Postoperative concomitant chemoradiotherapy in locally advanced rectal cancer

BACKGROUND/AIMS: To gain maximal effectiveness while decreasing toxicity by giving 5-fluorouracil for 45 minutes starting just within 5 minutes after the completion of radiotherapy thrice weekly. METHODOLOGY: Thirty-eight patients with locally advanced rectal cancer were enrolled in the study. Ranges of total radiation doses were between 50.4 Gy and 61.2 Gy with a median of 59.4 Gy with fraction size of 1.8 Gy five times weekly. 5-fluorouracil was administered thrice weekly with the dose of 250-300mg/m2/day concomitantly with radiation therapy. RESULTS: Median follow-up time was 30 months. Administration of chemotherapy concomitant with radiotherapy (p=0.089), AJCC stage III (p=0.079), Duke's stage C (p=0.079), presence of lymph node involvement (p=0.079) and presence of local recurrence (p=0.066) appeared to be effecting distant metastasis although differences did not reach statistically significance. Mean overall survival was 46 months in patients without any distant metastasis (SD: 3.28; 95% CI: 39.46 and 52.31) while it was 35 months in patients with distant metastasis (SD: 5.71; 95% CI: 23.52 and 45.90, p=0.016). CONCLUSIONS: Our results have provided further evidence of the ability of postoperative chemoradiotherapy to delay and prevent local recurrence and metastasis of rectal cancer.     

Preoperative chemoradiation with capecitabine in locally advanced rectal cancer

BACKGROUND: Preoperative radiation therapy in combination with 5-fluoracil (5-FU) improves local tumour control in locally advanced rectal cancer. The aim of our study was to evaluate the toxicity and efficacy of preoperative chemoradiation using the oral 5-FU prodrug capecitabine in locally advanced rectal cancer. METHODS: Sixty patients with locally advanced rectal cancer were treated with preoperative chemoradiation. Radiotherapy consisted of a total dose of 50 Gy delivered in 25 fractions to the pelvis. Chemotherapy was concurrently administered and consisted of oral capecitabine only on radiotherapy days. Surgery was performed six to ten weeks after completion of chemoradiation. RESULTS: The patient population consisted of 19 females and 41 males, with a median age of 61 years. All but two patients received the full dose of chemoradiation. No grade 3 or 4 haematological toxicities developed. Two patients (3%) developed grade 3 radiation dermatitis and one a grade 3 diarrhoea. All patients underwent definitive surgery; 19 patients underwent an abdominal perineal resection (APR), 25 a low anterior resection (LAR) and 16 patients a Hartmann's procedure. One patient with a low anterior resection developed an anastomotic leakage (4%). Final pathology demonstrated eight patients (13%) with a complete pathological response. Primary tumour and nodal downstaging occurred in 67 and 84% of the patients, respectively. Two patients (3%) had an R1 resection, one after an APR and one after an LAR. CONCLUSION: Preoperative chemoradiation with oral capecitabine is safe and well tolerated in locally advanced rectal cancer patients. This preoperative treatment has a considerable downstaging effect on the tumour and lymph nodes.     

Extensive surgery after high-dose preoperative chemoradiotherapy for locally advanced recurrent rectal cancer

PURPOSE: This was a pilot study of high-dose preoperative concurrent radiation and chemotherapy before extensive surgery in patients with locally advanced recurrent rectal cancer. Here we report on curative resectability, acute toxicities during chemoradiotherapy, surgical complications, local control, and three-year survival rates achieved with this aggressive multimodal regimen. METHODS: Between 1994 and 1997, 35 previously nonirradiated patients with pelvic recurrence of rectal cancer were entered in the study. All patients presented with tumor contiguous or adherent to adjacent pelvic organs and were not deemed amenable to primary curative surgery. A total radiation dose of 50.4 Gy with a small-volume boost of 5.4 to 9 Gy was delivered in conventional fractionation (single dose, 1.8 Gy). 5-Fluorouracil was scheduled as a continuous infusion of 1,000 mg/m²/day on Days 1 to 5 and 29 to 33. Six weeks after completion of chemoradiotherapy, patients were reassessed for resectability, and radical surgery was attempted whenever feasible. RESULTS: After preoperative chemoradiotherapy 28 of 35 patients (80 percent) underwent resection with curative intent. In 16 of 35 patients (57 percent) extended resection of adjacent organs was performed. Resections with negative margins were achieved in 17 patients (61 percent); 9 patients had microscopic, and 2 patients had gross residual disease. There was no postoperative mortality. Fourteen patients (44 percent) experienced postoperative complications. Toxicity from chemoradiotherapy occurred mainly as diarrhea (National Cancer Institute Common Toxicity Criteria Grade 3; 23 percent), dermatitis (Grade 3; 11 percent), and leucopenia (Grade 3; 11 percent). One patient died of tumortoxic multiple organ failure during chemoradiotherapy. With a median follow-up of 27 months, local re-recurrence after curative resection was observed in only three patients (18 percent); six patients developed distant metastases. Three-year actuarial survival rate was significantly improved after complete resection (82 percent) as compared with noncurative surgery (38 percent;P=0.03). CONCLUSION: A combination of high-dose preoperative chemoradiotherapy followed by extended surgery can achieve clear resection margins in more than 60 percent of patients with recurrent rectal tumor not amenable to primary surgery. An encouraging trend evolved for this multimodal treatment to improve long-term local control and survival rate.Presented at the meeting of the German Society for Radiation Oncology, Radiation Biology and Medical Physics (DEGRO), Nürnberg, Germany, November 7 to 10, 1998.     

