125) in five fractions, a median doseof 25 Gy/21 h.
on can cure early adenocarcinernaof the rectum with4mt rs as a s&i&ant improvement in the select&onof patients Ewtaoble to t&s rectricted to UT1 NO tumors, endocavitary irradiation should control IocaBy more than 90% of these patients. Any UN1 is a contraindication for endocavitary irradiition alone. Rectal carcinoma, Endocavitary irradiation, Transrectal ultrasound.
INTRODUCTION
4 cm in diameter have been treated with contact x-ray following the strict guidelines of Papillon. Since 1987, transrectal ultrasound (TRUS) has complemented the clinical staging system with a more reliable way of assessing the depth of rectal wall infiltration and the presence of pamrectal lymph nodes (10,27,28]. The aim of this study is to analyze the results of treatment in our institution’s series of 101 patients (36 staged by TRUS), to try to define the criteria of selection for such treatment, and to propose treatment recommendations for this technique of irradiation.
Well-differentiated rectal adenocarcinoma Tl has a less than 10% risk of lymphatic involvement (3, 16, 39). Because of this, these tumors can be treated by local endorectaJ therapy with a high chance of local control and cure. The benefits in terms of quality of life are obvious. Proposed therapies include local excision, coagulation, laser fulguration (4, 7, 12,13,21,25,40), and as a nonsurgical alternative, endocavitary contact x-ray therapy. Initially introduced by Chaoul in 1930,50 KV x-ray therapy was first used by Lamarque to treat rectal cancer ( 19). Papiilon popularized the technique and presented very successful results in the largest published series of 375 patients treated between 1950 and 1986 (2932). Other institutions have used this technique with encouraging results (2, 9, 15, 26, 36, 37). Since 1978, at the Hospices Civils de Lyon T 1 and T2 rectal cancers not exceeding
METHODS Patients
Between 1977 and 1993 a series of 101 patients has been treated in the Department of Radiotherapie-Oncolo-
Reprint requeststo: ProfessorJean-PierreGerard, Service de
Radioth&apie-Oncologic,
AND MATERIALS
thank Bruno Daligandfor his help in the preparationof this manuscript. Accepted for publication 6 July 1995.
Acknowledgement.s-We
Hospices Civils de Lyon, Chu Lyon
Sud, 69495 Pierre Benite Cedex, France.
77.5
776
1, J. Radiation oncology 8 Biology * Physics
gie of the Hospices Civils de Lyon. Digital rectal examination, an essential part of the work-up was always done
in the knee-chest position, with an empty rectal ampulla. An endoscopy was performed in the same position with a rigid proctoscope of 3 cm in diameter giving a direct view of the tumor. The radiation oncologist performing this clinical expiration was able to assess very accurately the stage of the tumor, its maximum diameter, its shape, its mobility, and consistency. According to the St. Mark’s Hospital (28) and UICC 1987 criteria, a tumor is staged Tl when it is polypoid and mobile, whatever the size and consistency. It is expected in such a situation that the tumor is not invading the muscularis propria. A tumor can also be staged Tl if it is polypoid with a very small ulceration, or flat and still mobile not exceeding 2 cm in m~imum diameter. A T2 tumor is always with an ulceration, is fungating, or is a flat lesion more than 2 cm in diameter, hard and tethered. In this case, it is assumed that the tumor is involving the muscularis propria. A careful digital exam for pararectal nodes was always done, and patients with a suspicious exam were referred for surgery, so there is no clinic~ly Nl patient in tbis series. Table 1 gives an overview of the different parameters of the patients and tumors. This group of patients was made mainly of frail patients with a median age of 75 years. Nine patients were assessed as inoperable for general condition, and 23 as high surgical risk. Diagnosis was proven by biopsy, and all patients presented with infiltrating adenocarcinoma usually well or moderately well differentiated. Four patients with poorly differentiated adenocarcinoma were accepted because they were inoperable. In 17 cases adenocarcinoma was described as developing on a preexisting villous or adenomatous polyp. These tumors were sessile in all cases, and in 12 cases aden~~cinoma involved more than 50% of the polyp as judged through multiple biopsies and clinical appreciation. In five cases adenocarcinoma was involving between 30 and 50% of the polyp. Tumors were usually situated in the lower rectum. Only two tumors were more than 10 cm from the anal margin. In 5 cases the tumor was invading the anal canal, and in 20 it was at the upper limit of the anal canal. The tumors were more often on the anterior rectal wall part than on the posterior. This difference may be related to a selection bias as the posterior tumors are sorne~~s technically mom difficult to irradiate in the knee-chest position. The maximum diameter of the tumor was between 0.5 and 5 cm (median at 2.6). In the majority of cases the tumor was polypoid in shape with or without a superficial ulceration in the middle of the polyp. In 15 cases the tumors presented as a de now flat tumor. The consistency of the lesion was assessed as hard in 30 cases, firm in 59, and soft in 13. This last situation was usually in relation to adenocarcinoma developing on a villous polyp. Liver sonography, chest x-ray, and liver functions tests were done in all patients. Computed tomo~aphy was not used in these early cases. A carcino embrionic antigen biological marker was performed in ‘77 patients.
Votume 34, Number
4, I996
Table 1. 101 patients treated by contact x-ray-Patient tumor characteristics Sex male/female Age median (years) Range < (years) Performance status (WHO}* O-l 2
Adenocarcinoma well differentiated M~erately ~fferentiat~ Poorly differentiate Aden~~c~no~ developed on Villous polyp
Adenomatous polyp Tl NO ‘l-2 NO UT1 NO’ UT2 NO UT2 Nl UT3 NO Distance vs. anal margin $3 cm
4-6 cm 7-12 cm Site Anterior POSttXkX
Rigin lateral Left lateral Maximum diameter 0.5-l cm 1.1-2 cm 2.1-3 cm >3 cm
Polypoid Polyp&d with ulceration Fungating Rat
and
46/55 73 35-91 87 14 59 21 4 12 5 65 36
21 10 3 1 32 50 19 39 19 21 22 7 15 42 37 38 32 16 15
* WHCk World E&altb org~~on. i tl: staging by transrectal ultrasound. It was normal in 74, and slightly elevated in 3. Another biological marker known as CA 19-9 was negative in 47 patients and slightly elevated in 7. Total colonoscopy was done in 78 patients. Other benign polyps were found and removed endoscopically in 17 cases. In three patients a s~c~nous color& cancer was discovered and treated by he~colectomy before or after the contact x-ray amend Since 1987, transrectal ~~s~~d has been routinely performed by a team of experienced g~~nterologists (27). A total of 36 patients were staged by transrectal ultrasound. in three cases, TRUS revealed a pararectal node that was considered to be highly suspicious of metastases. These nodes were not palpable on digital rectal examination. Because these three cases were seen during the early period of TRUS staging, they were treated by contact x-ray alone.
Truant was nonsurgical in all cases, and given by contact x-ray following the technical guidelines described
Endocavitary irradiation for early rectal carcinomas TI
by Papillon (29,33). Tbe machine’ used delivered a beam of 50 KV filtered with 0.5 mm burnt. The sourcetumor distance was 4 cm with the proctoscope. The radiation output was high at 20 Gy per min. The dose was prescribed and reported at the exit surface of the proctoscope, i.e., at the surface of the tumor. The percentage depth dose was 50% at 5 mm. The patient was in the knee-chest position, and treated on an outpatient basis with no anesthesia. In 15% of the cases a local anesthetic (10 cc of Xylocaine 1%) was necessary for the first treatment when the dilatation of the anus was painful. The session lasted 1 to 3 min. When the tumor is more than 3 cm in diameter, two overlapping fields may be used. A special proctoscope with a “cap” was sometimes useful for better visualization and irradiation of the tumor. The diameter of the rectoscope was 3 cm, but when the tumor regressed, we often use a 2 cm proctoscope so as not to overdose the normal mucosa around the tumor. The median dose for this series was 92 Gy (range: 60- 125 Gy). Median treatment time was 57 days (range: 19-195 days). The number of fractions was usually four or five according to the stage of the tumor and the response of the tumor after two sessions assessed on day 2 t . If there was on day 2 I a complete regression of the tumor, or a volume reduction of more than 90% the total dose was 80-90 Gy in four fractions over 42 days. If the volume reduction was 80% or less, the total dose was between 100 and 120 Gy in 63 to 80 days. If at the end of contact x-ray the rectal wall is not flat and supple, an iridium boost could be performed 4 to 6 weeks later to supplement the dose in the deeper layer of the rectal wall (33). This impl~t was performed with a perineal implant under general anesthesia if the tumor was situated within 6 cm of the anal margin, or with an endolu~n~ “fork’ ’ implant without anesthesia if the tumor was in the midrectum. Such an implant was used in 28 patients. The dose was prescribed and reported on the 85% isodose of the basal dose according to the Paris System (33). The median dose was 25 Gy in 21 h. Table 2 gives an overview of the treatment technique in this series of 101 patients. Follow-up Follow-up is a very important part of this conservative treatment. Every patient is seen 3 months after the end of iK~ation to evaluate response to the treatment. A complete response is defined as the total disappearance of the tumor, with a normal supple mucosa and rectal wall upondigital and proctoscopic examination. Control biopsy was not performed on a normal mucosa due to the risk of necrosis. Patients are then examined every 4 months for the first 2 years, then every 6 months until the fifth year, and then annually. The median length of follow-up for the whole series of 101 patients was 61 ’ Philips RT 50, Philips Medical System, Crawley, Sussex, England.
fT2)
0
J.-P. GBRARD
777
ef ai.
