Long-term results of concurrent chemoradiotherapy followed by high dose rate brachytherapy for T2-3 N0-1 M0 esophageal carcinoma

Background To assess the long-term efficacy and the pattern of failure of concurrent chemoradiotherapy followed by high dose rate (HDR) brachytherapy for stage T2-3 N0-1 M0 esophageal carcinoma. Methods Forty-six patients with clinical stage T2-3 N0-1 M0 esophageal cancer received concurrent chemoradiotherapy followed by HDR brachytherapy. The chemotherapy regimen was a combination of cisplatin 60 mg/m² on day 1 and fluorouracil 600 mg/m² continuous infusion from days 1 to 4 during the first and last week of external-beam irradiation. Radiotherapy consisted of external beam to a total dose of 40–60 Gy (median, 50 Gy) and high dose rate brachytherapy to 8–24 Gy (median, 16 Gy) in 2–4 fractions. External beam was delivered to a field of the primary lesion and the involved nodal lesions. All patients were followed up for at least 5 years. Results The 5-year overall survival rate was 28%. The median survival duration was 22 months. The 5-year cause-specific survival rate was 34% and the median was 22 months. Persistent disease was found in 7 of 46 patients (15%). Of the 39 patients with initial complete tumor disappearance, locoregional failure occurred ultimately in 13 patients. The ultimate local control rate was 57% (26/46). Three patients were salvaged successfully with surgery. Four patients (9%) had regional recurrence out of the irradiated fields as first failure site. Four patients (9%) had recurrence 3 years or longer after treatment. Twelve patients had transient ulcers, which healed spontaneously within a few months. Massive esophageal bleeding, thought to be treatment related, occurred in 2 patients, leading to death. Severe late toxicity with esophageal ulceration was found in patients receiving a dose of 16–24 Gy via brachytherapy. Conclusions Concurrent chemoradiotherapy followed by HDR brachytherapy achieved long-term effective and curative results for stage T2-3 N0-1 M0 esophageal carcinoma. However, severe late toxicity was observed with 16–24 Gy via brachytherapy. We recommend a dose via HDR brachytherapy should be 12 Gy or less following concurrent chemoradiotherapy.     

Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy for squamous cell carcinoma of the lower thoracic esophagus

AIM： To evaluate the clinical outcome of Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy for patients with squamous cell carcinoma of the lower thoracic esophagus. METHODS： From January 1998 to December 2001, 73 patients with lower thoracic esophageal carcinoma underwent Ivor-Lewis subtotal esophagectomy with two-field lymphadenectomy. Clinicopathological information, postoperative complications, mortality and long term survival of all these patients were analyzed retrospectively. RESULTS： The operative morbidity and mortality was 15.1% and the mortality was 2.7%. Lymph node metastases were found in 52 patients （71.2%）. Nodal metastases to the upper, middle, lower mediastini and upper abdomen were found in 13 （17.8%）, 15 （20.5%）, 30 （41.1%）, and 25 （34.2%） patients, respectively. Postoperative staging was as follows： stage Ⅰ in 5 patients, stage Ⅱ in 34 patients, stage Ⅲ in 32 patients, and stage Ⅳ in 2 patients, respectively. The overall 5-year survival rate was 23.3%. For NO and N1 patients, the 5-year survival rate was 38.1% and 17.3%, respectively （X^2 = 22.65, P 〈 0.01）. The 5-year survival rate for patients in stages Ⅱ a, Ⅱ b and Ⅲ was 31.2%, 27.8% and 12.5%, repsectively （X^2 = 29.18, P 〈 0.01）. CONCLUSION： Ivor Lewis subtotal esophagectomy with two-field （total mediastinum） lymphadenectomy is a safe and appropriate operation for squamous cell carcinoma of the lower thoracic esophagus.     

Increasing toxicity during neoadjuvant radiochemotherapy as positive prognostic factor for patients with esophageal carcinoma