Preoperative radiotherapy for locally advanced rectal cancer and prognostic factors influencing outcome

The aim of presented study was to evaluate the impact of different factors on survival, local recurrence and development of metastatic disease in patients with rectal cancer treated with preoperative radiotherapy or 5-fluorouracil (5-FU) based concurrent chemoradiation. Retrospective clinical evaluation was performed in 165 patients (33% women and 67% men) with locally advanced rectal adenocarcinoma treated with preoperative radiotherapy or chemoradiotherapy in the period January 1998 - March 2003. Tumor extent was evaluated by CT and/or MRI and/or TRUS examination and tumor biopsy was performed during colonoscopy. The median follow up is 21 month. All patients received preoperative external beam radiation to primary tumor, adjacent lymphnodes and presacral region. Computed tomography localisation of target volume was used for 3D radiotherapy treatment planning. Accelerated short term regimen (25 Gy/5 fraction/1 week) was performed in 14% of patients especially in year 1998-2000 and normofractionated regimen (40-50 Gy/20-25 fractions/4-5 weeks) was performed in 86% of patients. Chemoradiotherapy with 5-FU was carried out in 22% of patients. Radical resection underwent 85% of patients, inoperable tumor persisted in 7% and distant metastases were detected peroperatively in 8%. The 2-year overall survival (OS) was 84% and 5-year OS was 60% following radical resection. The important prognostic factors affecting survival were postradiotherapy determined pathological staging (p=0.005), postradiotherapy tumor grade (p<0.001) and the presence of angioinvasion and/or perineural spread (p=0.023). Prognostic factors for disease-free survival were identical with those for OS. Higher local recurrence rate was associated in preradiotherapy tumor staged T4 (p=0.048) and in presence of angioinvasion and/or perineural spread (0.049). Age, tumor location, histological grade before radiotherapy and tumor downstaging were not statistically significant for survival and/or for local recurrence rate. The best survival rates were obtained in patients with postradiotherapy grade 1 tumors (5-years survival 100%), tumors without angioinvasion and perineural spread (5-years survival 65%) and in patients who obtained complete remission after preoperative radiotherapy (5-years survival 86%).     

Predictive value of 18FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy

Purpose

Although ¹⁸fluorine-2-deoxy-D-glucose positron emission tomography-computed tomography (¹⁸FDG PET-CT) is considered a reliable modality for determining tumour response after neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC), the role of ¹⁸FDG PET-CT for predicting pathologic complete response (pCR) remains unclear. The aim of this study was to evaluate whether ¹⁸FDG PET-CT can predict tumour response after CRT in patients with LARC, in terms of downstaging and pCR.

Methods

Between March 2009 and February 2012, 151 patients with LARC treated with neoadjuvant CRT followed by radical surgery were reviewed retrospectively. Pre-CRT SUVmax (maximum standardized uptake value), post-CRT SUVmax, ΔSUVmax (difference between pre- and post-CRT SUVmax), and RI-SUV (response index) were measured before and after CRT. Univariate and multivariate analyses were used to analyse the association of PET-CT-related parameters and clinical variables, to assess downstaging and pCR.

Results

Downstaging occurred in 48 patients (31.7 %) and pCR in 19 patients (12.5 %). Univariate and multivariate analysis revealed post-CRT SUVmax as a significant factor for prediction of downstaging, with sensitivity of 60.4 %, specificity of 65.0 %, and accuracy of 55.9 %, for a cutoff value of 3.70. Regarding pCR, post-CRT SUVmax was again found as a significant parameter by univariate and multivariate analysis, with sensitivity of 73.7 %, specificity of 63.7 %, and accuracy of 64.9 %, for a cutoff value of 3.55.

