Plasma proteomic analysis of patients with squamous cell carcinoma of the uterine cervix

Objective

To compare plasma protein expression between patients with squamous cell carcinoma (SCC) of the cervix and normal controls.

Methods

Plasma samples from patients with benign gynecological disease (normal cervix, n=6) and cervical cancer (SCC, n=6) were subjected to plasma proteomic analysis using two dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). Western blotting and immunoturbidimetric assay were performed to validate the results of 2-DE.

Results

Eight proteins showed differential expression between controls and SCC patients; six (ceruloplasmin, complement C3, afamin precursor, alpha-1-B-glycoprotein, transferrin, alpha-fibrinogen precursor) were up-regulated, while two (chain A, crystal structure of antithrombin and apolipoprotein A-IV precursor) were down-regulated in the plasma of SCC patients. Western blotting analysis revealed significant elevation of ceruloplasmin, complement C3, afamin, and alpha-1-B-glycoprotein in the plasma of SCC patients in comparison to controls. Immunoturbidimetric assay of a larger group confirmed the results of 2-DE and Western blotting, and showed that ceruloplasmin and complement C3 were significantly elevated in the plasma of SCC patients in comparison with controls and patients with carcinoma in situ (CIS) of the uterine cervix.

Conclusion

Plasma protein expression determined using 2-DE and MALDI-MS will give a chance to identify tumor-specific biomarkers for SCC of the cervix.     

Time course and incidence of late complications in patients treated with radiation therapy for FIGO Stage IB carcinoma of the uterine cervix

: To determine the time course and incidence of late complications from radiation therapy in patients treated with radiation for FIGO Stage IB carcinoma of the uterine cervix, and to evaluate patient and tumor factors associated with an increased probability of treatment complications. : The medical records of 1784 patients with FIGO Stage IB cervical carcinoma who were treated with initial radiation therapy between 1960 and 1989 were retrospectively reviewed. Follow-up was obtained from clinic visits and correspondence with patients and their physicians. Treatment complications were graded retrospectively. Complication rates were calculated actuarially; patients who died of disease or intercurrent illness without experiencing a major complication were censored at the time of death. There were 1241, 924, 548, and 274 patients followed fro more than 5, 10, 15, and 20 years, respectively. : Of patients treated for Stage IB cervical carcinoma, 7.7% and 9.3% had experienced major (≥Grade 3) complications at 3 and 5 years, respectively. After 5 years, there was a small but continuous risk of approximately 0.34% per year, resulting in an overall actualrial risk of having had major complications of 14.4% at 20 years. The risk of developing major urninary tract complications was approximately 0.7% per year for the first 3 years of follow-up, decreasing to about 0.25% per year for at least 25 years. In contrast, the risk of developing rectal complications was about 1% per year during the first 2 years, with a subsequent sharp decline to about 0.06% per year between Years 2 and 25. The risk of fistula formation was approximately doubled in the 234 patients who underwent adjuvant extrafascial hystectomy (5.3 vs. 2.6% at 20 years; p = 0.04) and in the 111 patients who had pretreatment laparotomy (5.2 vs. 2.9%; p = 0.007). The risk of developing small bowel obstruction was increased in patients who underwent pretreatment laparotomy (14.5 vs. 3.7% at 10 years; p < 0.0001) and in patients who weighed <120 pounds (8.2 vs. 3.6%; p = 0.004), but was not increased in patients who underwent adjuvant hysterectomy. A signicantly greater risk of gastrointestinal complications was observed in black and non-Hispanic white patients than in Hispanic women (p = 0.01), even though there was no difference in the rate of developing urinary tract complications (p = 1.0). There was no correlation between the actuarial risk of developing major complications and the patients' age at the time of treatment, but not the cumulative risk was greater for patients who were treated at a young age because these patients were more likely to survive to be exposed to a very long period of risk. : Using techniques described by Fletcher and Delclos, the risk of major complications from aggressive irradiation for Stage IB carcinoma of the cervix is low and does not warrant compromises in the intensity of treatment that might decrease the high cure rates achieved in such patients. The long time course of some late complications also suggests that continued surveillance of survivors, by physicians experienced in the diagnosis and management of the sequelae of the curative radiation treatment of cervical center, is important.     

Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone: patterns of recurrence, latent periods, and prognosis

A retrospective analysis was performed with emphasis on the patterns of recurrence, latent period, and prognosis in patients with cervical squamous cell carcinoma of the uterus treated with definitive radiation therapy alone. Late recurrence, which was observed more than 5 years after the initial radiation therapy, was finally focused on and discussed.

Between 1976 and 1994, 256 patients with squamous cell carcinoma of the uterine cervix without hematogenous metastasis were treated with definitive radiation therapy alone. The patients were staged as follows according to the FIGO classification: 26 in Stage I, 56 in Stage II, 124 in Stage III, 28 in Stage IVa, and 22 in Stage IVb. All the patients were treated with external beam irradiation and low-dose-rate intracavitary brachytherapy.

A total of 74 patients had recurrence. The recurrence appeared in 67 cases (90.5%) within 5 years. Metastasis to para-aortic and/or supraclavicular nodes developed later than other types of recurrence. Among patients with lymphogenous metastasis, there were more 5-year survivors after recurrence than with other types of recurrence. Patients with early recurrence, within 2 years of the initial therapy, had a worse prognosis than those with recurrence more than 2 years after treatment. Seven patients (2.7%) in all developed late recurrence more than 5 years after the treatment. The first site of recurrence was an abdominal para-aortic or supraclavicular node in all patients, excluding one patient who developed intrapelvic lymph node metastasis. Six patients had pelvic node metastasis detected with lymphangiography at the initial treatment. Median survival after late recurrence was 16.0 months. Two of 7 patients survived more than 3 years after secondary radiation therapy, and the remainder died of recurrent disease.

Patients with para-aortic and/or supraclavicular node metastasis that developed late after the initial treatment are more likely to survive due to secondary radiation therapy. Careful follow-up is emphasized for long-term survivors.     

PF方案联合放疗治疗中晚期宫颈癌的疗效观察

目的：探讨PF方案联合放疗治疗中晚期宫颈癌的疗效及不良反应。方法：回顾分析52例中晚期宫颈癌的随访资料,根据PF方案联合放射治疗组和单纯放疗组进行比较,观察有效率及不良反应。结果：PF方案联合放疗组在肿瘤的缩小、消失方面优于单纯放疗组,两者差异有显著意义（P〈0.05）。PF方案联合放疗组有效率85%,单纯放疗组有效率68%,但化疗联合放疗组较单纯放疗组消化道Ⅰ-Ⅱ度不良反应发生率明显增加,骨髓抑制Ⅰ-Ⅱ度不良反应有增加。结论：PF方案联合放射治疗中晚期宫颈癌效果显著。     

Invasive carcinoma of the uterine cervix associated with pregnancy

BACKGROUND:

This study is a representation of 90 years of experience with carcinoma of the uterine cervix in pregnancy. The objective was to retrospectively study changes in the distribution of cervical carcinoma (CC) by age, disease stage, histopathology, survival, and the development of second primary cancers.

METHODS:

Altogether, 18,474 women with newly diagnosed CC were examined and treated at the Radiumhemmet between 1914 and 2004, including 9247 women who were of a childbearing age (<50 years) and 219 women who were pregnant.

RESULTS:

The mean patient age declined from 35 years (during 1914‐1943) to 32.2 years (during 1960‐2004). Similarly, the age range changed from ages 23 to 51 years (during 1914‐1943) to ages 21 to 47 years (during 1960‐2004). The relative incidence for all women aged <50 years who were treated for CC dropped considerably from 4.2% (during 1914‐1943) to 1.2% (during 1960‐2004), which translated into a reduction of by approximately 66%. At the time of diagnosis, stage I CC was observed in 75.6% of patients during 1960 to 2004 compared with 24.8% of patients during 1914 to 1943. The 10‐year actuarial survival rate improved significantly during the study period from 27% (1914‐2004) to 79% (1960‐2004). The 10‐year cause‐specific cumulative actuarial survival rate for 41 women who were treated during 1960 to 2004 did not differ statistically from the rate for an age‐matched, stage‐matched, and histopathology‐matched control series from the total cohort of women with CC who were treated at the Radiumhemmet during the same period (log‐rank test; P = .85).