Table 2. Techniquesof irradiation
I-Contact
x ray-50 k?’
Total dose 530 Gy 395 Gy Fractions 3 : 6-7
101 patients 3’) 6” $! 3h
2 overlappingfields Rectoscopewith cap Rectoscope2 cm
21: 31 sz
II- 192~r-l~lant Perinealimplant Number of active sources 4 5
2X patients 1Xpatients
Spacing between lines Active length of sources 4 cm 5 cm 6Cll
Median dose(Parissystem) Median time of irradiation Endorectal “fork” Numberof active sources Spacingbetweensources Active length of sources 3 cm 4cm Median dose(Paris System) Median time of irradiation (h)
? pts* 1f pts I cm 1 P( 1 f pts 4 pts
25 Gy (15-30 Gy) 21 h (14-37)
10 pts t. 1Xi cm
S patients 5 patients 25 Gy (W-SO, 21 (9-54) ---
* pts: patients.
months (range: 6 to 197 months) and for the 36 patients staged by TRUS, it was 46 mornhs (range: 6 to 81 months). At time of analysis only three patients among survivors had a follow up time shorter than 2 years. Salvage treatment in case of relapse was radical surgery in most instances. Statistical methoa3 All the patients have been ~~e~l~y followed, and none have been lost in follow-up. Data were stored on a computer, and statistical analysis was done using a statistical software* (38). The Kaplan-Meier method was used to construct curves for the overall survival, specific survival, and loco-regional relapse free interval ( 17). Data on patients who died from intercurrent disease were excluded from the calculation of the l~o-~~~~ relapse-free interval. Specific survival was calculated taking only death by rectal carcinoma as an event. The standard error was calculated for relevant percentage. The log rank statistic was used to compare ~s~~~ (22). The Cox proportional-hazards model was used for all multivariate analy’ SPSS@,SPSSFrance,Boulogne,France.
V&me 34, Nirriber 4, 1996 sis and for analysis of risk factors for loco-regional failure (5). A backward regression analysis was used to identify significant factors Variables were kept in the model anly if the standardized maximum likelihood-estimated statistics had a p-value below 0.05. RESULTS Table 3 gives the correlation between staging by digital rectal ex~nation and rectoscopy vs. staging by TRUS. It can be seen that during this second period mainly Tl patients were accepted for contact x-ray therapy, and mast of T2 were referred to other treatments. It appears that TRUS is more sensitive than digital rectal examination to detect infiltration of the muscularis propria, as nine patients clinically Tl were staged T2 or T3 with ultrasound. TRUS especially appears to more sensitively detect early nodal pamrectal me&stases as two patients staged UN1 developped a pararrectal nodal relapse after complete primary locat control. Digital rectal examination failed to detect these nodes at the time of initial staging. Icespcrnse to cmtaet x-ray treatment On day 21, 47 patients had a complete response or a reduction of 90% or more of the volume of the tumor. Fifteen patients had a reduction of between 50 and 60% of the initial volume, and 39 patients a reduction of between 70 and 85%” At the time of the last session of contact therapy a complete response was seen in 76 patients, 25 patients had a response between 90 and 95% of the initial volume. Out of 28 patients who underwent an iridium implant, 15 had no detectable lesion at the time of implant and 13 had superficial residual ideation. Three months after completion of irradiation all patients were estimated to be in complete remission, with five patients having some minimal residual thickening of the rectal wall at the site of the initial tumor. Local failure Local failure is defined as a recurrence in the tumor bed within the field of irradiation. It usually presents as an ulceration with some ~gating aspect and bleeding, Edison is always present. Such local failure was seen in eight cases (one Tl, sevenT2), with a median irtterval to recurrence of 19 months (range: G-42). Local failure was proven in all cases by cytology or biopsy, CEA and CA 19-9 were negative in all cases. CT scan and TRUS Table 3. Correlation between staging by digital rectal examinadon and rigid proctoscopy vs. staging by tramrectal ultrasound UT1 NO 31 l-1 NO 5T2NU
22 0
uT2NO 7 3
UTZNI 1 2
UT3 NO 1 0
did not appear useful in the diagnosis. A salvage treatment with surgery was attempted and successful in five of the eight recurrences (three Mile’s amputations and two restorative surgeries). In three cases only a local treatment was performed, which resulted in ultimate local control in two patients (one cryosurgery and one contact x-ray). Nodal failure N&d failure is defined as a recurrence in the pamrectal nodes with or witbout local relapse. It presents usually as a hard round nodule between 0.5 and 2 cm in size in the pararectal wall, with a normal mucosa on digital and proctoscopic examination. Such a failure was seen in seven cases (one Tl, six T2). One patient (T2) presented with a local failure and a nodal failure at the same time. The median interval to recurrence was 34 months (range: 12-46 months). The diagnosis was confirmed in all cases by surgery with pathologic examination. CT scan was able to show the nodes in three out of seven cases, and TRUS in three out of three cases. The metastatic nodes were situated at a mean distance of 2 cm (0.5-4 cm) above the primary. Meart diameter on digital examination was 1.5 cm. The nodule was located at the posterior half of the rectal circumference in five cases, and anteriorly in two cases. CEA and CA 19-9 were negative in all cases. All seven patients underwent surgical salvage with four Mile’s amputations and three restorative surgeries. Pathological reports showed only one metastatic node in four cases, and three to five positive nodes in three cases, One of these patients died of distant metastases (6 years after initial treatment, and 2 years after nodal recurrence). One died from inte~~nt disease. Five are alive with no evidence of disease (1 to 7 years after nodal failure).
Ultimate pelvic control is defined as no evidence of disease at time of last follow-up nor of death in the pelvis. Out of 101 patients, 14 relapsed either in the primq site (n = 8 patients) and/or in the pararectal nodes (n = 7 patients). One of them was treated only palliatively. Eleven underwent radical salvage surgery with 10 local control and one secondary recurrence in the pelvis. Ultimate local control has been achieved in 99 patients out of 101. Out of the 11 salvage surgeries, there were five restora~ve rectal resections, and six Miles abdominoperineal resections. Overall rectal preservation was possibie in 92 out of 99 patients, with local control in the pelvis. Distant me&stases and death-survival Six patients developed distant metastases, four of them without local or nodal failure and two after locoregiomd failure (synchronous in one case and metachronous in one). Overall, 26 patients have died: 5 of cancer, 15 of intercurrent disease, 2 of second rn~i~~ci~, and 3 of ~0~ cause. The overall p~bability of survival (Kapl~-M~i~r) is
Endocavitary irradiation for early rectal carcinomas Tf Cl”2) 0 J.-P. GERARD PTul.
779
99 T .-
78
L
,7
’6
,6
.-Z h = n 8
,5
2
,3
,4
2
Month Fig. 1. Specific andoverall survival of 101patientswith rectal ade~~cinoma
treatedwith endocavit~ irradia-
tion. Numberat risk: 3 years: 78; 5 years: 52; 8 years: 24.
83.3% at 5 years [standard error (SE}: 4.41 and 42.8% at 8 years (SE: 7.3). The specific probability of snrvival is 94.4% at 5 years (SE: 2.7%) and 89.1% at 8 years (SE: 4.6%) (Fig. 1). There is no significant difference in survival between Tl and T2 (Table 4).
by TRUS. The pararectal lymph~no~~y was not felt by digital rectal exam at the time of first treatment. All of these have been salvaged by surgery, preserving the anal sphincter in three out of five cases.
