3-year Locoregional Failure Research Articles

Pre-treatment magnetic resonance imaging in anal cancer: large-scale evaluation of mrT, mrN and novel staging parameters

BackgroundIn patients with squamous cell carcinoma of the anus (SCCA), magnetic resonance (MR) imaging is recommended for pre-treatment staging prior to chemo-radiotherapy (CRT), but large-scale evaluation of its staging performance is lacking.MethodsWe re-characterised pre-treatment MRs from 228 patients with non-metastatic SCCA treated consecutively by CRT (2006–2015) at one UK cancer centre. We derived TN staging from tumour size (mrTr) and nodal involvement (mrN), and additionally characterised novel beyond TN features such as extramural vascular invasion (mrEMVI) and tumour signal heterogeneity (mrTSH). Primary outcomes were 5-year overall survival (OS) and 3-year loco-regional failure (LRF). Time-to-event analyses used Kaplan-Meier estimates; Hazard Ratios (HRs) with confidence intervals (CIs) were derived from Cox models.ResultsWith a median follow up of 60.9 months, 5-year OS was 74%. Poor OS was associated with increasing mrT (HR: 1.12 per cm [95% CI: 1.07–1.33]), nodal positivity (HR 2.08 [95% CI 1.23–3.52]) and mrEMVI (HR 3.66 [95% CI: 1.88–7.41]). 3-year LRF rate was 16.5%. Increased LRF was associated with increasing mrT (HR: 1.43 per cm [95% CI: 1.26–1.63]), nodal positivity (HR 2.70 [95% CI 1.39–5.24]) and mrTSH (HR 2.66 [95% CI 1.29–5.48]).ConclusionsIn SCCA, the study demonstrates that mrT and mrN stages are prognostic, while mrEMVI and mrTSH may be novel prognostic factors.

Abstract 961: Detection of minimal residual disease in lymph predicts recurrence in HPV-negative head and neck cancer patients

Abstract Background: Locoregional cancer relapse remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC), particularly for HPV-negative patients whose 2-year locoregional failure rate is up to 50%. There is unmet need for an accurate diagnostic test that predicts risk of recurrence prior to adjuvant therapy selection. We present a novel proximal assay for minimal residual disease (MRD) profiled in lymphatic exudate collected via surgical drains (“lymph”). Methods: Lymph, plasma, and blood were collected from 46 HPV-negative HNSCC patients postoperatively at 24 hours along with resected tumor. Cell-free DNA was extracted from lymph and plasma and sequenced using the TruSeq Oncology 500 panel to a depth of >100 million reads. Somatic mutations were identified by exome sequencing (200x) tumor and blood. Five patients had <2 mutations in tumor and were excluded. Two patients were censored due to lack of clinical data, yielding 18 patients with disease recurrence (REC) and 21 with no evidence of disease (NED) with >1 year of follow-up. Tumor-specific variants were force-called in lymph and plasma using a custom pipeline. Patients were considered MRD positive if the mean variant allele fraction (mVAF) was greater than 0.015% (the estimated limit of detection). The Kaplan-Meier (KM) estimator with log-rank test and Cox proportional-hazards model were used for survival analyses. Logistic regression model was performed with 5-fold cross-validation. Results: KM survival analyses showed lymph accurately predicts recurrence (sensitivity (SN) = 78%, specificity (SP) = 67%; p = 0.003, Hazard ratio (HR) = 4.7), while plasma was not significant (p = 0.92) at this postoperative timepoint. Performance was enhanced for locoregional relapse (SN = 92%, SP = 67%; p = 0.001, HR = 13.9. N=33). We also observed accurate recurrence prediction (SN = 83%, SP = 69%, p = 0.03, HR = 7.7) in the 19 N0 patients (node-negative by pathology). Lymph MRD outperformed individual pathology features (extranodal extension, perineural invasion, lymphovascular invasion, and nodal disease status) for recurrence prediction (HR = 3.4, 0.88, 2.5, 2.4, respectively). A logistic regression model combining lymph MRD with these 4 high-risk pathologic features showed superior performance over lymph alone or pathology alone (SN = 89%, SP = 67%; p = 0.0007, HR = 8.6). Conclusions: ctDNA analysis of lymph from surgical drains represents a novel proximal MRD approach in HPV-negative HNSCC. Postoperative lymph significantly outperforms plasma for prediction of recurrence, particularly in patients with locoregional relapse. Accurate MRD identification in patients with lower risk pathologic features suggests that lymph MRD testing has potential to augment traditional pathology and provide more personalized adjuvant treatment decision-making in patients with HPV-negative HNSCC. Citation Format: Wendy Winckler, Zhuosheng Gu, Damion Whitfield, Noah Earland, Adam Harmon, Megan Long, Peter Harris, Zhongping Xu, Ricardo Ramirez, Sophie Gerndt, Maciej Pacula, Marra S. Francis, Jose P. Zevallos, Aadel A. Chaudhuri. Detection of minimal residual disease in lymph predicts recurrence in HPV-negative head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 961.

