Association of human papillomavirus and p16 status with mucositis and dysphagia for head and neck cancer patients treated with radiotherapy with or without cetuximab: Assessment from a phase 3 registration trial

BackgroundMucositis and dysphagia are common adverse effects of radiotherapy (RT) treatment of locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Chemotherapy added to RT increases survival rates but causes worse mucositis and dysphagia. The aim of this analysis was to assess the impact of p16 status on mucositis, dysphagia, and feeding tube use in LA-SCCHN among patients treated with RT ± cetuximab in the phase 3 IMCL-9815 trial.MethodsPatients received RT plus weekly cetuximab or RT alone. Subgroup analyses were conducted on patients with p16-positive (n = 75) or p16-negative (n = 106) oropharyngeal cancer (OPC), as determined by immunohistochemical analysis. The onset and duration of mucositis and dysphagia by treatment arm and p16 status were displayed using Kaplan–Meier curves and the log-rank test. P values for the incidence of mucositis and dysphagia were calculated using the Fisher exact test. Feeding tube use was assessed as the percent of patients reporting use.ResultsThe baseline characteristics of patients treated with RT ± cetuximab were similar in both the p16-positive and p16-negative OPC subgroups. Patients within the p16-positive OPC subgroup had higher Karnofsky scores and were more likely to have stage T1–T3 cancer and be from the United States. Regardless of p16 status, there was no difference in the onset or duration of grade 3/4 mucositis or dysphagia in patients receiving RT plus cetuximab compared with those receiving RT alone. In the overall population, and the p16-positive and p16-negative OPC subpopulations, feeding tube use was not different for patients receiving RT plus cetuximab compared with RT alone.ConclusionRegardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use.     

Prognostic factors for tube feeding dependence after curative (chemo-) radiation in head and neck cancer: A systematic review of literature

Background

Tube feeding dependence is a commonly observed debilitating side-effect of curative (chemo-) radiation in head and neck cancer patients that severely affects quality of life. Prevention of this side-effect can be obtained using advanced radiation techniques, such as IMRT. For radiotherapy treatment plan optimization, it has become increasingly important to develop prediction models that enable clinicians to predict the risk of tube feeding dependence for individual patients. To develop such a tool, information regarding the most relevant prognostic factors for tube feeding dependence is necessary.

Diffusion tensor imaging: possible implications for radiotherapy treatment planning of patients with high-grade glioma

AimsRadiotherapy treatment planning for high-grade gliomas (HGG) is hampered by the inability to image peri-tumoural white-matter infiltration. Diffusion tensor imaging (DTI) is an imaging technique that seems to show white-matter abnormalities resulting from tumour infiltration that cannot be visualised by conventional computed tomography or magnetic resonance imaging (MRI). We propose a new term, the image-based high-risk volume (IHV) for such abnormalities, which are distinct from the gross-tumour volume (GTV). For IHV based on DTI, we use the term IHV_DTI. This study assesses the value of DTI for the individualisation of radiotherapy treatment planning for patients with HGG.MethodsSeven patients with biopsy-proven HGG were included in a theoretical planning exercise, comparing standard planning techniques with individualised plans based on DTI. Standard plans were generated using a 2.5 cm clinical target volume (CTV) margin added to the GTV. For DTI-based plans, the CTV was generated by adding a 1 cm margin to the IHV_DTI. Estimates of normal tissue complication probability (NTCP) were calculated and used to estimate the level of dose escalation that could be achieved using the DTI-based plans.ResultsThe use of DTI resulted in non-uniform margins being added to the GTV to encompass areas at high risk of tumour involvement, but, in six out of seven cases, the IHV_DTI was encapsulated by the standard CTV margin. In all cases, DTI could be used to reduce the size of the planning-target volume (PTV) (mean 35%, range 18–46%), resulting in escalated doses (mean 67 Gy, range 64–74 Gy), with NTCP levels that matched the conventional treatment plans.ConclusionDTI can be used to individualise radiotherapy target volumes, and reduction in the CTV permits modest dose escalation without an increase in NTCP. DTI may also be helpful in stratifying patients according to the degree of white-matter infiltration.     

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.     

