Inr J Radmrron Oncology B~ol Ph.vs., Vol. Printed in the U.S.A. All rights reserved.
19, PP. 1221-1223
Copyright
0360.3016/YO $3.00 t .IKl 0 1990 Pergamon Press plc
??Brief Communication
COMBINED
CHEMOTHERAPY-RADIOTHERAPY R. ZUCALI,* Istituto
Nazionale
R. DOCI~ AND
Tumori,
20133 Milano,
OF ANAL CANCER
L. BOMBELLI~ Via Venezian
l--Italy
Forty-five patients were treated from 1984 to 1988. Thirty-eight, with a minimum follow-up of 6 months, are considered evaluable: median age, 62 years (25-88); males 6, females 32; Tl = 7, T2 = 21, T3 = 10; inguinal positive nodes, 5 patients. Chemotherapy (CT) (Mitomycin C, 15 mg/sqm, bolus day 1; 5-FU, 750 mg/sqm, 24 hr infusion, days 1 to 5) and radiotherapy (RT) started the same day. A dose of 36 Gy was given to the tumor and to the pelvis including inguinal nodes, in 20 fractions. After 2 weeks a boost of RT (18 Gy) to the ano-perineal area and a second cycle of CT completed the treatment. CR (biopsy) was achieved in 32/38 patients (84.2%). Among the six patients on PR, four received a Miles operation (2 NED), and two a wide local resection (both NED). Five out of 32 CRs relapsed: 2/5 were rescued with a Miles resection, 3 died from progression. In conclusion, 32/38 patients (84.2%) are NED after a median follow-up of 22 months and 28 of them retained their anal sphincter. A longer follow-up is needed to define optimal treatment modality, but it is clear that surgery must play a minor role in the treatment of anal cancer. Chemo-radiotherapy,
Anal cancer.
INTRODU(XION
changed from first choice treatment to rescue therapy for incomplete responders or relapsing patients.
It is well known that a uniform treatment policy for anal carcinoma is difficult to define for various reasons, namely the low incidence of this tumor, the different sites of origin (canal, anal margin), and the various extensions and criteria of classification. The most frequently adopted therapy has always been demolitive surgery, only very early lesions being treated with local excision. Unfortunately, despite apparently radical treatment, failures of surgery alone are frequent and overall survival is poor. Radiotherapy alone, external and/or interstitial, can control early and intermediate stages, but high doses of irradiation required for cure can produce side effects which are often severe (2, 6). The experiences of the group from Detroit (5) with primary chemo-radiotherapy, planned as a preoperative treatment, yielded such satisfactory results that surgery was progressively considered overtreatment in most cases. During the last decade combined chemo-radiotherapy has been adopted in many centers, sometimes with modification of the original schedule. Complete remission rates above 80% and overall survival rates at 5 years between 60-80% have been reported in the literature (1, 3, 4, 7). As a consequence, the role of surgery has
METHODS
AND MATERIALS
About 10 years ago, the treatment of anal cancer was started at Istituto Nazionale Tumori of Milan0 with a chemo-radiotherapeutic approach. From 1984 to 1988 a total of 45 patients were treated, 38 of these 45 patients with a minimum follow-up of 6 months after therapy are considered evaluable. There were 32 females (mean age 59, range 30-65), and 6 males (median age 64. range 2588). The site of the tumor was the anal margin in 4 cases, and the anal canal plus or minus adjacent extension in 34. The TNM classification (8) was as follows: T 1, 7 cases; T2, 21 cases; T3, 10 cases. Inguinal positive nodes were documented with cytology in 5 cases, 4 T2 and 1 T3. Histology of the primary was a squamous cell carcinoma in 37 cases and a basaloid carcinoma in 1 case. The outline of treatment is indicated in Table 1. Chemotherapy was the classic combination of Mitomycin C ( 15 mg/sqm, day 1, i.v. bolus) and 5-FU (750 mg/sqm, i.v. infusion, over 5 days).
Acknowledgment-The
authors thank Mrs. Donatella for help in preparing manuscript and tables. Accepted for publication 24 May 1990.
