© 2006 Foundation for Promotion of Cancer Research
Review Article |
Treatment Strategy for Locally Recurrent Rectal Cancer
Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Yoshihiro Moriya, Colorectal Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: ymoriya{at}ncc.go.jp
Received October 15, 2004; accepted February 15, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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Despite radical surgery, up to 33% of patients with rectal cancer will develop locoregional relapse. The management of these patients is particularly challenging. Surgery is the mainstay of treatment for those with a mobile recurrence. However, the majority of patients develop recurrence involving the pelvic wall. In these patients, multimodality therapy including radical surgery and intraoperative radiotherapy have been reported with 5-year survival of up to 31% and local control rates of 50–71%. The most important factor for obtaining long-term local control and survival is R0 resection. Extended surgery such as abdomino-sacral resection has not been popular because of 5-year survival rates of 16–31%, and significant postoperative morbidity. Re-recurrence following surgery occurs locally and in the lung, and remains a significant problem. In surgical treatment for local recurrence, surgeon-related factors are crucial. A staging system using degree of fixation and other prognostic factors should be developed so that appropriate treatment modalities are applied to each case.
Key Words: locally recurrent rectal cancer • multimodality therapy • extended surgery
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INTRODUCTION |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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In patients who undergo radical surgery for rectal cancer, 4–33% develop locoregional relapse. Without treatment, these patients with locally recurrent rectal cancer (LRRC) have a median survival of
8 months. If no treatment is given, they suffer from severe symptoms, especially pain, and their quality of life (QOL) becomes extremely poor (1–4). Nearly half of LRRCs are located in the pelvis without distant metastasis. The best treatment for LRRC in this setting is a complete resection of the recurrent tumor. There are a number of different options for treating LRRC. There options are influenced by the nature of the LRRCs, which may present as a mobile recurrence or a huge mass occupying the pelvis.
In non-fixed recurrent tumors, complete resection can be achieved with limited surgery such as abdomino-perineal resection and the outcomes are relatively favorable.
When an LRRC grows within the narrow pelvis, it can easily invade the pelvic wall, appearing in the form of fixed recurrent tumor (FRT). If FRT involves only anterior structures, total pelvic exenteration achieves adequate margins. However, the majority of patients with LRRC present with dorsal and/or dorsolateral involvement of the pelvis. These patients present a particular challenge. Extensive surgery such as abdomino-sacral resection may be required. However, inappropriate surgical intervention in these patients may cause an iatrogenic cancer spread, leading to impaired QOL.
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CONVENTIONAL TREATMENT |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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In patients with LRRC who are unsuitable for surgical intervention, chemoradation is the main therapeutic option available. The effect of radiotherapy depends on the tumor size and the total radiation dose given. A dose of 45 Gy provides good palliation of pain in 50–80% of patients (5), with low risk of toxicity to the small intestine. However, an antitumor effect that may achieve complete response or survival benefit cannot be expected at this dose. Another approach is to administer a dose of 50 Gy to the same radiation field used for the treatment of the primary rectal cancer. The radiation field is then reduced to include only the site of tumor recurrence and a total dose of 60–70 Gy is delivered to this site. However, external beam radiotherapy (EBRT) alone has not been shown to achieve significant survival benefit.
For this reason, the combination of radiotherapy and chemotherapy is usually employed. The rationale for combined therapy includes (i) enhancement of cytotoxicity using an antitumor agent and radiation, (ii) use of chemotherapy, which provides treatment of distant metastasis in addition to the local control of the tumor provided by radiotherapy and (iii) the potential to reduce the dosage of agents and therefore their toxicity by combining different treatment modalities without reducing the overall efficacy (6,7).
EBRT used alone or in combination with chemotherapy provides temporary symptomatic improvement in most patients. Median survival time is 14 months and time of local control is 5 months. Five-year survival rate in these patients is usually <5% (8).
Preoperative chemoradiation is used for primary rectal cancer to downstage the tumor and improve resectability. The same approach has also been used for LRRC. Rodel et al. (9) administered chemoradiotherapy preoperatively in 35 patients with LLRC using 5-FU (1000 mg/m2/day). They reported that they achieved margin-free resections in 17 cases (61%). Other chemotherapy agents such as CPT-11 and Oxaliplatin are expected to play an important role in the management of these patients in the future (10).
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MULTIMODALITY TREATMENT |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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Reports from some western centers suggest that improved local control and survival can be achieved in selected patients by the use of preoperative chemoradiotherapy, radical surgery and intraoperative radiotherapy (IORT) (11–22). This approach recognizes that satisfactory antitumor effect cannot be achieved by chemoradiation alone. The addition of IORT means that the maximum radiation dose possible can be delivered to the recurrent tumor. This has the potential to allow less extensive surgery to be undertaken.
