Japanese Journal of Clinical Oncology Advance Access originally published online on August 22, 2008
Japanese Journal of Clinical Oncology 2008 38(10):695-700; doi:10.1093/jjco/hyn083
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author (2008). Published by Oxford University Press. All rights reserved
Stereotactic Body Radiation Therapy in Patients with Pelvic Recurrence from Rectal Carcinoma
1 Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences
2 CyberKnife Center, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences
3 Department of General Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences
4 Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences
5 Department of Hemato-oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
For reprints and all correspondence: Mi-Sook Kim, Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea. E-mail: mskim{at}kcch.re.kr
Received June 10, 2008; accepted July 23, 2008
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Objective: To investigate the clinical applications of stereotactic body radiation therapy (SBRT) using the CyberKnife system for pelvic recurrence from rectal cancer with a focus on survival and toxicity.
Methods: Between 2002 and 2006, 23 patients with recurrent rectal cancer were treated with SBRT at our institution. The median follow-up was 31 months. Sites of recurrence were pre-sacral in seven patients and the pelvic wall in 16. SBRT doses ranged from 30 to 51 Gy (median 39 Gy) and were delivered in three fractions. Response to treatment was assessed by computed tomography. Overall and local progression-free survival and toxicities were recorded.
Results: Four-year overall survival and local control rates were 24.9 and 74.3%, respectively. No prognostic factor was found to affect patient survival or local progression. One patient developed a severe radiation-related toxicity, but recovered completely after treatment.
Conclusions: SBRT for pelvic recurrence was found to be comparable with other modalities with respect to overall survival and complication rates. Further studies are needed to confirm these preliminary results.
Key Words: rectal cancer • recurrence • CyberKnife • stereotactic body radiation therapy
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
A large number of patients (20–50%) who undergo radical surgery for rectal cancer develop locoregional relapse (1,2). Most patients are not candidates for curative resection of recurrent pelvic disease, and even when radical surgery is possible, the 5-year survival rate after reoperation is <35%. However, if no treatment is given, patients with locally recurrent rectal cancer have a median survival of up to 8 months. Also they are likely to experience severe symptoms, especially pain, and quality of life becomes extremely poor (2–4).
No standard for the treatment of rectal cancer local recurrence has been established. Radiotherapy and chemotherapy provide only temporary symptom relief in most cases. Furthermore, extended surgery is unpopular because of significant post-operative morbidity. On the other hand, stereotactic body radiation therapy (SBRT) is an emerging technology in the radiation oncology field. This technique utilizes stereotactic principles for localization and delivers multiple beams to well-defined targets in few fractions. Therefore, SBRT can deliver higher doses to tumors due to reduced mechanical error margin and cause less normal tissue damage, and furthermore, can have three times the biological effect of fractionated radiation therapy in cases of slowly proliferating tumor as rectal cancer.
The aims of this study were to evaluate the role of SBRT as a local treatment for pelvic lymph node (LN) recurrence after radical resection in rectal cancer, and to investigate long-term survival, local control, prognostic factors and complications in order to suggest optimal dose and to define selection criteria.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Patients
Inclusion criteria of SBRT for nodal recurrence from rectal cancer were as follows: (i) curative resection for rectal cancer; (ii) nodal recurrence after curative resection; (iii) inoperable for nodal recurrence; (iv) progression after chemotherapy for nodal recurrence; (v) size of recurrent node 2.5–8 cm; (vi) single conglomerate recurrent node or two to three recurrent nodes close each other (<3 mm); (vii) Eastern Cooperative Oncology Group (ECOG) performance 1 or 2. Exclusion criteria were as follows: (i) recurrent node attached to colon or intestine on computed tomography (CT); (ii) recurrence at anastomosis site or residual colon; (iii) latent time from operation to recurrence <6 months; (iv) extra-nodal active lesion on positron emission tomography (PET)/CT; (v) absolute neutrophil count <1800 cells/mm3; (vi) platelet count <100 000 cells/mm3. From September 2002 to December 2006, 35 patients with LN recurrent colorectal cancer after curative resection were treated with SBRT using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA). Of these, 23 patients were proved to have isolated pelvic area recurrence by PET or PET/CT and were enrolled for this retrospective analysis. Before starting SBRT for recurrent pelvic tumor, this method was approved at the gastrointestinal multidisciplinary tumor board, and patients or their guardians signed informed consents after receiving explanation about benefits and complications of SBRT.
