Phase 2 trial of concurrent 5‐fluorouracil,hydroxyurea, cetuximab,and hyperfractionated intensity‐modulated radiation therapy for locally advanced head and neck cancer

BACKGROUND:

The objective of this phase 2 study was to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated‐boost (SIB), intensity‐modulated radiation therapy (IMRT) into a well described 5‐fluorouracil (5‐FU) and hydroxyurea (HU)‐based chemoradiation regimen.

METHOD:

Patients with stage IVA and IVB or high‐risk stage III squamous cell carcinomas of the head and neck were enrolled on a phase 2 trial. Prior organ‐conserving surgery or induction chemotherapy was allowed off protocol. SIB‐IMRT was prescribed to low‐risk volumes (43.2 gray [Gy] to 48 Gy) and intermediate‐risk volumes (54‐63 Gy). A separate IMRT cone‐down plan was targeted to macroscopic disease (72 Gy). The median radiation dose was 72 Gy (range, 60‐72 Gy) administered in 1.5 Gy fractions twice daily during Weeks 1, 3, 5, 7 and 9. Concurrent systemic therapy consisted of 5‐FU (600 mg/m²), HU (500 mg twice daily), and cetuximab (250 mg/m²).

RESULTS:

From January 2007 through April 2008, 33 patients were enrolled. At a median follow‐up of 24 months, the 2‐year rates of locoregional control, distant control, disease‐free survival, and overall survival were 83%, 79%, 69%, and 86%, respectively. Grade 3 toxicity consisted of mucositis in 33% of patients, radiation dermatitis in 15%of patients, anemia in 18% of patients, leukopenia in 18% of patients, neutropenia in 12% of patients, and thrombocytopenia in 3% of patients. Most patients (64%) were able to tolerate treatment without a feeding tube, and there were no acute or late grade ≥4 adverse events.

CONCLUSIONS:

The current results indicated that concurrent 5‐FU, HU, and cetuximab plus SIB‐IMRT is a promising and reasonably well tolerated approach to incorporating molecularly targeted therapy into curative therapy for patients with locally advanced head and neck cancer. Cancer 2011. © 2010 American Cancer Society.     

Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: A meta analysis

BackgroundOxaliplatin (OX), in combination with fluoropyrimidine (5-fluorouracil or Capecitabine, FU)-based regimens and radiation, has been expected to both enhance primary tumour shrinkage and reduce micrometastases at distant sites in the neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, results in terms of pathologic complete response (pCR) and toxicities were inconsistent. The aim of this meta analysis was to evaluate the short term efficacy and toxicities of adding OX to FU in CRT for LARC.MethodsWe searched PubMed, EMBASE, ISI databases, Chinese Biomedical Literature Database and the Cochrane library before December, 2011. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2011, were searched to identify relevant clinical trials. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. Summary incidence rates and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Four randomised clinical trials comparing OX/FU versus FU alone regimens in CRT for LARC met our search criteria and were assessed. A total of 3863 patients (FU, n = 1937; OX/FU, n = 1926) were included in the analysis.FindingsThe addition of OX to FU significantly improved pathologic complete response (pCR), and reduced peri-operative metastases (including intra-abdominal metastases) with an odd ratios (OR) for OX/FU compared with FU of 1.20 (95% CI, 1.01–1.42; P = 0.04) and 0.51 (95% CI, 0.34–0.77; P = 0.001), respectively. The grade 3/4 toxicity rate was significantly higher for OX/FU versus FU alone with an OR of 2.29 (95% CI, 1.31–4.00; P = 0.004). There was no difference in the rates of positive circumferential resection margin, permanent stoma, surgical complication and death within 60 d between the OX/FU and FU alone patients. The OR for the proportion of patients completing full-dose radiotherapy and completing full-dose chemotherapy were 0.32 (95% CI, 0.15–0.69; P = 0.004), and 0.71 (95% CI, 0.35–1.42; P = 0.33), respectively.InterpretationAdding weekly OX to FU in neoadjuvant CRT of LARC appeared to modestly increase the pCR rate and reduced the rate of intra-abdominal or peri-operative metastases in this meta analysis. Although OX/FU significantly increased grade 3/4 toxicity, it did not result in more surgical complications or postoperative deaths within 60 d. The concept of combination of OX and FU in the pre-operative setting for LARC still seems promising, either with a modified schedule, or as induction therapy prior to CRT or after CRT, prior to surgery.     

Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial

BackgroundSquamous cell carcinoma of the anus (SCCA) is highly sensitive to chemoradiation (CRT) which achieves good loco-regional control and preserves anal function. However, some patients require permanent stoma formation either as a result of surgery on relapse, poor anal function or treatment-related symptoms. Our aim was to determine patient, tumour and treatment-related colostomy rates following CRT and maintenance chemotherapy in the ACT II trial.Patients and methodsThe ACT II trial recruited 940 patients comparing 5FU-based CRT using cisplatin (CisP) or mitomycin C (MMC) with or without additional maintenance chemotherapy. We investigated the association between colostomy-free survival (CFS) and progression-free survival (PFS) with age, gender, T-stage, N-stage, treatment and baseline haemoglobin.ResultsThe median follow-up was 5.1 years (n = 884 evaluable/940); tumour site canal (84%), margin (14%); stage T1/T2 (52%), T3/T4 (46%); N+ (32%), N0 (62%). Twenty out of 118 (17%) colostomies fashioned before CRT were reversed within 8 months. One hundred and twelve patients had a post-treatment colostomy due to persistent disease (98) or morbidity (14). Fifty-two per cent (61/118) of all pre-treatment colostomies were never reversed. The 5-year CFS rates were 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint. CRT with CisP did not improve CFS when compared with MMC (hazard ratio: 1.04, 95% confidence interval: 0.82–1.31, P = 0.74). The 5-year CFS rates were higher for T1/T2 (79%) than T3/T4 (54%) tumours and higher for node-negative (72%) than node-positive (60%) patients. Significant predictors of CFS were gender, T-stage and haemoglobin, while treatment factors had no impact on outcome. Similar associations were found between PFS and tumour/treatment-related factors.ConclusionsThe majority (52%) of pre-treatment colostomies were never reversed. Neither CRT with 5FU/CisP nor maintenance chemotherapy impacted on CFS. The low risk of colostomy for late effects (1.7%) is likely to be associated with the modest total radiotherapy dose. The predictive factors for CFS were T-stage, gender and baseline haemoglobin.Clinical trial registration numberISRCTN 26715889.     

Unexpected toxicity of cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: results of the UNICANCER ACCORD 16 phase II trial

BackgroundThe ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC).Patients and methodsImmunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m² with a loading dose of 400 mg/m² 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT.ResultsThe trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18–27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%–86%), 62% (95% CI: 36%–82%), and 92% (95% CI: 67%–99%), respectively.ConclusionCRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings.Eudra CT No2007-007029-38.     

Toxicity and efficacy of cetuximab associated with several modalities of IMRT for locally advanced head and neck cancer