Abstract PR09: Detection of minimal residual disease in post-surgical drain fluid can predict locoregional recurrence in HPV-negative head and neck cancer patients

Abstract Introduction: Locoregional cancer relapse remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC), particularly for HPV-negative patients whose 3-year locoregional failure rate is 32.5%. There is a major unmet need for an accurate diagnostic test that predicts risk of locoregional recurrence prior to adjuvant therapy selection. We present a novel proximal assay for minimal residual disease (MRD) profiled in lymphatic exudate collected via surgical drains (“lymph”). Methods: Lymph, plasma, and peripheral blood were collected from 22 HPV-negative HNSCC patients postoperatively at 24 hours along with resected tumor. Cell-free DNA was extracted from lymph and plasma and sequenced using the TruSeq Oncology 500 panel to a depth of >100 million reads. One plasma sample failed due to inadequate coverage. Two patients were censored due to lack of clinical data, yielding 9 patients with disease recurrence (REC) and 11 with no evidence of disease (NED) with >1 year of follow-up. Somatic mutations were identified from exome sequencing (200x) in tumor with matched blood. Tumor-specific variants were force-called in lymph and plasma using a custom bioinformatic pipeline. Mutation calls were filtered by a base-specific error model to eliminate artifacts. Student’s t-test was used for group comparisons. The Kaplan-Meier (KM) estimator with log-rank test and Cox proportional-hazards model were used for survival analyses. Results: ctDNA allelic fraction was 1.5x higher in lymph than in plasma (lymph = 0.11% ± 0.16%; plasma = 0.076% ± 0.12%. p = 0.018, N = 100 mutations). Significantly more mutations were detected in REC lymph compared to NED (p = 0.009), but not in plasma REC vs. NED (p = 0.16). We classified patients as positive (>1) or negative (£1) for detected mutations in each analyte and performed a KM survival analysis, showing lymph could accurately predict recurrence (sensitivity = 89%, specificity = 82%; p < 0.005) while plasma could not (sensitivity = 67%, specificity = 40%; p = 0.59). The hazard ratio in lymph was 12.52 (95% CI 1.54-101.61). We stratified REC patients by locoregional or locoregional + distant relapse and observed significantly more mutations detected in lymph (p = 0.01) from locoregional relapse while lymph and plasma performed similarly for locoregional + distant relapse (p = 1.0). We compared lymph MRD outcomes to extranodal extension (ENE), a high-risk pathologic feature. Lymph was concordant with ENE in 12/20 patients and identified an additional 6 ENE-negative relapse cases. Conclusion: Postoperative ctDNA analysis of lymph from surgical drains represents a novel MRD approach in HPV-negative HNSCC. Lymph significantly outperforms plasma for prediction of recurrence, particularly in patients with locoregional relapse. Accurate MRD identification in patients with lower risk pathologic features suggests that postoperative lymph MRD testing has the potential to significantly augment traditional pathology and provide more personalized adjuvant treatment decision-making in patients with HPV-negative HNSCC. Citation Format: Aadel A. Chaudhuri, Zhuosheng Gu, Damion Whitfield, Noah Earland, Adam Harmon, Megan Long, Peter Harris, Zhongping Xu, Ricardo Ramirez, Sophie Gerndt, Maciej Pacula, Marra S. Francis, Wendy Winckler, Jose P. Zevallos. Detection of minimal residual disease in post-surgical drain fluid can predict locoregional recurrence in HPV-negative head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR09.

Association of plasma tumor tissue modified viral HPV DNA (TTMV) with tumor burden, treatment type, and outcome: A translational analysis from NRG-HN002.

