Concomitant Concomitant Chemotherapy Research Articles

Unplanned Hospitalization and Subsequent Mortality in Lung Cancer Patients Undergoing Concomitant Chemo-/Immuno-Therapy and Radiotherapy: An Analysis of Over 10,000 Patients in a Nationwide Database

Radiotherapy (RT) and concomitant chemotherapy (CHT) is a major modality for treating many malignancies including lung cancer and is associated with toxicity-related unplanned hospitalization (UPH). Previous investigations of factors associated with UPH have been single institutional retrospective studies and none assessed the role of concurrent immunotherapy (IO). Here, we aimed to identify factors associated with UPH and in-hospital mortality by leveraging a multi-institutional nationwide database. The Vizient® Clinical Data Base which includes data from 98% of the AAMC hospitals and 110 cancer hospitals, was queried for lung cancer patients (any histology) treated in 2019-2021 with RT+CHT/IO. Endpoints were UPH and mortality during or within 30 days of completion of RT. The variables included age, sex, race, ethnicity, income level (quartile), an education level (quartile), any concomitant CHT or IO drugs, RT technique (3D vs. IMRT vs. SBRT), obesity, prior hospitalization within 3 months, prior oncologic surgery within 3 months, prior CHT and/or IO within 3 months, insurance types, hospital types (Rural vs. Urban, AAMC vs. non-AAMC, NCCN vs. non-NCCN, bed size tertile). Logistic regression was performed to identify variables associated with UPH and in-hospital mortality. Data from the Vizient Clinical Data Base used with permission of Vizient, Inc. All rights reserved. A total of 10,337 patients were included. The rate of UPH and mortality among UPH was 24.5% and 3.2%, respectively. Factors associated with UPH included other races (vs. White, OR 1.44; 95% CI 1.11-1.88; p<0.001), living in a low income zip code (OR 1.7; 95% CI 1.39-2.09; p = 0.0006), living in a zip code with lower education attainment (OR 0.71; 95% CI 0.58-0.86; p = 0.0007), CHT/IO types (cis-etoposide vs. carbo-Taxol, OR 1.33; 95% CI 1.13-1.57; p<0.0001), obesity (OR 1.71; 95% CI 1.53-1.92; p<0.0001), prior hospitalization (OR 2.0; 95% CI 1.80-2.22; p<0.0001), prior oncologic surgery (OR 0.34; 95% CI 0.22-0.52; p<0.0001), other primary payers (vs. commercial; OR 1.75; 95% CI 1.37-2.23; p<0.0001), rural hospital (OR 1.3; 95% CI 1.07-1.62, p<0.01), small bed size (OR 0.59; 95% CI 0.5-0.71; p<0.0001). Factors associated with in-hospital mortality included CHT/IO type (p<0.0001, but cis-etoposide vs. carbo-taxol no difference), prior hospitalization (OR 0.34; 95% CI 0.2-0.56; p<0.0001), AAMC (OR 2.12; 95% CI 1.23-3.67; p = 0.007), bed size (OR 0.58; 95% CI 0.38-0.88; p<0.01). In the largest study to date regarding UPH and in-hospital mortality related to lung RT, we identified factors contributing to these endpoints. Future prospective studies are warranted to develop strategies to prevent these complications in high-risk populations.

Radiotherapy Versus Chemoradiation in Elderly Head-and-Neck Squamous Cell Carcinoma Patients – A Retrospective International Multicenter Study

