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Annals of Surgical Oncology 9:444-449 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Preoperative Chemoradiation in Patients With Resectable Rectal Cancer: Results on Tumor Response

Federico Bozzetti, MD, Salvatore Andreola, MD, Dario Baratti, MD, Luigi Mariani, PhD, Simonetta C. Stani, MD, Francesca Valvo, MD and Pasquale Spinelli, MD

From the Departments of Surgical Oncology I (FB, DB), Pathology (SA), Medical Oncology A (SCS), Radiotherapy (FV), and Endoscopic Surgery (PS) and the Division of Medical Statistics and Biometry (LM), Istituto Nazionale per lo Studio e la Cura dei Tumori (National Cancer Institute), Milan, Italy.

Correspondence: Address correspondence and reprint requests to: Federico Bozzetti, MD, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1 20133 Milan, Italy; Fax: 39-02-23903259; E-mail: dottfb{at}tin.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: There is no consensus about the role of preoperative radiotherapy (RT) and chemotherapy (CT) in patients with resectable cancer of the distal rectum. This study analyzed the local clinical and pathologic response in patients receiving preoperative RT/CT for rectal cancer.

Methods: Thirty-two consecutive patients with a palpable adenocarcinoma of the rectum received preoperative RT (45 Gy in 25 fractions over 5 weeks) plus continuous chemotherapy with doxifluridine and leucovorin or 5-fluorouracil by continuous intravenous infusion during RT. Surgery was performed 8 weeks later. The Wilcoxon and {chi}2 tests were used for data analysis.

Results: Twelve patients had mild gastrointestinal toxicity, only one of whom required interruption of therapy. The tumor shrank to 57.8% of its original size, and at the echoendoscopy (u) there was a 58.7% decrease of the maximum diameter (P < .001). Downstaging from uT3 and uT2 to <uT3 and <uT2, respectively, occurred in 41.6% of patients (P = .0020). Total and major regression of the tumor at the histopathologic examination occurred in 12.5% and 50% of patients.

Conclusions: Local response to preoperative RT/CT was highly satisfactory and allowed conservative surgery in 81% of patients. Optimization of the combined therapy could achieve even better results.

Key Words: Rectal cancer • Neoadjuvant therapy • Preoperative chemoradiation • Preoperative radiotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is evidence in the literature of the efficacy of preoperative radiotherapy (RT) in rectal cancer as regards total local destruction of the tumor,1–6 decreased frequency of local recurrence, 7–15 and improvement in survival.8–10,14,16,17 Our recent experience18,19 is in keeping with these results. Other institutions, however, have reported favorable results with the preoperative association of chemotherapy (CT) with RT.20–26

In July 1997, we started a preoperative chemoradiation therapy program in patients with clinically resectable cancer of the distal rectum. We report here the preliminary results on tumor response and provide a tentative comparison with a retrospective series of patients treated for cancer in the same location with preoperative radiation only for cancer 3 years before 1997.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Thirty-two consecutive patients with histologically proven adenocarcinoma of the rectum and who were admitted to the Istituto Nazionale Tumori, Milan, between July 1997 and July 1999 entered a protocol of preoperative RT/CT followed by surgery. Table 1 lists the main characteristics of the patients.


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  		TABLE 1. Main characteristics of the patients
 
Patients were included in the combined-treatment protocol provided they met the following criteria: (1) histological diagnosis of adenocarcinoma located within 8 cm from the anal verge, as measured by rigid sigmoidoscopy; (2) clinical stage II or III (according to the York Mason classification), i.e., tumor with full mobility or tethered mobility at the rectal digital examination; (3) echoendoscopic stage uT2 to uT3,27 irrespective of the lymph node status (stages uT2 and uT3 signify involvement of the muscular layer and the perirectal adipose tissue, respectively); (4) no prior CT or RT; (5) absence of secondary malignancies; (6) absence of distant metastases (by whole-abdomen computed tomographic scan or nuclear magnetic resonance); (7) performance status <=2 (according to the Eastern Cooperative Oncology Group scale); and (8) written informed consent.

Endorectal ultrasound examination (EUS) was performed by using a flexible echoendoscope (Olympus GF or CF-UM20; Olympus, Tokyo, Japan) equipped with a mechanical radial scanner at an operative frequency of 7.5 to 12.0 MHz. The examination was performed just before the beginning of RT and was repeated 6 to 8 weeks after its completion, immediately before surgery. A single endoscopist was in charge of EUS and was not informed of the patients’ planned treatment.

Whenever there was a discrepancy between clinical and endosonographic assessment, the decision whether to include the patient in the protocol was left to the surgeon in charge of the study (F.B.), who relied on the clinical and rectal digital examination. All patients gave their written consent to the proposed treatment of preoperative RT/CT followed by surgery. Preoperative treatment included CT with fluoropyrimidine and RT.