Conclusions

The results indicate that post-CRT SUVmax independently predicts downstaging and pCR. However, the predictive values of post-CRT SUVmax for tumour response after neoadjuvant CRT are too low in sensitivity and specificity to change the treatment plan for LARC.     

Clinical implication of additional selective lateral lymph node excision in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy

Purpose

To identify the indication and prognostic significance of lateral lymph node (LLN) excision in locally advanced rectal cancer patients underwent preoperative chemoradiotherapy.

Methods

Included were 67 consecutive patients with suspicious LLN metastasis who underwent chemoradiotherapy and surgery including selective LLN excision (82 excisions). The excisions were grouped according to the presence of LLN metastasis and compared in terms of the clinicopathological findings and oncological results. The correlation between the largest short-axis diameter of LLN measured by imaging and metastasis rates was explored.

Results

LLN metastases were identified in 32 excisions (40.0 %). The calculated short-axis LLN diameter predicting metastasis was 11.7 mm (before chemoradiotherapy) and 11.4 mm (before surgery). LLN metastasis was observed more frequently in the low rectum (p?=?0.031) and associated with higher CEA levels (p?=?0.048). The 3-year overall survival rates for patients with and without LLN metastasis were 60.3 % and 90.3 % (p?=?0.048), while the 3-year disease-free survival rates were 31.4 % and 70.5 % (p?=?0.009). The hazard ratio of LLN metastasis for recurrence was 2.938 (95 % CI?=?1.258–6.863).

Conclusions

LLN metastasis in rectal cancer patients underwent chemoradiotherapy was a distinct poor prognostic factor. Selective LLN excision based on imaging studies may have a role for such patients.     

Preoperative chemoradiotherapy and radical surgery for locally advanced distal rectal adenocarcinoma: pathologic findings and clinical implications

PURPOSE: Preoperative chemoradiotherapy followed by radical surgical resection has been the preferred treatment for patients presenting with locally advanced distal rectal carcinoma at our institutions. We postulated that chemoradiotherapy-induced pathologic response of the primary tumor would identify which patients would be candidates for local excision as definitive surgical therapy. METHODS: A retrospective analysis of 60 patients with palpable, locally advanced, distal rectal adenocarcinomas treated from 1995 to 2000 was performed. All patients received preoperative chemoradiotherapy consisting of 5-fluorouracil (325 mg/m²) and leucovorin (20 mg/m²) by bolus infusion on Days 1 through 5 and 29 through 33 delivered concurrently with at least 45.0 to 50.4 Gy of pelvic radiation, followed six to eight weeks later by radical surgery and then adjuvant chemotherapy. RESULTS: Among 60 patients (20 females) there was a mean age of 58.7 (28–84) years. Clinical staging was as follows: Stage II, 14 patients (23 percent); Stage III, 35 patients (58 percent); and Stage IV, 11 patients (18 percent). Pathologic examination revealed that negative margins were obtained in 58 patients (97 percent). Downstaging to T0-2N0 was achieved in 17 patients (28 percent), with five (8 percent) achieving a pathologically complete response. Lymph nodes were positive in 24 patients (40 percent) despite chemoradiotherapy. Pathologic node positivity was found in 0 of 5 pT0 patients, 9 (41 percent) of 22 pT1 or pT2, and 15 (45 percent) of 33 pT3. Clinical stage, tumor size, pathologic stage, and adverse histologic features could not reliably predict pN0 status, except pT0 (5 patients only). CONCLUSIONS: Preoperative chemoradiotherapy often downsizes and downstages locally advanced rectal carcinoma. Neither pretreatment clinical characteristics, response to preoperative chemoradiotherapy, or pathologic features reliably predict pN0 status. Therefore, local excision is not recommended as an alternative to radical surgery for locally advanced adenocarcinoma of the distal rectum regardless of the response of the primary tumor to preoperative chemoradiotherapy.Presented at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 24 to 29, 2000.     