Group of patients staged by TRUS In the group of 36 patients staged by TRUS since 1987 with a median follow-up time of 43 months, there has been one death due to distant metastases without locoregional relapse and two deaths by intercurrent disease, giving an overall 4 years survival of 85% (SE: 7.7) with 14 patients at risk at 4 years. In this group there have been two local failures (two: both UT2 NO) and three nodal failures (one: UT2 NO, two: UT2 Nl). No local or nodal failure was seen for UT1 NO. Two out of three nodal failures were observed in patients staged as UN1
The immediate tolerance of contact x-ray therapy and iridium implant was very good even in very old and frail patients. Less than lS% of patients experienced moderate tenesmus, imperiosity, or diarrhea during the course of the treatment. Two to 3 months after completion of the treatment two types of side effects may occur: ulceration and bleeding. Ulceration of the rectal mucosa was usually superficial in the tumor bed. This has been observed in 27 cases with a median time of occurence of 4 months (range: 2- 14 months). The ulceration was usually symptomatic and
Table 4. Overall and specific survival according to clinical staging (C TN) 0 Years
5 Years
_-..--
8 Years
No. at risk
Survival
SE*
No. at risk
101 101
52 52
0.8334 0.9445
0.0047 0.0271
18 18
0.6264 0.8906
0.0739 0.0462
Overall survival CT1 NO CT2 NO
65 36
30 22
0.868 0.769
0.068 0.078
I1 7
0.678 0.553
0.095 0.109
0.730
Specific survivd CT1 NO CT2 NO
65 36
30 22
0.975 0.856
0.024 0.068
11
0.910 0.856
0.067 0.068
0.820
All patients OveralI survival Spezitic survival
7
SurvivaI --_.
SE-----
Log rank value
No. at risk
I. J. Radiation Oncology 0 Biology l F‘hysics
780
had a median duration time of 3 months (2-6 months). Local corticosteroids were given to six patients. All ulcerations healed with no late sequela. Mild rectorrhagia during bowel movement was usually seen 3 to 24 months after treatment (median time of occurence: 7 months). Some bleeding was observed in 46 cases with no instances of anemia. It may cause anxiety for the patient but does not require treatment; however, local laser or cryotherapy had good symptomatic results. Some bleeding may last for 1 to 4 years. Median duration time was 23 months in this series. The overall tolerance of this radiation treatment was usually very good, with no Grade 3 complications and no change of transit or sphincter function. The follow-up was very satisfactory because there was no modification of the rectal wall or pelvis, which remained very supple and easy to examine. One to 3 years after completion of therapy localized hypopigmentation was seen in the treated area. Biopsy of the irradiated mucosa is inadvisable if no obvious lesions are visible.
The main end point chosen in the analysis of prognostic factors was local and nodal failme. There were 14 such locoregional recurrences. Figure 2 shows that the probability of locoregional failure is 16.5% (SE: 6) at 4 years, with no other events after this interval. On univariate analysis with the log rank test (Table 5), four prognostic factors are significant: T and UT stage, maximum diameter, and type of tumor. The response at day 21 after two sessions of contact x-ray is of borderline significance. The
Volume 34, Number 4, 19%
Cox model with univariate procedure shows that T stage remains a significant prognostic factor with a relative risk (RR) of 25.99 (3.41-197. 86). The RR is not calculated for UT stage or maximum diameter as there is no relapse in UT1 or tumors smaller than 2 cm. On multivariate analysis, T2 NO vs. Tl NO shows a RR of 5.3.4 (1.192.39), which is not any more significant if the dose of contact x-ray is not included in the model. The risk of loco-regional failure is less than 10% in Tl NO, regardless of the staging (clinical or TRUS). Conversely, in T2 lesions the risk of Leo-regions failure is 40% at 4 years (Table 5), and out of three patients staged UNl, two developed a pararectal nodal recurrence. DISCUSSION Endocavitary irradiation appears to be a reproducible technique as the results of the present’series of 101 patients are comparable to those of Papillon (29, 33). The risk of local faihue (local and nodal) is between 10 and 20% after contact x-ray, and most of these relapses can be salvaged by subsequent cent usually surgery. Other authors report similar results (2, 11, 15, 20, 36, 37). In some series the rate of local failure is higher (9, 18,26). This can be due to selection bias or technical problems. It is important in this comparison to take into account onIy tumors treated by contact x-ray and to exclude those treated by adjuvant contact x-ray given after local excision or laser destruction, which often show better results (31). This is the first series of patients treated with contact x-ray that has been staged by TRUS. This method seems
2 a- 111 0,
.
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.
.
.
.
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w
12
l
,,.....,,-.
24
36
.,,,,.,,,-”
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48
w
60
,,,,
72
m
..,..,,
r(l
96
84
Month Fig. 2. Overall probabi~~ of locoregional failure (local + nodal) in 101 patients. No event observed after 48
months ~Kap~~-Meier Method).
End~avit~
Table 5. Loco-regionaI
i~adiatioR
for
early
rectal
Tl
c~in~mas
(T2)
l J.-P.
GERARD
er al.
781
failures (15 patients) and prognostic factors related to patient and tumor ~Kap~~-Meier~ “Loco-regional relapse-free interval
-
Risk factor
Sex Male Female Age 570 >70 Pe~~~~~ status <2 22 Differentiation =well =moderate =poor TN Tl NO T2 NO UT1 NO UT2 NO UT2 Nt LT3 NO Distance anal canal Upper limit Invaded At distance Locaiization
Anterior = N Anterior = Y Lateral left = N Lateral left = Y Lateral right = Y Posterior = N PosWior = Y Diameter F-32 cm >3 Type Polyp&d
Polypoid ulcu%ed Fungating Sessile plan Response at Day 21 90-100% W-90% do% * Statistically
significant
No. of patients
2 Years
4 Years
,--
46 55
0.960 (0.02) 0.826 (0.06)
0.874 (O”O5f 0.780 (0.07)
0.52
45 56
0.920 (0.04) 0.914 (O.~j
0.778 (0.07) 0.817 (0.06)
0.92
87 14
0.911 (0.O3f f
0.788 10.05) 1
0.22
59 21 4
0.902 (0.04) 0.947 (0.05) --
0.831 (0.05) 0.775 (0.11) -
65 36
0.984 (0.02) 0.8 I 1 (0.07)
0.933 (0.04) 0.5% (0.09)
0.0002’
22 10 3 I
:0.09, 0.900 0.666 (0.27) -
1 0.600 (0.18) 0.333 (0.271 --
0.023” -
20 5 77
0.928 (0.07) 0.888 (0.04)
0.759 (0.12) 0.792 (0.05’)
0.83
63 39 82 22 21 84 19
0.926 0.918 0.94 I 0.835 0.944 0.907
0.847 0.760 0.8 I I 0.771 0.877 0.793 0.875
22 42 37
0.911 iO.05) 0.811 (0.08)
0.680 (0.09) 0.703 (0.10)
o.O02* 0.002’
38 32 16 15
0.960 0.925 0.785 0.859
0.918 0.754 0.687 0.752
(0.06) (0.09) (0.131 (0.13)
0.09 0.037* 0.10
47 39 t.5
0.948 (0.03) 0.914 (0.05) 0.875 (0.08~
0.9 11 (0.05) 0.734 (0.08~ 0.715 (O.l2>
0.09 0.077
(0.04) (0.04) (0.03) (0.09) (0.05) (0.33)
(0.04) (0.05) (0.11) (0.09)
(0.05) (0.07) (0.05) (0.10) (0.08) fO.051 IO. 1 i j
p-value log rank -I
0.81
0.52 0.41 0.50 0.42
difference.