6006 Background: NRG-HN002 was a phase II trial that randomized patients with p16-positive oropharynx cancer to 60 Gy IMRT with concurrent cisplatin (IMRT-C) or 60 Gy accelerated IMRT. The protocol specified plasma collection at pretreatment (t0), intratreatment (20-28 Gy, t1), and 2 weeks to 1 month posttreatment (t2); at these timepoints, TTMV was assayed. A prespecified analysis evaluated: association of t0 TTMV to gross tumor volume (GTV) of primary and lymph nodes; t0-t1 decrease in TTMV; and association of t2 TTMV to treatment and outcome. Methods: TTMV was quantified as fragments/mL of plasma. If TTMV-HPV16 was not detected (<5 fragments/mL) or was a low value, the specimen was tested for TTMV-HPV18, -HPV31, -HPV33, and -HPV35. The distribution of t0 TTMV fragments was highly skewed, so these data were log-transformed; their correlation to GTV was measured by Pearson coefficient. Paired and two-sample t-tests were used to compare t0 and t1 log-transformed fragments within and between arms. Proportions of TTMV detection at t2 between arms were compared using Fisher’s exact test. Rates of undetectability and fragment clearance (≥94% reduction from t0) at t2 were estimated. The negative predictive value (NPV) was estimated for 2-year locoregional failure (LRF) and progression-free survival (PFS). Results: Of 306 eligible patients, 164 (53.6%) donated at least one specimen. The median collection time/RT dose was -2.6 days before RT (Q1-Q3, -4.0-0.0), at 24 Gy (22-28), and 25.5 days after RT end (18-31). The t0, t1, and t2 patient participation rates were 53.6%, 45.4%, and 42.5%. Zero TTMV fragments were detected in 10.4% at t0, 19.4% at t1, and 93.1% at t2. At t0, t1, and t2, 83.5%, 79.1%, and 6.2% had detectable TTMV; 78.0%, 73.4%, and 5.4% had TTMV-HPV16. In correlating GTV to t0 TTMV fragments, the Pearson coefficient was 0.30 (95% CI 0.15-0.44). In a linear model, T stage (p=0.01) and N stage (p=0.004) were positively associated with t0 TTMV fragments. On the IMRT-C arm, the t0-to-t1 mean change was -1.06 (p=0.0009), and for IMRT, it was -0.22 (p=0.35) (p=0.03 between arms). The t2 TTMV detectability rate was 3.3% for IMRT-C vs 8.7% for IMRT (p=0.28). The t2 TTMV undetectability rate was 93.8% and the fragment clearance rate was 95.4%. Two-year LRF and PFS were 6.2% and 91.4%. The NPV of t2 undetectability was 95.0% (95% CI 89.4-98.1) for 2-year LRF and 93.3% (95% CI 87.3-97.1) for 2-year PFS, and for fragment clearance was 94.3% and 92.7%. Conclusions: Feasibility of the TTMV-HPV assay in clinical trial specimens was established. About 10% of p16-positive patients had zero TTMV fragments at baseline. Among those with TTMV detectability, 6.6% had types other than TTMV-HPV16. T and N stage were positively associated with TTMV fragments. The IMRT-C arm achieved rapid TTMV undetectability unlike IMRT. The NPV of posttreatment undetectability was 93-95% for 2-year LRF and PFS.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy

AimsThe aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. Materials and methodsA retrospective review was conducted on patients with stages I–III pancreatic adenocarcinoma who underwent surgery at our institution (2005–2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. ResultsIn total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5–52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). ConclusionThis risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Increased rate of recurrence and high rate of salvage in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with adverse features treated with primary surgery without recommended adjuvant therapy.

Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged. Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates.

Patterns of Failure and the Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation.

This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT). In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4Gy (range 36-65Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-yearrecurrence-free survival (RFS), and 2-yearoverall survival (OS), and univariate predictors of LRF, RFS, and OSwere calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed. Of the 80 patients (median follow-up period, 30.5months; median OS, 33.9months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymphnode-positive, and 66.3% underwent margin-negative resection. For the entire cohort,2-year LRF was 23.8%, 2-yearRFSwas 43.7%, and 2-yearOS was62.1%. When patients with iCCA were excluded, the2-year LRF was22.6%, the 2-yearRFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greaterLRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications. The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yieldsignificant morbidity. Novel strategies to decrease the rates of LRF should be considered.

Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990\u20132014)

BackgroundWe evaluated oncological changes in patients with squamous cell carcinoma of the anus (SCCA) treated by chemoradiotherapy (CRT) from a large UK institute, to derive estimates of contemporary outcomes.MethodsWe performed a treatment-cohort analysis in 560 patients with non-metastatic SCCA treated with CRT over 25 years. The primary outcomes were 3-year loco-regional failure (LRF), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). We developed prediction models; and overlaid estimates on published results from historic trials.ResultsAge distributions, proportions by gender and cT stage remained stable over time. The median follow-up was 61 (IQR: 36–79) months. Comparing the first period (1990–1994) with the last period (2010–2014), 3-year LRF declined from 33 to 16% (Ptrends < 0.001); 5-year OS increased from 60% to 76% (Ptrends = 0.001); and 5-year CCS increased from 62% in to 80% (Ptrends = 0.001). For 2020, the models predicted a 3-year LRF of 14.7% (95% CIs: 0–31.3); 5-year OS of 74.7% (95% CIs: 54.6–94.9); and 5-year CSS of 85.7% (95% CIs: 75.3–96.0). Reported oncological outcomes from historic trials generally underestimated contemporary outcomes.ConclusionsCurrent and predicted rates for 3-year LRF and 5-year survivals are considerably improved compared with those in historic trials.

Could excision repair cross-complementing group-1 mRNA expression from peripheral blood lymphocytes predict locoregional failure with cisplatin chemoradiation for locally advanced laryngeal cancer?

The association of excision repair cross-complementing 1 mRNA (ERCC-1 mRNA) expression with the outcome has been reported with immunohistochemistry (IHC) using tumor tissue in head and neck cancer. We evaluated ERCC-1 mRNA expression by reverse transcription polymerase chain reaction (RT-PCR) from peripheral blood lymphocytes (PBLs) as bio-predictor of locoregional failure (LRF) to chemoradiation (CRT) for locally advanced laryngeal squamous cell cancer (LALSCC). A total of 107 male patients with LALSCC were enrolled in this prospective study. ERCC-1 mRNA expression by PBLs was determined by RT-PCR. Definitive CRT was delivered with 35mg/m2 weekly cisplatin. Response Evaluation Criteria in Solid Tumor 1.1 (RECIST 1.1) were used in evaluating treatment response. The primary objective was to assess LRF. The influence of patient characteristics, treatment response, weekly cisplatin cycles, ERCC mRNA expression was determined for LRF, progression-free survival (PFS) and overall survival (OS). A total of 98 patients completed definitive CRT. The median value of 2-ΔΔCT ERCC-1 mRNA expression was 3.9; based on which it was categorized as low and high. Correlation of ERCC-1 expression with treatment response was insignificant (P- .38). With a median follow-up of 33 months; 2-year LRF, PFS, and OS was 63.3%, 34.7% and 79.4%. The 2-year LRF, PFS and OS for low versus high expression were 53.1%versus 73.5% (P-value = 0.036), 44.9%versus 24.4% (P-value = 0.047) and 81.6%versus 77.2% (P-value = 0.33), respectively. In multivariate analysis, ERCC-1 expression, T-stage, N-stage and tumor subsite are predictive factors for LRF; T-stage and nodal recurrence for OS; stage and treatment response for PFS. LALSCC patient with ERCC-1 mRNA low expression was associated with lower LRF rate, and improved PFS.

Less Than Whole Uterus Irradiation for Locally Advanced Cervical Cancer Maintains Locoregional Control and Decreases Radiation Dose to Bowel

ObjectiveThis study aimed to evaluate whether our institutional standard of less-than-whole-uterus irradiation affects locoregional control in patients with locally advanced cervical cancer. Methods and MaterialsWe retrospectively reviewed 53 patients with stage IB to IVB cervical carcinoma who were treated with image guided intensity modulated radiation therapy and brachytherapy. The entire uterus was not included in the clinical target volume, as per our institutional standard. Dosimetric parameters were obtained, including positron emission tomography gross tumor volume (GTV), uterus volume excluding GTV, proportion of uterus included in the planning target volume (PTV; percentage), volume of overlap between uterus and prescription dose (cm3), minimum and mean dose to the uterus, and bowel V40 and D200cc. Local, regional, and distant failure and death were recorded. ResultsThe median proportion of the uterus included in the PTV was 66%. With a median follow-up of 44 months, no patient experienced isolated local recurrence, and 2-year locoregional failure was 10.9%. Positron emission tomography GTV correlated significantly with increased chance of any failure (P = .049; 95% confidence interval, 1.000-1.018). Compared with patients who had ≥90% of the uterus included in the PTV (n = 12), patients who had <90% (n = 41) of the uterus included in the PTV had significantly lower bowel V40 (P = .049) and D200cc (P = .006). ConclusionsLess-than-whole-uterus irradiation for locally advanced cervical cancer does not compromise locoregional control and reduces bowel V40 and D200cc. Further investigation is required to evaluate whether this reduction in bowel dose translates to a clinically significant reduction in bowel toxicity and whether modifications should be made to the recommended definitive cervix intensity modulated radiation therapy volumes.