Preoperative therapy in locally advanced esophageal cancer

Esophageal cancer is an aggressive malignancy associated with dismal treatment outcomes. Presence of two distinct histopathological types distinguishes it from other gastrointestinal tract malignancies. Surgery is the cornerstone of treatment in locally advanced esophageal cancer(T2 or greater or node positive); however, a high rate of disease recurrence(systemic and loco-regional) and poor survival justifies a continued search for optimal therapy. Various combinations of multimodality treatment(preoperative/perioperative, or postoperative; radiotherapy, chemotherapy, or chemoradiotherapy) are being explored to lower disease recurrence and improve survival. Preoperative therapy followed by surgery is presently considered the standard of care in resectable locally advanced esophageal cancer as postoperative treatment may not be feasible for all the patients due to the morbidity of esophagectomy and prolonged recovery time limiting the tolerance of patient. There are wide variations in the preoperative therapy practiced across the centres depending upon the institutional practices, availability of facilities and personal experiences. There is paucity of literature to standardize the preoperative therapy. Broadly, chemoradiotherapy is the preferred neo-adjuvant modality in western countries whereas chemotherapy alone is considered optimal in the far East. The present review highlights the significant studies to assist in opting for the best evidence based preoperative therapy(radiotherapy, chemotherapy or chemoradiotherapy) for locally advanced esophageal cancer.     

Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer

Purpose  

In rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and curative resection, we evaluated the influence of anemia on tumor response to preoperative CRT.     

局部进展期直肠癌新辅助同步放化疗病理完全缓解的影响因素

［摘要］　目的　探讨局部进展期直肠癌经新辅助同步放化疗获病理完全缓解(pCR)的影响因素。方法　回顾性收集中国医学科学院北京协和医学院肿瘤医院2013年1月至2017年5月收治的226例局部进展期直肠癌患者的临床资料,均接受新辅助同步放化疗并接受手术治疗。通过多因素logistic回归分析pCR与肿瘤位置、肿瘤T分期、肿瘤最大直径、肠壁外血管侵犯（EMVI）、直肠系膜筋膜(MRF)侵犯等临床病理因素的关联性,比较pCR组与非pCR组无病生存期（DFS）及总生存期（OS）的差异。结果　术前T分期为T₃期［OR(95%CI)=3.978(1.227～12.897),P=0.021］、肿瘤最大直径<4 cm［OR(95%CI)=2.439(1.046～5.685),P=0.039］、肿瘤距齿状线≤5 cm［OR(95%CI)=3.154(1.229～8.094),P=0.017］是局部进展期直肠癌患者经新辅助同步放化疗后获得pCR的独立影响因素。pCR组患者的5年DFS（82.1% vs 67.6%,P=0.046）和OS（87.2% vs 68.5%,P=0.015）均优于非pCR组患者。结论　术前T₃分期、肿瘤最大直径<4 cm、肿瘤距齿状线≤5 cm直肠癌患者是新辅助同步放化疗的潜在获益人群,并且获pCR患者的预后更好。     

Intraoperative radiotherapy vs concurrent chemoradiotherapy in the treatment of patients with locally advanced pancreatic cancer

PurposeThe purpose of the multi-institutional retrospective study was to evaluate whether intraoperative radiotherapy (IORT) has advantages in the treatment of patients with locally advanced pancreatic cancer (LAPC) compared with concurrent chemoradiotherapy (CCRT).Patients and methodsA total of 103 patients with LAPC whom was treated with IORT (Arm A; n = 50) or CCRT (Arm B; n = 53) from 2015.6 to 2016.7 were retrospectively identified. Data on feasibility, toxicity, and overall survival (OS) were evaluated.ResultsMost factors of the two cohorts were similar. The severe adverse events (grade 3 and 4) patients in Arm B were higher than patients in Arm A (34% vs 0%). Disease progression was noted in 38 patients (76%) in Arm A and 37 patients (69.8%) in Arm B. The median survival of patients in Arm A and B were 15.3 months (95% CI, 13.0–17.6 months) and 13.8 months (95% CI, 11.0–16.6 months), respectively. The 1-year survival rate were 66.3% in Arm A (95% CI, 52.3%–80.2%) and 60.9% in Arm B (95% CI, 46.4%–75.4%). There was no significant difference in OS between patients treated with IORT and with CCRT (p = 0.458).ConclusionOur results demonstrated that patients with LAPC treated with IORT showed fewer adverse events, less treatment time, and high feasibility compared to CCRT. Although, IORT has no advantages in survival and tumor control compared with CCRT.     