<h3>Purpose/Objective(s)</h3> While the proportion of elderly head-and-neck squamous cell carcinoma (HNSCC) patients is increasing, the evidence regarding the ideal treatment for this patient cohort is limited. The benefit of concomitant chemotherapy (CT) has been reported to decrease in elderly HNSCC patients; however, it remains unknown whether modern supportive treatments, state-of-the art radiotherapy (RT) techniques and the generally improved performance status of elderly patients nowadays may have altered this observation. <h3>Materials/Methods</h3> Elderly (≥65 years) patients with locoregionally advanced HNSCCs of the oral cavity, oropharynx, hypopharynx or larynx (cT3-4 and/or cN+) receiving definitive RT, with or without concomitant CT, between 2005 and 2019 were eligible for this analysis. Exclusion criteria were recurrent HNSCCs, distant metastases at the time of RT, or HNSCCs from the nasopharynx, salivary glands or the skin. <h3>Results</h3> A total of 824 elderly HNSCC patients from nine tertiary cancer centers met the inclusion criteria and were analyzed. The median age amounted to 72 years (range 65-96 years), and 568 patients (80% of the patients with known ECOG status, n=708) exhibited an ECOG performance status of 0 or 1. The median age-adjusted Charlson Comorbidity Index (CCI) ranged at 4 points (IQR 3-5). Only a minority of HNSCCs (n=140, 17%) exhibited p16 positivity. About half of the cohort suffered from oropharyngeal carcinomas (n=418, 51%), followed by cancers of the hypopharynx (n=151, 18%), oral cavity (n=124, 15%), larynx (n=102, 12%) and multi-level carcinomas (n=29, 4%). A positive smoking history was present in 473 patients (70% of the patients with known smoking status, n=674). Seven hundred thirty-six (89%) of the analyzed patients completed the pre-specified RT dose. OS/PFS amounted to 71%/56% at 1 year, 56%/45% at 2 years, and 46%/38% at 3 years, respectively. Chemoradiation (CRT) resulted in significantly improved OS (HR=0.49, <i>p</i><0.05) and PFS (HR=0.53, <i>p</i><0.05) compared to RT. Even for patients aged ≥75 years (n=329), CRT was associated with superior OS (HR=0.57, <i>p</i><0.05) and PFS (HR=0.61, <i>p</i><0.05). However, patients receiving concomitant CT were significantly younger (<i>p</i><0.05), exhibited a better ECOG performance status (<i>p</i><0.05) and fewer comorbidities (<i>p</i><0.05). In order to control for these disparities, a matched-pair analysis with the matching variables ECOG, CCI and age was conducted, resulting in 98 matching pairs (n=196): Here, both OS (HR=0.44, <i>p</i><0.05) and PFS (HR=0.45, <i>p</i><0.05) remained superior in the CRT compared to the RT group. <h3>Conclusion</h3> This analysis suggests a benefit of concomitant CT in elderly HNSCC patients receiving RT and does not support the usage of a strict age cut-off for CT. Structured assessment of patient performance and comorbidities may help to guide treatment decisions regarding CRT in elderly HNSCC patients.

P14.69 Trends in postoperative chemoradiotherapy for Glioblastoma patients: a Danish cohort study

Abstract BACKGROUND Postoperative chemoradiotherapy (CRT), using conventional radiotherapy (convRT), has a key role in the treatment of glioblastoma (GBM) supported by level 1A evidence. In the past decade, evidence supporting hypofractionated radiotherapy (HFRT) has emerged. However, GBM patients in clinical trials are highly selected. Consequently, real-world patients may not be able to undergo evidence-based treatments. The aim of this retrospective Danish cohort study was to evaluate the utilisation of and compliance with postoperative CRT in real-world GBM patients over time. MATERIAL AND METHODS All adults (≥18 years) with newly diagnosed GBM (histology confirmed) between 2011 and 2018 were identified via the Danish Neuro-Oncology Registry, which was furthermore used to extract all data. Radiotherapy (RT) was classified as convRT (≤2 Gy/fr, planned dose 44–66 Gy) or HFRT (&amp;gt;2 Gy/fr, planned dose 34 or 40 Gy). The utilisation of and compliance with CRT (only concomitant treatment assessed) was measured by intended and administered treatment, respectively. To assess trends, patients were grouped per year of diagnosis. Multivariable logistic regression was used to analyse the association of age (&amp;lt;/≥70), sex, performance status (PS) before surgery and RT, tumour focality, extent of surgery, concomitant chemotherapy (CT), hospital (4 University Hospitals), and year of diagnosis, with convRT or HFRT. RESULTS The cohort consisted of 2153 patients. For the entire period, postoperative RT was planned in 1743 patients: utilisation of 81%, over time fluctuating between 77 and 84%. ConvRT was planned in 1428 patients (66%), with a steadily decreasing utilisation from 73% in 2011 to 52% in 2018. Of those, 1346 (94%) could complete RT as planned (over time fluctuating between 88–97%). In this group, the utilisation of and compliance with concomitant CT was 86% (fluctuating between 80–93%) and 73% (fluctuating between 47–84%), respectively. HFRT was planned in 315 patients (15%), with a utilisation of up to 26% in 2018, after a more pronounced increase since 2014. The compliance with HFRT was 93%, fluctuating between 85–100%. In this group, the utilisation of and compliance with concomitant CT was 33% (fluctuating between 0–47%) and 78% (fluctuating between 33–100%), respectively. The utilisation of HFRT compared to convRT was significantly associated with higher age, poorer PS before RT, multifocal tumour, less extensive surgery, less frequent concomitant CT, one hospital of RT treatment, and more recent diagnosis years. CONCLUSION The increased utilisation of HFRT is in line with emerging evidence during the cohort period. However, while HFRT was developed as a more convenient schedule for those with a poorer PS and older age, the overall utilisation of postoperative RT did not increase. Nor did the compliance with CRT increase in real-world Danish GBM patients.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). ConclusionThe update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Radiation alone (RT) versus RT with concomitant chemotherapy (CT) in stages III and IV oropharynx carcinoma: Ten-year results of the 94-01 GORTEC randomized study.

