Adjuvant Concurrent Chemoradiation Therapy Research Articles

Parametric Response Mapping of Co-Registered Ivim MRI and PET to Identify Radioresistant Sub-Volumes in Locally Advanced Cervical Carcinoma Undergoing CCRT

To investigate parametric response mapping (PRM) of co-registered positron emission tomography (PET) and intravoxel incoherent motion (IVIM) MRI in locally advanced cervical carcinoma patients to identify sub-volumes that may predict treatment response to adjuvant concurrent chemoradiation therapy (CCRT). Pre- and on-treatment (∼after four weeks of CCRT) diffusion weighted images (DWIs) MRI and pre-treatment PET were performed on 20 cervical cancer patients (median [range] age: 63 [41 to 85]; FIGO staging: 3 IIB, 1 IIIB, 10 IIIC1, 4 IIIC2, 2 IVA; histology: 11 squamous cell carcinoma, 4 endocervical adenocarcinoma; LN status: 4 negative, 16 positive). IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs to produce three-dimensional diffusion coefficient (D) and perfusion fraction (f). Three-dimensional IVIM D and f maps were co-registered to PET standardized uptake value (SUV) maps. Population means of PET SUV, IVIM D and f from pre-treatment scans were calculated to generate thresholds to identify low versus high metabolic (μSUV) regions, low versus high diffused (μD) regions as well as low versus high perfused (μf) regions, respectively. PRM maps were generated using voxel-wise joint histogram analysis to classify voxels within the tumor as highly metabolic and with low cellular density (SUV↑D↑), highly metabolic and with high cellular density (SUV↑D↓), metabolically inactive and with high cellular density (SUV↓D↓), or metabolically inactive and with low cellular density (SUV↓D↑) tissue based on the population mean thresholds. Similar PRM maps were generated using the joint histogram analysis with SUV and f. Summary statistics for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (ΔGTV) and pre-treatment imaging measurements. In tumors, on- versus pre-treatment tumor volume (p<.001) significantly decreased, while IVIM f (p = .002) and D (p = .03) significantly increased. Pre-treatment tumor volume (r = .45, p = .04) and PRM SUV↑D↓ (r = .65, p = .002) regions were positively related with ΔGTV, while pre-treatment IVIM D (r = -.64, p = .002), PRM SUV↓f↑ (r = -.52, p = .02) and PRM SUV↓D↑ (r = -.74, p<.001) regions were negatively related with ΔGTV. The latter PRM result suggests that larger regions of low cellular density (as represented by elevated D) + low metabolism result in a reduced change in tumor volume on-treatment, potentially representing a radioresistant sub-volume. PRM, generated from PET and IVIM MRI, was applied to patients with locally advanced cervical carcinoma and radioresistant sub-volumes were identified which may predict treatment response. The complementary information provided from PET and IVIM, combined using PRM, may assist in decision-making to individualize therapies, such as with image guided brachytherapy, to improve patient outcomes.

Human papilloma virus associated primary vaginal adenocarcinoma

Primary vaginal adenocarcinoma associated with human papillomavirus (HPV) infection is extremely rare. We report a case of primary adenocarcinoma of the vagina associated with human papilloma virus successfully treated with anterior pelvic exenteration and adjuvant concurrent chemoradiation therapy. A 51-year-old postmenopausal woman (gravida 1, para 1) presented with intermittent vaginal bleeding and pelvic pain. She was found to have a 5 × 5 cm necrotic tumor took up the vaginal. She had no previous history of antenatal exposure to diethylstilbestrol (DES). Pelvic magnetic resonance imaging (MRI) demonstrated a 4.8 × 6.0 cm mass in the vaginal canal, an 1.1 × 2.6 cm mass at the urinary bladder dome and a 1.1 cm irregular lymph node at the right external iliac chain with increased fluorodeoxyglucose (FDG) uptake from Fused whole-body positron emission tomography-computed tomography (PET-CT). Based on clinical investigations, the patient was diagnosed with a primary adenocarcinoma of vagina, staged International Fedestration of Gynecology and Obstetrics (FIGO) IVa. Anterior pelvic exenteration, simple vulvectomy, total vaginectomy, both pelvic lymph node dissection, and para-aortic lymph node dissection with ileal conduit urinary diversion (Bricker’s operation) was done. Histologically primary vaginal HPV type 16-associated adenocarcinoma was confirmed. Both obturator lymph node was positive for metastasis. Postoperatively, the patient received weekly cisplatin regimen administered with a dose of 40 mg/m2 on day 1 of external radiation therapy (RT), 1 to 4 hours before RT initiation. External beam pelvic RT dose prescription to the whole pelvis was 59.4 Gy in 33 fractions at the isocenter. But, after total dose of 43.2 Gy, patient complained severe bowel habit change and discontinued further treatment. The patient remains free from recurrence 8 months after initial surgery. In the lack of information and comparative analysis of management options for the more unusual and rare varieties of primary vaginal neoplasms in the literature, this suggests the possibility that surgical treatment may be preferentially selected on a case-by-case basis.