Patterns of Failure and Need for Biliary Intervention among Patients with Biliary Tract Cancers Treated with Definitive Surgery and Adjuvant Chemoradiation

Adjuvant chemoradiation therapy (CRT) after surgical resection of biliary tract cancers (BTC) has been shown to improve patient outcomes. However, there are limited data regarding patterns of failure after adjuvant chemotherapy and CRT with modern treatment regimens. In this study, we sought to characterize patterns of failure and need for biliary intervention after adjuvant CRT for gallbladder carcinoma (GBC) and cholangiocarcinoma (CCA). We present a retrospective analysis of 80 patients with GBC (n=29), extrahepatic CCA (n=30), perihilar CCA (n=13), or intrahepatic CCA (n=8). All patients underwent curative-intent resection with adjuvant CRT at a single institution from 2007–2017. Median CRT dose was 50.4 Gy (range: 36–65 Gy), which was administered with concurrent 5-FU-based chemotherapy. All but two patients received adjuvant chemotherapy. Tumor genomic mutation profiling was available for 30 patients (38%). Kaplan-Meier method was used to calculate rates of overall survival (OS) and locoregional failure (LRF), and log rank method was used to compare groups. Biliary interventions included ERCP with and without biliary stenting and percutaneous biliary tube placement. Study variables included age, performance status, site of primary disease, margin status, stage, receipt of oncologic resection, lymph node (LN) positivity, presence of lymphovascular invasion (LVI), tumor differentiation, and KRAS and TP53 mutational status. The median follow-up time was 30.5 months, and the median OS was 35.0 months. Among the entire cohort, 34% had T1/T2 disease, 40% were LN positive, and 53% underwent margin-negative (R0) resection. The overall rates of LRF and OS at 2 years were 21% and 62%, respectively. LRF was the initial site of failure in 16/80 patients (20%), and 19 patients (24%) had any LRF. On univariate analysis, only LN positivity (p=0.02) was positively associated with LRF. Site of primary disease (GBC vs. CCA), stage, LVI, and tumor mutation profile were not associated with LRF. Margin status was also not associated with LRF (2-year LRF: 18% vs. 29% in R0 vs. margin-positive (R1) resections, respectively, p=0.76). Among all patients, 23 (29%) required subsequent biliary intervention. Biliary intervention was required in 63% (12/19) of patients with LRF, compared to 18% (11/61) of patients without LRF. Of the 12 patients with LRF who required biliary intervention, 4 (33%) went on to die from biliary complications. Despite adjuvant CRT, there are high rates of LRF among patients with BTC, including GBC. Lymph node positivity may increase the risk of LRF. R1 resection was not associated with higher rates of LRF, suggesting that CRT may partially mitigate the risk of LRF in this high-risk group. LRF results in high rates of subsequent biliary interventions and can yield significant morbidity. Novel strategies should be considered to further improve upon rates of LRF.

Concurrent Chemoradiotherapy With Cisplatin Versus Cetuximab for Squamous Cell Carcinoma of the Head and Neck

We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort. From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis. The median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP. With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.

Hypofractionated Conformal Radiotherapy in Combination with Chemotherapy in Limited Disease Small Cell Lung Cancer Patients