CONCLUSIONS:

During the study period, the incidence of CC during pregnancy declined, the cases were discovered at earlier stages, and survival improved. Furthermore, there was no increase in second primary cancers, and pregnancy did not appear to influence prognosis. Cancer 2010. © 2010 American Cancer Society.     

PF方案联合放疗治疗中晚期宫颈癌的疗效观察

目的:探讨PF方案联合放疗治疗中晚期宫颈癌的疗效及不良反应.方法:回顾分析52例中晚期宫颈癌的随访资料,根据PF方案联合放射治疗组和单纯放疗组进行比较,观察有效率及不良反应.结果:PF方案联合放疗组在肿瘤的缩小、消失方面优于单纯放疗组,两者差异有显著意义(P＜0.05).PF方案联合放疗组有效率85%,单纯放疗组有效率68%,但化疗联合放疗组较单纯放疗组消化道Ⅰ-Ⅱ度不良反应发生率明显增加,骨髓抑制Ⅰ-Ⅱ度不良反应有增加.结论:PF方案联合放射治疗中晚期宫颈癌效果显著.     

Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy: new insight into the value of total dose of cisplatin and radiation boost

This study was to report the long-term outcomes and toxicities of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). From 2009 to 2010, 869 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. With a median follow-up of 54.3 months, the 5-year estimated local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 89.7%, 94.5%, 85.6%, 76.3%, 84.0%, respectively. In locally advanced NPC, gender, T, N, total dose of cisplatin more than 300 mg/m² and radiation boost were independent prognostic factors for DMFS and DFS. Age, T, N and total dose of cisplatin were independent prognostic factors for OS. Radiation boost was an adverse factor for LRFS, RRFS, DMFS and DFS. Concurrent chemotherapy was not an independent prognostic factor for survival, despite marginally significant for DMFS in univariate analysis. Concurrent chemotherapy increased xerostomia and trismus, while higher total dose of cisplatin increased xerostomia and otologic toxicities. In conclusion, IMRT provided satisfactory long-term outcome for NPC, with acceptable late toxicities. Total dose of cisplatin was a prognostic factor for distant metastasis and overall survival. The role of concurrent chemotherapy and radiation boost in the setting of IMRT warrants further investigation.     

The relationship between early and late gastrointestinal complications of radiation therapy for carcinoma of the cervix

In a retrospective analysis of 1,390 consecutive patients with carcinoma of the cervix treated by high dose radiation therapy alone at the Queensland Radium Institute, we report a quantitative relationship between the early and late gastrointestinal complications arising from such treatment. Of these 1,390 patients, 157 (11.3%) experienced early, serious complications. For geographic reasons, it was only possible to evaluate 784 patients for late post-irradiation complications. Twenty-eight (3.6%) developed one or more late bowel complications, which included adhesions, fistulae, strictures, perforation, colitis and vascular occlusion. Factors affecting the relative risk of developing either an early or late complication were analyzed and are discussed. There was an 8.2% incidence of late complications developing in those patients who had experienced early complications, compared with a 3.0% incidence of late complications developing in patients without early complications. Thus, the risk of developing a late complication was greater by a factor of 2.7 in those patients developing an early one (p < 0.05). However, of the 28 patients developing late complications, 21 (75% ) did not experience a severe acute one.     

Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression

In an attempt to understand the molecular mechanisms for the different clinical features between adenocarcinoma/adenosquamous carcinoma (AC/ASC) and squamous carcinoma (SC) of the uterine cervix, we analyzed gene expression profiles of different histological subtypes of cervical cancer. Cancer specimens and the surrounding normal tissue counterparts were separately collected from cervical cancer patients undergoing type III radical hysterectomy. Paired total RNA (cancer and normal tissues) was isolated and analyzed with cDNA microarrays containing duplicate spots of 7 334 sequence-verified human cDNA clones. Selected differentially expressed genes specific for AC or SC were further verified using real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemistry. Genes, including CEACAM5, TACSTD1, S100P and MSLN were upregulated in AC. Contrarily, genes involved in epidermal differentiation complex such as S100A9 and ANXA8 were upregulated in SC. Cross-validation of the results using an independent but comparable group of patients with known long-term outcomes (n = 63, median follow-up 70.3 months; range, 4-208 months) showed that the correlation between the selected 6 differentially expressed genes and histology was highly significant. CEACAM5 (p < 0.0001) and TACSTD1 (p = 0.009) were significant prognostic factors by multivariate Cox proportional hazards regression analysis. The combination of cDNA microarray, RTQ-PCR and immunohistochemical results of this study showed that it is possible to define different gene profiles for AC and SC. Moreover, TACSTD1 expression may be a novel poor prognostic factor.     

Undifferentiated small cell carcinoma of the uterine cervix effectively treated with chemotherapy (cyclophosphamide, doxorubicin, vincristine) and whole brain irradiation

A 42-year-old woman had stage IV undifferentiated small cell carcinoma of the uterine cervix with metastasis to the brain, liver, adrenal gland, pelvic lymph nodes, superficial lymph nodes, and skin. She was treated with whole brain irradiation and systemic chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin; Pharmacia, Dublin, OH, USA) and vincristine. After completion of radiation therapy and 1 course of chemotherapy, there was no radiographic evidence of metastatic lesions, nor macroscopic or histologic evidence of the primary cervical lesion.     

Histiocytes in vaginal smears: As prognostic parameter in carcinoma of the uterine cervix

Pretreatment vaginal smears of 251 patients with carcinoma of the cervix were counted for the percentage of histiocyte count in relation to benign squamous epithelial cells. No correlation was found between the percentage of histiocyte count and the age of the patient, clinical stage, cell type of squamous cell carcinoma, and clinical radiation response. Also a high histiocyte count is found to be unrelated to 5-year survival, recurrence, metastasis, or death of these patients. The present study indicates that the histiocyte number appears to have no relationship with immediate or remote prognosis in patients with carcinoma of cervix uteri.     

Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies

Squamous cell carcinomas account for about 80% of cancers of the uterine cervix, and the majority of the remainder are adenocarcinomas. There is limited evidence on the extent to which these histological types share a common etiology. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 8,097 women with invasive squamous cell carcinoma, 1,374 women with invasive adenocarcinoma and 26,445 women without cervical cancer (controls) from 12 epidemiological studies. Compared to controls, the relative risk of each histological type of invasive cervical cancer was increased with increasing number of sexual partners, younger age at first intercourse, increasing parity, younger age at first full-term pregnancy and increasing duration of oral contraceptive use. Current smoking was associated with a significantly increased risk of squamous cell carcinoma (RR = 1.50, 95% CI: 1.35-1.66) but not of adenocarcinoma (RR = 0.86 (0.70-1.05)), and the difference between the two histological types was statistically significant (case-case comparison p < 0.001). A history of screening (assessed as having had at least one previous nondiagnostic cervical smear) was associated with a reduced risk of both histological types, but the reduction was significantly greater for squamous cell carcinoma than for adenocarcinoma (RR = 0.46 (0.42-0.50) and 0.68 (0.56-0.82), respectively; case-case comparison, p = 0.002). A positive test for cervical high-risk HPV-DNA was a strong risk factor for each histological type, with 74% of squamous cell carcinomas and 78% of adenocarcinomas testing positive for HPV types 16 or 18. Squamous cell and adenocarcinoma of the cervix share most risk factors, with the exception of smoking.     

Risk of second cancers after the diagnosis of Merkel cell carcinoma in Scandinavia

Background:

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumour of the skin that has been associated with a new tumour virus, the MCC polyomavirus.

