Failure patterns in patients with esophageal cancer treated with definitive chemoradiation

BACKGROUND:

Local failure after definitive chemoradiation therapy for unresectable esophageal cancer remains problematic. Little is known about the failure pattern based on modern‐day radiation treatment volumes. We hypothesized that most local failures would be within the gross tumor volume (GTV), where the bulk of the tumor burden resides.

METHODS:

We reviewed treatment volumes for 239 patients who underwent definitive chemoradiation therapy and compared this information with failure patterns on follow‐up positron emission tomography (PET). Failures were categorized as within the GTV, the larger clinical target volume (CTV, which encompasses microscopic disease), or the still larger planning target volume (PTV, which encompasses setup variability) or outside the radiation field.

RESULTS:

At a median follow‐up time of 52.6 months (95% confidence interval, 46.1‐56.7 months), 119 patients (50%) had experienced local failure, 114 (48%) had distant failure, and 74 (31%) had no evidence of failure. Of all local failures, 107 (90%) were within the GTV, 27 (23%) were within the CTV, and 14 (12%) were within in the PTV. On multivariate analysis, GTV failure was associated with tumor status (T3/T4 vs T1/T2; odds ratio, 6.35; P = .002), change in standardized uptake value on PET before and after treatment (decrease >52%: odds ratio, 0.368; P = .003), and tumor size (>8 cm, 4.08; P = .009).

CONCLUSIONS:

Most local failures after definitive chemoradiation for unresectable esophageal cancer occur in the GTV. Future therapeutic strategies should focus on enhancing local control. Cancer 2011;. © 2011 American Cancer Society.     

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer

IntroductionThe aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer.Materials and methodsPatients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses.ResultsIn 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8–61.5 months), 58% (95% CI 48–66), and 49% (95% CI 40–57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31–48), and 45% (95% CI 36–54). Three- and five-year risk of LRR were 26% (95% CI 19–33), and 30% (95% CI 22–38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached).ConclusionIn patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.     

Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy

PURPOSE: To identify clinical and dosimetric factors influencing the risk of pericardial effusion (PCE) in patients with inoperable esophageal cancer treated with definitive concurrent chemotherapy and radiation therapy (RT). METHODS AND MATERIALS: Data for 101 patients with inoperable esophageal cancer treated with concurrent chemotherapy and RT from 2000 to 2003 at our institution were analyzed. The PCE was confirmed from follow-up chest computed tomography scans and radiologic reports, with freedom from PCE computed from the end of RT. Log-rank tests were used to identify clinical and dosimetric factors influencing freedom from PCE. Dosimetric factors were calculated from the dose-volume histogram for the whole heart and pericardium. RESULTS: The crude rate of PCE was 27.7% (28 of 101). Median time to onset of PCE was 5.3 months (range, 1.0-16.7 months) after RT. None of the clinical factors investigated was found to significantly influence the risk of PCE. In univariate analysis, a wide range of dose-volume histogram parameters of the pericardium and heart were associated with risk of PCE, including mean dose to the pericardium, volume of pericardium receiving a dose greater than 3 Gy (V3) to greater than 50 Gy (V50), and heart volume treated to greater than 32-38 Gy. Multivariate analysis selected V30 as the only parameter significantly associated with risk of PCE. CONCLUSIONS: High-dose radiation to the pericardium may strongly increase the risk of PCE. Such a risk may be reduced by minimizing the dose-volume of the irradiated pericardium and heart.     

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.     

Feasibility of chemoradiation therapy with protracted infusion of5-fluorouracil for esophageal cancer patients not suitable for cisplatin

Background Chemoradiation therapy is the standard treatment for esophageal cancer in patients not fit for surgery. The regimen most commonly used includes cisplatin and 5-fluorouracil. Little data exists regarding alternative chemotherapy regimens in patients not suitable for cisplatin. We report on a regimen using protracted infusion 5-fluorouracil alone for both curative and palliative indications.Methods Twenty-two patients with localized esophageal cancer suitable for curative chemoradiation therapy and24 patients suitable for palliative therapy were enrolled. Chemotherapy consisted of 5-fluorouracil 225 mg/m² daily throughout the radiation therapy. The radiation dose was 56 to 60 Gy in 28 to 30 fractions (curative patients) and 30 to 35 Gy in 15 fractions (palliative patients).Results The median age of the patients was 75 years. The regimen was tolerable. Significant grade 3 toxicities experienced were esophagitis (11%) and venous catheter toxicity (9%). The median survival was 17 months for curative patients and 9 months for palliative patients. The complete response rate was 86% endoscopically and 45% radiologically for curative patients. Relief of dysphagia was experienced in 67% of palliative patients. Quality of life was satisfactory in both groups.Conclusions This study showed that continuous-infusion5-fluorouracil given concurrently with radiation therapy isa useful alternative to platinum-based chemoradiation therapy in patients with esophageal carcinoma.     