Presented at the 17th International Congress of Radiology, Paris, l-8 July 1989. * Division of Radiotherapy A. + Division of Surgical Oncology A. Reprint requests to: Roberto Zucali, M.D., Istituto Tumori, Via Venezian 1, 20 133 Milano, Italy. 1221
Orlandi
I. J. Radiation Oncology 0 Biology 0 Physics
1222
Radiotherapy was started on the same day. The target of irradiation was the anal region with perineum and lower and middle pelvis including inguinal and external iliac nodes. Two AP and PA opposed fields were used and a daily dose of 1.8 Gy (0.9 + 0.9) was given through both portals, up to a total dose of 36 Gy at midplane in 4 weeks, with a 6 MeV linear accelerator. After 2 weeks rest, at 6 weeks from the beginning of treatment, a second cycle of chemotherapy was scheduled and radiotherapy was simultaneously started again. A direct field was tailored to the ano-perineal region and 10 fractions of 1.8 Gy were given in 2 weeks. The dose was calculated according to the site and depth of the tumor in order to give the full dose to the proximal margin of the original lesion. In case of positive inguinal nodes they were boosted with electrons. The scheduled total dose to the tumor was 54 Gy. In a few cases with locally advanced disease the dose of the boost was raised to 20-24 Gy. No case received more than 60 Gy. A third cycle of chemotherapy was given to 16 patients, independent of the clinical situation, when feasible for hematologic and general conditions. The average number of cycles of chemotherapy was 2.4 in the whole series; there was no difference between patients in complete remission at the end of treatment and the minority of cases who did not achieve complete remission. The response was evaluated through biopsy at the end of treatment in all cases.
November 1990, Volume 19, Number 5 Table 2. Correlation
of treatment
Myto C ( 15 mg/m, Day 1 bolus I.V.) + 5-FU (750 mg/m I.V. infusion)
Radiotherapy on the pelvis X 4 weeks, 36 GY 2-week rest
(myelodepression;
CR
Tl T2 T3
7 21 10
617 19121 7110
616 16/19 517
I
1
2 3
2
Total
38
32138
27132
6138
4
5
415
414
1
0
N+ (T2-T3)
Maintained CR
Table 3. Breakdown
I
Complete
remission
of results 84.2%
32138
2 rescued with Miles Partial remission
6 patients
side effects of RT)
X 2 weeks, 18 GY if feasible
I
The new treatment modality of anal cancer, combined chemo-radiotherapy, not only achieves excellent short and long-term results, but eventually improves the quality of life of the patient, reducing indications for a radical surgery and minimizing the side effects of radiotherapy at high doses. The toxicity of treatment is low and for this reason it is feasible in old patients, also in poor conditions. As a consequence, ablative surgery is no longer the treatment of choice, but it has become a rescue therapy for the minority of patients who do not achieve a complete remission after combined treatment or who relapse later.
i
III cycle chemotheranv,
PR + rescued
been classified as T3NO and one as T2NO. An abdominoperineal resection was the rescue treatment in four patients. Two of them are disease-free after 11 and 16 months, whereas two died of progression. Eventually, two patients received a wide local excision and are free of disease at 27 and 46 months. Five patients presented a local recurrence during the follow-up. Two of them were operated on according to Miles technique and are alive without evidence of disease, whereas three patients died of pelvic progression after additional chemotherapy plus or minus radiotherapy. The overall results as of December 1988 are indicated in Table 3. In the whole series of 38 patients, 32 patients (84.2%) are alive and disease-free. Twenty-eight out of 32 patients retained their anal sphincter. The accrual of new patients and longer follow-up is in progress.
Start the same day
II cycle chemotherapy X 5 days
Radiotherapy on the perineum
and result
DISCUSSION
Median follow-up for the whole series as of December 1988 was 22 months. The breakdown of results is presented in Table 2. A complete remission was achieved in 32138 patients (84.2%) and it was maintained in 27132. Among the five patients presenting inguinal adenopathies, four achieved complete remission and remain diseasefree. Six patients only did not achieve a complete remission, despite adequacy of treatment. Five of them had
I cycle chemotherapy X 5 days
local extension
No. cases
RESULTS
Table 1. Outline
between
Start the same day (6 weeks after first cycle)
Maintained CR Relapsed after CR Dead for intercurrent disease Total alive, NED * 28/32 retained
26 patients 51 32/38* anal sphincter.
2 rescued with local excision 2 rescued with Miles
84.2%
Combined treatment of anal canal 0 R. ZUCALI et al.