The aim of this study was to correlate acute organ toxicity during preoperative radiochemotherapy with overall survival and tumor regression for patients with primarily operable esophageal carcinoma. From 1995 to 2002, 60 patients with primarily operable esophageal carcinoma were treated in a preoperative setting at our department. Thirty‐three percent of the patients had International Union against Cancer (UICC)‐stage II tumors, 62% had UICC‐stage III tumors, and 5% had UICC‐stage IVA tumors. All patients received irradiation (40 Gy at 2 Gy/fraction). Chemotherapy for all patients with adenocarcinoma and, from 2001, also for patients with squamous cell carcinoma consisted of two cycles, 5‐fluorouracil and cisplatinum; between 1995 and 2001, patients with squamous cell carcinoma received three courses of chemotherapy (folinic acid, etoposide, 5‐fluorouracil, and cisplatinum every 3 weeks) before and further cisplatinum and etoposide during radiotherapy. We found a significant correlation between acute organ toxicity and histopathological tumor regression, as well as overall survival. The probability to achieve tumor regression grade 1 after radiochemotherapy was nearly four times higher for patients with worsening of odynophagia than for those without an increase (odds ratio: 3.97). Patients with worsening of odynophagia had a 5‐year overall‐survival rate of 66% compared with 39% in patients without (P = 0.048). Our data indicate that normal tissue and tumor tissue may behave similar with respect to treatment response, as acute organ toxicity showed to be an independent prognostic marker in our patient population. The hypothesis should be further analyzed on biomolecular and clinical level in future clinical trials.     

Late course accelerated hyperfractionated radiotherapy for clinical T1－2 esophageal carcinoma

AIM: This retrospective study was designed to analyze the results and the failure patterns of late course accelerated hyperfractionated radiotherapy for clinical T(1-2)N(0)M(0) esophageal carcinoma. METHODS: From Aug. 1994 to Feb. 2001, 56 patients with clinical T(1-2) esophageal carcinoma received late course accelerated hyperfractionated radiotherapy in Cancer Hospital, Fudan University. All patients had been histologically proven to have squamous cell carcinoma (SCC) and were diagnosed to be T(1-2)N(0)M(0) by CT scan. All patients were treated with conventional fractionation (CF) irradiation during the first two-thirds course of the treatment to a dose of about 41.4Gy/23fx/4 to 5 weeks, Which was then followed by accelerated hyperfractionation irradiation using reduced fields, twice daily at 1.5Gy per fraction, to a dose about 27Gy/18 fx. Thus the total dose was 67-70Gy/40-43fx/40-49 d. RESULTS: The 1-, 3- and 5-year overall survival was 90.9 %, 54.6 %, 47.8 % respectively. The 1-, 3- and 5-year local control rate was 90.9 %, 84.5 % and 84.5 %, respectively. Twenty-five percent (14/56) patients had distant metastasis and/or lymph nodes metastasis alone. Eight point nine percent (5/56) patients had local disease alone. Another 3.6 % (2/56) patients had regional relapse and distant metastasis. CONCLUSION: Late course accelerated hyperfractionated radiotherapy is effective on clinical T(1-2) esophageal carcinoma. The main failure pattern is distant metastasis.     

Grading of tumor regression in non-small cell lung cancer : morphology and prognosis.

OBJECTIVE: Different types of multimodality therapy, including chemoradiotherapy and surgery, increasingly are being used for the treatment of patients with locally advanced non-small cell lung cancer (NSCLC; stages IIIA and IIIB). In this context, the applicability of a morphologic regression grading and its prognostic value were investigated. PATIENTS AND METHODS: In a multicenter phase II trial, 54 patients with locally advanced NSCLC received neoadjuvant bimodality treatment (ie, two cycles of ifosfamide, carboplatin, and etoposide, followed by twice-daily radiation up to 45 Gy with simultaneous administration of carboplatin and vindesine). Forty patients underwent resections. Using the corresponding resection specimens of the primary and regional lymph nodes, the following regression grading was established: grade I, no regression or only spontaneous tumor regression; grade II, morphologic evidence of therapy-induced tumor regression with at least 10% (grade IIa) or < 10% (grade IIb) vital tumor tissue; and grade III, complete tumor regression with no evidence of vital tumor tissue. Regression grading then was correlated with the survival time. RESULTS: Three tumors were classified as regression grade I, 10 were classified as regression grade IIa, 20 were classified as regression grade IIb, and 7 were classified as regression grade III. Patients with tumors of regression grades IIb or III showed significantly longer survival times than those with tumors of regression grades I or IIa (median survival time, 36 vs 14 months, respectively; 3-year survival rate, 52% vs 9%, respectively; p = 0.02). These survival times were also compared for patients who had undergone complete resection (median survival time, not reached vs 23 months, respectively; 3-year survival rate, 56% vs 11%, respectively; p = 0.03). The presurgical clinical response after patients had received neoadjuvant multimodality therapy had no predictive value in assessing the extent of therapy-induced tumor regression in the resection specimen. CONCLUSIONS: After neoadjuvant therapy of patients with NSCLC, the proposed tumor regression grading was of predictive value for long-term survival. Beyond the achievement of complete tumor resection (R0), a therapy-induced tumor regression of < 10% of vital tumor tissue is pivotal for superior long-term outcomes.     