5516 Background: The purpose of this study is to report long-term results of a randomized study designed to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma. Methods: Between July 1994 and September 1997, 226 patients with locally advanced oropharynx stage III and IV tumors have been entered in a phase III multicentric randomized trial comparing RT alone (arm A, 115 patients) to RT with concomitant CT (arm B, 111 patients). RT was identical in the two arms, delivering 70 Gy in 35 fractions. In arm B patients received simultaneously on d1, d22 and d43, 3 cycles of a 4 day regimen containing carboplatin (70 mg/m2/d) and 5FU (600 mg/m2/d) continuous infusion. 34% were stage III and 66% were stage IV. The 2 arms were equally balanced regarding to age, gender, stage, performance status, histology, tumor biology, and primary tumor site. Results: Results have been published in 1999 (G. Calais et al. J Natl Cancer Inst 91, 2081-2086, 1999) and updated in 2004 (F. Denis et al. J Clin Oncol 22,69-76, 2004). RT compliance was similar in the 2 arms regarding to total dose, treatment duration and treatment interruption. Relative dose intensity in arm B was 78% and 76% for carboplatin and 5FU. Grade 3 and 4 mucositis rate was significantly higher in arm B (67% vs. 36%). Skin toxicity was not different. Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level. With a median follow-up of 11 years, 78 patients have died in arm A versus 58 in arm B. Ten-year overall actuarial survival and disease- free survival rates were respectively 32% versus 18% and 30% versus 15% for patients treated with combined modality versus radiation alone (p = 0.03 and 0.04). Local and regional control rate has been improved in arm B. Actuarial grade 3 and 4 late toxicity rate was 30% in the RT-alone arm and 51% in the combined treatment arm. Quality of life and functional results of long-term survivors will be presented. Conclusions: The long-term results of this study support the use of concomitant CT combined with RT in the management of oropharynx carcinoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono

Hyperfractionated Radiotherapy: Improvement of Survival in Locally Advanced Nasopharyngeal Carcinoma

Standard treatment with concomitant chemotherapy (CT) and radiotherapy (RT) for nasopharyngeal cancer has shown rates of locoregional control of 80% and has improved the rate of 5-year survival to 67% to 84%. Hyperfractionated radiotherapy (HFRT) may increase locoregional control of tumors of the head and neck, but the addition of concomitant CT involves an unacceptable level of toxicity. Adding induction CT may control distant metastasis. Here we compare the results of our protocol with induction CT followed by HFRT alone with the results obtained with concomitant treatments. Between October 1994 and May 2002, 46 patients with nasopharyngeal carcinoma were treated with HFRT. The patients with N+ or T4 lesions also received cisplatin-based induction CT (55%). The patients received a mean of 3 CT cycles (range, 2 to 5). At 5 years, the rate of progression-free survival was 66% (range, 51.3% to 82.1%), and the global survival rate was 75.7% (range, 61.9% to 89.5%). The use of HFRT in association with induction CT in patients with the greatest risk of metastasis may be as effective as concomitant CT-RT for treatment of nasopharyngeal cancer. Efforts should now concentrate on minimizing the acute and chronic toxicities.

