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Pathologic response to preoperative chemoradiotherapy for rectal carcinoma predicts systemic recurrence
208
I. J. Radiation Oncology
1084
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
Pathologic Response to Preoperative Chemoradiotherapy for Rectal Carcinoma Predicts Systemic Recurrence
D.S. Parda, N. Patel, J. Celebrezze, S. Ching, M. Roh, D. Medich Allegheny General, Pittsburgh, PA Purpose/Objective: Current management of locally advanced distal rectal cancer (LADRC) with preoperative chemoradiotherapy (CRT) has increased the incidence of sphincter preservation and reduced locoregional recurrence. In our experience, more than 90% of patients presenting with LADRC will undergo sphincter preservation with a locoregional recurrence rate of approximately 3%. However, the relationship between the response to CRT and survival is unclear. The present study identifies the pattern of recurrence following CRT and radical resection as well as clinical and pathologic features that may predict recurrence in such patients. We hypothesize that the degree of tumor response to CRT and specific pathologic features will predict systemic recurrence Materials/Methods: Starting from December 1994, eighty-three patients presenting with LADRC were retrospectively reviewed. Preoperative staging included endorectal ultrasound and CT of the chest, abdomen and pelvis. Patients with stage II-III disease were treated with pelvic radiation (45.0 –55.8Gy in fractions of 180cGy/day) and 5-Fluorouracil (5-U) and leucovorin 6-8 weeks prior to definitive surgery. All patients received postoperative adjuvant chemotherapy consisting of 5FU and leucovorin. Tumor response to CRT was graded as complete (CR), ⬎50% reduction (PR), or no response (NR). Statistical analysis was performed using the student t-test. Results: Sixty-seven patients were included in this study. Sixteen patients were excluded: 9 with Stage IV disease and 7 who were treated by transanal excision. Overall, the mean age was 57 years and mean distance from the anal verge was 5.8cm (Table 1). Forty-six patients (69%) were male and 21 (31%) were female. Mean follow-up was 44 months. The mortality due to disease was 3% and overall recurrence rate was 19% (13/67). As shown in figure 1, two (3%) patients had local recurrence alone (iliac and inguinal nodes), 1 (1.5%) local and systemic (bladder and peritoneum), and 10 (15%) systemic recurrence alone (8 lung, 2 liver). Mean time to recurrence was 27 months. Overall recurrence was significantly correlated to degree of pathologic response. Tumor recurrence has not been observed in the patients who achieved a CR. Systemic recurrence in patients with a CR or a PR is significantly less than those with NR (p⫽ 0.0007 and p⫽ 0.0002, respectively). Among the patients who did not achieve a CR, 32% recurred if lymph node positive and 11% if lymph node negative (p⫽ 0.05). Similarly, 55% of patients with adverse histological features ((AHF) poor differentiation and/or lymphovascular invasion) developed a recurrence as compared to only 12% if not present (p⫽ 0.0012). Tumor fixation and residual tumor size after CRT did not correlate with recurrence. Conclusions: 1) While preoperative CRT and radical surgery results in acceptable rates of LR, systemic recurrence remains the greatest challenge to definitive management. 2) Patients with pathologic features that are associated with high recurrence rates should be considered for randomization into trials offering more aggressive postoperative adjuvant therapy. 3) Given the high incidence of pulmonary metastasis, routine CT imaging of the chest in follow-up protocols is recommended. 4) Future clinical trials should consider complete pathologic response as an endpoint in evaluating the efficacy of CRT regimens. Table 1 Patient Demographics Mean Age Gender Mean Distance from AV Endorectal US Stage II Stage III Fixation at Presentation No Yes
1085
57 years 46M, 31F 5.8 cm N⫽37 N⫽22 N⫽42 N⫽25
Adjuvant Therapy in Rectal Cancer: Dissecting the Role of Radiotherapy and Chemotherapy in Determining Response
H. Elsaleh1, D. Joseph2, B. Iacopetta3 1 Department of Radiation Oncology, UCLA, Los Angeles, CA, 2Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia, 3Department of Surgery and Molecular Oncology, University of Western Australia, Crawley, WA, Australia Purpose/Objective: The survival benefit seen with adjuvant therapy in rectal cancer was thought to be from chemotherapy rather than radiotherapy. However recent data from Europe and Australia does not support this. The concurrent preoperative administration of chemotherapy with radiation may contribute to improving local control, and hence survival through radiosensitization. In colon cancer the benefit from 5-FU chemotherapy is associated with molecular factors such as a polymorphism in the thymidylate synthase (TS) gene and mutations in the p53 gene. There is little data on the role of these molecular factors in the response of rectal cancers to pre-operative therapies. Our aim was to examine the influence of the TS genotype and p53 mutation in determining local recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy. Possible associations were compared to those observed in stage III colon cancer patients treated with chemotherapy alone.