PurposeIntensity-modulated radiation therapy (IMRT) has shown its interest for head and neck cancer treatment. In parallel, cetuximab has demonstrated its superiority against exclusive radiotherapy. The objective of this study was to assess the acute toxicity, local control and overall survival of cetuximab associated with different IMRT modalities compared to platinum-based chemotherapy and IMRT in the ARTORL study (NCT02024035).Patients and methodThis prospective, multicenter study included patients with epidermoid or undifferentiated nasopharyngeal carcinoma, epidermoid carcinoma of oropharynx and oral cavity (T1–T4, M0, N0–N3). Acute toxicity, local control and overall survival were compared between groups (patients receiving cetuximab or not). Propensity score analysis at the ratio 1:1 was undertaken in an effort to adjust for potential bias between groups due to non-randomization.ResultsFrom the 180 patients included in the ARTORL study, 29 patients receiving cetuximab and 29 patients treated without cetuximab were matched for the analysis. Ten patients (34.5%) reported acute dermal toxicity of grade 3 in the cetuximab group versus three (10.3%) in the non-cetuximab group obtained after matching (P = 0.0275). Cetuximab was not significantly associated with more grade 3 mucositis (P = 0.2563). There were no significant differences in cutaneous or oral toxicity for patients treated with cetuximab between the different IMRT modalities (P = 1.000 and P = 0.5731, respectively). There was no significant difference in local relapse-free survival (P = 0.0920) or overall survival (P = 0.4575) between patients treated with or without cetuximab.ConclusionPatients treated with cetuximab had more cutaneous toxicities, but oral toxicity was similar between groups. The different IMRT modalities did not induce different toxicity profiles.     

Optimal Target Delineation and Treatment Techniques in the Era of Conformal Photon and Proton Breast and Regional Nodal Irradiation

PurposeRegional nodal irradiation improves disease-free and distant disease–free survival in patients with high-risk breast cancer (BC). Trials demonstrating this used 2- or 3-dimensional conformal radiation therapy (2-dimensional or 3-dimensional [3D] conformal radiotherapy [CRT]) fields based on bony anatomy. Modern volumetric-modulated arc therapy (VMAT) and pencil beam scanning proton therapy (PBSPT) may underdose regional nodes (RNs) not contoured but covered by 3D CRT. Multiple atlases guide modern treatment planning. This study addresses the risk of underdosing when relying on published atlases and treating with 3D CRT, VMAT, and PBSPT.Methods and MaterialsTargets per the Radiation Therapy Oncology Group (RTOG), European Society for Radiotherapy and Oncology (ESTRO), and Radiotherapy Comparative Effectiveness Consortium (RADCOMP) atlases were contoured on a representative patient CT scan. 3D CRT plans based on anatomic borders and VMAT and PBSPT plans for each set of target volumes were generated. Positron emission tomography/computed tomography (PET/CT) scans were reviewed. CT-positive and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)–avid RNs (n = 389) were mapped from 102 patients with locally advanced (n = 51; median 2; range, 1-8 nodes) and metastatic (n = 51; median 4; range, 1-19 nodes) BC: axillary (AX; n = 284), supraclavicular (SCV; n = 60), and internal mammary nodal (IMN; n = 45). ¹⁸F-FDG-avid RNs falling within the 95% isodose line were considered adequately covered.Results3D CRT plans provided excellent RN coverage. Low AX nodes were covered (≥99%) in all plans. Underdosing of ¹⁸F-FDG–avid RNs falling in the high AX (78%-92%), SCV (52%-75%), and IMN (84%-89%) volumes was observed following the RTOG and ESTRO atlases for VMAT and PBSPT plans. Use of the RADCOMP atlas provided coverage of these areas (89%-100%) with slightly increased heart and lung doses. Atlas guided VMAT/PBSPT plans provided cumulative nodal coverage as follows: ESTRO (89%/88%), RTOG (93%/91%), and RADCOMP (98%/96%).ConclusionsVMAT and PBSPT for regional nodal irradiation in patients with high-risk BC risks underdosage in the high AX, SCV, and IMN nodal regions unless comprehensive target delineation is performed.     

