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Annals of Surgical Oncology 9:568-573 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Chemoradiation Instead of Surgery To Treat Mid and Low Rectal Tumors: Is It Safe?

Wilson T. Nakagawa, MD, Benedito M. Rossi, MD, PhD, FACS, CSSO, Fábio de O. Ferreira, MD, PhD, Robson Ferrigno, MD, Waldec J. David Filho, MD, Inês N. Nishimoto, MSc, Rene A. C. Vieira, MD and Ademar Lopes, MD, PhD, FACS, FSSO

From the Pelvic Surgery Department, A. C. Camargo Cancer Hospital, Antonio Prudente Foundation, São Paulo, Brazil.

Correspondence: Address correspondence and reprint requests to: Wilson T. Nakagawa, MD, Departamento de Cirurgia Pélvica, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, 01509-010, São Paulo, Brazil; Fax: 55-11-3272-5100; E-mail: wtnakagawa{at}uol.com.br


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The main treatment for rectal carcinoma is surgery. Preoperative chemoradiation (CRT) is advocated to reduce local recurrence and improve resection of mid and low tethered rectal tumors.

Methods: Fifty-two patients with mid or low rectal tumors underwent CRT (external beam radiation plus 5-fluorouracil plus folinic acid). Patients who had low rectal tumors with complete response (CR) were not submitted to surgical treatment. All other patients were submitted to surgery, independently of the response. Mean follow-up was 32.1 months.

Results: Five-year overall survival was 60.5%. Clinical evaluation after CRT showed CR in 10 cases (19.2%), all low tumors; incomplete response (>50%) in 21 (40.4%); and no response (<50%) in 19 (36.6%). Among the 10 cases with CR, 8 presented with local recurrence within 3.7 to 8.8 months. Two patients were not submitted to surgery and are still alive without cancer after 37 and 58 months. Thirty-nine patients had radical surgery. Seven had local recurrences after CRT plus surgery (17.9%). Overall survival was negatively affected by lymph node metastases (P = .017) and perineural invasion (P = .026).

Conclusions: Exclusive CRT approach is not safe to treat patients with low infiltrative rectal carcinoma.

Key Words: Rectal adenocarcinoma • Rectal cancer • Chemotherapy • Radiotherapy • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Surgery is the main treatment for patients with rectal carcinoma. Adjuvant treatment with chemotherapy and radiotherapy has been used to improve results related to local recurrence and distant dissemination. The association of radiation and chemotherapy has also been used to improve surgery viability (mainly in tethered tumors) and, therefore, survival rates.1–4 The objective of this study was to analyze the results of chemoradiation (CRT) alone or associated with surgery in the treatment of patients with mid or low infiltrative rectal tumors.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between 1993 and 1997, 104 consecutive patients with primary adenocarcinoma of the mid or low rectum were admitted for treatment. Patients’ assessments included complete clinical history and examination, proctoscopy, colonoscopy, chest x-ray, computed tomographic (CT) scan of the abdomen and pelvis, carcinoembryonic antigen, and cancer antigen 19.9.

Eligibility criteria for this study were (1) adenocarcinoma of the mid or low rectum, at or below 8 cm from the dentate line; (2) age younger than 75 years; (3) Karnofsky performance status higher than 70%; (4) no previous treatment; (5) absence of prior or coexisting tumors; (6) adequate clinical conditions to undergo the proposed treatment; (7) rectal tumors that could not be resected locally; and (8) absence of distant metastases. Fifty-two patients were excluded and 52 were included in this study (26 men and 26 women), with a median age of 61 years (range, 23 to 71 years). The median distance between the tumor and the dentate line was 3 cm (range, 0 to 8 cm).

The tumors were classified according to their circumferential involvement and mobility. In 29 patients (55.8%), the tumor occupied more than three fourths of the circumference of the rectal wall; in 35 patients (76.9%), the tumor was fixed, or tethered; and in 12, the tumor was considered mobile on clinical examination. The involvement of adjacent organs was observed in five patients (9.6%).