Prognostic Factors Associated with 5-Year Overall Survival in Cervical Cancer Patients Treated with Radical Hysterectomy Followed by Adjuvant Concurrent Chemoradiation Therapy at a Tertiary Care Center in Eastern Europe.

Background: This retrospective observational study aims to assess the 5-year overall survival and the prognostic significance of risk factors of patients who underwent radical hysterectomy followed by adjuvant concurrent chemoradiation therapy (CCRT) for FIGO stage IB1-IIB cervical cancer in a tertiary care center in Eastern Europe. Methods: From January 2010 to February 2019, 222 patients with stage IB1-IIB cervical cancer were treated with radical hysterectomy followed by adjuvant CCRT in our institution. The baseline information consisting of demographic and clinicopathologic data, treatment choices, recurrences, and outcome information was collected and examined. The survival rates were illustrated using Kaplan–Meier curves and prognosis analyses were accomplished using Cox multivariate analyses. Results: The 222 participants had a mean age of 51.2 years (28–76). The median follow-up time was 65.5 months (3–128). Tumor characteristics revealed FIGO stage (IB1 2.3%, IB2 35.1%, IB3 16.7%, IIA1 9%, IIA2 8.6%, IIB 28.4%) and the most encountered histologic cell type was squamous cell carcinoma (80.06%) followed by adenocarcinoma (11.3%). At the time of examination, 157 patients (70.07%) were alive, of which 135 (61%) were alive free of disease and 22 (9%) were alive with disease. The multivariate Cox regression analysis acknowledged stage IIB, parametrial involvement, and the presence of lymph node metastases as independent prognostic risk factors, significantly worsening the oncologic outcomes influencing the survival with a P-value of 0.076, 0.0001, and 0.008, respectively. The 5-year overall survival was 69.9%. Conclusions: Altogether, the study enhances the significance of prognostic risk factors on the 5-year overall survival of patients who underwent radical hysterectomy followed by adjuvant CCRT for FIGO stages IB1-IIB cervical cancer, allowing comparisons with other regions.

Clinical Outcomes and the Role of Adjuvant Concurrent Chemoradiation Therapy in D2-resected LN-positive Young Patients (≤45 Years) With Gastric Cancer.

This study aimed to investigate the clinical outcomes and role of adjuvant concurrent chemo-radiation therapy (CCRT) compared to adjuvant chemotherapy alone in young patients with gastric cancer (GC) defined as those ≤45 years old versus older patients. Data were collected from December 2004 to January 2013 on patients with pathologically confirmed, regional lymph node metastasis of GC who had undergone curative D2 resection. During the study period, a total of 1,633 patients (341 young and 1,292 older GC) was investigated. Female sex and diffuse type were more frequent among the younger group, but, lymphatic and venous invasion were less frequent. During the follow-up, there was no difference in recurrence-free survival (RFS; p=0.81), but RFS was significantly higher in young patients with stage II GC (p=0.02). In the younger group, adjusted RFS did not differ according to adjuvant treatment (p=0.98), but the RFS was significantly higher in the older group treated with CCRT than with chemotherapy alone after adjustment for significant prognostic factors (p=0.008). Although young patients with GC had different characteristics, their clinical outcomes did not differ from those of the older patients. In the present study performed in curatively D2-resected GC, there was no benefit from adjuvant CCRT over chemotherapy alone among young patients, unlike among the older patients.