Methods:

To investigate whether MCC may have a shared aetiology with other cancers, we investigated the risk of second cancers after the diagnosis of MCC using the national cancer registries in Denmark, Norway and Sweden.

Results:

The overall cancer incidence was increased among patients diagnosed with MCC compared with the general population in these countries (79 secondary cancers total, Standardized Incidence Ratio (SIR) 1.38 (95% confidence interval (CI): 1.10–1.72); 49 secondary cancer in females, SIR 1.7 (95% CI: 1.29–2.25); 30 secondary cancers in males and SIR 1.05 (95% CI: 0.73-1.5)). There were significantly increased incidence ratios for non-melanoma skin cancers (34 secondary cancers, SIR 8.35 (95% CI: 5.97–11.68)), melanoma of skin (6 secondary cancers, SIR 4.29 (95% CI: 1.93–9.56)) and laryngeal cancer (2 secondary cancers, SIR 9.51 (95% CI: 2.38–38)). The SIRs for these three cancer sites were also elevated on restricting the follow-up to cancers occurring at least one year after MCC diagnosis.

Conclusions:

Patients diagnosed with MCC are at increased risk of a second cancer, particularly, other skin cancers. Conceivable explanations include the impact of increased surveillance of the skin and shared causative factors, for example, ultraviolet light exposure or MCC polyomavirus infection.     

紫杉醇联合奈达铂同期放化疗及巩固化疗治疗局部晚期宫颈癌

背景与目的：以顺铂（cisplatin，DDP）为基础的同期放化疗（concurrent chemoradiotherapv，CCRT）已成为局部晚期宫颈癌的标准治疗方案，但DDP毒性大，而且Ⅲ／Ⅳ。期宫颈癌的疗效并未提高，所以仍需寻找高效低毒的治疗方案。本研究旨为探宄紫杉醇（paclitaxel，TXL）联合奈达铂（nedaplatin，NDP）同期放化疗及巩固化疗治疗晚期宫颈癌的疗效以及不良反应。方法：2007年2月5日--2007年12月10曰共收治ⅡB-ⅢB期宫颈鳞癌初治患者29例，中位年龄48岁（35-64岁）。放疗采用盆腔外照射＋高剂量率腔内后装，B点剂量ⅡB期45Gy，Ⅲ期50Gy；A点剂量ⅡB期50Gy，Ⅲ期35Gy。同期化疗方案为TXL35mg／m^2＋NDP20mg／m^2，与放疗同时开始，每周1次，共6次；巩固化疗方案为：TXL135mg／m^2＋NDP60mg／m^2，CCRT完成后1个月开始，间隔3周，共4个疗程。结果：所有患者完成TCCRT，25例完成4个疗程巩固化疗，2例完成3个疗程，2例完成2个疗程。临床完全缓解（complete response，CR）为89．7％（95％CI，78．6％～100％），部分缓解（partial response，PR）10．3％（95％CI,0～21．4％）。在中位随访14个月后，无瘤生存率和总生存率分别为86．2％（95％CI,73．7％-98．7％），96．7％（95％CI，90．2％～100％）。1例ⅡB期PR者在治疗后8个月死于疾病进展。CCRT期间，3．6％个疗程发生3级WBC降低，0．6％个疗程发生3级腹泻；巩固化疗期间，8．7％个疗程发生3级WBC以及中性粒细胞降低。2例患者发生晚期3级直肠反应。结论：TXL＋NDP同期放化疗及巩固化疗治疗局部晚期宫颈鳞癌疗效高，耐受性好，值得进入Ⅲ期前瞻性随机研究。     

Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal

BACKGROUND:

The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity‐modulated radiation therapy (IMRT) or conventional radiotherapy (CRT).

METHODS:

Forty‐six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty‐five patients received 5‐fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow‐up was 26 months (CRT) and 32 months (IMRT). T3‐T4 stage (P = .18) and lymph node‐positive disease (P = .6) were similar between groups.