BC2001: A multicenter phase III randomized trial of standard versus reduced volume radiotherapy for muscle invasive bladder cancer (ISCRTN:68324339)

5022 Background: Radiotherapy (RT) is an alternative to radical cystectomy in the management of muscle invasive bladder cancer. Limitations are probability of attaining and maintaining local tumour control and risk of late bladder toxicity. BC2001 tests whether concomitant chemotherapy (CT) improves loco-regional control and whether RT volume modification reduces late toxicity without detriment to tumour control. Methods: Pts were randomized in a 2x2 factorial design to (i) RT vs RT + concomitant CT (5FU 500mg/m2 d1–5 wks 1 &amp; 4 + mitomycin C 12mg/m2 d1) and/or (ii) standard RT to tumour and whole bladder with 1.5cm margin (sRT) vs reduced volume RT (rvRT) where tumour + 1.5cm margin was treated to 100(±5)% target dose and remaining bladder received 80% target dose. RT dose was 55Gy/20F or 64Gy/32F according to local practice. RT volume comparison results (primary endpoint RTOG toxicity at 1 yr) are reported. Target sample size was 480 pts but the RT randomisation closed early due to slow recruitment. Estimated power is 73% (two-sided α = 0.05) to detect a 20% difference in G3/4 toxicity. Results: 219 pts were recruited (108 sRT; 111 rvRT); 49 received neoadjuvant CT; 31 sRT and 33 rvRT were randomised to concomitant CT. Median age was 74 yrs. Median follow up is 36 mths. There was no difference in loco-regional disease-free survival (LRDFS: HR = 1.06, 95% CI: 0.62–1.84) nor overall survival (HR = 0.99, (0.61 - 1.35)) between randomised RT groups. 2yr LRDFS is 71% in both RT groups. 27 (16) sRT vs 32 (15) rvRT pts have had local (invasive) recurrences (p = 0.09); 32 pts have undergone salvage cystectomy. No difference was seen in CTC G3/4 acute toxicity (26% sRT vs 21% rvRT, p = 0.35), RTOG G3/4 toxicity at 12 mths (8% sRT vs 4% rvRT, p = 0.27) nor Lent Som G3/4 toxicity at 12 mths (45% sRT vs 34% rvRT, p = 0.21). Bladder capacity fell significantly in sRT group (mean reduction at 12 mths: 59mls, 95%CI: 47–118mls, p = 0.02) but not in rvRT group. Conclusions: RT in the modern era can attain local control in most patients with T2-T3 bladder cancer. Acute and late toxicity was less than anticipated in both treatment groups. Modifying standard RT volumes had minimal effect on local control and toxicity in this trial. 2 yr toxicity and quality of life data will be presented. No significant financial relationships to disclose.

Feasibility and Efficacy of Accelerated Weekly Concomitant Boost Postoperative Radiation Therapy Combined with Concomitant Chemotherapy in Patients with Locally Advanced Head and Neck Cancer

The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Further Improvement in Outcomes of Nasopharyngeal Carcinoma With Optimized Radiotherapy and Induction Plus Concomitant Chemotherapy: An Update of the Milan Experience

To report the outcome of a consecutive series of patients with nonmetastatic nasopharyngeal carcinoma (NPC), focusing on the impact of treatment-related factors. Between 2000 and 2006, 87 patients with NPC were treated with either conventional (two- or three-dimensional) radiotherapy (RT) or with intensity-modulated RT (IMRT). Of these patients, 81 (93%) received either concomitant CHT (24%) or both induction and concomitant chemotherapy (CHT) (69%). Stage was III in 36% and IV in 39% of patients. Outcomes in this study population were compared with those in the previous series of 171 patients treated during 1990 to 1999. With a median follow-up of 46 months, actuarial rates at 3 years were the following: local control, 96%; local-regional control, 93%; distant control (DC), 90%; disease-free survival (DFS), 82%; overall survival, 90%. In Stage III to IV patients, distant control at 3 years was 56% in patients treated with concomitant CHT only and 92% in patients treated with both induction and concomitant CHT (p = 0.014). At multivariate analysis, histology, N-stage, RT technique, and total RT dose had the strongest independent impact on DFS (p < 0.05). Induction CHT had a borderline effect on DC (p = 0.07). Most dosimetric statistics were improved in the group of patients treated with IMRT compared with conventional 3D technique. All outcome endpoints were substantially better in the study population compared with those in the previous series. Outcome of NPC has further improved in the study period compared with the previous decade, with a significant effect of RT technique optimization. The impact of induction CHT remains to be demonstrated in controlled trials.