Colloid Adenocarcinoma of the Lung: CT and PET/CT Findings in Seven Patients.

We aimed to assess CT and 18F-FDG PET/CT findings of colloid adenocarcinoma of the lung in seven patients. From 2010 to 2017, seven patients with surgically proven colloid adenocarcinoma of the lung were identified. CT (both enhanced and unenhanced) and PET/CT findings were analyzed, and the imaging features were compared with histopathologic reports. Clinical and demographic features were also analyzed. In all cases except one, tumors showed low attenuation on unenhanced CT scans, ranging in attenuation from -16.5 to 20.7 HU (median, 9.2 HU). After contrast medium injection, enhancement was scant, so net enhancement ranged from 0.4 to 29.0 HU (median, 4.1 HU). All tumors had a lobulated contour. Stippled calcifications within the tumor were seen in one patient. The maximum standardized uptake value of tumors on PET/CT ranged from 1.5 to 4.5 (median, 3.5). In six of seven patients, FDG accumulation was seen in the tumor walls (n = 3, curvilinear uptake) or in both the tumor walls and tumor septa (n = 3, crisscross uptake). Six patients were alive without recurrence after a median follow-up period of 2.3 years (range, 2 months to 5 years). In one patient, who was alive at follow-up 4 years after imaging and had received adjuvant concurrent chemoradiation therapy after lobectomy, recurrent disease was detected 6 months after completion of the therapy. On CT, pulmonary colloid adenocarcinomas present as lobulated homogeneously low-attenuation tumors. At PET, curvilinear or crisscross FDG uptake is seen within the tumor where tumor cells are lining the walls or septal structures.

Adjuvant concurrent chemoradiation therapy in patients with microscopic residual tumor after curative resection for extrahepatic cholangiocarcinoma.

We investigated the role of adjuvant concurrent chemoradiation therapy (CCRT) in patients with a microscopically positive resection margin (R1) after curative resection for extrahepatic cholangiocarcinoma (EHCC). A total of 84 patients treated with curative resection for EHCC were included. Fifty-two patients with negative resection margins did not receive any adjuvant treatments (R0+S group). The remaining 32 patients with microscopically positive resection margins received either adjuvant CCRT (R1+CCRT group, n=19) or adjuvant radiation therapy (RT) alone (R1+RT group, n=13). During the median follow-up period of 26months, the 2-year locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival rates (OS) were: 81.8, 62.6, and 61.5% for R0+S group; 71.8, 57.8, and 57.9% for R1+CCRT group; and 16.8, 9.6, and 15.4% for R1+RT group, respectively. Multivariate analysis revealed that the R1+CCRT group did not show any significant difference in survival rates compared with the R0+S group. The R1+RT group had lower LRRFS [hazard ratio (HR) 3.008; p=0.044], DFS (HR 2.364; p=0.022), and OS (HR 2.417; p=0.011) when compared with the R0+S and R1+CCRT group. A lack of significant survival difference between R0+S group and R1+CCRT group suggests that adjuvant CCRT ameliorates the negative effect of microscopic positive resection margin. In contrast, adjuvant RT alone is appeared to be inadequate for controlling microscopically residual tumor.

Fructose‑1,6‑bisphosphatase‑1 decrease may promote carcinogenesis and chemoresistance in cervical cancer.

Fructose-1,6-bisphosphatase-1 (FBP1), a gluconeogenesis rate-limiting enzyme expressed in various tissues, is important in the carcinogenesis of various cancers. To evaluate the association of FBP1 expression and carcinogenesis and chemoresistance in cervical cancer, the present study analyzed 140patients of squamous cell carcinoma of cervical cancer (CSCC) who had adjuvant concurrent chemoradiation therapy following radical surgery. By detecting FBP1 protein expression in paraffin‑embedded tumor tissues through immunohistochemistry, it was observed that 50% of the cases had a low expression of FBP1, which was associated with a shorter overall survival time (P=0.011). In addition, FBP1 mRNA level was downregulated in tumor tissues, compared with cervical normal tissues. Among the tumor‑associated prognostic factors, loss of FBP1 expression (χ2‑test, P=0.025) was significantly associated with the tumor recurrence and greater tumor stage of cervical cancer patients (2‑test, P<0.0001). In 3‑(4,5)‑dimethylthiahiazo(‑z‑y1)-3,5-diphenytetrazoliumromide (MTT) assay of primary tumor cells, the median invitro inhibition rate of cisplatin, carboplatin, nedaplatin, and oxaliplatin was 62, 47, 58 and 52%, respectively. Although there was no significant association between FBP1 expression and invitro tumor inhibition rates of primary tumor cells, overexpression of FBP1 markedly suppressed carcinogenesis and restored the chemosensitivity to cisplatin in cervical cancer cell lines of HeLa and CaSki. Overall, decreased levels of FBP1 may be used as a predictor for poor prognosis of cervical cancer patients, however the mechanism requires further investigation.