Sites of recurrence were dichotomized according to the following criteria: (i) pre-sacral, recurrence at the anterior portion of the sacrum below its second segment (S2–S5); (ii) pelvic, recurrence around the pelvic wall. Patient characteristics are summarized in Table 1. Briefly, patient ages ranged from 36 to 83 years (median 55) and the male:female ratio was 15:8. Initial patient characteristics were as follows. For initial surgery, 12 patients underwent lower anterior resection (LAR) and the remaining 11 abdomino-perineal resection. Sixteen patients received adjuvant chemotherapy, and four received concurrent chemoradiotherapy. Three patients did not undergo adjuvant therapy. Initial stages were as follows: stage I in one patient, stage II in 10 and stage III in 12. Intervals between initial operations and first relapse ranged from 7 to 65 months (median 32 months). Sites of recurrence were pre-sacral in seven and the pelvic wall in 16. After recurrence had been detected, all patients received salvage chemotherapy before SBRT. The salvage chemotherapy regimen was variable because the choice of regimen depends on initial adjuvant chemotherapy. Tumor volumes ranged from 12 to 122 cc (median 26 cc). Five patients had separated LN and the remaining 19 patients had conglomerated LN on CT.
|
Radiation Dose and the SBRT Technique
We calculated SBRT dose as the normalized total dose in 2 Gy using a linear quadratic model with alpha/beta=10 Gy. Our goal was to escalate the dose to >65 Gy in NTD to cover planned target volumes (PTV). Five patients with separated LN were treated with external beam radiation therapy (45 Gy in 1.8 Gy fraction) followed by a stereotactic single-fraction radiotherapy boost (16 Gy). The NTD was 65 Gy. For external beam radiation, the three-field technique (posterior–anterior and bilateral portals) was used to cover the separated LN area. SBRT technique following external beam radiation was performed as same procedure as SBRT alone. Eighteen patients with conglomerated LN were treated with SBRT alone. SBRT doses ranged from 36 to 51 Gy (median 39 Gy), which had been escalated step by step, and were delivered in three fractions. Eight to 12 patients who received pelvic SBRT irradiation due to LN metastasis from a variable primary tumor, mostly rectal or uterine cervical cancer, were included in each cohort. If at least five patients in each cohort did not show Grade 4 toxicity during 3–4 months, escalation of 1 Gy/fraction (total 3 Gy) were administered for the next cohort. However, this protocol did not apply strictly to all patients because it was not well controlled for the parameters of tumor dose and irradiated volume. During follow-up, Grade 4 toxicity as a perforation was developed in a patient to receive 51 Gy in three fractions and we stopped increasing above 51 Gy. Radiation doses, tumor volumes and estimated conventional radiotherapy doses are described in Table 1. For SBRT, we used gold fiducials (4 mm long and 0.8 mm in diameter) as markers for tumor localization. In total, six fiducials were placed percutaneously on the sacrum, pelvic bone or soft tissue located near the tumor using an 18-gauged spinal needle under fluoroscopic guidance. Patients were immobilized using an Alpha Cradle (Smithers Medical products, North Canton, OH, USA) 5–7 days after fiducial placement. A planning CT scan was taken in the required treatment positions in patients, and these images were then sent to the CyberKnife planning system. Gross tumor volume (GTV) was defined as a visible tumor as determined by CT. To better delineate tumor volumes, PET/CT images were used as references. The GTV was considered to be identical to the clinical target volume (CTV). PTV were expanded by a 3 mm margin to CTV in order to cover geometric uncertainties and infiltrative lesion. Radiation doses were prescribed to the 73–85% isodose line of the maximum dose to cover 98–99% of PTV. Approximately 50% isodose line covered GTV+prescribed dose covered GTV+7–12 mm (depending on the size of collimator) .
Follow-up, Response and Toxicity Assessments
Tumor response was assessed using Response Evaluation and Criteria in Solid Tumors (RECIST) at 
8 weeks post-SBRT. Local failure was defined as an increase in the targeted tumor size or the presence of a new lesion in the radiation field. However, if a new lesion developed outside the radiation field, it was interpreted as distant metastasis.
Acute and late toxicities were defined as symptoms that developed within 3 months post-SBRT or later, respectively. Radiation Therapy Oncology Group/European Organization for Research and the Treatment of Cancer (RTOG/EORTC) radiation morbidity criteria were used for toxicity scoring.