I. J. Radiation Oncology
1084
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
Pathologic Response to Preoperative Chemoradiotherapy for Rectal Carcinoma Predicts Systemic Recurrence
D.S. Parda, N. Patel, J. Celebrezze, S. Ching, M. Roh, D. Medich Allegheny General, Pittsburgh, PA Purpose/Objective: Current management of locally advanced distal rectal cancer (LADRC) with preoperative chemoradiotherapy (CRT) has increased the incidence of sphincter preservation and reduced locoregional recurrence. In our experience, more than 90% of patients presenting with LADRC will undergo sphincter preservation with a locoregional recurrence rate of approximately 3%. However, the relationship between the response to CRT and survival is unclear. The present study identifies the pattern of recurrence following CRT and radical resection as well as clinical and pathologic features that may predict recurrence in such patients. We hypothesize that the degree of tumor response to CRT and specific pathologic features will predict systemic recurrence Materials/Methods: Starting from December 1994, eighty-three patients presenting with LADRC were retrospectively reviewed. Preoperative staging included endorectal ultrasound and CT of the chest, abdomen and pelvis. Patients with stage II-III disease were treated with pelvic radiation (45.0 –55.8Gy in fractions of 180cGy/day) and 5-Fluorouracil (5-U) and leucovorin 6-8 weeks prior to definitive surgery. All patients received postoperative adjuvant chemotherapy consisting of 5FU and leucovorin. Tumor response to CRT was graded as complete (CR), ⬎50% reduction (PR), or no response (NR). Statistical analysis was performed using the student t-test. Results: Sixty-seven patients were included in this study. Sixteen patients were excluded: 9 with Stage IV disease and 7 who were treated by transanal excision. Overall, the mean age was 57 years and mean distance from the anal verge was 5.8cm (Table 1). Forty-six patients (69%) were male and 21 (31%) were female. Mean follow-up was 44 months. The mortality due to disease was 3% and overall recurrence rate was 19% (13/67). As shown in figure 1, two (3%) patients had local recurrence alone (iliac and inguinal nodes), 1 (1.5%) local and systemic (bladder and peritoneum), and 10 (15%) systemic recurrence alone (8 lung, 2 liver). Mean time to recurrence was 27 months. Overall recurrence was significantly correlated to degree of pathologic response. Tumor recurrence has not been observed in the patients who achieved a CR. Systemic recurrence in patients with a CR or a PR is significantly less than those with NR (p⫽ 0.0007 and p⫽ 0.0002, respectively). Among the patients who did not achieve a CR, 32% recurred if lymph node positive and 11% if lymph node negative (p⫽ 0.05). Similarly, 55% of patients with adverse histological features ((AHF) poor differentiation and/or lymphovascular invasion) developed a recurrence as compared to only 12% if not present (p⫽ 0.0012). Tumor fixation and residual tumor size after CRT did not correlate with recurrence. Conclusions: 1) While preoperative CRT and radical surgery results in acceptable rates of LR, systemic recurrence remains the greatest challenge to definitive management. 2) Patients with pathologic features that are associated with high recurrence rates should be considered for randomization into trials offering more aggressive postoperative adjuvant therapy. 3) Given the high incidence of pulmonary metastasis, routine CT imaging of the chest in follow-up protocols is recommended. 4) Future clinical trials should consider complete pathologic response as an endpoint in evaluating the efficacy of CRT regimens. Table 1 Patient Demographics Mean Age Gender Mean Distance from AV Endorectal US Stage II Stage III Fixation at Presentation No Yes
1085
57 years 46M, 31F 5.8 cm N⫽37 N⫽22 N⫽42 N⫽25
Adjuvant Therapy in Rectal Cancer: Dissecting the Role of Radiotherapy and Chemotherapy in Determining Response
H. Elsaleh1, D. Joseph2, B. Iacopetta3 1 Department of Radiation Oncology, UCLA, Los Angeles, CA, 2Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia, 3Department of Surgery and Molecular Oncology, University of Western Australia, Crawley, WA, Australia Purpose/Objective: The survival benefit seen with adjuvant therapy in rectal cancer was thought to be from chemotherapy rather than radiotherapy. However recent data from Europe and Australia does not support this. The concurrent preoperative administration of chemotherapy with radiation may contribute to improving local control, and hence survival through radiosensitization. In colon cancer the benefit from 5-FU chemotherapy is associated with molecular factors such as a polymorphism in the thymidylate synthase (TS) gene and mutations in the p53 gene. There is little data on the role of these molecular factors in the response of rectal cancers to pre-operative therapies. Our aim was to examine the influence of the TS genotype and p53 mutation in determining local recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy. Possible associations were compared to those observed in stage III colon cancer patients treated with chemotherapy alone.