All pathological T4 esophageal carcinomas should be categorized as stage IV

BACKGROUND/AIMS: The prognosis of pathological T4 (pT4) esophageal carcinoma is still dismal, however, the current TNM classification categorizes some pT4 cancers (pT4M0) as stage III. The purpose of this study was to evaluate of the relevance of this classification. METHODOLOGY: One hundred and thirty-five patients who underwent esophagectomy for pathological stage III (n = 85) and IV (n = 50) esophageal tumors were enrolled in the study. The outcomes and prognostic factors for these patients were examined. After the reclassification that pT4M0 tumors were categorized as stage IV, the two survival curves were compared between new stage III and IV. RESULTS: The 5-year survival rates for stage III and IV were 14.6%, 19.1%, respectively (P = 0.9). The 5-year survival rates for pT3N1M0 and pT4M0 were 21.1%, 0%, respectively (P < 0.0001). After the reclassification, the overall 5-year survival rates for new stage III and IV were 24.0%, 14.2%, respectively (P = 0.004). Curative resection (P = 0.002), radiotherapy (P = 0.001), depth of tumor invasion (pT3; P = 0.0004, pT1; P = 0.04) were the significant prognostic factors for stage III and IV carcinomas. Thirty-one (83.8%) of 37 patients with pT4 tumor had received non-curative esophagectomy. CONCLUSIONS: All pathological T4 esophageal carcinomas should be categorized as stage IV in the TNM classification.     

Adjuvant sunitinib following chemoradiotherapy and surgery for locally advanced esophageal cancer: a phase II trial

The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m²) + Cisplatin (30 mg/m²) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4–8. Sunitinib was commenced 4–13 weeks after surgery and continued for one year. Sixty‐one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12‐month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3‐year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2‐year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2‐year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer.     

Stage I-III Hodgkin's Disease: Outcome and Pattern of Failure Following Treatment with Radiation Therapy and Chemotherapy in a Modern Era

Purpose: To analyse the long term outcome, pattern of failure and treatment related complications after radiation therapy (RT) with or without chemotherapy for stage I—III Hodgkin's disease (HD).

Material and methods: Detailed records from 86 patients with stage I—III HD treated between 1989 and 1998, were retrospectively reviewed. Seventeen patients with favourable stage I-IIA were treated with RT alone, and the remaining 69 patients with combined modality treatment (CMT). Patients treated with RT received extended-field or subtotal nodal irradiation (STNI) to a total dose of 36–54 Gy, and patients with CMT, received involved-field irradiation to a lower doses, 26–40 Gy. The median follow-up time was 50 months (range 16–180).

Results: The 10-year overall survival (OS) for the whole group was 96% (SE 2%), 100% for stage I, 95% for stage II and 100% for stage III patients. Of potential prognostic factors analysed for statistical significance, only the response to chemotherapy (p = 0.0393) was found to influence significantly OS rates. Twelve patients (13.9%) relapsed. Salvage treatment was effective in 10 of the 12 relapsed patients. The 10-year freedom from treatment failure (FFTF) was 79% (SE 6%). Although 8 (9.6%) of the 83 surviving patients developed late effects that could represent toxicity from the treatment, no patient died of late complications.

Conclusions: RT alone for favourable early stage HD attains good survival rates with a modest treatment related morbidity. For patients with unfavourable stage II and stage III HD, CMT with limited RT provides a good to excellent prognosis.     