Radiotherapy in the adjuvant setting of cervical carcinoma: treatment, results, and prognostic factors

To evaluate the efficacy of postoperative radiotherapy and to investigate prognostic factors for early-stage cervical cancer patients. From December 1993 to December 2001, 141 patients with stage I–II cervical cancer without para-aortic lymph node (LN) metastases and treated by surgery and postoperative radiotherapy (RT) were included in this study. Indications for postoperative external RT were based on pathologic findings, including LN metastasis, positive surgical margins, parametrial involvement, pT2 tumor, and presence of any two minor risk factors like lymphvascular space involvement, deep stromal invasion, and tumor diameter between 2–4 cm. Sixty-six (47%) patients received RT alone, whereas 59 (42%) were treated with RT and concomitant chemotherapy (CT), and 16 received neoadjuvant CT. Patients with positive vaginal margins also received 27.5 Gy high–dose rate vaginal cuff brachytherapy in five fractions. Median follow-up time was 55 months. The actuarial 5-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRFS), and distant metastases-free (DMFS) survival rates are 70%, 68%, 77%, and 88%, respectively. Univariate and multivariate analyses revealed that level and number of metastatic LNs and concomitant CT were unique significant prognostic factors for OS, DFS, and LRFS. Endometrial involvement, on the other hand, was proven to be significant for DFS and DMFS. Patients with less than three LN metastases or having only obturator LN involvement showed similar prognosis with their counterparts having no LN metastases. On the other hand, patients with either common iliac LN or more than three LN metastases had significantly worse outcome. Our results indicate that level and number of metastatic LNs are the most important prognostic factors determining the survival rates, and patients with upper lymphatic involvement or more than three metastatic LNs seem to need more effective treatment approaches

Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma

Purpose To evaluate the outcome after definitive whole pelvis external beam radiotherapy (EBRT) followed by brachytherapy (BT) boost after treatment break vs. external beam boost without break in the treatment of anal carcinoma. Methods and materials Eighty-one consecutive patients with invasive anal carcinoma were analyzed retrospectively. Patients treated with an interstitial 192Ir high-dose-rate (HDR) implant boost of 14 Gy/7 fractions/3 d given 3 weeks after completion of whole pelvis 45 Gy EBRT were compared with those treated with external beam boost of 14.4 Gy, started immediately after completion of whole pelvis 45 Gy EBRT. Concomitant chemotherapy (CT) with mitomycin C was applied during whole pelvis EBRT depending on tumor stage. Pattern of care, local disease control (LC), cancer-specific survival (CSS), overall survival (OS), toxicity, and quality of life (QOL) were assessed. Results Radiotherapy with or without concomitant CT achieved clinical complete response in 93.4% of patients. In early stage tumors, 192Ir-HDR BT boost with CT resulted in a 5-year LC and CSS of 100%. In all patients, BT boost did not result in improved LC, OS, and CSS compared with EBRT boost, despite stage and treatment bias favoring small tumors to be treated with BT. The 5-year and 10-year OS were 66% and 44% (BT boost) and 66% and 52% (EBRT boost), respectively. Subgroup analysis of Stages I and II disease revealed no significant improvement after BT boost compared with EBRT boost. Acute skin toxicity was less common in the BT boost group (whole cohort: p = 0.14; Stages I–IIIa: p = 0.05), but long-term morbidity and QOL were similar. No local necrosis was seen after BT boost and the 10-year sphincter preservation rate was 87% in these patients. Conclusions Interstitial 192Ir-HDR implant boost with break and EBRT boost without break yield similar results. Acute skin toxicity is reduced with BT boost but long-term morbidity and QOL are identical. BT boost is most beneficial in early stage tumors but the advantage of BT seems to be limited due to its invasiveness, doctor dependence, and logistic circumstances.