’ Strong difference. i- Very high difference.
more reliable than digital rectal ex~ati~~ to assess the depth of penetration of the tumor within the rectal wall (14, 27), although the clinical staging performed by an experienced specialist is well correlated with the pathologic staging (23). In this series of 101 patients three points can be seen. First, in CT1 patients (65 patients) the risk of foco=regiomtI relapse is 6.6% (2 patients) vs. no relapse in 22 UT1 patients. This difference is not very
large for this group of patients and TRWS will not greatly modify the selection process and the m&ts. Second, in CT2 NO (36 patients), as in UT2 NO (10 patients), the risk of loco-regional relapse is the same after e&ocavitary irradiation (40%). Such a alit atone c-o! be recommended ix3 this situation. Thh$ the most important benefit of TRUS is its capacity to detect am& ~~ nodes in the pararfzctal wall. Out of three patients UNf
182
I. J. RadiationOncology 0 Biology l Physics
and clinically NO, two have presented pararectal nodal failure. At the present time, TRUS appears essential for the selection of patients as it is more sensitive and specific than digital rectal examination in assessing the infiltration of the muscularis propria, and most of all because any patient with a suspicious pararectal node should not be treated by endocavitary local treatment alone. Tumors suitable for treatment by contact x-ray (or other local curative treatment) should always be selected after a careful TRUS when it is feasible. Patient selection also relies upon careful digital rectal ex~nation in the knee-chest position, rigid proctoscopy, and histological subtypes. A patient of any age with a Tl NO lesion staged by TRUS, not exceeding 4 cm in largest diameter, would be suitable for endocavitary irradiation alone. The tumor must be well or moderately well ~fferentiated. Poor differentiation is associated with a higher risk of lymphatic spread and usually represents a contraindication for purely local treatment (16, 39). The tumor must be accessible to the contact tube, i.e., within the first 12 cm of the distal rectum. If there is a complete response on day 2 1, this is a good confi~a~on for the indication of end~avi~ irradiation alone. Patients with T2 NO lesions should not be treated by endocavitary irradiation alone, but in patients for whom external beam radiation therapy proves difficult to perform, contact x-ray can be used to treat ~l~oid T2 tumors (or tumors with a small superficial ulceration) not exceeding 3 cm in diameter. If the response on day 21 is not complete, or if there is some residual lesion at the end of the contact x-ray, treatment an iridium implant is recommended. Patients with an Nl tumor diagnosed either by digital exa~nation or TRUS should never be treated by endocavitary irradiation alone. The protocol for irradiation can currently be standardized according to tumor volume. For tumors smaller than 2 cm in diameter: day 1: 30 Gy; day 7: 25 Gy; day 21: 20 Gy; day 36: 15 Gy; total dose: 90 Gy in four fractions, For tumors between 2 and 4 cm in diameter: day 1: 35 Gy; day 7: 25 Gy; day 21: 20 Gy; day 36: 15 Gy; day 51: 15 Gy; total dose: 110 Gy in five fractions. If the response is not complete at the end of contact x-ray a boost with an iridium implant is given after a rest period of 4 weeks. The dose of ~~~ is 25 Gy in 1 day. These are general ~co~endations that can be modulated according to type of tumor and the pace of regression.
Volume 34, Number 4, 19%
With such a selection and technique one can expect to have a high rate of local control with no complications except moderate rectal bleeding due to late radiation telangiectasia of the rectal mucosa. This is a fully ambulatory treatment, requiring no general anesthesia, and suitable for all patients. A close follow-up is necessary to detect unusual locoregional failures. In case of loco-regional relapse, salvage treatment is often efficient, sometimes preserving anal sphincter function. It is possible to treat similar tumors with other techniques like local excision (7, 12) laser destruction (13, 21), and transrectal endoscopic microsurgery (4). Comparisons between these different approaches are sometimes difficult because the selection of patients varies from one series to the other, and end points are analyzed in different ways. Endocavitary vacation compares favorably in terms of cost/benefit ratio with the other techniques. It is true that with contact x-ray there is no objective data to assess the pathologic stage of the tumor (degree of infiltration in the rectal wall) but TRUS appears very accurate in such an evaluation (14,27) and the good correspondence between TRUS staging and results with contact x-ray seems a reliable criterion. The very low rate of complication, the simplicity, and the low cost of the technique are strong arguments in favor of contact x-ray. Purely endocavitary treatment of rectal cancer with contact x-ray or local excision is possible only if the risk of lymphatic spread is low. If this criterion is not fulfilled, radical surgery usually associated with external beam irradiation is the standard treatment. In inoperable patients it is possible to have a curative effect on T2 or small T3 tumors by external beam irradiation with or without chemotherapy and local excision (1, 24, 25, 34, 35, 40), or endocavitary irradiation (5,8, 11,30,32). These ongoing pilot studies will define the indications and limits of such approaches. In conclusion, curative ~eatment of small rectal cancer with contact x-ray therapy according to Papillon’s technique appears to be efficient, safe, cheap, and reproducible. It is, of course, necessary to use a dedicated low voltage machine with a tube, which can be used by hand. With strict selection of tumors using transrectal ultrasound and good technique of irradiation, such a treatment could be very beneficial and have great applications.
REFEXElNCES
1. Bennet, C. J.; Sombeck, M. D.; Mende~~l, W. M.; Million, R. R.; Bland, K. I.; Cop&and, E. M. Conservative alternatives in the management of early adenocarcinoma of the rectum. South. Med. J. 86:409-413; 1993. 2. Bey, P.; Peiffert, D.; Denis, B. J.; Pemot, M. Radiotherapie exclusive des petits cancers du rectum. Gastroenterol. Clin. Biol. 16:A123; 1992. 3. Brodsky, 3. T.; Righard, G. K.; Cohen, A. M.; Minsky, B. D. Variable correlated with the tisk of lymph node metastasis in early rectal cancer. Cancer 69:22-326; 1992. 4. Buess, G.; Mentges, B.; Manncke, K. et al. Technique and
results of transanal endoscopic microsurgery in early rectal cancer. Am. J. Surg. 163:63-70, 1992. 5. Calitchi, E.; Otmezguine, Y.; Julien, M.; Le Bourgeois, J. P. Combined approach in the conservative management of rectal cancer (Abst). Eur. 3. Cancer 29A(Suppl. 6):521; 1993. 6. Cox, D. R. Regression model and life-tables. J. R. Stat. Sot (B) 34:187-220; 1972. 7. Decosse, J. J.; Wang, R. J.; Quan, S. H.; Friedman, N. B.; Stemberg, S. S. Conservative treatment of distal rectal cancer by local excision. Cancer 63:219-223; 1989.
~nd~avit~
i~adiation for early rectal carcinomas Tf
8. Deprets, J.; Gtmezguine, Y.; Grimard, L.; &lit&i, E.; Julien, M. Conservative management of tumors of tnmors of the rectum by radiotherapy and local excision. Dis. Colon Rectum 33:113-116; 1990. 9. Fabri, M. C.; Kac, J.; Zimmermann, P.; Rougier, Ph.; Eschwege, F. Traitement conservateur des ad&mcarcinomes du rectum par contactherapie (Abst). Gastroenterol. Clin. Biol. 16:A123; 1992. 10. Feifel, G.; Hildebrandt, V.; Dhom, G. Assessment of depth of invasion in rectal cancer by endosonography. Endoscopy 1964-67; 1987. Il. Gerard, J. P. The use of radio~empy for patients with low rectal cancer: An overview of the Lyon experience. Aust. N.Z. J. Surg. 64:457-463; 1994. 12. Graham, R. A.; Garnsey, L.; Jessup, 3. M. Local excision of rectal carcinoma. Am. J. Surg. 160:306-312; 1990. 13. Herrera, L.; Petrelli, N. J.; Mittelman, A.; Boyes, D. G. Photodynamic therapy in patients with colorectal cancer. Cancer 57:677-684; 1986. 14. Hildebrandt, V.; Feifel, G. Preoperative staging of rectal cancer by intrarectal ultasound. Dis. Colon Rectum 28:4246; 1985. 15. Horiot. J. C.; Roth, S. L.; Calais, G.; Nabid, A.; Bone Lepinoy, M. C.; Loiseau, D. The Dijon clinical staging system for early rectal carcinoma ~enabIe to in~acavi~ ~eat~nt techniques. Radiother. Gncol. 18:329-337; 1990. 16. Huddy, S. P.; Husband, E. M.; Cook, M. G.; Gibbs, N. M.; Marks, C. G.; Heald, R. J. Lymph node metastases in early rectal cancer. Br. J. Surg. 80:1457-1458; 1993. 17. Kaplan, E. L.; Meier, P. Non parametric estimation from incomplete observation. J. Am. Stat. Assoc. 53:457-481; 1958. 18. Kovalic, J. J. Endocavitary irradiation for rectal cancer and villous adenomas. Int. J. Radiat. Gncol. Biol. Phys. 14:261264; 1988. 19. Lamarque, P. L.; Gras, C. G. La radiotherapie de contact des cancers du rectum. J. Radiol. Electroi. 27:333-348; 1946. 20. Lavery, J. C.; Jones, I. T.; We~ey, F. L.; et al. Definitive m~agement of rectal cancer by contact (endocavitary) irradiation. Dis. Colon Rectum 30:835-838; 1987. 21. Madden, 3. L.; Kandalaf, J. S. Clinical evaluation of electrocoagulation in the treatment of cancer of the rectum. Ann. Surg. 166:413-419; 1967. 22. Mantel, N.; Haensenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. Natl. Cancer Instit. 22:719-748; 1959. 23. Marks, G.; Mobiuddin, M.; Masoni, L. The reality of radical sphincter preservation surgery for cancer of the distal 3 cm of rctum following high dose radiation. Int. J. Radiat. Oncof. Biol. Phys. 27:779-783; 1993. 24. MC Cready, D. R.; Gta, D.; Rich, J. A.; Thielvoldt, D.; Jcssup, J. M. Prospective phase I trial of conservative man-
25. 26.