Statistics
Survivals were measured from SBRT or external beam radiation therapy commencement using the Kaplan–Meier method, and are reported as median values. Prognostic comparisons were performed by log-rank analysis. All calculations were performed with SPSS, version 13.0 (SPSS, Inc., Chicago, IL, USA), and P values <0.05 were considered statistically significant.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Overall Survival and Prognostic Factor
The final status of all 23 patients were confirmed using the National Database of the Ministry of Internal Affairs. Follow-up durations ranged from 7 to 65 months (median 31 months), and the 5-year overall survival rate and median survival time were 23.2% and 37 months, respectively (Fig. 1). There were no significant prognostic factors found to affect patients' survival (Table 2).
|
|
Local Response and Disease Progression-Free Survival
Twenty patients underwent CT scans at
8 weeks after SBRT. The remaining three patients were lost to follow-up after completing radiotherapy, and their responses could not be evaluated. In CT scans, five of the 20 patients showed a complete response, six partial response, eight stable disease, and one patient showed local progression. During follow-up, disease progression, including local progression and/or distant metastasis, was detected in nine of 20 patients (45%). Of these, two patients had local progression, six had distant metastasis including pelvic out-field recurrence (one patient) and two had both local progression and distant metastasis. The 4-year actuarial local progression-free survival rate (follow-up duration 2–55 months) was 74.3%. The 4-year disease progression-free survival rate (follow-up duration 2–55 months) and median time to disease progression were 51.1% and 55 months, respectively.
Toxicity
Nine (39%) of the 23 patients exhibited Grade 1 or 2 toxicities (nausea, vomiting and/or pain) during treatment or for a short period of time after radiation treatment. Grade 3 toxicity was not reported. Grade 4 toxicity was reported in one patient (Case 23 in Table 1). Initially, this patient had undergone LAR, and pre-sacral recurrence was detected at 61 months post-operatively (a spherical tumor of diameter 2.7 cm). He received 51 Gy in three fractions followed by chemotherapy (FOLFOX), and a rectal perforation developed 1 month post-SBRT. He underwent an emergency operation to insert a drain tube and recovered completely. No complications occurred in the four re-irradiated patients who had initially undergone post-operative concurrent chemoradiotherapy, and no late complications were observed in any patient.
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
The management of patients with locally recurrent rectal cancer is challenging. For non-fixed recurrent rumors, complete resection can be achieved by limited surgery and outcomes are relatively favorable. Vassilopoulos et al. (5) and Pihl et al. (6) reported 5-year survival rates of 49 or 42%, respectively, after resection for anastomotic recurrence. However, in most cases, recurrence is detected as a fixed mass that invades the pelvic wall or sacrum, and in such cases, extensive surgery, including abdomino-sacral resection or pelvic exenteration, might be required in order to achieve adequate margins. However, inappropriate surgical intervention can cause cancer spread, severe morbidity and even mortality.
Several studies (7–11) have been undertaken to investigate the therapeutic efficacies of various treatment modalities for recurrent pelvic tumors, e.g. surgery, radiation, chemotherapy and combination therapy. Radical surgery is rarely feasible for patients with local recurrence. Moreover, the 5-year overall survival rate for complete resection without any adjuvant treatment ranges from 19 to 55%. Some reported outstanding survival rates seem to have resulted from the selection of patients with a resectable mass at the time of recurrence. However, in most recurrent cases, EBRT with or without chemotherapy is usually recommended pre-operatively, and in such cases, patient survival appears to depend mainly on resectability. After complete resection, the reported 5-year survival rates range from 18.7 to 57%, whereas those after incomplete resection range from 0 to 18% (Table 3). Some institutes have reported promising results for multimodality treatments such as pre-operative chemo-radiotherapy, radical surgery and intraoperative radiotherapy (IORT). Using this multimodality therapy, survival increased up to 53% in cases of complete resection, but the associated side effects were significantly more common (Table 3). In our institute, to give a high dose comparable with IORT to the tumor non-invasively, SBRT has been performed in isolated and inoperable pelvic nodal recurrence, and the 4-year survival rate and median survival were 23.2% and 37 months, respectively. Although comparisons across different studies can be problematic due to selection bias, our results are comparable with previously reported findings (Table 3).
|
Theoretically, rectal cancer is classified as slowly growing tumor and would have biological benefit through hypofraction. However, to our knowledge, the optimal dose, fraction number and planning constraints for SBRT of pelvic recurrence are not available in the review of literatures. As based on reports for lung or liver metastasis from colorectal cancer treated by SBRT, the dose and fraction was started from 36 Gy in three fractions in our protocol and escalated step by step. Intriguingly, only one patient was found with grade 4 toxicity who required an operation, and this patient recovered after surgery. This patient received 51 Gy in three fractions, which was the highest dose administered to any patient. We suppose that the single most important factor that contributes to severe complications is the SBRT dose administered. Therefore, we stopped escalating more dose than 51 Gy in three fractions in the pelvic tumor.