1223
Obviously, many problems remain unsolved and a larger experience is needed. The following issues are frequently raised: What is the optimal chemotherapy? Must any drug be substituted or added to the classic scheme? What is the optimal timing for chemotherapy and radiotherapy? Which is the optimal modality of administering chemotherapy? The infusion of 5-FU must be modified,
of the tumor to date, whereas more toxicity was correlated with the use of this drug. As far as the timing of chemotherapy and radiotherapy is concerned, our experience confirms the importance of starting the combined treatment at the same time. On the contrary, the sequential approach, chemotherapy followed by radiotherapy did not yield similar excellent results in
should it be more prolonged during the course of radiotherapy? What are the targets of radiotherapy for thera-
our hands.
peutic and adjuvant treatment? What is the optimal schedule of radiotherapy in terms of fractionation, single and total doses and characteristics of the final boost to the anal region? The classic chemotherapy is really effective at the expense of an acceptable toxicity. The addition of Platinum to the antiblastic combination, with or without Mitomycin C, failed to improve the response rate and the control rate
Our study confirms the results of other workers and can contribute to answer some open questions. However the most important message is that it is once more confirmed that surgery plays a minor role in the definitive treatment of anal cancer. Our knowledge will be improved through the experience of many centers facing these problems. Their results will be continuously evaluated and discussed, and multicentric trials in progress will be followed with great interest.
REFERENCES Cummings, B.; Keane, T.; Thomas, G.; Harwood, A.; Rider, W. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54:2026-2068; 1984. Eschwege, F.; Lasser, P.; Chavy, A.; Wibault, P.; Kac, J.; Rougier, P.; Bognel, C. Squamous cell carcinoma of the canal anal: treatment by external beam irradiation. Radiother. Oncol. 3:145-150; 1985. Mitchell, E. Carcinoma of the anal region. Sem. Oncol. 15: 146-153; 1988. Nigro, N. D.; Seydel, H. G.; Considine, B. Combined preoperative radiation and chemotherapy of squamous cell carcinoma of the anal canal. Cancer 5 1:1826- 1829; 1983.
Nigro, N. D.; Vaitkevicius, V. K.; Considine, B. Combined therapy for cancer of the anal canal. A preliminary report. Dis. Colon Rectum 3:354-359: 1974. Papillon, J. Rectal and anal cancers. Conservative treatment by irradiation, an alternative to radical surgery. Heidelberg: Springer-Verlag; 1982. Sischy, B.; Remington, J. H.; Hinson, E. Definitive treatment of anal canal carcinoma by means of radiation therapy and chemotherapy. Dis. Colon Rectum 25:685-688; 1986. 8. TNM classification of malignant tumors, 4th edition. Berlin: Springer-Verlag;
1987.
19, PP. 1221-1223
Copyright
0360.3016/YO $3.00 t .IKl 0 1990 Pergamon Press plc
??Brief Communication
COMBINED
CHEMOTHERAPY-RADIOTHERAPY R. ZUCALI,* Istituto
Nazionale
R. DOCI~ AND
Tumori,
20133 Milano,
OF ANAL CANCER
L. BOMBELLI~ Via Venezian
l--Italy
Forty-five patients were treated from 1984 to 1988. Thirty-eight, with a minimum follow-up of 6 months, are considered evaluable: median age, 62 years (25-88); males 6, females 32; Tl = 7, T2 = 21, T3 = 10; inguinal positive nodes, 5 patients. Chemotherapy (CT) (Mitomycin C, 15 mg/sqm, bolus day 1; 5-FU, 750 mg/sqm, 24 hr infusion, days 1 to 5) and radiotherapy (RT) started the same day. A dose of 36 Gy was given to the tumor and to the pelvis including inguinal nodes, in 20 fractions. After 2 weeks a boost of RT (18 Gy) to the ano-perineal area and a second cycle of CT completed the treatment. CR (biopsy) was achieved in 32/38 patients (84.2%). Among the six patients on PR, four received a Miles operation (2 NED), and two a wide local resection (both NED). Five out of 32 CRs relapsed: 2/5 were rescued with a Miles resection, 3 died from progression. In conclusion, 32/38 patients (84.2%) are NED after a median follow-up of 22 months and 28 of them retained their anal sphincter. A longer follow-up is needed to define optimal treatment modality, but it is clear that surgery must play a minor role in the treatment of anal cancer. Chemo-radiotherapy,
Anal cancer.
INTRODU(XION
changed from first choice treatment to rescue therapy for incomplete responders or relapsing patients.