The first 23 patients received doxifluridine 500 mg/m2/day per os, plus leucovorin 30 mg per os as a radiosensitizer. The remaining nine patients received 5-fluorouracil 225 mg/m2/day via continuous intravenous infusion because doxifluridine was no longer available. CT was administered throughout the entire duration of RT. Prophylactic antiemetic therapy was not mandatory. Nystatin and loperamide were strictly recommended for candidiasis of the oral cavity and diarrhea, respectively.

The RT was delivered with 15-MV photons by using a three-field technique. A total dose of 45 Gy in 25 fractions over 5 weeks was prescribed to the isocenter. All fields were treated daily. The superior border was placed at the L5-S1 space, and the inferior border was placed under the obturator foramen. To encompass the iliac lymph node chains, the lateral borders of the posterior portal laid 2.0 cm outside the true bony pelvis. The lateral fields encompassed the sacrum and coccyx posteriorly and the femoral head anteriorly to include the obturator nodes.

A single pathologist (S.A.) was in charge of examining all surgical specimens. Lymph nodes were sought by using the manual technique after fixation in formalin (10%) for 24 hours. Lymph nodes found between the margin of surgical resection of the inferior mesenteric artery and its bifurcation into the superior rectal arteries were labeled inferior mesenteric. Lymph nodes found below the bifurcation of the superior rectal arteries were labeled pararectal. The widest diameter of each lymph node was measured on the histological section. The T class of the primary tumor was determined.

The tumor regression grade (TRG) was quantified, according to the criteria proposed by Mandard et al.28 for esophageal carcinoma treated with chemoradiotherapy, as follows: TRG1 (complete regression), absence of residual tumoral cells; TRG2, presence of rare residual cancer cells and prominent fibrosis; TRG3, fibrosis outgrowing residual cancer cells; TRG4, residual cancer cells outgrowing fibrosis; and TRG5, absence of regression. Evaluation of the TRG was based on the percentage of fibrous tissue versus the amount of the residual tumor. According to these criteria, the original size of the tumor (before RT) was evaluated approximately as the total area of fibrous tissue around the mucosal ulcer that is always present after RT. In TRG2 and TRG3, the fibrous tissue exceeds 50% of the above-mentioned area, and neoplastic remnants are only small foci of the tumor. In grades 4 and 5, there is little fibrous tissue, and the tumor does not show evidence of RT regression. The pathologist who examined the specimen was not aware of the preoperative therapy delivered to the patient.

Tumor response was also assessed by comparing pre-RT/CT and preoperative endoscopic and echoendoscopic features of the tumor. Statistical analysis of data was performed by means of the Wilcoxon and {chi}2 tests, as appropriate.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Surgery was performed after 6 to 8 weeks and was considered curative (R0) in all cases because the margins of resection were microscopically tumor free. A total mesorectal excision was performed both in sphincter-saving resections and in Miles’ abdominal-perineal resection, because it is our policy in tumors of the lower-middle rectum.

All patients were evaluated for toxicity and response.

Toxicity
Combined CT plus RT was well tolerated by all patients. Grade 2 diarrhea was the most common treatment-related effect (12 patients), but only 1 patient required interruption of CT because of persisting grade 3 diarrhea.

Mild to moderate proctitis was reported in 10 patients and cystitis in 3 patients: all patients recovered without requiring interruption of treatment. No bone marrow toxicity was observed.

Tumor Response
The main pathologic features of the resected tumors are listed in Table 2. Tumor response was assessed mainly from change in tumor size, as determined by pre-RT/CT and post-RT/CT endoscopic or EUS examination. As regards the endoscopic evaluation or the direct measurement of the lesion, the maximal diameter of the tumor mass or excavation was measured before and after therapy. Furthermore, the degree of rectal wall infiltration and the histological TRG were observed at the pathologic examination of the resected specimen.


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  		TABLE 2. Pathologic features of cancer in 32 patients
 
Tumor Size
Endoscopic measurement of the tumor before RT/CT and pathologic examination of the freshly resected specimen showed that, in the 29 patients for whom it was possible to make an accurate estimate, there was a mean tumor size (maximum diameter) of 4.5 cm (range, 3–8 cm), which decreased to a mean of 1.9 cm (range, 0–3.5 cm). Therefore, the reduction in size was approximately 2.6 cm, or 57.8%.

In 19 patients, it was possible to use EUS to calculate the effect of the RT/CT on the maximum tumor length. A decrease from a mean of 4.6 cm (range, 3–7 cm) to a mean of 1.9 cm (range, 1–4 cm) was observed; this means that there was a reduction in length of approximately 2.7 cm, that is, 58.7% (P < .001).

