Preoperative Cetuximab,Irinotecan, Cisplatin,and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

Purpose.

To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer.

Methods and Materials.

Patients with stage IIA–IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon''s two-stage phase II study. Patients received weekly cetuximab on weeks 0–8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1–6), followed by surgical resection.

Results.

In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection.

Conclusions.

This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.     

Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus--a prospective randomized trial.

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradiotherapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 patients given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all 53 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26.9%) and of two patients in the CR therapy group (7.7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.     

局部晚期食管癌放化疗综合治疗新进展

食管癌（esophagea cancer)起病隐袭,早期诊断率低,绝大部分失去手术机会。单纯放疗生存率较低,因此放化联合治疗成为治疗食管癌的趋势。但放化疗中放疗剂量、化疗药物选择、放化顺序仍未统一。靶向药物联合放化疗仍处于研究的初期,结果令人期待。另外,免疫治疗、生物化疗等新治疗手段和理念也逐渐成为学者关注及研究热点。     

Combined radiotherapy and pre-radiation chemotherapy with cisplatin and 5-fluorouracil for advanced esophageal carcinoma. II. Clinical evaluation in cases with higher than T2 stage

Thirteen patients with previously untreated advanced squamous cell carcinoma of the esophagus were treated with pre-radiation chemotherapy followed by radiation therapy. The chemotherapy consisted of two or three cycles of Cisplatin and 120 hour continuous infusion of 5-Fluorouracil. Three patients showed complete response (CR), three partial response (PR), three minor response (MR) and four non-response (NR). The overall response rate was 46%. The predominant side effects were nausea, vomiting and anorexia. Mild or moderate degree of anemia and leukocytopenia were also noticed. However, no serious toxicity was observed. Radiation therapy was administered to eleven of the thirteen patients, excluding one patient who refused it and one patient who died during chemotherapy. In two of the eleven cases, however, radiotherapy was discontinued because of MR, and surgery was performed. In one additional case, post-radiotherapy surgery was performed. One of these three cases received curative esophagectomy. After definitive treatment, CR was obtained in 54% (7 of 13), PR in 15% (2 of 13), MR in 15% and NR in 15%. The non-effective patients (PR + MR + NR) died within nine months after the initiation of treatment. Two of the CR patients later died, one due to local recurrence and another due to aortic-esophageal fistula with no residual cancer discovered at autopsy. The remaining CR patients are still alive and well, after 11.5 to 32 months. Although the follow-up period is yet short, the combination of radiation therapy with pre-radiotherapy chemotherapy appears to be an effective treatment.     

Significant role of cisplatin and 5-FU combination chemotherapy for first-line intensive treatment for advanced esophageal cancer]

We evaluated the efficacy of first-line chemotherapy consisting of cisplatin and 5-fluorouracil combination therapy (in the following, FP) in intensive treatment for esophageal cancer. This first-line chemotherapy was administered to 18 patients with squamous cell carcinoma. Three patients had T2 tumor, 10 had T3 and 5 had T4. Lymph node metastasis was detected in 10 patients and not detected in 8 patients. Five patients had distant metastasis. Ten patients showed a partial response and the response rate was 55.6%. Of these 10 patients, 5 were followed with surgery, 3 of whom survived without recurrence of the disease. Five patients were treated by FP, radiation therapy or combination of FP and radiation. Of these 5 patients, 2 showed a complete response. On the other hand, 8 nonresponders died from progressive disease, despite following intensive treatment. These results suggest that first-line chemotherapy by FP, which requires following intensive treatment, improves the overall long-term survival of advanced esophageal cancer patient.     

Five cases of early gastric cancer in the reconstructed gastric tube after radical resection for esophageal cancer

We report seven early gastric cancers in five patients, which arose in the reconstructed gastric tube after radical resection for esophageal cancer. Four of them occurred in the middle gastric tube and three in the distal gastric tube. Three of 5 cases were reconstructed via the retromediastinal route and two via the presternal route. They all were diagnosed by follow-up endoscopy from 8 months to 5 years after esophagectomy. All of them were treated surgically with partial resection of the gastric tube because they were suspected to have invaded the submucosal layer or large enough to be treated with endoscopic mucosal resection (EMR). Histologically, six of seven were diagnosed as well differentiated adenocarcinoma and one as signet ring cell carcinoma. Although one of them died for reasons other than cancer itself, the others are alive and well without any recurrence. Recently, gastric tube cancer after esophagectomy has been increasingly reported to be accompanied with prolongation of survival of esophageal cancer patients. Total or partial gastrectomy is proposed for surgical treatment of gastric tube cancer, but the operating procedure is complicated and invasive, especially in the case of gastric tube reconstructed via the retromediastinal route. Total gastrectomy is much more invasive because it needs re-reconstruction with other organs. Therefore, it is important to detect the lesion in early stages so as to treat it with minimally invasive surgery such as EMR or partial resection. Hence intensive follow up with endoscopy is necessary after resection of esophageal cancer.     