紫杉醇联合铂类与放疗同步治疗局部晚期食管癌的临床研究

目的探讨常规剂量紫杉醇联合铂类与放疗同步治疗食管癌的疗效,以及扩大照射野对同步放化疗疗效的影响。方法89例局部晚期食管癌初治患者,采用根治性同步放化疗,扩大野组51例,常规野组38例。放疗总剂量60 Gy(分两阶段进行),放疗的第1周和第4周给予常规剂量的紫杉醇和铂类化疗。结果87.6%的患者完成了治疗计划,扩大野组和常规野组的治疗有效率分别为75.5%和66.7%(P=0.37)。两组的Ⅲ级以上急性毒副反应主要为白细胞、血小板下降和放射性食管炎,主要远期放射损伤为肺纤维化,两组间各种毒副反应发生率差异均无统计学意义。患者总的3年生存率为32.8%,3年无复发转移生存率为34.5%,3年局部控制率为44.0%;扩大野组和常规野组的3年生存率、3年无复发转移生存率、3年局部控制率之间差异均无统计学意义。完成治疗计划的Ⅱ、Ⅲ期患者中,扩大野组3年生存率、3年无复发转移生存率及3年局部控制率较常规野组显著提高。结论常规剂量紫杉醇联合铂类化疗同步扩大野放疗对食管癌患者是安全的,可增加Ⅱ、Ⅲ期食管癌患者的局部控制率,提高3年生存率。     

A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of carboplatin, given weekly to patients with advanced esophageal or gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males; median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and 10 had stable disease, accounting for an overall response rate of 54%. CONCLUSIONS: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x min/ml.     

Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum

BACKGROUND: The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum. METHODS: Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel (200 mg/m(2) for 3 h) and carboplatin [area under the concentration-time curve (AUC = 6)] on day 1 and in 21 day cycles. RESULTS: A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10-34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10-18), and the median overall survival was 32 weeks (95% CI, 26-38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths. CONCLUSIONS: Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum.     

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m(-2) and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3-4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.     

Neoadjuvant chemotherapy with cisplatinum and 5-fluorouracil in advanced head and neck cancer

Forty-one patients affected by solid tumors of the head and neck were treated with neoadjuvant therapy before radiotherapy or surgery. All patients received therapy with cisplatinum 100 mg/m2 day 1 and 5-fluorouracil 1000 mg/day for days 1-5 by continuous infusion with a portable chronoinfusor. After three cycles, we observed an objective response in 34/41 patients (82.9%), with 9 (21.9%) complete remissions and 25 (61%) partial remissions. The main side effects were few and controllable. In our experience, neoadjuvant chemotherapy was able to induce a significant remission in 4/5 of patients, with better prospects for subsequent surgery and/or radiotherapy.     

Evaluation of paclitaxel and carboplatin in patients with endometrial cancer

The purpose of this study was to evaluate the combination of paclitaxel and carboplatin in patients with endometrial cancer who have high-risk histopathologic criteria with vessel permeation and low grade, advanced or recurrent disease. The combination of paclitaxel (180 mg/m2 over 3 hours) and carboplatin (dosed at an area under the curve of 5-6) was given intravenously every 3 weeks. Response and toxicity were evaluated according to the Japan Society of Clinical Oncology's response and adverse effect criteria. Eighteen patients were entered in this study and a total of 94 courses were administered. Eleven patients had evaluable lesions. Complete and partial responses were achieved in 5 (45.5%) and 3 (27.3%) patients, respectively. Grade 3 or 4 leukopenia and neutropenia occurred in 49.2% and 90.5% of the patients. G-CSF support was needed in 52.4% of the patients. Only one patient received a platelet transfusion. As a high response rate was obtained, this regimen is considered to be promising treatment for endometrial carcinoma. Prospective comparative study between this combination therapy and the conventional therapy for endometrial carcinoma is warranted.     