进展期直肠癌新辅助放化疗研究进展

我国结直肠癌发病率和死亡率居高不下,直肠癌的发病率与术后局部复发率(LRR)通常高于结肠癌,且手术难度高。目前为了防止直肠癌的局部复发大多采取多学科方法医治。新辅助放化疗(nCRT)作为一种发展中的多学科方法,可提高治愈率又可维持器官功能,在直肠癌治疗中起着至关重要的作用。本综述旨在阐明nCRT的现状与未来的改进方向。     

Pre-operative radiochemotherapy of locally advanced rectal cancer

AIM. To evaluate results of pre-operative radiochemotherapy followed by surgery for 15 patients with locally advanced un-resectable rectal cancer.METHODS: 15 patients with advanced non-resectable rectal cancer were treated with pre-operative irriadiation of 40-46Gy plus concomitant chemotherapy (5-FU+LV and 5‘-DFuR) (RCS group). For comparison, 27 similar patients,treated by preoperative radiotherapy (40-50Gy) plus surgery were served as control (RS group).RESULTS: No radiochemotherapy or radiotherapy was interrupted and then was delayed because of toxicities in both groups. The radical resectability rate was 73.3% in the RCS group and 37.0% (P=0.024) in RS group. Sphincter preservation rates were 26.6% and 3.7% respectively(P=0.028). Sphincter preservation rates of lower rectal cancer were 27.3% and 0.0% respectively (P=0.014). Responserates of RCS and RS groups were 46.7 % and 18.5 %(P=0.053). The tumor downstage rates were 8(53.3%)and 9 (33.3%) in these groups (P=0.206). The 3-year overall survival rates were 66.7% and 55.6% (P=0.485), and the disease free survival rates were 40.1% and 33.2%(P=0.663). The 3-year local recurrent rates were 26.7% and 48.1% (P=0.174). No obvious late effects were found in either groups.CONCLUSION: High resectability is possible following preoperative radiochemotherapy and can have more sphincters preserved. It is important to improve the quality of the patients‘ life even without increasing the survival or local control rates. Preoperative radiotherapy with concomitant full course chemotherapy (5-Fu+LV and 5‘-DFuR) is effective and safe.     

Combined-modality therapy in locally advanced primary rectal cancer

PURPOSE: Patients with unresectable, locally advanced rectal cancer are reported to have a dismal prognosis. The aim of this study was to analyze the effect of combined-modality therapy on clinical outcome. METHODS: From March 1990 to December 1997, 43 patients (28 males; median age, 62 years; median follow-up, 74 months) with locally advanced (T4 and/or N3) nonmetastatic rectal cancer received external-beam radiation (23.6 plus 23.6 Gy (split course), 8 patients; 45 Gy, 35 patients) plus 5-fluorouracil (96-hour continuous infusion, Days 1–4, at 1,000 mg/m2/day) and mitomycin C (10 mg/m2, intravenous bolus, Day 1). Concomitant chemotherapy was repeated at the beginning of the second course (split-course group) or in the last week of radiotherapy (continuous-course group). After 6 to 8 weeks, patients were evaluated for surgical resection and intraoperative radiation therapy (10 to 15 Gy). Thereafter, adjuvant chemotherapy (5-fluorouracil plus leucovorin, 6–9 courses) was prescribed. RESULTS: During chemoradiation, 5 patients (11.6 percent) developed Grade 3 to 4 hematologic toxicity. After chemoradiation, 29 patients (67.4 percent) had an objective clinical response (complete response, 2.3 percent; partial response, 65.1 percent). Thirty-eight patients underwent radical surgery (anterior resection, 24 patients; abdominoperineal resection, 14 patients; intraoperative radiation therapy boost on the tumor bed, 19 patients), and 2 patients had partial tumor resection. No perioperative deaths occurred in the patient group. Five-year survival and local control rates were 59.9 and 69.1 percent, respectively. Distant metastasis occurred in 44.2 percent of patients. Statistically significant relationships between intraoperative radiation therapy and local control (P = 0.0104), radical surgery and survival (P = 0.0120), and adjuvant chemotherapy and disease-free survival (P = 0.0112) were observed. CONCLUSIONS: Our data suggest that combined-modality therapy was relatively well tolerated and resulted in good local control and survival. With regard to the impact of surgical resection on survival, additional studies aimed at improving the local response rate are necessary, whereas the positive impact of intraoperative radiotherapy on local control appears to justify the inclusion of this therapeutic modality in prospective multi-institutional trials.     

High survivin expression as a predictor of poor response to preoperative chemoradiotherapy in locally advanced rectal cancer

Purpose  

To evaluate seven molecular markers including cyclooxygenase -2, epidermal growth factor receptor, Ki-67, p21, survivin, thymidylate synthase, and vascular endothelial growth factor for prediction of response to preoperative chemoradiotherapy in locally advanced rectal cancer.