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agement of low rectal lesions. Arch. Surg. 124:67-70; 1989. Minsky, B. D. Clinical experience with local excision and post operative radiation therapy for rectal cancer. Dis. Colon Rectum 36405-409; 1993. Myerson, R.; Walz, B. J.; Kodner, I. J.; Fry, R. Endocavitary radiation for early rectal carcinomas: The experience at Washington University (Abst). Int. Radiat. Gncol. Bial. Phys. 13(Suppl. I): 194; 1987. Napoleon, B.; Pnjol, 8.; Berger, F.; Valette, P. J.; Gerard, J. P.; Souquet, 3. C. Accuracy of endosonog~hy in the staging of rectal cancer treated by radio~er~y. Br. J. Surg, 78:785-788; 1991. Nicholls, R. J.; Galloway, J.; Mason, Y .: Boyle, P. Clinical staging of rectal cancer. Br. J. Sug. Suppl. 72:551-552; 1985. Papillon, J. Intracavitary irradiation of early rectal cancers for cure. A series of 186 cases. Cancer 36:696-701; 1975. Papillon, J. Present status of radiation therapy in the conservtive management of rectal cancer. Radiother. Oncol. 17:275-283: 1990. Papillon J. Rectal and anal cancers. Conservative treatment by irradiation. An alternative to radical surgery. Berlin: Springer; t982. Papillon, J. Role de la radio~~rapie dans la preservation anale pour le cancer du bas rectum. Lyon Chir. X7:21 -24; 1991. Papitlon, 3.; Montb~~n, J. F.; Gerard, J. P.; Chassard, J. L.; Ardiet, J. M. Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int. J. Radiat. Oncol. Biol. Phys. 17: 116 I- 1169; 1989. Rosenthal, S. A.; Yeunc, R. S.; Weese, J. L.; Coaia, L. R.; Hanks, G. E. Conservative managemlent of extensive low lying rectal carcinomas with transanal local excision and combined preoperative and postoperative radiation therapy. Cancer 69:335-341; 1992. Rouanet, P.; Saintaubert, B.; Fabre, B.; Astre, J. M.; Dubois, J. B.; Solassol, H.; Pujol, H. Conservative treatment for low rectal carcinoma by local excision with or without radio~erapy. Br. J. Surg. 80:1452- J4S655: 1993. Sischy, B.; Graney, M. J.; Hinson, E. J.; ef al. ~nd~avit~ irradiation for aden~~cinoma of the rectum. Cancer 34:333-339; 1984. Sischy, B.; Himson, E. J.; Wilkinson, D. K. Definitive radiation therapy for selected cancers of the rectum. Br. J. Surg. 75901903; 1988. SPS Base system user’s Guide-Release 6.0. Chicago, IL: SPSS Inc.; 1993. Willet, C. G.; Compton, C. C.; Shellito, P. C.; Efird, J. T. Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. 6.‘ancer73:27162720; 1994. Wong, G. S.; Stem, H. S.; C~ngs, B. J. Local excision and post operative radiation therapy for rectal carcinoma. lnt. J. Radiat. Oncol. Biol. Phys. 25:569--675: 1993.
ELSEVIER
0 Clinical Original Contribution ENDOCAVITARY IRRADIATION FOR EARLY RECTAL CARCINOM Tl (T2). A SERIES OF 101 PATIENTS TREATED WITH THE PAPILLON’S TECHNEQUE JEAN-PIERRE GI%ARD, M.D.,* LOUIS AYZAC, M.D.,* RI~GIS COQUARD, M.D.,* PASCALE ROMESTAING, M.D.,* JEAN-MICHJZL ARDIET, M.D., * FRANCOIS-PIERRE ROCHER, M.D.,* NICOLAS BARESETM.D.,* JEAN-LOUIS CENNI, M.D.* AND JEAN-CHRISTOPHE SOUQUET, M.D.+ *University
Hospital Lyon-Sud and the ‘University
Hospital Croix Rousse, Lyon
Pu-: This work is a retrospective analysis of a series of patients treated with endocavitary irr&ation stressmg the role of transrectal ultrasound (TRUS), which has been used routinely in the staging since 1987. : Between was 65 Tl . Contact x was 92 Gy (60-125) in five fractions, a median doseof 25 Gy/21 h.
on can cure early adenocarcinernaof the rectum with4mt rs as a s&i&ant improvement in the select&onof patients Ewtaoble to t&s rectricted to UT1 NO tumors, endocavitary irradiation should control IocaBy more than 90% of these patients. Any UN1 is a contraindication for endocavitary irradiition alone. Rectal carcinoma, Endocavitary irradiation, Transrectal ultrasound.
INTRODUCTION
4 cm in diameter have been treated with contact x-ray following the strict guidelines of Papillon. Since 1987, transrectal ultrasound (TRUS) has complemented the clinical staging system with a more reliable way of assessing the depth of rectal wall infiltration and the presence of pamrectal lymph nodes (10,27,28]. The aim of this study is to analyze the results of treatment in our institution’s series of 101 patients (36 staged by TRUS), to try to define the criteria of selection for such treatment, and to propose treatment recommendations for this technique of irradiation.
Well-differentiated rectal adenocarcinoma Tl has a less than 10% risk of lymphatic involvement (3, 16, 39). Because of this, these tumors can be treated by local endorectaJ therapy with a high chance of local control and cure. The benefits in terms of quality of life are obvious. Proposed therapies include local excision, coagulation, laser fulguration (4, 7, 12,13,21,25,40), and as a nonsurgical alternative, endocavitary contact x-ray therapy. Initially introduced by Chaoul in 1930,50 KV x-ray therapy was first used by Lamarque to treat rectal cancer ( 19). Papiilon popularized the technique and presented very successful results in the largest published series of 375 patients treated between 1950 and 1986 (2932). Other institutions have used this technique with encouraging results (2, 9, 15, 26, 36, 37). Since 1978, at the Hospices Civils de Lyon T 1 and T2 rectal cancers not exceeding
METHODS Patients
Between 1977 and 1993 a series of 101 patients has been treated in the Department of Radiotherapie-Oncolo-
Reprint requeststo: ProfessorJean-PierreGerard, Service de
Radioth&apie-Oncologic,
AND MATERIALS
thank Bruno Daligandfor his help in the preparationof this manuscript. Accepted for publication 6 July 1995.
Acknowledgement.s-We
Hospices Civils de Lyon, Chu Lyon
Sud, 69495 Pierre Benite Cedex, France.
77.5
776
1, J. Radiation oncology 8 Biology * Physics
gie of the Hospices Civils de Lyon. Digital rectal examination, an essential part of the work-up was always done
in the knee-chest position, with an empty rectal ampulla. An endoscopy was performed in the same position with a rigid proctoscope of 3 cm in diameter giving a direct view of the tumor. The radiation oncologist performing this clinical expiration was able to assess very accurately the stage of the tumor, its maximum diameter, its shape, its mobility, and consistency. According to the St. Mark’s Hospital (28) and UICC 1987 criteria, a tumor is staged Tl when it is polypoid and mobile, whatever the size and consistency. It is expected in such a situation that the tumor is not invading the muscularis propria. A tumor can also be staged Tl if it is polypoid with a very small ulceration, or flat and still mobile not exceeding 2 cm in m~imum diameter. A T2 tumor is always with an ulceration, is fungating, or is a flat lesion more than 2 cm in diameter, hard and tethered. In this case, it is assumed that the tumor is involving the muscularis propria. A careful digital exam for pararectal nodes was always done, and patients with a suspicious exam were referred for surgery, so there is no clinic~ly Nl patient in tbis series. Table 1 gives an overview of the different parameters of the patients and tumors. This group of patients was made mainly of frail patients with a median age of 75 years. Nine patients were assessed as inoperable for general condition, and 23 as high surgical risk. Diagnosis was proven by biopsy, and all patients presented with infiltrating adenocarcinoma usually well or moderately well differentiated. Four patients with poorly differentiated adenocarcinoma were accepted because they were inoperable. In 17 cases adenocarcinoma was described as developing on a preexisting villous or adenomatous polyp. These tumors were sessile in all cases, and in 12 cases aden~~cinoma involved more than 50% of the polyp as judged through multiple biopsies and clinical appreciation. In five cases adenocarcinoma was involving between 30 and 50% of the polyp. Tumors were usually situated in the lower rectum. Only two tumors were more than 10 cm from the anal margin. In 5 cases the tumor was invading the anal canal, and in 20 it was at the upper limit of the anal canal. The tumors were more often on the anterior rectal wall part than on the posterior. This difference may be related to a selection bias as the posterior tumors are sorne~~s technically mom difficult to irradiate in the knee-chest position. The maximum diameter of the tumor was between 0.5 and 5 cm (median at 2.6). In the majority of cases the tumor was polypoid in shape with or without a superficial ulceration in the middle of the polyp. In 15 cases the tumors presented as a de now flat tumor. The consistency of the lesion was assessed as hard in 30 cases, firm in 59, and soft in 13. This last situation was usually in relation to adenocarcinoma developing on a villous polyp. Liver sonography, chest x-ray, and liver functions tests were done in all patients. Computed tomo~aphy was not used in these early cases. A carcino embrionic antigen biological marker was performed in ‘77 patients.