To evaluate the results of hypofractionated conformal radiotherapy (RT) in limited disease small cell lung cancer (LD-SCLC) patients, with particular interest in the value of "early" RT, i.e. given before the 3rd chemotherapy (CHT) cycle. Outcome of hypofractionated RT (42 Gy, 2.8 Gy/fraction, given over 19-21 days, using "concomitant boost" technique - elective volume [39 Gy, 2.6 Gy/fraction] and tumour volumes treated during the same fraction) combined with CHT in 100 consecutive LD-SCLC patients, was retrospectively assessed. The outcomes were compared with a previously published series of 117 LD-SCLC patients treated in the same institution with hyperfractionated or conventionally fractionated RT. Forty-two patients (42%) received "early" RT. Grade 3 NCI CTC acute oesophageal toxicity appeared in 5% of patients. There were three treatment-related deaths. Three-year overall survival (OS) rate was 39.4%, median - 24 months in the examined group vs. 26.0%, and 18 months in historical control, P = 0.02. Three-year OS for 78 patients with completed CHT was 42.2%, median - 28 months vs. 30%, and 14 months for 22 patients who received ≤ 3 CHT cycles, (P = 0.03). The actuarial 3-year locoregional failure risk (LRFR) was 34.0% in the examined group vs. 51.0% in the historical control, P = 0.04. Multivariate analysis showed a marginally significant correlation between the "early" use of RT and LRFR: RR = 0.43 (95% CI: 0.17-1.04), P = 0.06, with no significant impact on OS. Shorter duration of RT using hypofractionation results in encouraging outcomes and acceptable toxicity. Completion of all planned CHT cycles is the most important factor for OS.

Outcomes of definitive chemoradiation for squamous cell carcinoma of the anus and the effect of radiation technique on hematologic parameters.

580 Background: Chemotherapy-radiation (CRT) is an established therapy for squamous cell carcinoma of the anus. A limiting factor in the successful completion of CRT is bone marrow toxicity. The effect of intensity modulated radiation therapy (IMRT) on marrow toxicity is not well defined. We evaluated the effect of IMRT on the severity of cytopenias for patients receiving CRT. We also explored the influence of cytopenias on disease outcome both pre-CRT or during CRT. Methods: 43 patients were treated with CRT between 1994-2010. The median delivered dose was 50.4 Gy (range, 32.4-59.4). 31 patients (72%) were treated with IMRT. All patients received concurrent chemotherapy, usually 5FU and mitomycin-C (n = 34, 79%). White blood cell (WBC), hemoglobin (Hg), and platelet counts were recorded pre- CRT, weekly during CRT, and within 7 days post-CRT. Hematologic values were analyzed according to type of RT and for association with treatment outcome. Results: 2-year locoregional failure (LRF) and distant failure were 14% and 14%, respectively. 21 patients required a treatment break due to any cause. In 9 (43%) patients the break was due to hematologic toxicity. 34 patients had complete blood values available. IMRT did not affect the rate of ≥ grade 2 cytopenia (p = 0.64) or median treatment nadirs; Hg (9.1 vs. 8.3 g/dL, p = 0.24), WBC (1.7 vs. 1.2 K/uL, p = 0.95), or platelets (90.5 vs. 61.5 k/uL, p = 0.88). Median time to nadir was not different for WBC (7 vs. 7 days, p = 0.36) or Hg (36 vs. 22 days, p = 0.29), but patients treated with IMRT did have a delayed platelet nadir (33 vs. 14 days, p = 0.01). Hg nadir ≤ 9 g/dL was associated with a higher rate of 2- year LRF (&gt; 9 g/dL 100% vs. ≤ 9 g/dL 73%, p = 0.03). No other hematologic values were associated with LRF. Conclusions: In this cohort of patients, nearly 50% of patients required a treatment break, which was related to a cytopenia 43% of the time. IMRT did not appear to have significant impact on acute marrow toxicity, although sample size may limit our power to detect a difference. Low Hg during CRT appears to influence LRF. More detailed dose volume histogram analysis will be useful to further explore how IMRT might influence acute hematologic toxicity, and therefore treatment outcomes. No significant financial relationships to disclose.

Concurrent Cisplatin and Radiation Versus Cetuximab and Radiation for Locally Advanced Head-and-Neck Cancer