It is well known that a uniform treatment policy for anal carcinoma is difficult to define for various reasons, namely the low incidence of this tumor, the different sites of origin (canal, anal margin), and the various extensions and criteria of classification. The most frequently adopted therapy has always been demolitive surgery, only very early lesions being treated with local excision. Unfortunately, despite apparently radical treatment, failures of surgery alone are frequent and overall survival is poor. Radiotherapy alone, external and/or interstitial, can control early and intermediate stages, but high doses of irradiation required for cure can produce side effects which are often severe (2, 6). The experiences of the group from Detroit (5) with primary chemo-radiotherapy, planned as a preoperative treatment, yielded such satisfactory results that surgery was progressively considered overtreatment in most cases. During the last decade combined chemo-radiotherapy has been adopted in many centers, sometimes with modification of the original schedule. Complete remission rates above 80% and overall survival rates at 5 years between 60-80% have been reported in the literature (1, 3, 4, 7). As a consequence, the role of surgery has
METHODS
AND MATERIALS
About 10 years ago, the treatment of anal cancer was started at Istituto Nazionale Tumori of Milan0 with a chemo-radiotherapeutic approach. From 1984 to 1988 a total of 45 patients were treated, 38 of these 45 patients with a minimum follow-up of 6 months after therapy are considered evaluable. There were 32 females (mean age 59, range 30-65), and 6 males (median age 64. range 2588). The site of the tumor was the anal margin in 4 cases, and the anal canal plus or minus adjacent extension in 34. The TNM classification (8) was as follows: T 1, 7 cases; T2, 21 cases; T3, 10 cases. Inguinal positive nodes were documented with cytology in 5 cases, 4 T2 and 1 T3. Histology of the primary was a squamous cell carcinoma in 37 cases and a basaloid carcinoma in 1 case. The outline of treatment is indicated in Table 1. Chemotherapy was the classic combination of Mitomycin C ( 15 mg/sqm, day 1, i.v. bolus) and 5-FU (750 mg/sqm, i.v. infusion, over 5 days).
Acknowledgment-The
authors thank Mrs. Donatella for help in preparing manuscript and tables. Accepted for publication 24 May 1990.
Presented at the 17th International Congress of Radiology, Paris, l-8 July 1989. * Division of Radiotherapy A. + Division of Surgical Oncology A. Reprint requests to: Roberto Zucali, M.D., Istituto Tumori, Via Venezian 1, 20 133 Milano, Italy. 1221
Orlandi
I. J. Radiation Oncology 0 Biology 0 Physics
1222
Radiotherapy was started on the same day. The target of irradiation was the anal region with perineum and lower and middle pelvis including inguinal and external iliac nodes. Two AP and PA opposed fields were used and a daily dose of 1.8 Gy (0.9 + 0.9) was given through both portals, up to a total dose of 36 Gy at midplane in 4 weeks, with a 6 MeV linear accelerator. After 2 weeks rest, at 6 weeks from the beginning of treatment, a second cycle of chemotherapy was scheduled and radiotherapy was simultaneously started again. A direct field was tailored to the ano-perineal region and 10 fractions of 1.8 Gy were given in 2 weeks. The dose was calculated according to the site and depth of the tumor in order to give the full dose to the proximal margin of the original lesion. In case of positive inguinal nodes they were boosted with electrons. The scheduled total dose to the tumor was 54 Gy. In a few cases with locally advanced disease the dose of the boost was raised to 20-24 Gy. No case received more than 60 Gy. A third cycle of chemotherapy was given to 16 patients, independent of the clinical situation, when feasible for hematologic and general conditions. The average number of cycles of chemotherapy was 2.4 in the whole series; there was no difference between patients in complete remission at the end of treatment and the minority of cases who did not achieve complete remission. The response was evaluated through biopsy at the end of treatment in all cases.
November 1990, Volume 19, Number 5 Table 2. Correlation
of treatment
Myto C ( 15 mg/m, Day 1 bolus I.V.) + 5-FU (750 mg/m I.V. infusion)
Radiotherapy on the pelvis X 4 weeks, 36 GY 2-week rest
(myelodepression;
CR
Tl T2 T3
7 21 10
617 19121 7110
616 16/19 517
I
1
2 3
2
Total
38
32138
27132
6138
4
5
415
414
1
0
N+ (T2-T3)
Maintained CR
Table 3. Breakdown
I
Complete
remission
of results 84.2%
32138
2 rescued with Miles Partial remission
6 patients
side effects of RT)
X 2 weeks, 18 GY if feasible
I
The new treatment modality of anal cancer, combined chemo-radiotherapy, not only achieves excellent short and long-term results, but eventually improves the quality of life of the patient, reducing indications for a radical surgery and minimizing the side effects of radiotherapy at high doses. The toxicity of treatment is low and for this reason it is feasible in old patients, also in poor conditions. As a consequence, ablative surgery is no longer the treatment of choice, but it has become a rescue therapy for the minority of patients who do not achieve a complete remission after combined treatment or who relapse later.