One of the benefits of IORT is that it produces up to three times the biological effect produced by fractionated EBRT. In addition, IORT has the advantage of delivering radiation accurately to the tumor bed while displacing adjacent normal structures from the irradiation field. The use of IORT allows a reduction of the EBRT dose and so reduces toxicity of this modality. Mayo Clinic researchers reported a 3-year survival rate of 39% and a 5-year survival rate of 20% in 123 patients with LRRC who were treated with IORT and surgery (14). Mannaerts et al. (16,18) in the Netherlands used a preoperative radiotherapy dose of 50.4 Gy (30 Gy in patients who had received ratiotherapy) before surgery, during which they carried out IORT. The dose of IORT was determined by the R status of the resection. Patients who had undergone R0 resection (microscopically negative margins) were treated with a dose of 10 Gy, R1 resections (microscopically positive margins) with a dose of 15 Gy and R2 cases (macroscopically positive margins) with a dose of 17.5 Gy. Overall 3-year survival rate reached 58%. However, patients who had undergone R2 resection showed a worse prognosis in this series. Wiig et al. (19) reported a 5-year survival rate of 60% in patients given preoperative irradiation who had R0 resection. This does raise the question as to whether IORT is really necessary in cases with previous R0 resection, particularly as not all R0 cases in this series received IORT. It can be argued that a true R0 resection leaves no cancer cells to be eradicated by IORT. In clinical practice, however, because it is not always easy to differentiate fibrosis from recurrent cancer, some patients who undergo R0 resection may have residual disease and may benefit from IORT (20,21).
Abuchaibe et al. (12) and Bussieres et al. (15) have reported on patients with R2 resection given IORT but no postoperative EBRT. This strategy resulted in a poor outcome and suggests that additional EBRT is important in achieving local control. Irradiation of patients who have received radiotherapy previously has generally been avoided because of the fear of severe late radiation toxicity. Mohiuddin et al. (2,23) reported on 103 cases who received reirradiation and showed acceptable late toxicity (17% with chronic severe diarrhea, 15% with small bowel obstruction and 4% with fistula).
Despite the use of multimodality therapy, 5-year survival rates of patients with LRRC remain 22–31% and local control rates 50–71% (Table 1). IORT cannot be expected to compensate for R2 resection (13) and is itself associated with potential complications. The commonest side effects are ureteric stenosis and peripheral neuropathy. In a series of 123 cases at the Mayo Clinic (14), partial ureteric stenosis as a complication occurred in 6% of patients with 10% requiring insertion of ureteric stents. Peripheral neuropathy was observed in 16–34% of the patients.
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Brachytherapy uses gamma rays or beta rays emitted by the encapsulated sealed radioactive source to carry out interstitial irradiation. More recently, concerns about the surgeon's exposure to radiation and patient isolation have seen the increased use of high-dose-rate remote afterloading system (24,25). Goes et al. (24) reported the use of afterloading tubes inserted intraoperatively after tumor reduction surgery to deliver brachytherapy in 30 previously irradiated patients. In these patients with LRRC, local control was achieved in 18 cases (64%) with a median follow-up period of 36 months. The advantage of brachytherapy is that it minimizes the amount of radiation to which surrounding tissues are exposed, and hence it is a useful method for previously irradiated patients. However, accurate placement of the afterloading tubes can be difficult because the recurrent lesion is surrounded by scar tissue and is deep within the pelvis. Alternative methods for placing the tubes accurately include CT-guided percutaneous insertion, but this is associated with the risk of small bowel injury and fistula formation if the tube damages a part of the small intestine lying within the pelvis. Consequently, brachytherapy has not yet become a standard therapy for LRRC.
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COMBINED RESECTION |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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To achieve long-term local control and survival benefit in patients with LRRC, it is clear that it is necessary to achieve an R0 resection. This is a particular challenge when patients have FRTs with dorsal and/or dorsolateral involvement.
In 1981 Wanebo introduced the technique of abdomino-sacral resection, which was adopted by other surgeons (26–39). Extended surgery for FRT has not become popular because of reported 5-year survival rates of 16–31% (Table 2). Bozzetti et al.(34) indicated limitations of surgical treatment, and Wiggers et al. (33) showed a critical attitude toward extended surgery. In 1999, Wanebo et al. (36) reviewed the outcome of extended surgery in 53 patients. The operative mortality was 8%, the mean blood loss was more than 8000 ml and the mean operative time was 20 h. All the patients had been irradiated previously. The overall 5-year survival rate was 31%, and the disease-free 5-year survival rate was 23%. High amputation of the sacrum was performed in 32 cases (60%) for pelvic recurrences extending to the sacral promontory or sciatic notch. In all cases, the internal iliac vessels were preserved and lymph node dissection in the pelvis was performed. Lateral node metastasis was observed only in one case (1.8%), which is a surprisingly low rate. It remains unclear as to whether this was due to the influence of radiation or due to the method used for searching the metastasis. One can hardly assert that extended surgery is acceptable in terms of both surgical invasiveness and oncological outcomes, and consequently this therapy has been positioned as a formidable and demanding treatment.