Cisplatin, 5-fluorouracil, mitomycin C, and concurrent radiation therapy with and without esophogectomy for esophageal carcinoma

Twenty-nine patients with carcinoma of the esophagus were treated with 5-fluorouracil (5-FU) (1000 mg/m2/d as a continuous intravenous [IV]infusion on days 1 through 4), cisplatin (100 mg/m2 IV on day 1), mitomycin C (10 mg/m2 IV on day 1), and concurrent radiation therapy (4500 cGy/4.5 wk). If no disease progression was observed, operable patients underwent surgery 4 to 6 weeks after completion of radiation therapy. A thoracotomy with a gastric pull-through operation was performed in the first six patients. Subsequently, a transhiatal ("blunt") esophagectomy was used. Twenty-five patients had squamous cell histology and four had adenocarcinoma. Of 25 patients with squamous cell carcinoma, 13 underwent esophagectomy. The clinical complete response rate was 61% (eight of 13 patients), with a pathologic complete remission documented in five of 13 patients (38%). The overall local tumor sterilization rate was 53% (seven of 13 patients). In the 12 patients who did not undergo surgery after chemoradiotherapy, four had a complete clinical response (33%) and five had a partial response (41%). Symptoms or signs of local disease recurrence or stricture were noticed in ten of 12 patients who did not undergo surgery (83%), compared with 28% of patients who underwent surgery. The median survival time of the group receiving surgery was 10 months, compared with 5 months for those who did not undergo operation (P = 0.027). Patients undergoing transhiatal esophagectomy had shorter postoperative hospital stays and fewer serious complications, compared with patients undergoing transthoracic esophagectomy. The use of chemoradiotherapy and transhiatal esophagectomy for esophageal carcinoma should be evaluated using alternative sequences of treatment (e.g., postoperative therapy) to reduce toxicity while maintaining local control of disease.     

不可手术切除的食管癌同步放化疗进展

食管癌起病隐袭,早期诊断率低,发现时绝大部分已失去手术机会,放疗或化疗生存率也不乐观。近年研究表明,对于不可手术切除的食管癌,同步放化疗成为标准治疗方式。我国食管癌以鳞癌为主区别于欧美国家,研究适合于我国食管癌特点的同步放化疗方案尤为重要。本文就近年来不可手术切除的食管癌同步放化疗的新进展做一综述。     

Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer

Simultaneous chemoradiation is used in unresectable pancreatic cancer for palliation. It is not known if the use of adjuvant surgery will benefit this group of patients. From November 1991 to September 1998, 47 patients with unresectable pancreatic cancer were treated with simultaneous preoperative radiation therapy (45 Gy) and chemotherapy. Chemotherapy followed three different protocols: cisplatin, 5-fluorouracil +/- paclitaxel; cisplatin, 5-fluorouracil (protracted infusion); and docetaxel and gemcitabine. Whipple pancreatoduodenectomy was performed 1 month after the end of radiation in patients selected for resection. Twenty-three unresectable tumors after preoperative treatment (47%) received an additional dose (10-12 Gy) of radiotherapy using intraoperative or external radiation therapy. Twelve patients (26%) were considered to have clinically resectable tumors after the preoperative treatment. Nine patients had surgery (19% of the total number of patients), and 2 of them had complete pathologic response. After chemoradiation, two patients died of pneumonia and gastrointestinal bleeding, respectively, and another two patients died in the postoperative period. Local recurrence was observed in 22% of the patients and 57% had distant metastases. Three-year survival rates for patients with unresectable and resectable tumors was 0% (median survival 10 months) and 48% (median survival 23 months), respectively (p = 0.0004). Preoperative treatment with chemotherapy and radiotherapy in patients with unresectable pancreatic cancer is feasible. In some patients, the tumor can be resected, and in addition some cases of complete pathologic response were found. Long-term survivors were observed in the group of resected tumors. More effective chemotherapy regimens are needed because the majority of the patients died of metastatic disease.     

Reply to the Letter to the Editor

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradio-therapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 paitents given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all S3 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26·9%) and of two patients in the CR therapy group (7·7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.     

食管癌术后局部复发转移的放射治疗疗效分析

 目的 探讨食管癌术后局部复发转移的放射治疗疗效. 方法 对52例纵隔和/或锁骨上复发及转移病灶进行放射治疗,常规分割,DT 4800cGy～7000cGy.22例放疗后予PF方案（顺铂＋5-Fu）或NP方案（长春瑞滨＋顺铂）化疗. 结果 全组总的中位生存期为12个月,1、2、3年生存率分别是48.1%、25.4%和14.0%.术后分期、放疗剂量、放疗后化疗及近期疗效与预后相关.结论放射治疗是食管癌术后局部复发和淋巴结转移的有效治疗方法,放疗结合化疗可能对患者有益.     