Transitional cell carcinoma involving graft kidney in a kidney transplant recipient: a case report

BackgroundKidney transplantation (KT) is the treatment option for patients with end stage renal disease (ESRD) to prolong survival and improve quality of life. Although the use of potent immunosuppressive agents increases graft survival in kidney transplantation recipients (KTRs), it may lead to the development of malignancy, including transitional cell carcinoma (TCC). TCC developing in the pelvis of graft kidney is very rare in KTRs.Case PresentationA 40-year-old male visited hospital with complaints of nausea, vomiting and gross hematuria. Eleven years ago, he was diagnosed ESRD of unknown origin, and received a living related KT from his father 1 year later. Radiologic findings showed a huge polypoid mass in the pelvis of graft kidney with pelvo-calyceal dilation and a 3.3 cm-sized nodule in aortocaval chain and a 2.5 cm-sized nodule in right iliac chain as TCC stage IV. Sonography-guided percutaneous needle biopsy of pelvis mass in the graft kidney revealed a low grade urothelial cell carcinoma. Radical graft nephroureterectomy was performed and histopathological diagnosis confirmed as a low grade urothelial carcinoma of graft pelvis and ureter lumen, which invaded to perirenal fat and renal parenchyma with lymphovascular presence (T3Nx). The patient started with adjuvant concurrent chemo-radiation therapy and returned to regular hemodialysis.ConclusionsWe report a rare case of TCC in the pelvis of graft kidney with already advanced disease at diagnosis in a young KTR. For the early diagnosis of TCC in KTRs, exposure history to Chinese herb or analgesics should be investigated before KT and high risk population in KTRs should be tightly performed regular postoperative surveillance for TCC and considered of less calcineurin inhibitor-based immunosuppressant protocol.

Predictors of Positive Margins After Definitive Resection for Gastric Adenocarcinoma and Impact of Adjuvant Therapies

Positivemargins after definitive resection in gastric adenocarcinoma are associated with inferior outcomes. There are few randomized data to guide optimal adjuvant therapy after positive margins. Using the National Cancer Database, we identified 24,619 nonmetastatic gastric adenocarcinoma patients who received diagnoses from 2004 to 2013 and underwent definitive resection to analyze for predictors of positive surgical margins. Of these patients, 2754 had positive margins (11.2%). Multivariate prevalence ratios were used to determine predictors. Survival analyses were performed with a Cox proportional hazards model by use of several methods of propensity score analysis. Increasing T and/or N category, high grade, and lymphovascular invasion predicted higher rates of positive margins. Asian race, treatment at an academic center, and robotic surgery predicted lower rates of positive margins. Among positive-margin patients with adjuvant treatment (n=1021), with a median follow-up period of 55months, age, comorbidity score, nodal disease, and T4 disease predicted for worse overall survival (OS). Treatment at an academic center was associated with improved OS. Use of adjuvant concurrent chemoradiation therapy (CCRT) was associated with higher OS compared with chemotherapy alone after positive margins (hazard ratio, 0.72; 95% confidence interval, 0.58-0.91; P=.005) after propensity matching adjusting for predictors of OS. The 2-year and 3-year OS for positive-margin patients with chemotherapy alone was 43% and 29%, respectively, compared with 53% and 38%, respectively, with adjuvant CCRT. The log-rank P value for survival was .0015. Stage, race, treatment center, and surgery approach predict for margin status after resection. Adjuvant CCRT after positive margins is associated with improved OS after accounting for available clinical variables.