紫杉醇脂质体联合卡铂与紫杉醇联合卡铂治疗卵巢癌的疗效比较

目的探讨和比较紫杉醇脂质体联合卡铂与紫杉醇联合卡铂治疗卵巢癌的疗效。方法选取2012年5月至2015年5月间收治的60例卵巢癌患者,按照随机数字表法分为研究组和对照组,每组30例。研究组患者采用紫杉醇脂质体联合卡铂治疗,对照组患者采用紫杉醇联合卡铂治疗,比较两组的疗效及不良反应。结果研究组患者的总有效率为73.3%(22/30),对照组为70.0%(21/30),差异无统计学意义(P>0.05)。研究组患者的过敏反应、白细胞减少、血红蛋白减少、血小板减少、皮疹、肌痛、胃肠道反应发生率均显著低于对照组,差异有统计学意义(P<0.05),但两组患者的脱发发生率差异无统计学意义(P>0.05)。结论紫杉醇脂质体联合卡铂治疗卵巢癌与紫杉醇联合卡铂治疗卵巢癌疗效相当,但不良反应少。     

A phase II study of 5-fluorouracil/cisplatinum in recurrent cervical cancer

Thirty-seven patients with recurrent cervical carcinoma entered a phase II study of cisplatinum and 5-fluorouracil (5-FU). They were divided into patients with recurrent lesions outside previously irradiated area (group 1) and those with at least one recurrent lesion inside this volume (group 2). The treatment schedule consisted of 5-FU 1,000 mg/m2 i.v. days 1 to 5 and cisplatinum 100 mg/m2 i.v. day 1. Thirty-two patients were evaluable for response and toxicity. In group 1, 4 out of 19 patients had complete response with a median duration of 18 months, 9 out of 19 had partial response with a median duration of 10 months. Only 2 out of 13 patients in group 2 achieved partial response. All patients suffered from nausea and vomiting. The dose limiting factor was bone marrow suppression. The response rate in group 1 (68%) is impressive and higher than previously reported after other chemotherapy regimens. We found, however, the regimen too toxic for patients with central recurrences in previously irradiated areas, though some of these patients achieved substantial pain relief.     

Phase II study of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer

Purpose  There is no effective salvage regimen for failed gemcitabine-based chemotherapy. This study evaluated the efficacy and toxicity of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer. Methods  Between January 2004 and December 2007, 28 patients with pancreatic cancer previously treated with gemcitabine-based chemotherapy were enrolled. 5-Fluorouracil 1,000 mg/m² was infused (days 1, 2, and 3) and paclitaxel 175 mg/m² (day 1) was administered every 4 weeks. The primary endpoint of this study was efficacy and toxicity and the secondary endpoint was time to progression and overall survival. Results  A total of 75 cycles were given, for a mean of 2.68 cycles per patient. The response could be evaluated in 20 patients. Two patients (10%) obtained a partial response, and four patients (20%) had stable disease. The median time to progression and overall survival was 2.5 and 7.6 months, respectively. Grade 3/4 hematological toxicity included neutropenia in six patients (21.4%), anemia in one (3.6%), and thrombocytopenia in one (3.6%). One (3.6%) patient experienced grade 4 neuropathy, and two (7.2%) patients experienced grade 3 diarrhea. Conclusion  The 5-fluorouracil and paclitaxel combination treatment seems to be effective in patients with advanced pancreatic cancer that did not respond to a gemcitabine-based regimen.     

Pre-operative chemoradiation therapy with 5-fluorouracil and low-dose daily cisplatin for esophageal cancer: a preliminary report

BACKGROUND: A combination of chemotherapy and radiotherapy (chemoradiation therapy; CRT) has recently been developed to improve the survival of esophageal cancer patients. However, the optimal choice of chemotherapeutic agents and their doses, as well as chemotherapy and radiotherapy regimens, remain unclear. METHODS: Based on recent advances in knowledge on the radiosensitizing and biochemical modulation effects of chemotherapeutic agents, we have recently developed concurrent CRT which consisted of continuous 5-fluorouracil (5FU) administration (600 mg/m2/day, days 1-5) combined with a low dose of daily cisplatin administration (10 mg/m2/day, days 1-5, and 5 or 10 mg/m2/day, days 8-12 and 15-19) before each fraction of radiation (2 Gy each). To evaluate the efficacy and safety of our concurrent CRT, 10 esophageal cancer patients received one or one and a half courses of the CRT. RESULTS: All patients tolerated and completed a full course of the CRT. The effectiveness of the CRT on the primary tumor included pathologically or endoscopically complete responses in three patients (30%), partial response in five (50%), no response in two (20%) and tumoral downstaging (T-classification) in five (50%). Grade 2 and Grade 3 toxicity, seen in six patients, did not affect surgical operation. No patients showed CRT-related deaths. Eight patients (80%) underwent resection with no operative mortality. Of these, two patients (25%) showed pathologically or endoscopically complete responses, and four (50%) showed partial response. Three patients died of cancer after resection. The two inoperable patients showed a pathologically complete response and partial response, respectively. They were relieved of their cancer-related complaints and were living without hospitalization at the time of this analysis. CONCLUSIONS: These results suggest that the concurrent CRT based on the theoretical backgrounds is effective and has acceptable toxicities with maintaining its efficacy for the treatment of esophageal cancer patients.     