S-1 chemotherapy for cancer of the gastric tube used for esophageal reconstruction following surgery for esophageal cancer

We used S-1 chemotherapy to treat 5 patients with cancer of the gastric tube used for esophageal reconstruction through the posterior mediastinal route following surgery for esophageal cancer. The response rate was 40%, the median survival 15 months, and 3 patients still survive. In those 3 patients, the gastric tube cancer was at a resectable stage, but the patients elected to have chemotherapy instead. One patient has survived 21 months after responding completely to 2 cycles of combined chemotherapy with S-1 and cisplatin. Another has survived 15 months after partially respondingto S-1 chemotherapy. And the third has survived 46 months after endoscopic treatment, radiation therapy and S-1 chemotherapy. S-1 chemotherapy thus appears to be an effective treatment for cancer of the gastric tube after surgery for esophageal cancer.     

Esophageal cancer: outcomes of surgery, neoadjuvant chemotherapy, and three-dimension conformal radiotherapy

Neoadjuvant chemotherapy and radiation are being utilized with increasing frequency in the multimodal treatment of esophageal cancer, although their effects on morbidity, mortality, and survival remain unclear. The objective of this study was to determine the outcome of multimodal treatment in patients with localized esophageal cancer treated at a single institution. Between 1995 and 2002, 118 patients underwent treatment for localized esophageal cancer, utilizing surgery alone, chemoradiation alone, or surgery following neoadjuvant chemoradiation. There was no statistically significant difference in morbidity, mortality, or length of stay between the patients who received multimodal therapy when compared to surgery alone. A surgical resection after down-staging was possible in 9 out of 28 patients (32%) with a clinically non-resectable tumor (T4 or M1a). Forty-seven percent of the patients who received neoadjuvant therapy had a complete pathologic response with a 3-year survival of 59% as compared to only 20 months in those patients who did not achieve a complete response (P = 0.037). Neoadjuvant chemotherapy administered concomitantly with conformal radiotherapy can be performed safely in the treatment of esophageal cancer, without increasing the operative morbidity, mortality, or length of stay. The higher complete response rates to neoadjuvant treatment (as compared to other reports) may be due to the use of three-dimensional conformal radiation therapy or the novel use of weekly carboplatin and paclitaxel.     

Preoperative intra-arterial infusion chemotherapy for advanced squamous cell carcinoma of the mouth and oropharynx

Twelve patients with advanced locoregional (Stage III and IV) squamous cell carcinoma of the oral cavity and oropharynx underwent treatment with cisplatin, vinblastine, bleomycin, and 5-fluorouracil, given by intra-arterial infusion, as primary adjuvant therapy, in preparation for radiation therapy and surgery. Responses were observed during or immediately after infusion therapy in 8 of 12 (67%) of patients (1 complete response, 7 partial responses). Infusion chemotherapy was followed by radiation therapy alone in five patients and by radiation and surgery in six patients. The protocol was initiated in August 1981, and six patients are now free of their primary cancer, at 21 to 36 months, whereas six have died with disease. Arterial infusion of a combination of effective antineoplastic agents is a promising method for the preparation of selected patients for radiation therapy and surgery, as it is less likely to produce serious systemic toxicity and it requires a shorter period than systemic neoadjuvant chemotherapy.     

Preoperative hyperthermo-chemo-radiotherapy effective for carcinoma of the esophagus

We prescribed hyperthermo-chemo-radiotherapy preoperatively for 13 patients with esophageal carcinoma. Viable cancer cells disappeared in four out of 13 patients, and all of these four patients survive without recurrence 3 to 34 postoperative months, at this writing. In another seven out of the 13, cancer cells were extensively damaged, despite the presence of a small number of viable cancer cells, and three out of these seven died with a recurrence. For two, the treatment was ineffective, and they died of liver metastasis and a local recurrence, respectively. These findings suggest that preoperative hyperthermia combined with chemotherapy and radiation is highly effective for treatment of carcinoma of the esophagus.     

Superficial spreading esophageal cancer controlled by hyperthermo-chemo-radiotherapy: a case report

Hyperthermo-chemo-radiotherapy (HCR) was prescribed for a patient with superficially spreading esophageal cancer, since severe lung dysfunction presented too great a surgical risk. Viable cancer cells completely disappeared after HCR and 8 months later, at this writing, the patient is living in good condition. Conservative treatment with HCR for patients with esophageal cancer is effective for carefully selected patients.     