A retrospective comparison of outcome in IB2 and IIA cervical cancer patients treated with primary concurrent chemoradiation versus radical hysterectomy with or without tailored adjuvant therapy.

ObjectiveThe aim of our study is to compare the overall survival (OS), progression-free survival (PFS), and treatment-related morbidities between primary concurrent chemoradiation therapy (CCRT) vs. radical hysterectomy (RH) with or without tailored adjuvant therapy in patients with stages IB2 and IIA cervical cancer.MethodsThis was a retrospective study of 113 patients with IB2 or IIA cervical cancer treated with either primary CCRT (n=49) or RH (n=64) with or without tailored adjuvant therapy between 2002 and 2011 at Keimyung University Dongsan Medical Center. Patients in RH group was divided into those undergoing surgery alone (n=26) and those undergoing surgery with adjuvant therapy (n=38).ResultsThe median follow up period was 66 months. The 5-year OS by treatment modality was 88.7% for the 64 patients in the RH group and 72.8% for 49 patients in the CCRT group (P=0.044). The 5-year PFS was 82.3% and 65.6% after RH group and CCRT group (P=0.048), respectively. Grade 3–4 complication was less frequent after RH alone (7.7%) than RH with adjuvant therapy (34.2%) or CCRT group (28.6%) (P=0.047).ConclusionThe RH group seems to be superior to the CCRT group in oncologic outcomes. However, considering the selection bias including tumor size, lymph node meta, and parametrial invasion in pretreatment magnetic resonance imaging, both treatment modalities are reasonable and feasible in cervical cancer IB2 and IIA. It is important to choose the appropriate treatment modality considering the age and general condition of the patient. Randomized controlled study is needed to confirm the result of our study and determine the optimal treatment.

Treatment outcomes in patients with FIGO stage IB–IIA cervical cancer and a focally disrupted cervical stromal ring on magnetic resonance imaging: A propensity score matching study

ObjectiveThe aim of this study was to compare treatment outcomes of primary concurrent chemoradiation therapy (CCRT) versus radical hysterectomy (RH) followed by adjuvant RT or CCRT in patients with FIGO stage IB–IIA cervical cancer with focal disruption of the cervical stromal ring on magnetic resonance imaging (MRI). MethodsWe retrospectively analyzed the clinicopathological data of 156 patients with FIGO stage IB–IIA cervical cancer showing a focal disruption of the stromal ring on MRI between March 2000 and March 2015. Treatment outcomes were compared between the RT-based (n=54) group and RH-based group (n=54) after propensity score matching of each of the patients using a logistic regression model, including age, tumor size on MRI, pelvic lymph node enlargement on MRI, and histology. ResultsFive-year disease-free survival rate was 83.1% for the RT-based group and 77.4% for the RH-based group (p=0.228). Five-year disease-specific survival rate was 84.3% for the RT-based group and 83.5% for the RH-based group (p=0.434). Incidence rates of late grade 3 genitourinary adverse reactions (14.8% vs. 0.0%, p=0.006) were significantly higher in the RH-based group than those in the RT-based group. ConclusionsPrimary CCRT might be the preferred treatment for FIGO stage IB–IIA cervical cancer patients with focal disruption of cervical stromal ring on MRI given that no difference in patient's survival was found, but higher incidence of treatment-related complications was observed in the RH-based group. Also, primary radical surgery should be done more cautiously in these patients.

Radiographic extracapsular extension (ECE) and treatment outcomes in locally advanced oropharyngeal carcinoma (OPC).