基于三维适形放疗技术研究剂量递增治疗局部晚期非小细胞肺癌的效果

目的利用三维适形放疗技术,通过剂量递增试验来获得非小细胞肺癌（NSCLC）的最大耐受剂量（MTD）并观察近期疗效及其放疗反应。方法有病理证实为非小细胞肺癌的病人,完成肝肾功能,胸部CT,腹部B超,心电图及全身骨扫描检查,根据1997年围际抗癌联盟UICC制定的标准,选择未经手术的II期III期局部晚期非小细胞肺癌病人,放疗前曾经过2～3次以DDP为基础的化疗;对肺癌原发灶及纵膈淋巴结进行照射,剂量1．8～2．0Cy,1次／d,5次／w,达40Gy后复查CT缩野,纵膈淋巴结加量至60Gy,对原发病灶加最至66GY后开始剂量递增;总剂量依次为68Gy、70Gy、72Gy、74Cy、76Cy,每组5例病人,采用适形放疗技术,剂量计算参考点为等中心点,一组5例病人中有1例发生RTOG3级以上急性放射性肺损伤则再人组5例,冉有3级以}=反应则终止剂量递增。结果30例病例进入本研究,剂量递增到78Gy仍能耐受,全组病人近期疗效：完全缓解率13.3％（4／30）,部分缓解率70％（21／30）,无进展（SD）率16．7％（5／30）,总有效率（CR＋PR）83．3％（25／30）。1、2、3年生存率分别为66．7％、40％,、30％。1年局部控制率76,7％（23／30）,2年局部控制率53．3％（16／30）。结论利用三维适形放疗技术治疗非小细胞肺癌,剂量递增至68Gy以上,局部控制率及生存率有明显提高,而早期放射反应并未明显增加。     

Definite intensity-modulated radiotherapy with concurrent chemotherapy more than 4 cycles improved survival for patients with locally-advanced or inoperable esophageal squamous cell carcinoma

We investigated which prognostic factor could improve survival for esophageal cancer patients who received definite concurrent chemoradiation (CCRT). Eighty patients with age ≥18, Karnofsky Performance Scale (KPS) ≥ 60, and clinical stage T1-4N0-3M0 esophageal squamous cell carcinoma were enrolled from July 2004 to December 2015. They underwent definite intensity-modulated radiotherapy (IMRT) with or without simultaneous integrated boost to the primary tumor, and reception of concurrent chemotherapy ≥ 1 cycle. The primary endpoints were overall survival (OS), locoregional progression-free survival (LRPFS) and distant metastasis-free survival (DMFS). The median follow-up duration for alive patients was 21.5 months. The rates of 2-, 3- and 5-year OS/LRPFS/DMFS were 23.8%/53.5%/49.3%, 19.1%/44.6%/49.3%, and 13.0%/44.6%/43.9%, respectively. Only the non-clinical complete response (non-cCR) after CCRT was an independent poor prognostic factor in OS (HR 3.101, 95% CI 1.535–6.265, p = 0.0016). Radiation dose >50.4 Gy and chemotherapy ≥4 cycles significantly predicted better LRPFS (p = 0.0361 and 0.0163, respectively). Poorly differentiated tumor and stage III disease have poor DMFS (p = 0.0336 and 0.0411, respectively), and chemotherapy ≥ 4 cycles was a better predictor (p = 0.0004). In subgroup analysis, patients who received radiation dose ≤50.4 Gy with concurrent chemotherapy ≥4 cycles had the best survival outcome with 1-, 2-, 3- and 5-year survival rates of 73.7%, 39.4%, 31.5% and 17.5%, respectively. In conclusion, definite radiotherapy with concurrent chemotherapy ≥4 cycles improved the survival for patients with inoperable or locally-advanced esophageal squamous cell carcinoma.     

Concurrent low-dose cisplatin and thoracic radiotherapy in patients with inoperable stage III non-small cell lung cancer: a phase II trial with special reference to the hemoglobin level as prognostic parameter

Purpose To evaluate the efficacy of concurrent radiochemotherapy in patients with stage III non-small cell lung cancer (NSCLC), and to examine the effect of hemoglobin levels on survival of those patients. The negative impact of anemia on survival has been noticed for other cancer sites including the head and neck, and the uterine cervix, but it has been rarely described in NSCLC cancer patients treated with radiotherapy.Methods From April 1995 through March 2002, 56 patients with inoperable stage III non-small lung cancer were treated with radiotherapy consisting of 60 Gy (50 Gy+10 Gy boost) given in 30 fractions of 2 Gy daily, 5 days a week, over a period of 6 weeks, and concurrent low-dose daily chemotherapy (CHT) consisting of 6 mg/m² of cisplatin given Mondays–Fridays during weeks 1–2 and 5–6. All patients had stage III disease and ages ranged from 39 to 81 years old (median 63.9 years).Results The 2-year and 3-year survival rates were 34% and 16%, respectively. Patients with a pretreatment hemoglobin level superior or equal to 11.6 g/dl had a 2-year survival rate of 52% as compared to 15.5% for patients with a pretreatment hemoglobin level inferior to 11.6 g/dl (p=0.0075). Patients with higher KI (>70%) showed better survival rates than those with lower KI. Surprisingly, patients in stage IIIA did not survive significantly longer than those in stage IIIB. Hematological toxicity (grade 2) prevailed (25%), followed by esophageal (5.4%) and bronchopulmonary (2%) toxicity. Only three patients experienced acute grade 3 hematological toxicity. Because of acute toxic effects, irradiation was interrupted in 8 patients (14.3%) for 7–13 days (median 7.5 days). Late high-grade (3) toxicity was not found. No grade 4 toxicity or treatment-related deaths were observed during this study.Conclusion Our data show that concurrent radiotherapy with daily low dose cisplatin is well tolerated, and shows survival rates comparable to more aggressive treatment regimens. A combination of this chemotherapy with accelerated hyperfractionated radiotherapy might improve the results in the future. Furthermore, we could show that the hemoglobin levels prior to therapy have an influence on the prognosis, where lower levels were associated with worse outcome. Further trials should consider supplementation with erythropoietin.     