A phase II study of concurrent cetuximab-cisplatin and intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma

BackgroundBased on our previous work on the clinical activity of cetuximab in recurrent nasopharyngeal carcinoma (NPC), we evaluated the feasibility of adding cetuximab to concurrent cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced NPC.Patients and methodsPatients with American Joint Committee on Cancer stage III–IVB NPC were given an initial dose of cetuximab (400 mg/m²) 7–10 days before receiving concurrent IMRT, weekly cisplatin (30 mg/m²/week) and cetuximab (250 mg/m²/week).ResultsThirty patients (median age of 45 years) with stage III (67%), IVA (30%) and IVB (3%) nonkeratinizing NPC were enrolled. Grade 3–4 oropharyngeal mucositis occurred in 26 (87%) patients and 10 (33%) patients required short-term nasogastric feeding. Grade 3 radiotherapy-related dermatitis occurred in six patients (20%) and three patients (10%) had grade 3 cetuximab-related acneiform rash. These grade 3–4 skin and mucosal toxic effects were manageable and reversible. At a median follow-up of 31.8 months [95% confidence interval (CI) 26.2–32.1 months], the 2-year progression-free survival was 86.5% (95% CI 74.3% to 98.8%).ConclusionsConcurrent administration of cetuximab, weekly cisplatin and IMRT is a feasible strategy against locoregionally advanced NPC. Preliminary survival data compare favorably with historic data and further follow-up is warranted.     

DCF (docetaxel,cisplatin and 5-fluorouracil) chemotherapy is a promising treatment for recurrent advanced squamous cell anal carcinoma

BackgroundSquamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed at early stage. After concurrent chemoradiation (CRT) with mitomycin C and 5-fluorouracil (5FU), local or metastatic recurrences occur in >20% of the patients. After treatment failure, cisplatin (CDDP)-based chemotherapy is the standard option, but complete response (CR) is a rare event and the prognosis remains poor.Patients and methodsEight consecutive patients with advanced recurrent SCCA after CRT were treated with DCF regimen (docetaxel 75 mg/m² day 1, CDDP 75 mg/m² day 1 and 5FU at 750 mg/m²/day for 5 days every 3 weeks). Tumour samples were analysed for human papillomavirus (HPV) genotyping, as well as p16 and p53 expression.ResultsAfter a median follow-up of 41 months, the overall survival rate at 12 months was 62.5% (95% CI 22.9–86.1 months). Four patients achieved a complete remission and remain relapse-free at the time of analysis with a progression-free survival of 19, 33, 43 and 88 months. Three of these patients underwent surgery for all involved metastatic sites. For all of them, pathological CR was confirmed. DCF regimen appeared feasible in these patients previously exposed to pelvic CRT, and no grade IV toxicity occurred. All patients in complete remission had HPV-16-positive SCCA, while HPV could only be detected among 50% of the non-responding patients. Of interest, immunohistochemical study revealed a p16⁺/p53^- phenotype in these patients, while none of non-responders expressed p16.ConclusionThe high level of complete and long-lasting remission among SCCA patients treated with DCF regimen supports the assessment of this strategy in prospective cohorts.     

Radiotherapy for unresectable sinonasal cancers: Dosimetric comparison of intensity modulated radiation therapy with coplanar and non-coplanar volumetric modulated arc therapy

Background and purposeTo compare volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) plans for treatment of unresectable paranasal sinuses cancers (PNSCs) with different clinical presentations.Material and methodsFour patients treated for primary target volume only (group 1), four requiring elective nodal irradiation (group 2) and four with positive nodes in macroscopic disease (group 3) were selected. For each patient were generated 7 fields IMRT, coplanar VMAT (c-VMAT) and non-coplanar VMAT (nc-VMAT) treatment plans. Total doses were 70 Gy and 54 Gy to high dose planning target volume (HD-PTV) and low-dose-PTV, respectively. Dose–volume histogram, conformity and homogeneity index (CI and HI), and monitor units (MUs) per Gy were evaluated.ResultsVMAT provided significantly better target coverage, in terms of V_100% (Volume encompassed by the isodose 100%), than IMRT, in particular when nc-VMAT was used. In general, organ at risk sparing is similar with the three approaches, although nc-VMAT can allow a statistically significant reduction of dose to contralateral parotid gland and cochlea for all three groups.ConclusionsVMAT can offer significant improvement of treatment for all unresectable PNSCs over existing IMRT techniques. In particular, nc-VMAT may be a further advantage for those patients with sinonasal cancers and involvement of the nodes in whom large volumes and complex/irregular shape have to be irradiated, even if clinical benefits should be established in the future.     