6019 Background: Pathologic ECE (pECE) of tumor through lymph node (LN) is a poor prognosticator for OPC and typically diagnosed upon surgical LN removal. At our institution, experienced radiologists routinely identify ECE on pretreatment CT. The prognostic value of radiographic ECE (rECE) is less clear and may prove clinically useful. In this study, we evaluate rECE as an independent prognosticator in OPC. Methods: Retrospective review of 185 patients with locally advanced OPC treated in our department from 2006-2012. 109 patients had accessible pretreatment CT reports clearly stating the presence or absence of rECE. Patients were treated with definitive concurrent chemoradiation therapy (CCRT) (30%), induction chemo then CCRT (47%), or surgery with adjuvant CCRT (14%) or RT (9%). Kaplan-Meier survival analysis compared these cohorts for locoregional control (LRC), distant control (DC), and progression-free (PFS) and overall survival (OS); log-rank tests were performed for significance. Multivariate analysis was conducted via cox-regression. Results: Median follow-up of the 109 patients was 31 months (range: 1-80 months). 61 patients had rECE(+) and 48 had rECE(-) scans. There was no significant difference between the cohorts in terms of median age, stage, treatment type, smoking history, or tumor HPV status. There was a difference in nodal stage with 83% of rECE(+) patients having N2-3 disease versus 67% of rECE(-) patients (p=0.02). On univariate analysis, there were differences between the rECE(-) versus rECE(+) cohorts in OS (4yr: 92% vs 72%, p=0.01), PFS (4yr: 92% vs 62%, p=0.002), and DC (4yr: 98% vs 76%, p=0.006), with no difference in LRC (4yr: 95% vs 91%, p=0.35). On multivariate analysis factoring in age, smoking history, stage, and treatment type, rECE presence was a negative predictor of OS (hazard ratio, 0.26; 95% CI, 0.07 to 0.95) and PFS (hazard ratio, 0.23; 95% CI, 0.06 to 0.81), with DC approaching significance (hazard ratio, 0.13; 95% CI, 0.02 to 1.05). Conclusions: While pECE is an established risk factor for locally advanced OPC, this study suggests that rECE may be an independent poor prognosticator of PFS, OS and DC with potential importance in guiding clinical management.

DNA polymerase ζ as a potential biomarker of chemoradiation resistance and poor prognosis for cervical cancer

DNA Polymerase ζ (Polζ), an error-prone DNA polymerase involved in translesion DNA synthesis, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of several cancers. To evaluate the association of Polζ with chemoradiation resistance and prognosis in cervical cancer, we enrolled 123 patients with squamous cell carcinoma of cervical cancer, who had adjuvant concurrent chemoradiation therapy after radical surgery treated at Fudan University Shanghai Cancer Center between 2008 and 2009, and tested their in vitro tumor inhibition rates using the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide method and Polζ protein expression in paraffin-embedded tissues using immunohistochemistry. We found that the Polζ-positive expression was detected in 22 % of the cases. The median in vitro inhibition rate of tumor cell growth by cisplatin, carboplatin, nedaplatin, and oxaliplatin was 80, 37, 78, and 51 %, respectively. Among the tumor-related variables, FIGO stage, tumor grade, and Polζ protein expression (adjusted HR 6.7, 4.2 and 6.7; 95 % CI 1.7-26.3, 1.0-17.3 and 1.8-25.4; P = 0.007, 0.046 and 0.005, respectively) were found to be significant predictors for recurrence. Kaplan-Meier survival estimates showed that the patients with more advanced stage (IIB) or Polζ-positive expression had a significantly shorter progression-free survival. Polζ-positive expression was significantly associated with depth of cervical stromal invasion (P = 0.012). However, the association between Polζ expression and in vitro tumor inhibition rates was not significant. Taken together, Polζ expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration.

A Case of Actinomycosis in a Patient Treated with Chemotherapy Due to Recurrent Pancreatic Cancer

A 46-year-old male patient with recurrent pancreatic cancer was admitted with a newly developed abdominal mass. The patient had a history of diabetes and underwent total pancreatectomy with partial gastrectomy followed by adjuvant concurrent chemoradiation therapy and palliative chemotherapy. Abdominal CT scan during palliative chemotherapy showed an abdominal wall mass. We performed excisional biopsy for diagnosis. Histological examination revealed actinomycosis of the abdominal wall. The patient was treated with penicillin G. This case showed that actinomycosis can occur in a patient receiving chemotherapy and may mimic cancer recurrence. Therefore, when evaluating a newly developed abdominal mass in patients who are receiving chemotherapy or radiotherapy, the probability of actinomycotic infection must also be considered, especially in patients with a history of surgery and diabetes mellitus. (Korean J Med 2013;85:401-405)