Rectal Wall Invasion and T Downstaging
Table 3 shows a comparison of uT before and after RT/CT with pT classes. Twenty-four patients were suitable for evaluation because they had undergone both pre- and post-RT/CT EUS examinations. On the whole, uT3 accounted for 20 (83.3%) of 24 patients before RT/CT and decreased to 12 (50%) at the evaluation after RT/CT. A downstaging from uT3 to <uT3 and from uT2 to <uT2 occurred in 10 patients, i.e., 41.7% of the series (P = .0020).


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  		TABLE 3. uT Classification and T downstaging after RT/CT
 
EUS did not prove to be very accurate in assessing the pT stage after RT/CT. The overall accuracy of the 25 patients with a post-RT evaluation was 60%, and only when the u class was defined T3 it corresponded to a pT3 stage in 84.6% of cases (Table 4).


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  		TABLE 4. Distribution of patients by post-RT/CT uT and pT classes
 
Pathologic TRG
Histopathologic regression of the tumor was assessed in 32 patients and showed a significant regression in almost two thirds of them. In fact, 4 patients (12.5%) showed complete regression (TRG1); 16 others (50.0%) showed the presence of rare residual cells and prominent fibrosis (TRG2); another 4 (12.5%) had fibrosis outgrowing residual cancer cells (TRG3); and 7 (21.9%) had residual cancer cells outgrowing fibrosis (TRG4). One patient (3.1%) presented no regression at all (TRG5).

Comparison With Patients Receiving Preoperative RT Only
Corresponding figures observed in 59 patients enrolled in a previous protocol at our institution18 who had similar location and u stage of tumor and who received only preoperative RT were a 23.2% to 32.6% decrease in tumor size (at the macroscopic and EUS examination, respectively), a T downstaging in 24.5% of patients, and a TRG1 or TRG2 classification in 34.0%.

Despite the relatively small number of patients, comparison of the frequency of TRG1 and TRG2 obtained in these two consecutive series of patients demonstrated a statistically significant difference (P < .014) in favor of the RT/CT combination.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These data show the preliminary favorable results we obtained by using preoperative RT/CT in patients with clinically resectable and palpable rectal cancer. Preoperative therapy was well tolerated: two thirds of the patients had a major histopathologic response to RT/CT, with only one patient showing no regression, and we were able to perform sphincter-saving operations in most of them (81.2%). These data compare well with the 26.5% of sphincter-saving resections in our experience with surgery without preoperative RT or RT/CT in palpable cancer of the middle-low rectum.29

It is noteworthy that we found a complete pathologic response in 12.5% of subjects, a figure quite similar to that recently reported at the Memorial Sloan-Kettering Cancer Center21 but lower than some others recently published in the literature (Table 5). It is likely that this discrepancy reflects differences in therapeutic regimens (dosage, drug, and manner of administration), methods, and, mainly, in the accuracy of assessing the response.


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  		TABLE 5. Summary of the results of literature on preoperative RT/CT in patients with operable rectal cancer
 
Reduction in tumor size was approximately 58%, downstaging of the T class was observed in 41.7% of the patients, and a consistent regression (TRG1 and TRG2) was present in 62.5% of patients; this is a value significantly better than that reported in patients receiving preoperative RT only.

In conclusion, data on preoperative RT/CT seem to be promising and are shared by other authorities.34 Although long-term clinical results are still lacking, patients are amenable to sphincter-saving resection in a high percentage of cases, pathologic regression and downstaging occur frequently, and this sort of response in our18 and other authors’21,24 experience has proven to be associated with a favorable oncological outcome.

Two major problems remain unsolved. First, we do not yet know whether to base the decision regarding extension of surgery on the initial stage and tumor spread or on the post-RT/CT assessment. This may be crucial, particularly when an apparent tumor regression could change the indication from demolitive surgery to a sphincter-saving operation. Second, it will become increasingly important to try to assess the tumor response to RT/CT before surgery to optimize the time and extent of the resection or even to avoid a potentially unnecessary operation.

At present, we expect that the optimization of RT and its association with more active drug combinations will achieve even better results, as a multicenter Italian experience has preliminarily shown by obtaining a complete pathologic regression in 44% of patients through dose intensification.35 However, the continuous infusion of 5-fluorouracil through RT can be safely increased to 300 mg/m2/day, and the use of new oral fluoropyrimidines, such as capecitabine, or the association of irinotecan with 5-fluorouracil during RT seems to improve the efficacy of preoperative CT without significant toxicity.29,36,37

Received for publication September 4, 2001. Accepted for publication February 9, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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