All 52 patients were submitted to CRT. Radiotherapy was performed with a 4-MEV linear accelerator by using a four-pelvic-fields technique, with a total dose of 5040 cGy (28 x 180 cGy). The boundaries of the radiation field were determined by the transition between L4 and L5, 2 cm lateral to the iliopectineal line and 2 cm below the inferior tumor edge.

Patients received 5-fluorouracil (425 mg/m2/day) associated with folinic acid (20 mg/m2/day) during the first 3 days and the last 3 days of radiation by intravenous bolus at the outpatient clinic. Thirty-three patients of the 52 included in this study received chemotherapy at the proposed dose, and 19 patients (36.5%) received just the first 3 days. Inability to receive the second chemotherapy cycle was related to toxicity. Radiotherapy doses ranged from 1140 to 5040 cGy. Four patients received <4500 cGy, and 42 patients (80.8%) received the proposed dose (5040 cGy). Four patients received doses lower than 4500 cGy, mainly because of local intolerance. Patients with low rectal tumors who presented with complete response (CR) underwent supplementary radiation by brachytherapy with a template schedule or iridium implantation in the tumor area. The proposed dose was 2000 cGy.

Patients were evaluated with proctoscopy and biopsy approximately 3 to 4 weeks after CRT was over. We compared the tumor characteristics before and after CRT. The changes observed in the lesion were classified as follows: CR, complete regression of the lesion and negative biopsy; incomplete response (IR), regression rate was >50%; without response, regression rate was <50%; and disease progression, lesion was increased >25%.

During CRT, patients were evaluated by the medical team for complications and side effects related to the disease or its treatment. The toxicity level was defined according to the World Health Organization criteria, and grades 3 and 4 were considered the most severe. The decision about interrupting treatment temporarily or permanently was made by the medical team.

Surgery was proposed to patients with residual tumor, independently of its localization. Only patients with distal rectal tumors and CR (clinical and pathologic) received supplementary radiation and did not undergo surgery. All patients underwent surgery aiming at cure, and the most suitable technique was chosen for each case. We used the initial (before CRT) low edge of the tumor plus 2 cm as a distal surgical margin.

Follow-up was performed every 3 months during the first 2 years, then every 6 months up to 5 years, and yearly afterward. The examinations included in yearly follow-up were carcinoembryonic antigen, cancer antigen 19.9, chest x-ray, ultrasound or CT scan of the abdomen and pelvis, and colonoscopy. Those patients with CR who were not operated on underwent proctoscopy every 3 months. Overall survival was defined as the time interval from admission to treatment until the last follow-up appointment or death.

Nominal variables were compared by using the {chi}2 test or Fisher’s exact test, as appropriate. Survival was evaluated with the Kaplan-Meier method; comparisons between groups were established by the log-rank test. Differences were considered significant at the P < .05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Grade 3 and 4 toxicity was observed during the CRT: in 1 patient for nausea, vomiting, and mucositis; 4 for anorexia; 8 for diarrhea; 39 for perineal dermatitis; and 7 for hematological toxicity with leukopenia, including 2 deaths due to septicemia. Regarding the tumor response, we observed CR in 10 cases (19.2%), IR in 21 (40.4%), no response in 16 (30.8%), and disease progression in 3 (5.8%). Two patients were not evaluated (dead with septicemia)

Tumor mobility, circumferential involvement of the rectal wall, tumor location, sex, ethnic group, weight loss at the time of hospitalization, age, involvement of adjacent organs, length of time of evolution before treatment, number of cycles of chemotherapy, and radiation dose were not statistically significant in the analysis. Patients who received <4,500 cGy during radiation had significantly lower rates of objective response (P = .022).