P2.27 DNA Polymerase ζ as a Prognostic Biomarker for Cervical Carcinoma

ABSTRACT Objective DNA Polymerase ζ (Polζ), an error-prone DNA polymerase involved in translesion DNA synthesis, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of several cancers. The association of Polζ with chemoradiation resistance and prognosis of cervical cancer patients needs exploration. Methods One hundred and twenty three patients with squamous cell carcinoma of cervical cancer (CSCC) who had adjuvant concurrent chemoradiation therapy after radical surgery treated at Fudan University Shanghai Cancer Center between 2008 and 2009 were enrolled in this study. We tested their in vitro platinum resistance using the MTT method and the expression of Polζ in paraffin-embedded tissue samples using immunohistochemistry. Results Expression of Polζ was detected in 22 % (25/116) of the specimens. The median in vitro inhibition rate of tumor cell growth by cisplatin, carboplatin, nedaplatin and oxaliplatin was 80 %, 37 %, 78 % and 51 %, respectively. Among the tumor-related variables, FIGO stage (adjusted HR 6·7, 95 % CI 1·7-26·4, P = 0·007) and the Polζ protein expression (adjusted HR 6·5, 95 % CI 1·7-25·0, P = 0·006) were found to be significant predictors of progression-free survival (PFS) for the multivariate analysis. Kaplan-Meier survival estimates showed that the patients with high stage and Polζ-positive expression had a significantly shorter PFS. However, the association between Polζ expression and in vitro platinum-inhibition rates was not significant. Conclusion Polζ expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the patients. The mechanism deserves further exploration.

Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: Which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study

BackgroundThere is currently no standard adjuvant therapy for patients with curatively resected extrahepatic biliary tract cancer (EHBTC). The aim of this study was to analyze the clinical features and outcomes between patients undergoing adjuvant concurrent chemoradiation therapy (CCRT) alone and those undergoing CCRT followed by adjuvant chemotherapy after curative resection.MethodsWe included 120 patients with EHBTC who underwent radical resection and then received adjuvant CCRT with or without further adjuvant chemotherapy between 2000 and 2006 at Seoul National University Hospital.ResultsOut of 120 patients, 30 received CCRT alone, and 90 received CCRT followed by adjuvant chemotherapy. Baseline characteristics were comparable between the two groups. Three-year disease-free survival (DFS) rates for CCRT alone and CCRT followed by adjuvant chemotherapy were 26.6% and 45.2% (p = 0.04), respectively, and 3-year overall survival (OS) rates were 30.8% and 62.6% (p < 0.01), respectively. CCRT followed by adjuvant chemotherapy showed longer survival than did CCRT alone, especially in R1 resection (microscopically positive margins) or negative lymph node.ConclusionAdjuvant CCRT followed by adjuvant chemotherapy prolonged DFS and OS, compared with CCRT alone in patients with curatively resected EHBTC. Adjuvant chemotherapy deserves to consider after adjuvant CCRT. In the future, a randomized prospective study will be needed, with the objective of investigating the role of adjuvant chemotherapy.

Differing prognosis of cervical cancer patients with high risk of treatment failure after radical hysterectomy: To the editor

gested that there was a subgroup of patients with increased risk of treatment failure after adjuvant concurrent chemoradiation therapy (CCRT) within high-risk group of patients with early-stage cervical cancer. And, they advocated new strategies, such as consolidation chemotherapy after CCRT, in these very high-risk patients. This study may be informative in that it proposed the selection criteria for more aggressive therapy including consolidation chemotherapy among high-risk cervical cancer patients. However, there are some limitations to be overcome in this study. First, the criteria of dividing patients into two groups were not supported sufficiently. In the present study, high-risk patients who were candidates for adjuvant CCRT were arbitrarily divided into two groups; group A with negative parametrium, negative resection margins, and unilateral pelvic lymph node metastasis (involved lymph nodes ≤ 2), and group B with either bilateral pelvic lymph node involvement or more than 2 lymph node involvement or positive parametrium with lymph node involvement. The selection criteria were based on the results of previous retrospective studies identifying risk factors for recurrence in early-stage cervical cancer after radical hysterectomy and/or postoperative radiation therapy. 2-4 These include number of positive lymph nodes (2 or more in most studies), parametrial invasion, tumor size, lymphovascular tumor emboli, and histologic types. Among these, the number of positive lymph nodes, bilaterality of lymph node involvement, and parametrial involvement were selected in this study. Even though a significant difference in survival between the two groups was demonstrated, assessment of potential risk factors, including stage, invasion depth of cervix, and above mentioned variables, for correlation with treatment failure after CCRT using univariate/multivariate analysis is required before developing the selection criteria. Secondly, there has not been any definite evidence of survival benefit of consolidation chemotherapy after adjuvant CCRT so far. There has been only one prospective study, which showed no survival benefit of consolidation chemotherapy after adjuvant CCRT. 5 However, there have been several studies suggesting that the number of chemotherapy cycles may affect survival. 6,7 Recently, a phase III randomized study of CCRT with or without adjuvant chemotherapy in high-risk patients with early-stage cervical carcinoma following radical hysterectomy is under development (RTOG-0724). We have to wait for the results of this prospective study and other phase II studies to validate the hypothesis of this study, and to determine which subgroup of patients with early-stage cervical cancer can benefit from more aggressive therapy.