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In 2004, we reported the treatment outcome of total pelvic exenteration with distal sacrectomy (TPES) in 57 patients with FRT (39). The operative mortality was 3.5%, and the median blood loss and operative time were 2500 ml and 682 min, respectively. These results are different from those reported by Wanebo et al. (36). We have analyzed factors that may be responsible for this difference. Our patients with primary rectal cancer undergo total mesorectal excision or a more extended surgery, whereas in the US less extensive surgery was generally performed. All Wanebo's patients received preoperative radiotherapy resulting in pelvic fibrosis. However, in our patients postoperative scarring after extensive primary resection leads to more technical difficulties in the resection of the recurrent disease. In addition, half of our patients received preoperative radiotherapy. Our conclusion is that overall the difference in results is not related to the extent of the initial surgery the patient had undergone or to whether radiation was given preoperatively. The major difference between the two series is the extent of the sacral resection. In contrast to Wanebo, we limited the level of the sacral amputation to the inferior margin of the second sacral vertebra or below in order to preserve the second sacral nerves. High sacral amputation is associated with more severe morbidity including mobility difficulties and a significantly impaired QOL. After less extensive sacral amputation, patients achieved an acceptable QOL except for living with double stomas and temporary pain owing to the resection of sacral nerves (39,40). For our patients, we achieved survival rate of 61% at 3 years and 46% at 5 years. Despite these improved results compared with the Wanebo's series, local re-recurrence and lung metastasis occur in more than 90% of the patients.
Measures to prevent further local recurrence and metastatic disease remain a challenge in the management of these patients. We conclude that surgical treatment including pelvic wall resection and IORT is the optimum method for improving local control rates in patients with LRRC. New antitumor agents such as CPT-11, UFT, Capecitabine and Oxaliplatin have shown efficacy in the treatment of rectal cancer and will play an increasing role in patients with metastatic disease.
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PROGNOSTIC FACTORS |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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The factors that predict the success of the surgery for LRRC remain controversial. Several parameters such as the type of initial surgery, tumor size, presence of severe symptoms and the serum CEA level before re-resection have been assessed as potential prognostic indicators (41). Willet and Wanebo found improved resectability in patients having initial low anterior resection compared with initial APR (11,31). In contrast, we found no difference in either resectability or survival in patients who developed FRT (39). Among other factors, negative CEA and R0 resection were associated with better prognosis. Shoup et al. (42) reported that vascular invasion and R1/R2 resection are factors for poor prognosis. Both reports emphasize that the most important prognostic factor is whether R0 resection was achieved or not.
It has already been shown that in surgical treatment for primary rectal cancer, surgeon-related factors as well as biological factors are crucial. Surgical margin status and complications are exclusively determined by the surgeon's technical skills (43). Complicated surgery such as TPES or abdomino-sacral resection should be undertaken only in specialized centers that have particular expertise with such complex surgery.
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STAGING SYSTEM |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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There is no established method of staging for patients with LRRC. Suzuki et al. (44,45) have assessed the degree of tumor fixation to surrounding structures according to surgical and pathological findings, and proposed their own staging method. Valentini et al. (17) also reported a similar staging system based on CT scan. They mentioned that degree of fixation is an independent prognostic factor. Wanebo et al. (36) have proposed a new staging system for stages TR1-2–TR-5, which are determined by the extent of invasion.
It is very important that a staging system is developed for these complex patients so order that the appropriate therapy is undertaken.
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CONCLUSION |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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The management of patients with LRRC presents a formidable challenge. Potentially, there are a large number of therapeutic options available. Surgery remains the optimum treatment of local recurrence, if this can be achieved with acceptable QOL. The role of chemotherapy and radiotherapy remains to be clarified. IORT has the potential to improve local disease control in patients in whom an R0 or R1 resection can be achieved.
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References |
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TOPAbstractINTRODUCTIONCONVENTIONAL TREATMENTMULTIMODALITY TREATMENTCOMBINED RESECTIONPROGNOSTIC FACTORSSTAGING SYSTEMCONCLUSIONReferences |
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