RESULTS:

The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3‐year overall survival (OS), locoregional control (LRC), and progression‐free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC.

CONCLUSIONS:

The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal. Cancer 2011. © 2011 American Cancer Society.     

早期宫颈癌术后预后与不同放疗方式的疗效及并发症比较

  目的  探讨影响早期宫颈癌患者术后预后的因素和不同放疗方式的疗效及并发症情况。  方法  回顾性分析2013年3月至9月100例新疆医科大学附属肿瘤医院及中山大学附属肿瘤医院收治的早期宫颈癌术后患者资料,并对影响患者预后的因素进行分析。根据放疗方式分为常规放疗（conventional radiotherapy,CRT）组50例,图像引导调强放疗（image guided radiotherapy,IGRT）组50例,并比较两组的疗效和并发症情况。  结果  100例患者3年生存率和无瘤生存率分别为89%和78%。CRT组和IGRT组3年生存率分别为78.57%和89.06%,两组比较差异具有统计学意义（P=0.034）;CRT组和IGRT组3年无瘤生存率分别为66.67%和87.36%,两组比较差异具有统计学意义（P=0.042）。CRT组和IGRT组早期、晚期并发症的比较差异具有统计学意义（P < 0.05）。单因素分析显示宫旁浸润、淋巴结转移、肿瘤浸润深度、淋巴脉管间隙浸润、神经侵犯、术后放疗与早期宫颈癌3年生存率相关（P < 0.05）。Cox多因素分析显示术后放疗方式、宫旁浸润、淋巴结转移、淋巴脉管间隙浸润、神经侵犯及肿瘤浸润深度均为影响早期宫颈癌患者预后的独立危险因素。  结论  早期宫颈癌的预后是多因素相互作用的结果,术后IGRT组3年生存率明显优于CRT组,放疗不良反应小,有益于患者的生存质量。      

Analysis of pelvic tumor control and impact on survival in carcinoma of the uterine cervix treated with radiation therapy alone

A total of 1054 patients with histologically confirmed invasive carcinoma of the uterine cervix were treated with radiation therapy alone between 1959 and 1982. All patients are available for a minimum of 3 years follow-up. Radiation therapy consisted of external irradiation to the whole pelvis (1000-2000 cGy) and parametria (for a total of 4000-6000 cGy) combined with two intracavitary radioactive source insertions (6000-7500 cGy to point A). Patients with Stage IIB, III, and IVA have been consistently treated with somewhat higher doses of external irradiation and intracavitary insertions. A small group of 54 patients with Stage IIB or IIIB had pelvic lymphadenectomy following the irradiation (1960-1964). There was a strong correlation between the tumor regression within 30 days from completion of radiotherapy and the incidence of pelvic recurrences or distant metastases for each of the anatomical stages. The 10-year survival rate for Stage IB was 76%, Stage IIA 60%, Stage IIB 45%, and Stage III 25%. Many of the deaths were due to intercurrent disease. Thus, the 10-year tumor-free survival was 80% for Stage IB, 60% for Stages IIA and IIB and 35% for Stage III. In Stage IB total doses of 6000 cGy or higher to point A resulted in 94% pelvic tumor control. In Stage IIA, the pelvic tumor control was 87% with doses of 6000 cGy to point A or higher. However, in Stage IIB the pelvic tumor control was 58% with doses below 6000 cGy, 78% with 6001-7500 cGy and 82% with higher doses. In Stage IIIB the pelvic tumor control was 42% with doses below 6000 cGy, 57% with 6001-7500 cGy and 68% with higher doses. Tumor control in the pelvis was correlated with the following 5 year survivals: Stage IB-95% (353 patients); Stage IIA-84% (116 patients); Stage IIB-84% (308 patients); Stage IIIB-74% (245 patients). The 5-year survival for patients that recurred in the pelvis was 30% for Stage IB, about 15% for Stages IIA-B and only 5% in Stage III. Patients with tumor control in the pelvis had a significantly lower incidence of distant metastases than patients who initially failed in the pelvis (9.3% vs. 58.6% in Stage IB, 21.6% vs 52.6% in Stage IIA, 19.8% vs 16.7% in Stage IIB, and 31.2% vs 50% in Stage III). In Stage IIB the figures were 19.8% and 16.7% because the initial pelvic recurrence was frequently concurrent with distant metastases.(ABSTRACT TRUNCATED AT 400 WORDS)     