Intensified intensity-modulated radiotherapy in anal cancer with prevalent HPV p16 positivity

AIM: To investigate the toxicity and response of intensity-modulated radiotherapy schedule intensified with a simultaneous integrated boost in anal canal cancer.METHODS: From March 2009 to March 2014, we retrospectively analyzed 41 consecutive patients treated with intensity-modulated radiotherapy(IMRT) and concurrent chemotherapy for anal canal squamous cell carcinoma at our center. Radiotherapy was delivered via simultaneous integrated boost(SIB) technique by helical tomotherapy, and doses were adapted to two clinical target volumes according to the tumor-nodemetastasis(TNM) stage: 50.6 Gy and 41.4 Gy in 23 fractions in T1N0, 52.8 Gy and 43.2 Gy in 24 fractionsin T2N0, and 55 Gy and 45 Gy in 25 fractions in all patients with N positive and/or ≥ T3, respectively, to planning target volumes 1 and 2. The most common chemotherapy regimen was 5-fluorouracil and mitomycin-based. Human papilloma virus(HPV) p16 expression was performed by immunohistochemistry and evaluated in the majority of patients. Acute and late toxicity was scored according to CTCAe v 3.0 and RTOG scales.RESULTS: The median follow-up was 30 mo(range:12-71). Median age was 63 years(range 32-84). The stage of disease was: stage Ⅰ in 2 patients, stage Ⅱin 13 patients, stage ⅢA in 12 patients, and stage ⅢB in 14 patients, respectively. Two patients were known to be HIV positive(4.9%). HPV p16 expression status was positive in 29/34(85.3%) patients. The 4-year progression-free survival and overall survival in HPVpositive patients were 78% and 92%, respectively.Acute grade 3 skin and gastrointestinal toxicities were reported in 5% and 7.3% of patients, respectively;patients' compliance to the treatment was good due to a low occurrence of severe acute toxicity, although treatment interruptions due to toxicity were required in 7.3% of patients. At 6 mo from end of treatment,36/40(90%) patients obtained complete response;during follow-up, 5(13.8%) patients presented with disease progression(local or systemic).CONCLUSION: In our experience, intensified SIBIMRT with chemotherapy is very feasible in clinical practice, with excellent results in terms of overall survival and local control.     

Radiation therapy alone for stage I (UICC T1N0M0) squamous cell carcinoma of the esophagus: indications for surgery or combined chemoradiotherapy

BACKGROUND AND AIM: The aim of this study was to clarify the efficacy and limitations of radiation therapy (RT) for superficial esophageal carcinoma, and to explore the indications for more aggressive therapy, such as combined chemo-radiotherapy. METHODS: Sixty-eight patients with stage I (UICC T1N0M0) esophageal squamous cell carcinoma treated by definitive RT alone were analyzed. Brachytherapy was administered in 36 patients as a boost, and the prescribed doses were 10 Gy (5 Gy x 2 times) at a low dose rate (19 patients) and 9 Gy (3 Gy x 3 times) at a high dose rate (17 patients). Recurrence patterns and survival rates were assessed and the factors predisposing to recurrences after RT were statistically investigated by univariate analysis. RESULTS: The 5-year cause-specific survival rate and the locoregional control rate were 79.9% and 82.1%, respectively. No case of recurrence or disease-related death was observed in any of the patients with mucosal cancer. Among the cases with the cancer invading the submucosa, there were 12 cases with locoregional recurrence and two cases with distant metastases. In cases of submucosal esophageal cancer, the tumor length was the only statistically significant factor predicting locoregional control. The 5-year locoregional control rate in cases with a short length of the tumor (5 cm in length was 57.8% (P = 0.036). Patients treated by additional brachytherapy exhibited better cause-specific survival and locoregional control rates than those receiving external RT alone, however, the addition had no statistically significant influence on the outcome. CONCLUSIONS: RT was a successful treatment for stage I esophageal cancer, and the treatment outcome using RT was nearly comparable to that of surgery. However, it is suggested that chemo-radiation should be considered in inoperable cases of submucosal cancer when the tumor is more than 5 cm in length.     