Votume 34, Number
4, I996
Table 1. 101 patients treated by contact x-ray-Patient tumor characteristics Sex male/female Age median (years) Range < (years) Performance status (WHO}* O-l 2
Adenocarcinoma well differentiated M~erately ~fferentiat~ Poorly differentiate Aden~~c~no~ developed on Villous polyp
Adenomatous polyp Tl NO ‘l-2 NO UT1 NO’ UT2 NO UT2 Nl UT3 NO Distance vs. anal margin $3 cm
4-6 cm 7-12 cm Site Anterior POSttXkX
Rigin lateral Left lateral Maximum diameter 0.5-l cm 1.1-2 cm 2.1-3 cm >3 cm
Polypoid Polyp&d with ulceration Fungating Rat
and
46/55 73 35-91 87 14 59 21 4 12 5 65 36
21 10 3 1 32 50 19 39 19 21 22 7 15 42 37 38 32 16 15
* WHCk World E&altb org~~on. i tl: staging by transrectal ultrasound. It was normal in 74, and slightly elevated in 3. Another biological marker known as CA 19-9 was negative in 47 patients and slightly elevated in 7. Total colonoscopy was done in 78 patients. Other benign polyps were found and removed endoscopically in 17 cases. In three patients a s~c~nous color& cancer was discovered and treated by he~colectomy before or after the contact x-ray amend Since 1987, transrectal ~~s~~d has been routinely performed by a team of experienced g~~nterologists (27). A total of 36 patients were staged by transrectal ultrasound. in three cases, TRUS revealed a pararectal node that was considered to be highly suspicious of metastases. These nodes were not palpable on digital rectal examination. Because these three cases were seen during the early period of TRUS staging, they were treated by contact x-ray alone.
Truant was nonsurgical in all cases, and given by contact x-ray following the technical guidelines described
Endocavitary irradiation for early rectal carcinomas TI
by Papillon (29,33). Tbe machine’ used delivered a beam of 50 KV filtered with 0.5 mm burnt. The sourcetumor distance was 4 cm with the proctoscope. The radiation output was high at 20 Gy per min. The dose was prescribed and reported at the exit surface of the proctoscope, i.e., at the surface of the tumor. The percentage depth dose was 50% at 5 mm. The patient was in the knee-chest position, and treated on an outpatient basis with no anesthesia. In 15% of the cases a local anesthetic (10 cc of Xylocaine 1%) was necessary for the first treatment when the dilatation of the anus was painful. The session lasted 1 to 3 min. When the tumor is more than 3 cm in diameter, two overlapping fields may be used. A special proctoscope with a “cap” was sometimes useful for better visualization and irradiation of the tumor. The diameter of the rectoscope was 3 cm, but when the tumor regressed, we often use a 2 cm proctoscope so as not to overdose the normal mucosa around the tumor. The median dose for this series was 92 Gy (range: 60- 125 Gy). Median treatment time was 57 days (range: 19-195 days). The number of fractions was usually four or five according to the stage of the tumor and the response of the tumor after two sessions assessed on day 2 t . If there was on day 2 I a complete regression of the tumor, or a volume reduction of more than 90% the total dose was 80-90 Gy in four fractions over 42 days. If the volume reduction was 80% or less, the total dose was between 100 and 120 Gy in 63 to 80 days. If at the end of contact x-ray the rectal wall is not flat and supple, an iridium boost could be performed 4 to 6 weeks later to supplement the dose in the deeper layer of the rectal wall (33). This impl~t was performed with a perineal implant under general anesthesia if the tumor was situated within 6 cm of the anal margin, or with an endolu~n~ “fork’ ’ implant without anesthesia if the tumor was in the midrectum. Such an implant was used in 28 patients. The dose was prescribed and reported on the 85% isodose of the basal dose according to the Paris System (33). The median dose was 25 Gy in 21 h. Table 2 gives an overview of the treatment technique in this series of 101 patients. Follow-up Follow-up is a very important part of this conservative treatment. Every patient is seen 3 months after the end of iK~ation to evaluate response to the treatment. A complete response is defined as the total disappearance of the tumor, with a normal supple mucosa and rectal wall upondigital and proctoscopic examination. Control biopsy was not performed on a normal mucosa due to the risk of necrosis. Patients are then examined every 4 months for the first 2 years, then every 6 months until the fifth year, and then annually. The median length of follow-up for the whole series of 101 patients was 61 ’ Philips RT 50, Philips Medical System, Crawley, Sussex, England.
fT2)
0
J.-P. GBRARD
777
ef ai.
Table 2. Techniquesof irradiation
I-Contact
x ray-50 k?’
Total dose 530 Gy 395 Gy Fractions 3 : 6-7
101 patients 3’) 6” $! 3h
2 overlappingfields Rectoscopewith cap Rectoscope2 cm
21: 31 sz
II- 192~r-l~lant Perinealimplant Number of active sources 4 5
2X patients 1Xpatients
Spacing between lines Active length of sources 4 cm 5 cm 6Cll
Median dose(Parissystem) Median time of irradiation Endorectal “fork” Numberof active sources Spacingbetweensources Active length of sources 3 cm 4cm Median dose(Paris System) Median time of irradiation (h)
? pts* 1f pts I cm 1 P( 1 f pts 4 pts
25 Gy (15-30 Gy) 21 h (14-37)
10 pts t. 1Xi cm
S patients 5 patients 25 Gy (W-SO, 21 (9-54) ---
* pts: patients.
months (range: 6 to 197 months) and for the 36 patients staged by TRUS, it was 46 mornhs (range: 6 to 81 months). At time of analysis only three patients among survivors had a follow up time shorter than 2 years. Salvage treatment in case of relapse was radical surgery in most instances. Statistical methoa3 All the patients have been ~~e~l~y followed, and none have been lost in follow-up. Data were stored on a computer, and statistical analysis was done using a statistical software* (38). The Kaplan-Meier method was used to construct curves for the overall survival, specific survival, and loco-regional relapse free interval ( 17). Data on patients who died from intercurrent disease were excluded from the calculation of the l~o-~~~~ relapse-free interval. Specific survival was calculated taking only death by rectal carcinoma as an event. The standard error was calculated for relevant percentage. The log rank statistic was used to compare ~s~~~ (22). The Cox proportional-hazards model was used for all multivariate analy’ SPSS@,SPSSFrance,Boulogne,France.