A phase II study of cetuximab,capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer

Background

Neoadjuvant chemoradiotherapy (CRT) reduces local tumor recurrence in locally advanced rectal cancer (LARC). This phase II study assessed neoadjuvant cetuximab with capecitabine-based CRT in LARC.

Methods

Patients with stage II/III LARC received capecitabine 1250 mg/m² twice daily for 2 weeks followed by intravenous cetuximab 400 mg/m² at week 3, then weekly intravenous 250 mg/m² cetuximab plus CRT including capecitabine 825 mg/m² twice daily (including weekends during radiotherapy) with radiotherapy of 45 Gy (25 × 1.8 Gy), 5 days a week for 5 weeks. Total mesorectal excision was scheduled 4–6 weeks following completion of CRT. The primary endpoint was pathological complete response (pCR).

Results

Thirty-seven patients were eligible for safety and efficacy. TMN staging at baseline was: T4N2, 11%; T3N2, 40%; T2N2, 3%; T3N1, 35%; T2N1, 3% and T3N0 8%. The most common adverse events included, grade 1/2 acneiform skin rash (86%), and grade 3 radiodermatitis, (16%), diarrhea (11%) and hypersensitivity (5%). pCR was achieved in 3 patients (8%). Overall-, T- and N-downstaging rates were 73%, 57% and 81% respectively. Total sphincter preservation rate was 76%, and 53% in 17 patients whose tumors were located within 5 cm from the anal verge. Non-fatal perioperative complications occurred in 13 patients (35%) with delayed wound healing occurring in 6 patients (16%). One death was recorded due to sepsis following colonic necrosis.

Conclusion

Neoadjuvant cetuximab with capecitabine-based CRT is tolerable in patients with resectable LARC. Whilst the pCR rate was similar to recent reports, a high pathological downstaging rate was achieved.     

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)

BackgroundThere is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes.Patients and methodsThis was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m²), given with standard weekly cetuximab (450 mg/m² loading dose followed by 250 mg/m² weekly) and concurrent IMRT (total dose, 70 Gy).ResultsTwenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46–84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m²) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m²), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69–97).ConclusionThe recommended phase II dose for nab-paclitaxel is 60 mg/m² weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone.Clinicaltrials.gov IDNCT00736619.     

Neoadjuvant cetuximab,twice-weekly gemcitabine,and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma

BackgroundNeoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC.Experimental designTreatment consisted of cetuximab load at 400 mg/m² followed by cetuximab 250 mg/m² weekly and gemcitabine 50 mg/m² twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection.ResultsThirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status.ConclusionsNeoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.     

Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression

BackgroundDespite the advent of highly active antiretroviral therapy, anal cancer remains a significant health problem in human immunodeficiency virus (HIV) patients. We present the clinical features and treatment outcomes of anal cancer in 60 HIV-positive patients over a 20-year period.Patients and methodsA prospective database of all HIV-positive individuals managed in a specialist unit since 1986 includes 11 112 patients (71 687 person-years of follow-up). Sixty patients with anal cancer were identified. Their clinicopathological and treatment details were analysed.ResultsAt anal cancer diagnosis, the mean age was 44 years (range: 28–75 years) and the median CD4 cell count was 305 mm^-3 (range: 16–1252 mm^-3). Fifty (83%) had chemoradiotherapy (CRT). Forty-six (92%) responded, of whom 10 (22%) subsequently relapsed with locoregional (70%), metastatic disease (10%) or both (20%). The overall 5-year survival is 65% (95% confidence interval 51% to 78%). The median CD4 count fell from 289 mm^-3 before CRT to 132 mm^-3 after 3 months and to 189 mm^-3 after 1 year (P < 0.05). Six patients in remission of anal cancer died of acquired immunodeficiency syndrome defining illnesses.ConclusionsThe management of anal cancer with CRT achieves similar outcomes as the general population. CRT is associated with significant prolonged CD4 suppression that may contribute to late deaths of patients in remission.     