Prospective study of definitive chemoradiotherapy with S-1 and nedaplatin in patients with stage II/III (non-T4) esophageal cancer

Background

Standard chemoradiotherapy (CRT) using 5-FU and CDDP is the optimal treatment for patients with stage II/III (non-T4) esophageal carcinoma. However, patient quality of life (QOL) cannot necessarily be maintained during this therapy, because 5-FU must be continuously infused for 24?h and CDDP administration requires a large transfusion volume. Therefore, hospitalization is unavoidable. We conducted a study of definitive CRT with S-1 and nedaplatin.

Methods

The study was conducted between July 2004 and December 2006. Eligibility criteria were stage II/III (non-T4), PS 0?C2, age 20?C79?years, and adequate organ function. S-1 80?mg/m² was given on days 1?C14, and nedaplatin 90?mg/m² on day 1 every 4?weeks. Patients received two courses with concurrent radiotherapy of more than 50?Gy.

Results

Twenty patients (age range, 50?C75?years; PS 0/1, 8/12; stage IIA/IIB/III, 11/2/7) were enrolled. Grade 4 leukopenia, thrombocytopenia, and anemia occurred in 15%, 10%, and 5% of patients, respectively. Grade 3 nonhematotoxicity included esophagitis in 3 patients (15%) and anorexia in 2 (10%). One patient developed febrile neutropenia; another developed an esophageal fistula. Complete response was achieved in 80%. The 3-year overall survival rate was 58.0%. Thirteen subjects received treatment as outpatients.

Conclusions

S-1 and nedaplatin in combination with radiotherapy is feasible, and toxicity is tolerable. This treatment method has the potential to shorten hospitalization and maintain patient QOL without impairing the efficacy of CRT.     

Concurrent concentrated radio-chemotherapy of epidermoid cancer of the esophagus. Long-term results of a phase II national multicenter trial in 122 non-operable patients (FFCD 8803)

OBJECTIVES: Concomitant radiochemotherapy improves survival from inoperable esophageal cancer compared to radiotherapy alone. Several regimens of radiotherapy (standard or concentrated split course radiotherapy) are used, however the optimum protocol remains to be determined. The aim of this study was to analyze the efficacy and tolerance of concentrated concomitant split course radiochemotherapy. Prognostic factors as well as those positively influencing complete response were also studied. METHODS: This multicentric phase II trial looked at patients with histologically proven, inoperable, squamous cell esophageal carcinoma without metastases or invasion of the tracheobronchial mucosa. Treatment included 3 cycles of chemotherapy by 5-FU continuous infusion (800 mg/m2.d D1-D5, D22-D26, D43-D47), cisplatin (70 mg/m2 D2, D23, D44) and radiotherapy 15 Gy/5d (D1-D5, D22-26, D43-D47). Efficacy was analyzed by endoscopy, biopsy and computerized axial tomography during the 12th week of treatment. RESULTS: The trial included 122 patients from 21 centers (110 M and 12F, mean age 63.1 +/- 8.6 years, range 40-78). In accordance with the TNM-UICC classification (1978), 8 patients were classified stage I (T1 N0), 13 stage II (T2 N0), 100 stage III (T3 and/or N1) and stage was unknown in 1 patient. Median follow-up was 63 months. Treatment was complete in half of the patients. 5 premature deaths (4.1%) were recorded over the treatment period, one of which was directly linked to the toxicity of the treatment. 16% of patients showed at least one severe side-effect. 117 patients received all 3 cycles of the treatment, 88 of them without delay, and all were evaluated. 58 (47.5% of the patients included) showed a complete response with a negative biopsy, 36 (29.5%) showed a partial response, 13 (10.7%) were stable and 10 (8.2%) showed progressive disease. The median duration of complete responses was 11.5 months. Symptomatically, dysphagia improved in 80% of the cases, performance status in 40%, and weight gain was observed in 30% of the patients with weight loss. At evaluation, oral feeding was impossible in 4 patients only and possible in 113 patients; however, endoscopic treatment of the dysphagia remained necessary in 28 patients. Median survival in the 122 patients included was 13.0 +/- 1.6 months and survival rates were 52.9, 29.8 and 12.1% at 1, 2 and 5 years, respectively. Three pretherapeutic prognostic factors influenced survival in a multivariate analysis: initial severe dysphagia (risk of premature death increased 3-fold in the first year), circumferential extension and the differentiated nature of the tumor (risk of death doubled regardless of the time delay). Factors influencing a complete clinical response were an early tumor stage, a poorly differenciated tumor in patients older than 65, and no circumferential extension. The risk of recurrence was 54.8% at 1 year in the 58 patients with complete remission. Complete circumferential extension and a well or moderately differentiated tumour influenced recurrence. CONCLUSION: This trial confirms the efficacy and good tolerance of concentrated split course radiochemotherapy in patients with inoperable esophageal cancer with a 5-year survival rate of 12%. This reinforces the need for a comparative trial (split course irradiation vs standard irradiation) such as the one currently being conducted in France.     