V&me 34, Nirriber 4, 1996 sis and for analysis of risk factors for loco-regional failure (5). A backward regression analysis was used to identify significant factors Variables were kept in the model anly if the standardized maximum likelihood-estimated statistics had a p-value below 0.05. RESULTS Table 3 gives the correlation between staging by digital rectal ex~nation and rectoscopy vs. staging by TRUS. It can be seen that during this second period mainly Tl patients were accepted for contact x-ray therapy, and mast of T2 were referred to other treatments. It appears that TRUS is more sensitive than digital rectal examination to detect infiltration of the muscularis propria, as nine patients clinically Tl were staged T2 or T3 with ultrasound. TRUS especially appears to more sensitively detect early nodal pamrectal me&stases as two patients staged UN1 developped a pararrectal nodal relapse after complete primary locat control. Digital rectal examination failed to detect these nodes at the time of initial staging. Icespcrnse to cmtaet x-ray treatment On day 21, 47 patients had a complete response or a reduction of 90% or more of the volume of the tumor. Fifteen patients had a reduction of between 50 and 60% of the initial volume, and 39 patients a reduction of between 70 and 85%” At the time of the last session of contact therapy a complete response was seen in 76 patients, 25 patients had a response between 90 and 95% of the initial volume. Out of 28 patients who underwent an iridium implant, 15 had no detectable lesion at the time of implant and 13 had superficial residual ideation. Three months after completion of irradiation all patients were estimated to be in complete remission, with five patients having some minimal residual thickening of the rectal wall at the site of the initial tumor. Local failure Local failure is defined as a recurrence in the tumor bed within the field of irradiation. It usually presents as an ulceration with some ~gating aspect and bleeding, Edison is always present. Such local failure was seen in eight cases (one Tl, sevenT2), with a median irtterval to recurrence of 19 months (range: G-42). Local failure was proven in all cases by cytology or biopsy, CEA and CA 19-9 were negative in all cases. CT scan and TRUS Table 3. Correlation between staging by digital rectal examinadon and rigid proctoscopy vs. staging by tramrectal ultrasound UT1 NO 31 l-1 NO 5T2NU
22 0
uT2NO 7 3
UTZNI 1 2
UT3 NO 1 0
did not appear useful in the diagnosis. A salvage treatment with surgery was attempted and successful in five of the eight recurrences (three Mile’s amputations and two restorative surgeries). In three cases only a local treatment was performed, which resulted in ultimate local control in two patients (one cryosurgery and one contact x-ray). Nodal failure N&d failure is defined as a recurrence in the pamrectal nodes with or witbout local relapse. It presents usually as a hard round nodule between 0.5 and 2 cm in size in the pararectal wall, with a normal mucosa on digital and proctoscopic examination. Such a failure was seen in seven cases (one Tl, six T2). One patient (T2) presented with a local failure and a nodal failure at the same time. The median interval to recurrence was 34 months (range: 12-46 months). The diagnosis was confirmed in all cases by surgery with pathologic examination. CT scan was able to show the nodes in three out of seven cases, and TRUS in three out of three cases. The metastatic nodes were situated at a mean distance of 2 cm (0.5-4 cm) above the primary. Meart diameter on digital examination was 1.5 cm. The nodule was located at the posterior half of the rectal circumference in five cases, and anteriorly in two cases. CEA and CA 19-9 were negative in all cases. All seven patients underwent surgical salvage with four Mile’s amputations and three restorative surgeries. Pathological reports showed only one metastatic node in four cases, and three to five positive nodes in three cases, One of these patients died of distant metastases (6 years after initial treatment, and 2 years after nodal recurrence). One died from inte~~nt disease. Five are alive with no evidence of disease (1 to 7 years after nodal failure).
Ultimate pelvic control is defined as no evidence of disease at time of last follow-up nor of death in the pelvis. Out of 101 patients, 14 relapsed either in the primq site (n = 8 patients) and/or in the pararectal nodes (n = 7 patients). One of them was treated only palliatively. Eleven underwent radical salvage surgery with 10 local control and one secondary recurrence in the pelvis. Ultimate local control has been achieved in 99 patients out of 101. Out of the 11 salvage surgeries, there were five restora~ve rectal resections, and six Miles abdominoperineal resections. Overall rectal preservation was possibie in 92 out of 99 patients, with local control in the pelvis. Distant me&stases and death-survival Six patients developed distant metastases, four of them without local or nodal failure and two after locoregiomd failure (synchronous in one case and metachronous in one). Overall, 26 patients have died: 5 of cancer, 15 of intercurrent disease, 2 of second rn~i~~ci~, and 3 of ~0~ cause. The overall p~bability of survival (Kapl~-M~i~r) is
Endocavitary irradiation for early rectal carcinomas Tf Cl”2) 0 J.-P. GERARD PTul.
779
99 T .-
78
L
,7
’6
,6
.-Z h = n 8
,5
2
,3
,4
2
Month Fig. 1. Specific andoverall survival of 101patientswith rectal ade~~cinoma
treatedwith endocavit~ irradia-
tion. Numberat risk: 3 years: 78; 5 years: 52; 8 years: 24.
83.3% at 5 years [standard error (SE}: 4.41 and 42.8% at 8 years (SE: 7.3). The specific probability of snrvival is 94.4% at 5 years (SE: 2.7%) and 89.1% at 8 years (SE: 4.6%) (Fig. 1). There is no significant difference in survival between Tl and T2 (Table 4).
by TRUS. The pararectal lymph~no~~y was not felt by digital rectal exam at the time of first treatment. All of these have been salvaged by surgery, preserving the anal sphincter in three out of five cases.
Group of patients staged by TRUS In the group of 36 patients staged by TRUS since 1987 with a median follow-up time of 43 months, there has been one death due to distant metastases without locoregional relapse and two deaths by intercurrent disease, giving an overall 4 years survival of 85% (SE: 7.7) with 14 patients at risk at 4 years. In this group there have been two local failures (two: both UT2 NO) and three nodal failures (one: UT2 NO, two: UT2 Nl). No local or nodal failure was seen for UT1 NO. Two out of three nodal failures were observed in patients staged as UN1
The immediate tolerance of contact x-ray therapy and iridium implant was very good even in very old and frail patients. Less than lS% of patients experienced moderate tenesmus, imperiosity, or diarrhea during the course of the treatment. Two to 3 months after completion of the treatment two types of side effects may occur: ulceration and bleeding. Ulceration of the rectal mucosa was usually superficial in the tumor bed. This has been observed in 27 cases with a median time of occurence of 4 months (range: 2- 14 months). The ulceration was usually symptomatic and
Table 4. Overall and specific survival according to clinical staging (C TN) 0 Years
5 Years
_-..--
8 Years
No. at risk
Survival
SE*
No. at risk
101 101
52 52
0.8334 0.9445
0.0047 0.0271
18 18
0.6264 0.8906
0.0739 0.0462
Overall survival CT1 NO CT2 NO
65 36
30 22
0.868 0.769
0.068 0.078
I1 7
0.678 0.553
0.095 0.109
0.730
Specific survivd CT1 NO CT2 NO
65 36
30 22
0.975 0.856
0.024 0.068
11
0.910 0.856
0.067 0.068
0.820
All patients OveralI survival Spezitic survival
7
SurvivaI --_.
SE-----
Log rank value
No. at risk
I. J. Radiation Oncology 0 Biology l F‘hysics
780
had a median duration time of 3 months (2-6 months). Local corticosteroids were given to six patients. All ulcerations healed with no late sequela. Mild rectorrhagia during bowel movement was usually seen 3 to 24 months after treatment (median time of occurence: 7 months). Some bleeding was observed in 46 cases with no instances of anemia. It may cause anxiety for the patient but does not require treatment; however, local laser or cryotherapy had good symptomatic results. Some bleeding may last for 1 to 4 years. Median duration time was 23 months in this series. The overall tolerance of this radiation treatment was usually very good, with no Grade 3 complications and no change of transit or sphincter function. The follow-up was very satisfactory because there was no modification of the rectal wall or pelvis, which remained very supple and easy to examine. One to 3 years after completion of therapy localized hypopigmentation was seen in the treated area. Biopsy of the irradiated mucosa is inadvisable if no obvious lesions are visible.
The main end point chosen in the analysis of prognostic factors was local and nodal failme. There were 14 such locoregional recurrences. Figure 2 shows that the probability of locoregional failure is 16.5% (SE: 6) at 4 years, with no other events after this interval. On univariate analysis with the log rank test (Table 5), four prognostic factors are significant: T and UT stage, maximum diameter, and type of tumor. The response at day 21 after two sessions of contact x-ray is of borderline significance. The
Volume 34, Number 4, 19%
Cox model with univariate procedure shows that T stage remains a significant prognostic factor with a relative risk (RR) of 25.99 (3.41-197. 86). The RR is not calculated for UT stage or maximum diameter as there is no relapse in UT1 or tumors smaller than 2 cm. On multivariate analysis, T2 NO vs. Tl NO shows a RR of 5.3.4 (1.192.39), which is not any more significant if the dose of contact x-ray is not included in the model. The risk of loco-regional failure is less than 10% in Tl NO, regardless of the staging (clinical or TRUS). Conversely, in T2 lesions the risk of Leo-regions failure is 40% at 4 years (Table 5), and out of three patients staged UNl, two developed a pararectal nodal recurrence. DISCUSSION Endocavitary irradiation appears to be a reproducible technique as the results of the present’series of 101 patients are comparable to those of Papillon (29, 33). The risk of local faihue (local and nodal) is between 10 and 20% after contact x-ray, and most of these relapses can be salvaged by subsequent cent usually surgery. Other authors report similar results (2, 11, 15, 20, 36, 37). In some series the rate of local failure is higher (9, 18,26). This can be due to selection bias or technical problems. It is important in this comparison to take into account onIy tumors treated by contact x-ray and to exclude those treated by adjuvant contact x-ray given after local excision or laser destruction, which often show better results (31). This is the first series of patients treated with contact x-ray that has been staged by TRUS. This method seems
2 a- 111 0,
.