Feasibility and effectiveness of postoperative adjuvant concurrent chemoradiation therapy in Japanese patients with high-risk early-stage cancer of the uterine cervix

This study was undertaken to evaluate the feasibility and effectiveness of postoperative concurrent chemoradiation (CCRT) in patients with high-risk early-stage cervical cancer who were treated by radical hysterectomy and pelvic lymphadenectomy. From July 2001 to September 2005, CCRT was performed in 37 patients who had undergone radical hysterectomy with pelvic lymph node dissection at Nagoya University Hospital. Adjuvant chemotherapy consisted of cisplatin (70 mg/m(2) on day 1) and 5-fluorouracil (5-FU; 700 mg/m(2) per day on days 1-4) every 4 weeks for a total of three cycles. Pelvic radiotherapy was started concurrently with the first cycle of chemotherapy. The radiation dose was 45 Gy in 25 fractions. A nonrandomized control group of 52 patients who had undergone radiation therapy alone after radical hysterectomy between 1991 and 2000 served for historical comparison. In the CCRT group, the incidences of grade 3/4 toxicities were 24.3% for neutropenia, 8.1% for nausea and vomiting, and 18.9% for diarrhea. The 5-year progression-free survival (PFS) rates in the CCRT group and control group were 89.2% and 69.2%, respectively (P = 0.0392). This study showed that adjuvant CCRT with cisplatin and 5-FU could be safely performed and improved the prognosis in Japanese patients with high-risk early-stage cervical cancer after radical hysterectomy.

Adjuvant CCRT for locally advanced rectal cancer: Uracil-tegafur? Or intravenous fluorouracil?

13582 Background: This prospective, nonrandomized study was conducted to compare the efficacy and toxicity of postoperative concurrent chemoradiation therapy (CCRT) using daily oral uracil-tegafur plus leucovorin (UFUR/LV) vs. weekly intravenous fluorouracil plus leucovorin (5-FU/LV) in patients with locally advanced rectal cancer. Methods: From November 1996 through December 2004, 30 patients with stage II or III rectal cancer were enrolled. Seventeen received oral UFUR/LV regiment and thirteen with intravenous 5-FU/LV regiment during CCRT. A weekly infusion of 400 to 450 mg/m2 of 5-FU plus a bolus injection of 80 to 100 mg/m2 of LV and 250 to 300 mg/m2/d of oral UFUR plus 30 to 45 mg /m2/d of oral LV were given separately during RT and for an additional 42 weeks thereafter. Forty-five Gy of whole-pelvis irradiation was followed by a local boost of 5.4 to 14.4 Gy to the tumor bed delivered in 33 fractions. Analytical method was Kaplan-Meier method. Results: Mean survival in the UFUR/LV group was 36 months compare with 30 months in the 5-FU/LV group. The 2-year OS, DFS and LCR were 68.1% vs. 65.8%, 54.9% vs. 50.4%, and 79.4% vs. 83.9%, (p &gt; 0.05), respectively. There were no treatment-related deaths and grade 4 toxicity in both groups. Grade 3 of dermatitis, gastrointestinal, and hematologic toxicity was noted in the 5-FU/LV group. Conclusions: Postoperative CCRT with oral UFUR/LV in locally advanced rectal cancer provides an alternative way for those who have difficulty with an intravenous regimen due to it was more tolerable and less toxicity and has similar survival rate. No significant financial relationships to disclose.