To compare concurrent cisplatin (CDDP) and radiation (RT) with cetuximab (C225) and RT for locally advanced head-and-neck cancer (LAHNC). This study retrospectively compared 174 consecutive, newly diagnosed LAHNC patients definitively treated from March 1, 2006, to April 1, 2008, with single-agent CDDP/RT (n = 125) or C225/RT (n = 49). We excluded patients who received additional concurrent, induction, or adjuvant systemic therapy; weekly cisplatin; prior head-and-neck radiotherapy; or primary surgical resection. Outcomes were analyzed by the Kaplan-Meier method, Cox model, and competing-risks analysis tools. The C225/RT patients were older and had decreased creatinine clearance. At a median follow-up of 22.5 months for living patients, the 2-year locoregional failure rate was 5.7% for CDDP/RT and 39.9% for C225/RT (p < 0.0001). The 2-year failure-free survival (FFS) and overall survival (OS) rates were 87.4% vs. 44.5% (p < 0.0001) and 92.8% vs. 66.6% (p = 0.0003), respectively, in favor of CDDP/RT. When the Cox proportional hazards model was used for multivariate analysis, treatment with CDDP/RT predicted for improved locoregional control (p < 0.0001), FFS (p < 0.0001), and OS (p = 0.01). Late Grade 3 or 4 toxicity or feeding tube dependence 9 months after completion of RT was observed in 21% of patients in the CDDP/RT cohort and 24% in the C225/RT cohort (p=0.66). In this study of LAHNC patients, CDDP/RT achieved better locoregional control, FFS, and OS than C225/RT. Although the results were upheld on multivariate analysis, they must be interpreted cautiously because of the retrospective nature of the study and significant differences in patient selection. There was no statistically significant difference in late Grade 3 or 4 effects or feeding tube dependence.

Squamous Cell Carcinoma of the Anal Canal: Patterns and Predictors of Failure and Implications for Intensity-Modulated Radiation Treatment Planning

Intensity-modulated radiation treatment (IMRT) is increasingly used in the treatment of squamous cell carcinoma of the anal canal (SCCAC). Prevention of locoregional failure (LRF) using IMRT requires appropriate clinical target volume (CTV) definition. To better define the CTV for IMRT, we evaluated patterns and predictors of LRF in SCCAC patients given conventional radiation treatment. We reviewed records of 180 SCCAC patients treated with conventional radiation with or without chemotherapy at our institution between January 1990 and March 2007. All patients received radiation; the median primary tumor dose was 45 Gy. A total of 173 patients also received mitomycin-based chemotherapy. Median follow-up was 40 months. Actuarial 3-year colostomy-free survival was 89% and overall survival (OS) 88%. Actuarial 3-year LRF was 23%. A total of 45 patients had LRF, with 35 (78%) occurring locally in the primary site (25 local only, 10 local and regional); however, 20 (44%) had regional components of failure within the pelvis or inguinal nodes (10 regional only, 10 local and regional). Cumulative sites of LRF (patients may have one or more site of failure) were as follows: primary, 35; inguinal, 8; external perianal, 5; common iliac, 4; presacral, 3; distal rectum, 2; external iliac, 2; and internal iliac, 2. All patients with common iliac failure had cT3 or N+ disease. The observed patterns of failure support inclusion of the inguinal and all pelvic nodal groups in the CTV for IMRT. In patients with advanced tumor or nodal stage, common iliac nodes should also be included in the CTV.

Phase II study of preoperative chemoradiotherapy (CRT) with irinotecan plus S-1 in locally advanced rectal cancer

Background and purpose The aim of this study is to evaluate the efficacy and safety of preoperative radiation therapy combined with S-1 and irinotecan (SI) in LARC. Materials and methods Patients were considered LARC if they had a T3/T4 lesion or node positive. Weekly doses of 40 mg/m 2 irinotecan were intravenously administered once per week during weeks 1–5 of radiotherapy. S-1 (70 mg/m 2) was given from Monday to Friday in all weeks of radiotherapy. 3-D conformal radiotherapy was given at daily fractions of 1.8 Gy for 5 days for a total dose of 50.4 (45 + 5.4) Gy. Surgery was performed 4–6 weeks following the completion of chemoradiation. Results Between June 2006 and November 2007, 43 pts were enrolled. The stage was: cT3 24 patients, cT4 6 patients; 28 patients were cN+. Forty-one patients completed the chemoradiation and 42 patients underwent operation: a low anterior resection was performed in 36 patients, a total colectomy in 1 patient, and an abdominal perineal resection in 5 patients. T downstaging was observed in 50%; 23 N+ patients became N− (55%). The complete pathological response was observed in 9 patients (21%). The 3-year locoregional failure rate, distant failure rate, disease-free survival, and overall survival were 9.5%, 18.6%, 72.1%, and 94.3%, respectively. Only three patients experienced G3 diarrhea; one had G3 sepsis and two had septic shock. Hematological toxicity (G3–G4) was observed in five patients. Conclusions This study demonstrated the efficacy of preoperative CRT with S-1 and irinotecan with 21% of complete response. However, prompt recognition and management of infection is needed to use it in patients with locally advanced rectal cancer.