This preliminary study demonstrates that SBRT for pelvic recurrence is comparable with other modalities in terms of overall survival and complication rate. Therefore, this study suggested that SBRT could be considered as a non-invasive local modality for inoperable, isolated metastasis less than four pelvic LN recurrence of rectal cancer when definite salvage treatment including chemotherapy was not available. Further, a well-controlled phase I/II study is necessary to confirm the optimal dose and constraints for SBRT in a large number of patients.
Conflict of interest statement
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer (1983) 52:1317–29.[CrossRef][Web of Science][Medline]
2 Pilipshen SJ, Heilweil M, Quan SH, Sternberg SS, Enker WE. Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer (1984) 53:1354–62.[CrossRef][Web of Science][Medline]
3 McCall JL, Cox MR, Wattchow DA. Analysis of local recurrence rates after surgery alone for rectal cancer. Int J Colorectal Dis (1995) 10:126–32.[CrossRef][Web of Science][Medline]
4 McDermott FT, Hughes ES, Pihl E, Johnson WR, Price AB. Local recurrence after potentially curative resection for rectal cancer in a series of 1008 patients. Br J Surg (1985) 72:34–7.[Web of Science][Medline]
5 Vassilopoulos PP, Yoon JM, Ledesma EJ, Mittelman A. Treatment of recurrence of adenocarcinoma of the colon and rectum at the anastomotic site. Surg Gynecol Obstet (1981) 152:777–80.[Web of Science][Medline]
6 Pihl E, Hughes ES, McDermott FT, Price AB. Recurrence of carcinoma of the colon and rectum at the anastomotic suture line. Surg Gynecol Obstet (1981) 153:495–6.[Web of Science][Medline]
7 Lopez-Kostner F, Fazio VW, Vignali A, Rybicki LA, Lavery IC. Locally recurrent rectal cancer: Predictors and success of salvage surgery. Dis Colon Rectum (2001) 44:173–8.[CrossRef][Web of Science][Medline]
8 Moriya Y, Akasu T, Fujita S, Yamamoto S. Total pelvic exenteration with distal sacrectomy for fixed recurrent rectal cancer in the pelvis. Dis Colon Rectum (2004) 47:2047–53. discussion 2053–4.[CrossRef][Web of Science][Medline]
9 Shoup M, Guillem JG, Alektiar KM, Liau K, Paty PB, Cohen AM, et al. Predictors of survival in recurrent rectal cancer after resection and intraoperative radiotherapy. Dis Colon Rectum (2002) 45:585–92.[CrossRef][Web of Science][Medline]
10 Gunderson LL, Nelson H, Martenson JA, Cha S, Haddock M, Devine R, et al. Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer. Dis Colon Rectum (1996) 39:1379–95.[CrossRef][Web of Science][Medline]
11 Bussieres E, Gilly FN, Rouanet P, Mahe MA, Roussel A, Delannes M, et al. Recurrences of rectal cancers: Results of a multimodal approach with intraoperative radiation therapy. french group of IORT. intraoperative radiation therapy. Int J Radiat Oncol Biol Phys (1996) 34:49–56.[Web of Science][Medline]
12 Wong CS, Cummings BJ, Brierley JD, Catton CN, McLean M, Catton P, et al. Treatment of locally recurrent rectal carcinoma–results and prognostic factors. Int J Radiat Oncol Biol Phys (1998) 40:427–35.[CrossRef][Web of Science][Medline]
13 Valentini V, Morganti AG, De Franco A, Coco C, Ratto C, Battista Doglietto G, 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]
14 Bozzetti F, Bertario L, Rossetti C, Gennari L, Andreola S, Baratti D, et al. Surgical treatment of locally recurrent rectal carcinoma. Dis Colon Rectum (1997) 40:1421–4.[CrossRef][Web of Science][Medline]
15 Hahnloser D, Nelson H, Gunderson LL, Hassan I, Haddock MG, O'Connell MJ, et al. Curative potential of multimodality therapy for locally recurrent rectal cancer. Ann Surg (2003) 237:502–8.[CrossRef][Web of Science][Medline]
16 Willett CG, Shellito PC, Tepper JE, Eliseo R, Convery K, Wood WC. Intraoperative electron beam radiation therapy for recurrent locally advanced rectal or rectosigmoid carcinoma. Cancer (1991) 67:1504–8.[CrossRef][Web of Science][Medline]
17 Palmer G, Martling A, Cedermark B, Holm T. A population-based study on the management and outcome in patients with locally recurrent rectal cancer. Ann Surg Oncol (2007) 14:447–54.[CrossRef][Web of Science][Medline]
18 Wiig JN, Poulsen JP, Larsen S, Braendengen M, Waehre H, Giercksky KE. Total pelvic exenteration with preoperative irradiation for advanced primary and recurrent rectal cancer. Eur J Surg (2002) 168:42–8.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||