Neoadjuvant chemoradiotherapy followed by esophagectomy versus definitive chemoradiotherapy in resectable stage II/III (T1-3N0, 1M0) esophageal squamous cell carcinoma

Background There are two intensive modalities for the treatment of resectable esophageal carcinoma: esophagectomy and definitive chemoradiotherapy (CRT). Esophagectomy with preoperative CRT was retrospectively compared with CRT alone in resectable stage II/III esophageal squamous cell carcinoma. Methods Seventy-four patients with resectable stage II/III (T1-3N0, 1M0) esophageal squamous cell carcinoma were treated with preoperative CRT by 5-fluorouracil (5-FU) 700 mg/m² on days 1 to 5, nedaplatin 80 mg/m² on day 1, and concurrent radiation for a total of 30 Gy in 3 weeks. If patients decided to undergo surgery, esophagectomy from the thoracoabdominal approach was carried out 6 weeks after the completion of CRT (CRT + Surg group, n = 51). If patients decided not to undergo surgery, they were treated with one more course of CRT (CRT-alone group, n = 23). Results There was no significant difference in overall survival between the two groups (P = 0.1006), whereas the disease-free survival in the CRT + Surg group was improved compared with the CRT-alone group (P = 0.0186). In the patients with clinical stage III carcinoma or with regional lymph node metastasis, the overall survival rate was significantly improved in the CRT + Surg group compared with the CRT-alone group. The rate of local failures in the CRT + Surg group was significantly lower compared with the CRT-alone group (P = 0.0011). Conclusions Preoperative CRT followed by esophagectomy provides better local control, but does not prolong overall survival, compared with definitive CRT. However, in clinical stage III or N1, esophagectomy with preoperative CRT could contribute to the improvement of survival in esophageal squamous cell carcinoma.     

Inhibition of HMG-CoA reductase in mononuclear cells during gemfibrozil treatment.

The effect of gemfibrozil treatment (900 mg/day) on serum levels of total cholesterol, HDL-cholesterol, triglyceride, apoproteins A-I, A-II and B as well as HMG-CoA reductase in mononuclear cells was studied in patients with hyperlipoproteinemia types IIa and IIb. After 4 weeks of treatment gemfibrozil reduced total serum cholesterol (IIa: -17%, IIb: -26%), triglyceride (IIa: -39%, IIb: -47%) and apoprotein B (IIa: -22%, IIb: -15%). HDL cholesterol was increased by 20-22% and apoproteins A-I and A-II by 4-11%. Concomitantly, HMG-CoA reductase activity in freshly isolated mononuclear cells was suppressed by 78% in type IIa and 51% in type IIb patients. Continuation of treatment for up to 16 weeks prompted a further decline to 8 and 5% of the initial values, respectively. However, gemfibrozil failed to affect HMG-CoA reductase directly in homogenized or cultured mononuclear cells and did not further promote the suppressive action of LDL when added to the culture medium. Similarly, preincubation with the drug did not significantly modulate the binding or degradation of LDL in the cultured cells. However, LDL from patients with hyperlipoproteinemia types IIa and IIb exhibited enhanced binding and more potent HMG-CoA reductase suppression when isolated after compared to before gemfibrozil treatment. It is suggested that the HMG-CoA reductase inhibition observed in mononuclear cells during gemfibrozil treatment is due to changes in LDL structure affecting LDL receptor binding rather than direct effects of the drug on cellular cholesterol metabolism.     