Thirty-nine patients were considered eligible for surgery. Sphincter preservation was achieved in 17 patients (33.1%) with anterior resection, with the single-stapled technique in 5 patients (9.6%), the double-stapled technique in 11 patients (21.6%), and Parks’ anastomosis technique in 1 patient (1.9%). Permanent colostomy was performed in 22 patients (42.3%) after abdominoperineal resection (APR) in 21 patients (40.4%) and Hartman’s procedure in 1 (1.9%).

Thirteen patients were not operated on: eight refused, one presented with an unresectable tumor (intraoperative evaluation), two presented with CRs, and there were two deaths due to toxicity. Four patients (10.3%) had involvement of adjacent organs and were submitted to extended surgeries: vagina (n = 2); uterus (n = 1); and bladder, prostate, and seminal vesicles (total pelvic exenteration with sphincter preservation; n =1).

Protective stoma was performed in 16 of 17 patients who underwent surgery with sphincter preservation. Closure was performed in 15 of 16 patients. Pathologic examination after the surgical procedure showed absence of tumor in the primary site and in resected lymph nodes in three patients (7.7% of patients who underwent surgery), despite a positive preoperative evaluation.

There were no deaths related to surgery. The most frequent surgical complications were wound abscess (n = 11; 28.2%), dehiscence of the anastomosis (n = 1; 2.6%), urinary complications (n = 1; 2.6%), cardiovascular complications (n = 1; 2.6%), and other (n = 2; 5.1%).

All 10 patients who presented with clinical CR had the absence of neoplasia confirmed by biopsy during proctoscopy. The tumors were located in the low rectum, and the patients did not undergo surgery. Eight of the 10 patients (80%) presented with recurrence between 3.7 and 8.8 months after the end of chemoradiation (median, 6.0 months). Six of the 8 patients with local recurrence underwent salvage surgery. Only two patients were still alive without disease at 37.5 and 58 months. Table 1 shows detailed information about this group of patients with CR.


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  		TABLE 1. TABLE 1. Clinical characteristics, treatment, and follow-up of the 10 patients with CR after CRT
 
Local recurrence was observed in 7 of 39 patients (17.9%) who underwent surgery. Distant metastases were observed in 10 patients. Twenty-nine patients did not present evidence of distant metastasis during follow-up. Surgical treatment of metastases was performed in five cases (liver, n = 3; lung, n = 2), and four patients are still alive without evidence of disease. The median follow-up of this study was 32.1 months (range, 1.4 to 64 months). Figure 1 shows the actuarial survival rate related to the lymph node status of patients who underwent surgery



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  		FIG. 1. Overall survival of patients who underwent surgery (lymph node status).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The rate of objective response (CR plus IR) reached by preoperative CRT in this study was high (59.6%). Eight of the 10 patients with CR presented with local recurrence within a few months (mean, 6 months). This probably indicates the existence of residual tumor not detected by proctoscopy with biopsy or by CT scan. Biopsy is generally superficial and may fail to detect the presence of deep tumor foci. Ultrasonography also may fail to define tumor reduction or fibrosis.5,6

It is interesting to note that because of the substantial improvement of symptoms (such as pain and bleeding) after CRT, even with residual tumor, we observed an increased rate of refusal of surgical treatment. This constitutes a problem for the patient, so the surgeon must clearly explain the disease status and the future consequences of surgery refusal.

Chari et al.,7 using preoperative CRT for rectal tumors in 43 cases, reported a CR rate of 51% (proctoscopy and biopsy). However, after surgery, only 27% of the surgical specimens were negative in the pathologic examination.

CRT toxicity was relatively low in this study, but perineal dermatitis was frequent (75%), and two deaths were related to septicemia. Two similar studies reported one death each during CRT, also related to infection.8,9 Other series also reported severe complications, but these complications rarely led to death.10–12

Another serious problem in infiltrative rectal tumors is the lymph nodes status. Lymphatic dissemination can reach 30%, and evaluation by clinical methods poses many difficulties.13 Residual tumors in the lymph nodes are a definite cause of recurrence, mainly in extrarectal fat. Salvage surgeries for these patients may be more difficult because of radial pelvic margins and may have lower curative rates. Table 2 shows local recurrence rates after CRT plus surgery in some studies.