A case of advanced esophageal carcinoma successfully treated with chemoradiation therapy with low-dose cisplatin and 5-fluorouracil

We have experienced a case of advanced esophageal carcinoma successfully treated with chemoradiation therapy together with low-dose cisplatin and 5-fluorouracil, having only minor toxicity. A 55-year-old man was admitted to our hospital because of dysphagia. Cervical esophageal carcinoma was found to have invaded the larynx through endoscopy, and invasion to thyroid gland and trachea was suspected from a cervical CT. We diagnosed the condition as advanced esophageal carcinoma (A2N(-)M0Pl0 Stage III). We then treated the patient by chemoradiation therapy. After the treatment, the carcinoma could not be detected by CT and endoscopy, and endoscopic biopsy revealed there were no active carcinoma cells. The side effects of the therapy were very mild, therefore the patient could be discharged after a short time. No evidence of a tumor relapse was found 5 months after the therapy. We treated 4 patients with esophageal carcinoma using the same regimen, and the results of the therapy were 2 CR, 1 PR, and 1 PD, with an overall response rate of 75%.     

Promising outcomes of definitive chemoradiation and cetuximab for patients with esophageal squamous cell carcinoma

This study investigated cetuximab added to definitive concurrent chemoradiation for esophageal squamous cell carcinoma (ESCC). Previously untreated patients with stage II–IVa ESCC received cetuximab (400 mg/m² per week in week 1, then 250 mg/m² per week during weeks 2–8), paclitaxel (45 mg/m² per week) and cisplatin (20 mg/m² per week) in weeks 2–8 with 59.4 Gy radiotherapy. Epidermal growth factor receptor (EGFR) status in tumor specimens was assessed. Thirty‐one patients were enrolled and evaluated for toxicity. Of the 29 patients assessable for a response, 20 (69.0%) had a clinical complete response (CR). Over a median follow up of 23.6 months, disease progression was observed in seven patients. The 1‐ and 2‐year progression‐free survival (PFS) rates were 85.5% and 75.1%, respectively. The PFS was shorter for patients with lymphatic metastatic disease than for those with locally confined tumor; the 1‐year PFS rates were 78.7% and 92.3%, respectively (P = 0.038). Sixteen (55.2%) patients were immunohistochemically positive for EGFR. The patients with EGFR‐expressing tumor had a CR rate of 75.0% compared with 61.5% in those with negative EGFR expression (P = 0.024). The PFS for patients with EGFR‐expressing tumor was longer compared with the PFS of patients with negative EGFR (P = 0.133). The patients with prominent cetuximab‐induced rash (≥grade 2) had a better CR rate and PFS than those with no or grade 1 rash (P < 0.05). The rates of grades 3/4 esophagitis, hematological and dermatological toxicities were 9.7%, 29.0% and 16.1%, respectively. The regimen of definitive chemoradiation plus cetuximab achieved good clinical response and has an acceptable safety profile in Chinese ESCC patients.     

Preoperative chemoradiation in rectal cancer: Retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil

BACKGROUND: We compared the efficacy and toxicity of oral capecitabine and continuous infusion of 5-fluorouracil (5-FU) in the preoperative chemoradiation treatment of patients with rectal cancer. PATIENTS AND METHODS: The files of 89 patients with rectal cancer, 43 treated preoperatively with oral capecitabine and 46 with intravenous 5-FU, were reviewed, and the outcome of the groups was compared. RESULTS: There was no statistically significant difference in the complete pathological response rate between the capecitabine and the 5-FU groups (30% vs. 17%, P = 0.15). The downstaging rate was higher in the capecitabine group (77% vs. 50%, P = 0.009). Toxicity was mild in both groups. The rate of Grade 3 gastrointestinal toxicity was similar in the two groups (diarrhea 2% vs. 4%, proctitis 5% vs. 7%), except for one patient in the 5-FU group (2%) who developed a rectovaginal fistula. In the capecitabine group, one patient (2%) had Grade 3 hand-foot syndrome, and another had an acute myocardial infarction. In the 5-FU group, two patients (4%) had Grade 3 hematological toxicity, and three (6%) had complications from Port-a-Cath insertion. CONCLUSION: Preoperative chemoradiation with oral capecitabine appears to be safe and well tolerated, and at least as good as continuous 5-FU.