0
.
.
.
.
:.,.
w
12
l
,,.....,,-.
24
36
.,,,,.,,,-”
,s~,,-mI,m,m~m~
48
w
60
,,,,
72
m
..,..,,
r(l
96
84
Month Fig. 2. Overall probabi~~ of locoregional failure (local + nodal) in 101 patients. No event observed after 48
months ~Kap~~-Meier Method).
End~avit~
Table 5. Loco-regionaI
i~adiatioR
for
early
rectal
Tl
c~in~mas
(T2)
l J.-P.
GERARD
er al.
781
failures (15 patients) and prognostic factors related to patient and tumor ~Kap~~-Meier~ “Loco-regional relapse-free interval
-
Risk factor
Sex Male Female Age 570 >70 Pe~~~~~ status <2 22 Differentiation =well =moderate =poor TN Tl NO T2 NO UT1 NO UT2 NO UT2 Nt LT3 NO Distance anal canal Upper limit Invaded At distance Locaiization
Anterior = N Anterior = Y Lateral left = N Lateral left = Y Lateral right = Y Posterior = N PosWior = Y Diameter F-32 cm >3 Type Polyp&d
Polypoid ulcu%ed Fungating Sessile plan Response at Day 21 90-100% W-90% do% * Statistically
significant
No. of patients
2 Years
4 Years
,--
46 55
0.960 (0.02) 0.826 (0.06)
0.874 (O”O5f 0.780 (0.07)
0.52
45 56
0.920 (0.04) 0.914 (O.~j
0.778 (0.07) 0.817 (0.06)
0.92
87 14
0.911 (0.O3f f
0.788 10.05) 1
0.22
59 21 4
0.902 (0.04) 0.947 (0.05) --
0.831 (0.05) 0.775 (0.11) -
65 36
0.984 (0.02) 0.8 I 1 (0.07)
0.933 (0.04) 0.5% (0.09)
0.0002’
22 10 3 I
:0.09, 0.900 0.666 (0.27) -
1 0.600 (0.18) 0.333 (0.271 --
0.023” -
20 5 77
0.928 (0.07) 0.888 (0.04)
0.759 (0.12) 0.792 (0.05’)
0.83
63 39 82 22 21 84 19
0.926 0.918 0.94 I 0.835 0.944 0.907
0.847 0.760 0.8 I I 0.771 0.877 0.793 0.875
22 42 37
0.911 iO.05) 0.811 (0.08)
0.680 (0.09) 0.703 (0.10)
o.O02* 0.002’
38 32 16 15
0.960 0.925 0.785 0.859
0.918 0.754 0.687 0.752
(0.06) (0.09) (0.131 (0.13)
0.09 0.037* 0.10
47 39 t.5
0.948 (0.03) 0.914 (0.05) 0.875 (0.08~
0.9 11 (0.05) 0.734 (0.08~ 0.715 (O.l2>
0.09 0.077
(0.04) (0.04) (0.03) (0.09) (0.05) (0.33)
(0.04) (0.05) (0.11) (0.09)
(0.05) (0.07) (0.05) (0.10) (0.08) fO.051 IO. 1 i j
p-value log rank -I
0.81
0.52 0.41 0.50 0.42
difference.
’ Strong difference. i- Very high difference.
more reliable than digital rectal ex~ati~~ to assess the depth of penetration of the tumor within the rectal wall (14, 27), although the clinical staging performed by an experienced specialist is well correlated with the pathologic staging (23). In this series of 101 patients three points can be seen. First, in CT1 patients (65 patients) the risk of foco=regiomtI relapse is 6.6% (2 patients) vs. no relapse in 22 UT1 patients. This difference is not very
large for this group of patients and TRWS will not greatly modify the selection process and the m&ts. Second, in CT2 NO (36 patients), as in UT2 NO (10 patients), the risk of loco-regional relapse is the same after e&ocavitary irradiation (40%). Such a alit atone c-o! be recommended ix3 this situation. Thh$ the most important benefit of TRUS is its capacity to detect am& ~~ nodes in the pararfzctal wall. Out of three patients UNf
182
I. J. RadiationOncology 0 Biology l Physics
and clinically NO, two have presented pararectal nodal failure. At the present time, TRUS appears essential for the selection of patients as it is more sensitive and specific than digital rectal examination in assessing the infiltration of the muscularis propria, and most of all because any patient with a suspicious pararectal node should not be treated by endocavitary local treatment alone. Tumors suitable for treatment by contact x-ray (or other local curative treatment) should always be selected after a careful TRUS when it is feasible. Patient selection also relies upon careful digital rectal ex~nation in the knee-chest position, rigid proctoscopy, and histological subtypes. A patient of any age with a Tl NO lesion staged by TRUS, not exceeding 4 cm in largest diameter, would be suitable for endocavitary irradiation alone. The tumor must be well or moderately well ~fferentiated. Poor differentiation is associated with a higher risk of lymphatic spread and usually represents a contraindication for purely local treatment (16, 39). The tumor must be accessible to the contact tube, i.e., within the first 12 cm of the distal rectum. If there is a complete response on day 2 1, this is a good confi~a~on for the indication of end~avi~ irradiation alone. Patients with T2 NO lesions should not be treated by endocavitary irradiation alone, but in patients for whom external beam radiation therapy proves difficult to perform, contact x-ray can be used to treat ~l~oid T2 tumors (or tumors with a small superficial ulceration) not exceeding 3 cm in diameter. If the response on day 21 is not complete, or if there is some residual lesion at the end of the contact x-ray, treatment an iridium implant is recommended. Patients with an Nl tumor diagnosed either by digital exa~nation or TRUS should never be treated by endocavitary irradiation alone. The protocol for irradiation can currently be standardized according to tumor volume. For tumors smaller than 2 cm in diameter: day 1: 30 Gy; day 7: 25 Gy; day 21: 20 Gy; day 36: 15 Gy; total dose: 90 Gy in four fractions, For tumors between 2 and 4 cm in diameter: day 1: 35 Gy; day 7: 25 Gy; day 21: 20 Gy; day 36: 15 Gy; day 51: 15 Gy; total dose: 110 Gy in five fractions. If the response is not complete at the end of contact x-ray a boost with an iridium implant is given after a rest period of 4 weeks. The dose of ~~~ is 25 Gy in 1 day. These are general ~co~endations that can be modulated according to type of tumor and the pace of regression.
Volume 34, Number 4, 19%
With such a selection and technique one can expect to have a high rate of local control with no complications except moderate rectal bleeding due to late radiation telangiectasia of the rectal mucosa. This is a fully ambulatory treatment, requiring no general anesthesia, and suitable for all patients. A close follow-up is necessary to detect unusual locoregional failures. In case of loco-regional relapse, salvage treatment is often efficient, sometimes preserving anal sphincter function. It is possible to treat similar tumors with other techniques like local excision (7, 12) laser destruction (13, 21), and transrectal endoscopic microsurgery (4). Comparisons between these different approaches are sometimes difficult because the selection of patients varies from one series to the other, and end points are analyzed in different ways. Endocavitary vacation compares favorably in terms of cost/benefit ratio with the other techniques. It is true that with contact x-ray there is no objective data to assess the pathologic stage of the tumor (degree of infiltration in the rectal wall) but TRUS appears very accurate in such an evaluation (14,27) and the good correspondence between TRUS staging and results with contact x-ray seems a reliable criterion. The very low rate of complication, the simplicity, and the low cost of the technique are strong arguments in favor of contact x-ray. Purely endocavitary treatment of rectal cancer with contact x-ray or local excision is possible only if the risk of lymphatic spread is low. If this criterion is not fulfilled, radical surgery usually associated with external beam irradiation is the standard treatment. In inoperable patients it is possible to have a curative effect on T2 or small T3 tumors by external beam irradiation with or without chemotherapy and local excision (1, 24, 25, 34, 35, 40), or endocavitary irradiation (5,8, 11,30,32). These ongoing pilot studies will define the indications and limits of such approaches. In conclusion, curative ~eatment of small rectal cancer with contact x-ray therapy according to Papillon’s technique appears to be efficient, safe, cheap, and reproducible. It is, of course, necessary to use a dedicated low voltage machine with a tube, which can be used by hand. With strict selection of tumors using transrectal ultrasound and good technique of irradiation, such a treatment could be very beneficial and have great applications.
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