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  		TABLE 2. TABLE 2. Local recurrence rates after CRT and surgery for rectal tumors
 
In this study, the analysis of variables related to the tumor or its treatment showed no correlation with CR or IR for patients who underwent CRT with doses of radiation higher than 4500 cGy. Valentini et al.,8 using a univariate analysis, observed that the radial tumor involvement of the rectal wall was important regarding the radiotherapy response. Kaminsky-Forret et al.17 analyzed 88 patients with T3/T4 rectal tumors who underwent CRT and reported that the rate of objective response was important in determining local control and better survival results. In this study, the response rate had no effect on survival rates.

We observed CR on pathologic examination in three patients who underwent surgery (7.6%). These numbers are listed and compared with those in the literature in Table 3.


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  		TABLE 3. TABLE 3. Rates of CR and histological assessment of the resected specimen after CRT
 
Regarding the surgical treatment, we believe that the distal margin in the rectum should be >=2 cm, taking into account the proctoscopy before CRT. The surgeon should not use the area previously occupied by tumor as a margin with an objective of sphincter preservation. Thus, patients with an indication for APR before CRT should not have their sphincter spared because of preoperative treatment response.

There were no deaths related to the surgical procedure in this study, and the morbidity rate was compatible with those in other studies. We observed just 1 case of anastomosis dehiscence (1 in 17; 5.9%). Similar studies show leak rates ranging from 1.5% to 8%.9,19,21 The most common complication after APR was wound and perineal infection, similar to results in the literature.9,19,22

Sphincter preservation was achieved in 18 cases, 2 with CR to CRT and 16 submitted to anterior resection (34.6%). As we have already shown, response rates to CRT may be high; however, it is uncommon for patients with CR to maintain this status.23 Habr-Gama et al.21 observed maintained CRs in 30.5% of the patients without surgery with a median follow-up of 36 months. Another recent study by the Memorial Sloan-Kettering Cancer Center group, from New York, showed that surgery is necessary after CRT to achieve cure in patients with infiltrative rectal cancer.24

The overall survival rate observed in this study was 60.7%; this is smaller compared with results in the literature (Table 4). This fact could be related to tumor staging, CRT toxicity or morbidity, the number of patients who refused surgery after CRT, and the metastasis rate observed in our study. Statistical analysis (univariate) showed a significant correlation of lymph node involvement (P = .017) and perineural invasion (P = .026) with survival.


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  		TABLE 4. TABLE 4. Five-year actuarial survival rate after CRT and surgery
 
In conclusion, objective response (CR plus IR) was frequent; however, it was not maintained. The toxicity of the treatment proposed was within acceptable levels, but for a few patients it was stronger and led to severe consequences, including two deaths. Lymph node status and perineural invasion were important pathologic findings that interfered with the survival rate. Patients with infiltrative rectal tumors should be operated on, even reaching CR after CRT. In other words, it is not safe to use exclusive CRT for patients with low infiltrative rectal tumors.

Received for publication June 18, 2001. Accepted for publication March 29, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  10. Pucciarelli S, Toppan P, Friso ML, et al. Preoperative combined radiotherapy and chemotherapy for rectal cancer does not affect early postoperative morbidity and mortality in low anterior resection. Dis Colon Rectum 1999; 42: 1276–83.[CrossRef][Medline]
  11. Valentini V, Morganti AG, De Franco A, et al. Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome. Cancer 1999; 86: 2612–24.[CrossRef][Medline]
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  17. Kaminsky-Forrett MC, Conroy T, Luporsi E, et al. Prognostic implications of downstaging following preoperative radiation therapy for operable T3-T4 rectal cancer. Int J Radiat Oncol Biol Phys 1998; 42: 935–41.[CrossRef][Medline]
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