Combined chemotherapy with twice-daily radiation therapy for inoperable squamous cell carcinoma of the thoracic esophagus

Background A study with chemotherapy and twice-a-day radiotherapy in patients with esophageal carcinoma was performed to evaluate toxicity and efficacy. Methods Thirty-seven patients with squamous cell carcinoma of the thoracic esophagus (1, stage IIB; 19, stage III; 17, stage IV) were enrolled. The chemotherapy regimen consisted of 3 cycles with cisplatin (70 mg/m² on day 1) and 96-hour continuous infusion 5-fluorouracil (700 mg/m² per day on days 1 to 4). Second and third cycles were initiated on day 22 and day 92, respectively. Radiotherapy was administered twice daily with concomitant boost technique over days 43 to 75, up to a total dose of 60 Gy. Daily fractions were 2.0 Gy for large fields and 1.0 Gy for small fields at 4- to 6-hour intervals. Results Twenty-nine patients (78%) received the full treatment. Of the 36 patients who started radiotherapy, 94% were able to complete the full course. Grade 3+toxicities observed were leukopenia 5%, anemia 14%, thrombocytopenia 5%, vomiting 14%, esophagitis 5%, pulmonary toxicity 5%, cardiac toxicity 3%, hepatic dysfunction 3%, and nephrotoxicity 3%. Of the 36 patients who started radiotherapy, 8 (22%) showed complete response, and 16 (44%) had partial response. The median survival time was 9 months, with a 1-year actuarial survival rate of 33%. Death was due to local-regional tumor manifestations in 18 patients. Conclusion The preliminary analysis showed that this treatment scheme was well tolerated with acceptable toxicity, but local-regional failure remains the principal cause of death. New treatment schemes such as concurrent use of chemotherapy with radiation warrant further investigation.     

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

Poor outcome of treatment in advanced cervix carcinoma has been shown to be associated with poor oxygenation of the primary tumour. Hypoxia may cause radiation resistance and promote lymph-node metastasis. The purpose of the study reported here was to investigate whether hypoxia-induced treatment failure in advanced cervix carcinoma is primarily a result of hypoxia-induced radiation resistance or the presence of hypoxia-induced lymph-node metastases at the start of treatment. Thirty-two patients with squamous cell carcinoma of the uterine cervix were included in the study. Radiation therapy was given with curative intent as combined external irradiation and endocavitary brachytherapy. The oxygenation status of the primary tumour was measured prior to treatment using the Eppendorf PO2 Histograph. Pelvic and para-aortal lymph-node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. The primary tumours of the patients with metastases (n = 18) were significantly more poorly oxygenated than those of the patients without metastases (n = 14). Multivariate Cox regression analyses involving biological and clinical parameters identified the tumour subvolume having PO2 values below 5 mmHg (HSV (pO2 < 5 mmHg) as the only significant, independent prognostic factor for locoregional control, disease-free survival and overall survival. The probabilities of locoregional control, disease-free survival and overall survival were significantly lower for the patients with HSV (PO2 < 5 mmHg) above the median value than for those with HSV (PO2 < 5 mmHg) below the median value. On the other hand, the outcome of treatment was not significantly different for the patients with metastases and the patients without metastases at the start of treatment, irrespective of clinical end-point. Consequently, treatment failure was primarily a result of hypoxia-induced radiation resistance rather than hypoxia-induced lymph-node metastasis, suggesting that novel treatment strategies aiming at improving tumour oxygenation or enhancing the radiation sensitivity of hypoxic tumour cells may prove beneficial in attempts to improve the radiation therapy of advanced cervix carcinoma.