Dosimetric Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiation Therapy for Soft Tissue Sarcoma of the Extremities

PurposeRadiation therapy is a standard part of limb conserving therapy for extremity soft tissue sarcoma (STS) at high risk of recurrence. Toxic effects increase with radiation dose and volume of normal tissue irradiated. This study sought to compare dosimetry of volumetric modulated arc therapy (VMAT) with intensity modulated radiation therapy (IMRT) and to investigate the optimal planning technique.Methods and MaterialsTwenty patients with extremity STS who underwent preoperative radiation therapy (50 Gy in 25 fractions) between 2016 and 2020 at a specialised sarcoma center were included. The original treatment techniques were sliding window IMRT or 3-dimensional conformal. VMAT plans were retrospectively generated according to the original tumor and organ-at-risk constraints. Quality assurance was performed as per departmental protocol. Wilcoxon signed-rank test was used to compare dosimetric parameters (for planning target volume [PTV], in-field bone, and soft tissue structures), monitor units (MUs), and treatment time.ResultsMedian patient age was 65 years and the majority were male (n = 14, 70%). The most common subtype was undifferentiated pleomorphic sarcoma (n = 14, 70%), and most tumors were located on the thigh (n = 12, 60%). Median PTV was 1110 cm³ and median volume of in-field bone 236 cm³. VMAT plans had significantly lower average MU (480 vs 862 MU, P < .001) and overall treatment time (300 vs 153 seconds, P < .001). PTV coverage favored VMAT, with marginally higher mean, minimum, and maximum doses and higher conformity index. However, differences were not statistically significant. Dose to infield bone and soft tissue structures were similar or slightly lower with VMAT.ConclusionsIn extremity STS, VMAT plans demonstrated a favorable trend toward tumor coverage and dose conformity compared with IMRT along with significantly lower MUs and half the overall treatment time.     

Long term clinical outcomes and associated predictors of progression free survival in anal canal cancer

BackgroundReports of long term clinical outcomes for patients with squamous cell carcinoma (SCC) of the anal canal treated with chemotherapy and intensity modulated radiation therapy (IMRT) are limited. Pre-treatment hematologic variables associated with outcomes remain understudied. We sought to report the long-term clinical outcomes of a cohort of patients treated with definitive chemoradiation (CRT) utilizing helical tomotherapy (HT) IMRT at a single tertiary referral center. We further sought to examine for any correlations between pre-treatment hematologic parameters and progression free survival (PFS).MethodsData from patients with SCC of the anal canal treated with definitive CRT using HT IMRT from 2005 to 2017 were collected. Pre-treatment patient characteristics examined for correlations with PFS included: hemoglobin (Hgb) level, age, diabetes mellitus (DM) status, smoking status, neutropenia, thrombocytopenia, leukopenia, neutrophil/lymphocyte ratio, neutrophil/WBC ratio, lymphocyte/WBC ratio, sex, transplant status, HIV status, Karnofsky performance score, T-stage, and N-stage. Pre-treatment Hgb levels were recorded within two weeks prior to starting CRT. Clinical outcomes, including PFS, were described using the Kaplan-Meier estimator. A multivariable (MVA) Cox model of PFS evaluated the impact of pre-treatment Hgb and diabetes while adjusting for T-stage and age.ResultsThe median patient age was 57 years old (range, 26–87) and there were 39 females (63.9%) with the remaining patients identifying as males. Median patient follow up was 5.8 years. The PFS was 83% at 5 years. The median pre-treatment Hgb was 13 g/dL. On multivariable analysis (MVA), Hgb ≤10 g/dL (HR: 11.891, 95% CI: 2.649–53.391, P=0.001) and a diagnosis of diabetes mellitus (HR: 4.524, 95% CI: 1.436–14.252, P=0.010) were both significantly associated with a worse PFS. These factors were independent of T-stage and age.ConclusionsLong-term clinical outcomes for patients with SCC of the anal canal treated with definitive CRT are presented. Pre-treatment hemoglobin of ≤10 g/dL and diabetes were both independently associated with worse PFS on MVA. This retrospective data supports further prospective study of the impact of hematologic markers and medical co-morbidities such as DM and their management on clinical outcomes for patients with SCC of the anal canal treated with curative-intent CRT.     