i
III cycle chemotheranv,
PR + rescued
been classified as T3NO and one as T2NO. An abdominoperineal resection was the rescue treatment in four patients. Two of them are disease-free after 11 and 16 months, whereas two died of progression. Eventually, two patients received a wide local excision and are free of disease at 27 and 46 months. Five patients presented a local recurrence during the follow-up. Two of them were operated on according to Miles technique and are alive without evidence of disease, whereas three patients died of pelvic progression after additional chemotherapy plus or minus radiotherapy. The overall results as of December 1988 are indicated in Table 3. In the whole series of 38 patients, 32 patients (84.2%) are alive and disease-free. Twenty-eight out of 32 patients retained their anal sphincter. The accrual of new patients and longer follow-up is in progress.
Start the same day
II cycle chemotherapy X 5 days
Radiotherapy on the perineum
and result
DISCUSSION
Median follow-up for the whole series as of December 1988 was 22 months. The breakdown of results is presented in Table 2. A complete remission was achieved in 32138 patients (84.2%) and it was maintained in 27132. Among the five patients presenting inguinal adenopathies, four achieved complete remission and remain diseasefree. Six patients only did not achieve a complete remission, despite adequacy of treatment. Five of them had
I cycle chemotherapy X 5 days
local extension
No. cases
RESULTS
Table 1. Outline
between
Start the same day (6 weeks after first cycle)
Maintained CR Relapsed after CR Dead for intercurrent disease Total alive, NED * 28/32 retained
26 patients 51 32/38* anal sphincter.
2 rescued with local excision 2 rescued with Miles
84.2%
Combined treatment of anal canal 0 R. ZUCALI et al.
1223
Obviously, many problems remain unsolved and a larger experience is needed. The following issues are frequently raised: What is the optimal chemotherapy? Must any drug be substituted or added to the classic scheme? What is the optimal timing for chemotherapy and radiotherapy? Which is the optimal modality of administering chemotherapy? The infusion of 5-FU must be modified,
of the tumor to date, whereas more toxicity was correlated with the use of this drug. As far as the timing of chemotherapy and radiotherapy is concerned, our experience confirms the importance of starting the combined treatment at the same time. On the contrary, the sequential approach, chemotherapy followed by radiotherapy did not yield similar excellent results in
should it be more prolonged during the course of radiotherapy? What are the targets of radiotherapy for thera-
our hands.
peutic and adjuvant treatment? What is the optimal schedule of radiotherapy in terms of fractionation, single and total doses and characteristics of the final boost to the anal region? The classic chemotherapy is really effective at the expense of an acceptable toxicity. The addition of Platinum to the antiblastic combination, with or without Mitomycin C, failed to improve the response rate and the control rate
Our study confirms the results of other workers and can contribute to answer some open questions. However the most important message is that it is once more confirmed that surgery plays a minor role in the definitive treatment of anal cancer. Our knowledge will be improved through the experience of many centers facing these problems. Their results will be continuously evaluated and discussed, and multicentric trials in progress will be followed with great interest.
REFERENCES Cummings, B.; Keane, T.; Thomas, G.; Harwood, A.; Rider, W. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54:2026-2068; 1984. Eschwege, F.; Lasser, P.; Chavy, A.; Wibault, P.; Kac, J.; Rougier, P.; Bognel, C. Squamous cell carcinoma of the canal anal: treatment by external beam irradiation. Radiother. Oncol. 3:145-150; 1985. Mitchell, E. Carcinoma of the anal region. Sem. Oncol. 15: 146-153; 1988. Nigro, N. D.; Seydel, H. G.; Considine, B. Combined preoperative radiation and chemotherapy of squamous cell carcinoma of the anal canal. Cancer 5 1:1826- 1829; 1983.
Nigro, N. D.; Vaitkevicius, V. K.; Considine, B. Combined therapy for cancer of the anal canal. A preliminary report. Dis. Colon Rectum 3:354-359: 1974. Papillon, J. Rectal and anal cancers. Conservative treatment by irradiation, an alternative to radical surgery. Heidelberg: Springer-Verlag; 1982. Sischy, B.; Remington, J. H.; Hinson, E. Definitive treatment of anal canal carcinoma by means of radiation therapy and chemotherapy. Dis. Colon Rectum 25:685-688; 1986. 8. TNM classification of malignant tumors, 4th edition. Berlin: Springer-Verlag;
1987.