Stereotactic radiotherapy (SBRT) as a sole or salvage therapy in non-small cell lung cancer patients

The aim of this study is to present evaluation of treatment toxicity and the rate of local control in non-small cell lung cancer patients (NSCLC) treated with stereotactic body radiotherapy (SBRT). The analysis was performed on heterogenous group of 61 NSCLC patients, treated with SBRT between 2005 and 2008. It included 26 patients in clinical stage I, 5 in stage II, 22 in III and 8 in stage IV. In 30 patients SBRT was the only treatment, in 20 patients SBRT was a salvage therapy and in 11 patients SBRT was used as a boost after conventionally fractionated radiotherapy (CRT). The mean age was 67 yrs. Fifteen patients received chemotherapy in the course of treatment. Radiation doses were converted into Linear Quadratic Equivalent Dose at 2Gy per fraction (LQED2). The survival curves were plotted using Kaplan-Maier estimator and analyzed using log-rank test and Cox method. The LQED2 doses administered in stereotactic technique ranged from 8 Gy to 150 Gy and the fraction doses from 5 Gy to 24 Gy. The rate of 2 years local control correlated with LQED2: it was 81% in a group of patients who received over 110 Gy, compared to 51% and 33% in a group of patients who received 60-110 Gy and less than 30 Gy respectively. Prior radiotherapy and advanced clinical stage correlated with lower doses at SBRT and hence lower rate of local control. The tolerance of SBRT was satisfactory: there was no RTOG grade 3 - 4 toxicity. The results are consistent with findings of other authors and indicate that LQED2 doses delivered by SBRT in the treatment of NSCLC should be higher than 110 Gy whenever clinically feasible. SBRT used as a salvage therapy was less effective, because use of high doses was precluded due to consideration of normal tissue tolerance.     

Efficacy and toxicity of MDR versus HDR brachytherapy for primary vaginal cancer

The retrospective analysis includes a group of 50 patients with primary, invasive vaginal cancer treated with brachytherapy in the period of 1982-1993. Over 80% cases were squamous cell carcinoma. There were 14 patients in stage I according to FIGO classification and 20%, 36%, and 16% of patients in stage II, III and IV, respectively. Twenty one patients (42%) received MDR brachytherapy using Cs137 source, the remaining 29 (58%) were treated with HDR using Co60 or Ir192 sources. Among 50 patients 31 (62%) received also external beam irradiation. An overall 5-year actuarial disease-free survival was 40%, and it was 78.6% (11/14), 40% (4/10), 27.8% (5/18), 0% (0/8) for stage I, II, III and IV, respectively. For MDR or HDR5-year disease-free survival was 38% and 41%, respectively. No influence of dose rate on survival has been found (p=0.7). Local failure occurred in 20 patients (40%). Recurrences appeared in 10 patients (20%). Late complications rate was 0% and 17% for MDR and HDR, respectively. Effectiveness of brachytherapy MDR and HDR was similar, whereas serious late complications developed more often after HDR brachytherapy.     

Prognostic factors in definitive radiochemotherapy of advanced inoperable esophageal cancer

The aim of this study was to assess the efficacy and prognostic factors of definitive radiochemotherapy (RCT) for inoperable esophageal cancer. Between 1995 and 2005 all patients with inoperable esophageal cancer that underwent concurrent RCT were included in this retrospective study. Conventional computed tomography-based treatment planning as well as 3D-conformal radiotherapy (RT) was used. Maximum radiotherapy dose was 63 Gy. Chemotherapy consisted of cisplatin (20 mg/m(2) d1-5 and 29-33) and 5-FU (650-1000 mg/m(2) d1-5 and 29-33). Patients not suitable for RCT received radiotherapy alone. Toxicity was measured according to common toxicity criteria (CTC). Two hundred three consecutive patients with inoperable esophageal cancer that received definitive therapy were identified in this time period (160 with squamous cell carcinoma and 43 with adenocarcinoma). The 2-year overall survival probability was 21.2% whereas the progression-free survival at 2 years was 13.8% for all patients. In the univariate analysis, type of histology, T-stage, N-stage, application of chemotherapy, and the radiation dose were significantly correlated with overall/progression-free survival. Moreover, multivariate analysis revealed an independent prognostic impact for N-stage, radiation dose, and concurrent chemotherapy. Definitive RCT is an important palliative treatment option for patients with inoperable esophageal cancer. N-stage, radiation dose, and concurrent chemotherapy are important prognostic factors for survival.