HER2 expression and HER2:HER2 dimerization identifies subpopulations of metastatic breast cancer patients with different probabilities of long-term survival following trastuzumab treatment and with different requirements for concomitant chemotherapy

10557 Background: Selection of patients for treatment with trastuzumab is currently based on the semi-quantitative measurement of HER2 protein expression (IHC) or gene amplification (FISH). We made quantitative measurements of HER2 expression and homodimerization using a novel assay, eTag, and correlated them with overall survival (OS) and time-to-progression (TTP) following trastuzumab treatment in a cohort of patients with metastatic breast cancer (MBC). We also examined the benefit of concomitant chemotherapy (CT) depending on quantitative HER2 expression. Methods: The Jules Bordet cohort (Brussels, Belgium, N=71) had MBC and prior treatment with at least two CT regimens. Patients received trastuzumab alone or combined with predominantly paclitaxel. Independent medical data review and central confirmation of HER2 overexpression by FISH (N=64) or IHC (N=7) were mandatory. The eTag assay was used to quantitate HER2 protein expression and HER2:HER2 dimers in FFPE specimens. eTag measurements were correlated with OS and TTP using Kaplan-Meier and Cox Proportional Hazards regression analyses. Results: Cox analyses identified three independent correlates of OS and TTP: number of metastatic sites (HROS = 2.4/site, 95%CI 1.5–3.9, p = 0.00019), treatment with trastuzumab only (HROS = 2.8, 95%CI 1.1–7.3, p = 0.036), and HER2 expression level (HROS = 0.24/log10(HER2), 95%CI 0.09–0.7, p = 0.0058). Patients with high HER2 (above median expression) experienced better OS than those with low HER2 (HR 0.24, p = 0.0014). Patients with high HER2 expression did not benefit from added CT (HR = 0.95, 95%CI 0.24–3.8, p = 0.94), while patients with low HER2 expression did (trastuzumab alone HR 4.4, 95% CI 1.3–18, p = 0.018). Similar results were observed for HER2:HER2 dimerization. Conclusions: Within a population of patients selected by FISH or IHC to receive trastuzumab, higher HER2 expression or HER2:HER2 dimerization correlated with better outcomes. Patients with high HER2 expression derived no benefit from concomitant CT, while patients with low HER2 expression benefited significantly from the addition of CT to trastuzumab. No significant financial relationships to disclose.

Radiotherapy in the adjuvant setting of cervical carcinoma: treatment, results, and prognostic factors

To evaluate the efficacy of postoperative radiotherapy and to investigate prognostic factors for early-stage cervical cancer patients. From December 1993 to December 2001, 141 patients with stage I-II cervical cancer without para-aortic lymph node (LN) metastases and treated by surgery and postoperative radiotherapy (RT) were included in this study. Indications for postoperative external RT were based on pathologic findings, including LN metastasis, positive surgical margins, parametrial involvement, pT2 tumor, and presence of any two minor risk factors like lymphvascular space involvement, deep stromal invasion, and tumor diameter between 2-4 cm. Sixty-six (47%) patients received RT alone, whereas 59 (42%) were treated with RT and concomitant chemotherapy (CT), and 16 received neoadjuvant CT. Patients with positive vaginal margins also received 27.5 Gy high-dose rate vaginal cuff brachytherapy in five fractions. Median follow-up time was 55 months. The actuarial 5-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRFS), and distant metastases-free (DMFS) survival rates are 70%, 68%, 77%, and 88%, respectively. Univariate and multivariate analyses revealed that level and number of metastatic LNs and concomitant CT were unique significant prognostic factors for OS, DFS, and LRFS. Endometrial involvement, on the other hand, was proven to be significant for DFS and DMFS. Patients with less than three LN metastases or having only obturator LN involvement showed similar prognosis with their counterparts having no LN metastases. On the other hand, patients with either common iliac LN or more than three LN metastases had significantly worse outcome. Our results indicate that level and number of metastatic LNs are the most important prognostic factors determining the survival rates, and patients with upper lymphatic involvement or more than three metastatic LNs seem to need more effective treatment approaches.

Impact of age on treatment effect in locally advanced head and neck cancer (HNC): Two individual patient data meta-analyses