Chemotherapy Rapidly Alternating with Twice-a-Day Accelerated Radiation Therapy in Carcinomas Involving the Hypopharynx or Esophagus: An Update

Laboratory studies have suggested that rapidly alternating chemotherapy and radiation therapy might act synergistically. We undertook this study to evaluate the toxicity and effectiveness of this approach in patients with carcinoma involving the hypopharynx or esophagus. Between 1987 and 1991, we treated 47 patients (23 with carcinoma involving the hypopharynx arid 24 with carcinoma involving the esophagus) by three cycles of chemotherapy (during weeks 1, 4, and 7) rapidly alternating with twice-a-day radiution therapy (during weeks 2, 5, atid 8). Chemotherapy consisted of cisplatin 100 mg/m² and 5-fluorouracil 3-4 g/m² given over 4 days. Radiation therapy consisted of 180-200 cCy twice each day to 2000 ccylcycle, total 6000 cCy over 7 weeks. The histology was squamous cell carcinoma in 44 patients and adenocarcinoma in 3 patients with esophagus cancer. Median follow-up is 2 years (range 1-5 years). The observed survival rate for all 47 patients was 54% at 1 year and 38% at 2 years. Acute toxicity was considerable. Twelve patients (25%) died during therapy porn toxicity, without timor progression, leaving 35 patienrs (18 hypopharynx, 17 esophagus) evaluuble for response. Among the hypopharyngeal patients, 83% had a complete response, 11% had a partial response, and 6% had no response. Among the esophageal patients, 94% had a complete response, and 6% had a partial response. Local control was better for the esophageal patients than the hypopharyngeal patients (98% vs. 52% at 2 years, p = 0.038). The incidence of distant metastases was 25% at 2 years and not significantly different between the two groups. A high rate of local control was achieved, particularly in esophugeal cancer, by delivering chemotherapy and radiation therapy in a rapidly alternating fashion. This was achieved at a considerable cost in terms of toxicity, however. Although our response rates and local control compare favorably with those of other recently published studies of combined modality therapy in esophugus or head and neck cancer, much additional work is required to reduce the toxicity and, in hypopharyngeal cancer, to further improve the local control.     

食管癌术中放疗30例疗效观察

目的 观察食管癌手术切除加术中放疗的疗效,并对放射并发症及其预防进行探讨。方法 全组60例均行食管胸段癌剖右胸切除术,其中30例术中加一次性15—25Gy的放疗;30例为单纯手术切除。结果 围手术期术中放疗组并发症有局限性肺部感染2例,吻合区瘘1例,切口感染1例,均治愈;单纯手术组有脓胸1例,吻合口瘘1例,均治愈。两组无围手术期死亡。术后3年随访,术中放疗组死亡3例,2例分别于术后2年及2年2个月死于放射性肺炎,其中1例合并支气管食管痪;1例死于两肺广泛转移。3年生存率放射组为88．0％(22/25),单纯手术组为76．0％(19／25)。结论 凡胸段食管癌病例,无胸部手术禁忌证、无远处转移者均适宜行术中放疗。术中放疗可降低局部复发率,但放射性肺炎较多见,治疗较难,预后不佳,故术中放疗时须特别注意保护健肺及支气管等,以减少或免受放射的伤害。     

Combined Bleomycin and Irradiation in Preoperative Treatment of Advanced Squamous Cell Carcinoma of the Vulva

Forty-two patients with advanced squamous cell carcinoma of the vulva were treated with a combination regimen of bleomycin 180 mg and external irradiation 30-45 Gy. Twenty patients had primary lesions, and 22 patients had recurrent disease. Fifteen (75%) of the patients with primary disease showed objective response (five complete and ten partial response). Four underwent surgery. of these, one is alive after 60 months with no evidence of disease. Two have died of unrelated causes without signs of recurrence. Seventeen relapsed and died of carcinoma of the vulva. Median survival for patients treated for primary disease was 8.0 months. Thirteen (59%) of 22 patients treated for recurrence showed objective response (two complete and eleven partial responses). None underwent surgery. All these patients died of carcinoma of the vulva. Median survival was 6.4 months. Toxicity was acceptable, and there were no treatment-related deaths. Even taking into account that our patients had very advanced disease, the results are disappointing. An increase of the radiation dose beyond the maximum of 45 Gy given, and more aggressive surgery, might have improved the results.     

Radiotherapy for anaplastic esophageal cancer

We report our experience with radiation therapy in 2 patients with anaplastic esophageal cancer with extensive distant metastases. Radiotherapy was given to the primary esophageal lesions and in both patients the tumors completely disappeared after irradiation with 2000 to 3000 rads. However, the metastatic lesions of the bone and liver did not respond despite the administration of BLM + PT -207 + BEMP in one case and METVFC + FT -207 in the other. Both patients died 4 and 5 months, respectively, after beginning the treatment. Effective chemotherapy of metastases needs to be developed because the primary lesions of anaplastic esophageal cancer are highly sensitive to radiation therapy.