Chemoradiation versus local excision in treatment of stage I anal squamous cell carcinoma: A population-based analysis

IntroductionChemoradiation therapy (CRT) is the standard treatment for anal squamous cell carcinoma (ASCC) but can have significant treatment related toxicities. Recent studies have demonstrated the effectiveness of local excision (LE) for stage I ASCC with comparable oncologic outcomes to CRT. We aimed to evaluate this finding in a large population-based database.MethodsPatients diagnosed with stage I (T1N0M0) ASCC were identified from the Surveillance, Epidemiology, and End Results database, 2004–2015. Treatment approach was categorized as CRT or LE. Factors associated with treatment approach and cause-specific survival (CSS) were analyzed for the entire cohort and after stratification by tumor size (≤1 cm and 1–2 cm).ResultsAmong 883 patients, 56% had ASCCs 1–2 cm in size and 77% received CRT. Mean age was 60 years, 65% were female, and 90% were White. Factors independently associated with receiving CRT were, being female, higher tumor grade, and tumor size 1–2 cm. Unadjusted 5-year CSS for CRT was 96% while for LE it was 98% (p = 0.048). After adjusting for available confounders, treatment approach was not associated with worse CSS, however being Black (HR = 8.7) and uninsured (HR = 13.7) were independently associated with worse prognosis. After stratification by tumor size, there was still no significant difference in 5-year CSS by treatment approach.ConclusionsLE was performed in a significant proportion of patients but was not independently associated with worse CSS compared to CRT. In appropriately selected patients with well differentiated ASCCs ≤1 cm, LE could be an acceptable management option but studies measuring outcomes such as local recurrence are needed.     

Radiotherapy combined with cetuximab for locally advanced head and neck cancer: Results and toxicity

PurposeTo describe the clinical results and tolerance of the combined treatment with radiotherapy and cetuximab for locally advanced head and neck cancer.Patients and methodsFrom August 2006 and October 2010, 36 patients with advanced squamous cell head and neck carcinoma were treated with radiotherapy (70 Gy/35 fractions) and cetuximab (400 mg/m² one week before radiotherapy, following by 250 mg/m² once weekly, until week 7 of radiotherapy). Tolerance was evaluated every week. All patients were examined every 3 months the first 3 years after therapy, and then every year.ResultsThe median follow-up was 14 months. The majority of patients were male (31 out of 36). Mean age was 59 years. The tumours sites were: oral cavity (n = 8); oropharynx (n = 15); hypopharynx (n = 5); larynx (n = 8). Ninety percent of tumors were T3 or T4, and 45% were N2 or N3. Complete response was seen in 74% of patients, partial response in 17% and no response in 9% of patients. The overall survival was 44.4%. Relapse occurred in six patients. Anaphylactic reaction during the first infusion of cetuximab was observed in one patient. One patient developed severe aplasia after 48 Gy and 5 weeks of cetuximab, and died of sepsis. Eighty percent of patients presented acne, 16 patients developed a mucositis grade 2–3 and 23 patients a grade 2 skin reaction.ConclusionThe concomitant use of cetuximab and radiotherapy in locally advanced head and neck carcinoma is well tolerated in this group of patients. The results seem comparable to those in the literature.