5501 Background: The Meta-Analysis of Radiotherapy in Carcinomas of Head &amp; Neck (MARCH; Bourhis J, ASTRO 2002) showed that altered fractionation radiotherapy (Alt-RT) could improve survival as compared to standard RT in patients with locally advanced HNC (pooled hazard ratio - HR -: 0.92, 95% confidence interval: 0.86–0.97). The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC; Bourhis J, ASCO 2004) demonstrated that concomitant chemotherapy (CT), added to RT, improved survival (HR: 0.82, 95% CI: 0.78–0.86). This study considers age as a potential modifier of the treatment effect. Methods: 15 randomized trials with 6,515 patients were included in MARCH (median follow up: 6.0 years), and 50 with 9,471 patients in concomitant part of MACH-NC (median follow up: 5.6 years). The interaction between age and treatment effect, using HR of death, was tested with heterogeneity test. Effect of prognostic factors on the interaction was analysed using Cox model. Results: The effect of Alt-RT in MARCH and of concomitant CT in MACH-NC on overall survival decreased with increased age ( table ). Patients aged 71+ had a lower performance status, less advanced stage, and more often laryngeal cancer than the younger patients; there were more women in the oldest patients group. However, adjusting on covariates did not modify the results. Causes of death was available in MARCH and in recent (1994–2000) trials of MACH-NC. The proportion of deaths not due to HNC increased with age, from 18% at age 50 to 41% at age 71+ in MARCH, and from 15% to 39% in MACH-NC. Conclusions: Treatment benefit decreases with increasing age. Patients aged 71+ did not benefit from Alt- RT nor from concomitant CT. The increasing risk of death from other causes with age may explain part of these observations. Supported by PHRC, ARC, LNCC [Table: see text] No significant financial relationships to disclose.

Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis.

A systematic review was conducted to develop clinical recommendations for concomitant chemotherapy (CT) and radiotherapy (RT) in patients with locally advanced squamous cell head and neck cancer (SCHNC). Results of published randomized controlled trials (RCTs) were pooled using Meta-analyst(0.988) software. A pooled analysis of 18 RCTs (20 comparisons) involving 3,192 patients detected a reduction in mortality for concomitant therapy compared with RT alone (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.52-0.74; relative risk, 0.83; risk reduction, 11%; p < .00001). Platinum-based regimens involving 1,514 patients from nine trials (10 comparisons) were most effective (OR, 0.57; 95% CI, 0.46-0.71; p < .00001; risk reduction, 12%). Concomitant therapy produced more acute adverse effects than RT alone. Platinum-based concomitant CT and RT is superior to conventional RT alone in improving survival in locally advanced SCHNC. Subgroup analyses can be used to help in choosing the most appropriate concomitant regimen.

Radiotherapy with high dose rate brachytherapy boost and concomitant chemotherapy for stages IIB and III esophageal carcinoma: Results of a pilot study

Radiotherapy (RT) and concomitant chemotherapy (CT) is the standard treatment for non resectable esophageal cancer. Usual total radiation dose is 50 Gy. In order to enhance local control rate a Phase II study was initiated to evaluate the feasibility of a combined treatment with an external radiation dose of 60 Gy and three cycles of concomitant CT, using the three main active drugs (CDDP, 5 FU and MMC), followed by a high dose rate (HDR) brachytherapy delivering 10 Gy. Fifty-three patients, 48 men and 5 women, were entered in this study. Stages were evaluated with CT scan and with endoscopic sonography. Fifteen were Stage IIB, 38 Stage III. Treatment consisted of conventional fractionated RT to a total dose of 60 Gy delivered with 2 Gy per fraction, one fraction per day and five fractions per week. The CT regimen was a combination of Cisplatinum (CDDP) 20 mg/m2 and 5 Fluorouracil (5FU) 600 mg/m2 continuous infusion, from days 1-4 Mitomycin C (MMC) was given at 6 mg/m2 on day 1. Three cycles were administered on days 1, 22, and 43. Brachytherapy was delivered one week after the end of external radiation therapy. Full radiation therapy dose was delivered for 94% of the patients. CT compliance, evaluated on the mean relative dose-intensity was 85% for CDDP, 81% for 5FU and 51% for MMC. Overall grade 3 and 4 WHO toxicity rates were 23% and 7%, respectively. Haematologic toxicity was the most limiting factor. One patient died from treatment toxicity. Local control rate at one year was 74%. Three-year actuarial survival rate was 27%. Distant metastasis was the main cause of treatment failure. Swallowing score was good for 75% of the patients. Stage, performance status and weight loss were prognostic factors. This regimen with high dose RT, HDR brachytherapy and concomitant CT is feasible; however, a high level of haematologic toxicity was observed with the CDDP, 5FU and MMC regimen. Despite a poor compliance with CT, treatment results are very encouraging for patients with locally advanced disease.