Target volume definition for head and neck intensity modulated radiotherapy: pre-clinical evaluation of PARSPORT trial guidelines

AimsThere is considerable controversy surrounding target volume definition for parotid-sparing intensity modulated radiotherapy (IMRT) for head and neck cancer. The aim of this study was to evaluate the dosimetric and radiobiological predictors of outcome anticipated by application of the detailed target volume definition guidelines agreed for the UK multicentre randomised controlled trial of parotid-sparing IMRT (PARSPORT).Materials and methodsFive patients eligible for the study were delineated using the trial guidelines. Following the protocol, plans were produced to treat these volumes with three-dimensional radiotherapy (control arm) and IMRT aimed to spare dose to the contralateral parotid gland (experimental arm). Dosimetric comparisons were made between plans, and normal tissue complication probability (NTCP) modelling for salivary glands was carried out.ResultsDoses delivered to the planning target volumes (PTV) were similar with each technique, although IMRT produced more homogeneous irradiation of the PTV. Mean doses to the contralateral parotid gland were 22.4 ± 1.7 Gy with the IMRT plans vs 60.0 ± 7.2 Gy with three-dimensional radiotherapy, P = 0.0003. Calculated contralateral parotid gland NTCP values for grade 2 xerostomia were 20–22% for IMRT and 98–100% for three-dimensional radiotherapy (P < 0.0001).ConclusionPre-clinical evaluation of the PARSPORT trial target volume definition guidelines provides theoretical support for a significant reduction in xerostomia rates. These data await confirmation from the clinical trial results.     

Induction chemotherapy with docetaxel,cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck

PurposeTo determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer.Patients and methodsForty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and infusional 5-fluorouracil 750 mg/m²/day on days 1–5 followed by radiotherapy plus C at 250 mg/m²/week (after an initial loading dose of 400 mg/m²).ResultsAfter completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively.ConclusionConcurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted.     

Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck

BackgroundThe optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC.Materials and methodsPatients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m² was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m² and cisplatin 30 mg/m² concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60–66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible.ResultsFrom 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36–85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT.ConclusionsConcurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS.ClinicalTrials.Gov IdentifierNCT00833261     

Direct use of multivariable normal tissue complication probability models in treatment plan optimisation for individualised head and neck cancer radiotherapy produces clinically acceptable treatment plans

Background and purpose

Recently, clinically validated multivariable normal tissue complication probability models (NTCP) for head and neck cancer (HNC) patients have become available. We test the feasibility of using multivariable NTCP-models directly in the optimiser for inverse treatment planning of radiotherapy to improve the dose distributions and corresponding NTCP-estimates in HNC patients.

Material and methods

For 10 HNC cases, intensity-modulated radiotherapy plans were optimised either using objective functions based on the ‘generalised equivalent uniform dose’ (OF_gEUD) or based on multivariable NTCP-models (OF_NTCP). NTCP-models for patient-rated xerostomia, physician-rated RTOG grade II-IV dysphagia, and various patient-rated aspects of swallowing dysfunction were incorporated. The NTCP-models included dose–volume parameters as well as clinical factors contributing to a personalised optimisation process. Both optimisation techniques were compared by means of ‘pseudo Pareto fronts’ (target dose conformity vs. the sum of the NTCPs).

Results

Both optimisation techniques resulted in clinically realistic treatment plans with only small differences. For nine patients the sum-NTCP was lower for the OF_NTCP optimised plans (on average 5.7% (95%CI 1.7–9.9%, p < 0.006)). Furthermore, the OF_NTCP provided the advantages of fewer unknown optimisation parameters and an intrinsic mechanism of individualisation.

Conclusions

Treatment plan optimisation using multivariable NTCP-models directly in the OF is feasible as has been demonstrated for HNC radiotherapy.     

Induction Chemotherapy Followed by Chemoradiation in Locally Advanced Pancreatic Cancer: an Effective and Well-tolerated Treatment

AimsThe treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone.Materials and methodsCase notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500–5040 cGy in 25–28 daily fractions with gemcitabine as a radiosensitiser.ResultsOf the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n = 26) was 9.2 (6.8–11.9) months and was 15.3 (11.6–upper limit not reached) months for patients who received chemoradiation (n = 16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered.ConclusionsIn this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that ‘consolidation’ chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer.     

Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer

AimsPatients with oesophageal cancer undergoing chemoradiation with curative intent are at high risk of malnutrition and its complications, including increased side effects of treatment. We have developed a nutrition pathway (NP), involving the early then periodic nutrition assessment of all patients presenting to the multidisciplinary oesophageal clinic who were planned to receive definitive chemoradiation.Materials and methodsPatients were assessed as at ‘low’, ‘moderate’ or ‘severe’ nutrition risk, and were provided with appropriate nutrition intervention ranging from preventative advice (low risk), oral nutrition support (moderate risk) to enteral feeding (severe risk). Outcomes for 24 patients treated before implementation of the NP were compared with those of 24 patients treated using the NP.ResultsPatients managed using the NP experienced less weight loss (mean weight change −4.2 kg ±6.4 cf. −8.9 kg ±5.9, P = 0.03), greater radiotherapy completion rates (92% cf. 50%, P = 0.001), fewer patients had an unplanned hospital admission (46% cf. 75%, P = 0.04), and those that did had a shorter length of stay (3.2 days ±5.4 cf. 13.5 days ±14.1, P = 0.002).ConclusionEarly and regular nutrition assessment/intervention and a multidisciplinary approach to nutrition care results in improved treatment tolerance for patients with oesophageal cancer receiving chemoradiation.     

Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study

BackgroundIntensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab.Patients and methodsEligible patients had stage III–IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m²/day × 5 days) and fluorouracil (200 mg/m²/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS).ResultsFourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3–4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients.ConclusionsThe combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.     

Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal

PurposeTo identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT).Methods and materialsWe analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥ 3 HT (HT3 +). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters.ResultsTen patients (31%) experienced HT3 +. While dose to both LSS and PBM significantly predicted for HT3 +, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3 + yielded the parameters m = 0.21, n = 1, and TD₅₀ = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3 +, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3 +.ConclusionsFor predicting the risk of HT3 +, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT.     

Consolidating duodenal and small bowel toxicity data via isoeffective dose calculations based on compiled clinical data

PurposeTo consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose–volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented.Methods and MaterialsA set of NTCP model parameters for duodenum toxicity were estimated by the χ² fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D_MLQED2,v) and convert these parameters to an isoeffective dose at another NTCP (D_MLQED2’,v).ResultsThe literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD₅₀(1)^model = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy^- 1. Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D_MLQED2’,v) between different NTCP levels remain consistent over a range of 5%-20%.ConclusionsMLQ-based isoeffective calculations of dose–response data corresponding to grade ≥ 2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D_MLQED2,v) data could be used to determine duodenum and small bowel dose–volume constraints for new dose escalation strategies.     

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy—final results of the larynx organ preservation trial DeLOS-II

BackgroundThe German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC).Patients and methodsTreatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m²/day 1, 5-FU (F) 750 mg/m²/day days 1–5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B.ResultsOf 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%.ConclusionsDespite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS.Clinical trial informationNCT00508664.     

Radiobiological Modelling of the Therapeutic Ratio for the Addition of Synchronous Chemotherapy to Radiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

AimsTo model the therapeutic gain from the addition of synchronous chemotherapy to radiotherapy in locally advanced head and neck cancer.Materials and methodsRefinements to previous methodology, including the derivation of weighted estimates of key parameters from randomised studies and the use of the expected mucosal biologically effective dose concept, have been used to produce an evidence-based assessment of the benefit from the addition of chemotherapy when considering acute grade 3 mucositis and rates of 5-year local control.ResultsFor a value of α = 0.3Gy^?1 the additional contribution from chemotherapy to local control was estimated to be 9.3 Gy₁₀ and to grade 3 mucositis 6.4 Gy₁₀. The additional expected mucosal biologically effective dose if radiotherapy dose escalation had been used instead of chemotherapy would have been 11.6 Gy₁₀. Therefore, the mucosal sparing by using synchronous chemotherapy rather than radiotherapy dose escalation was found to be 5.2 Gy₁₀ or the equivalent dose in 2 Gy fractions 4.3 Gy EQD₂.ConclusionThis modelling suggests a small therapeutic gain for the use of synchronous chemotherapy instead of radiotherapy dose escalation. This conclusion is dependent on the linear quadratic model and takes no account of late side-effects. This gain would be greater for agents that enhance the mucosal reaction to a lesser degree. This gain may be less when data for radiotherapy dose escalation to smaller high dose volumes using intensity-modulated radiotherapy are considered.     

Comparison of dosimetric parameters and acute toxicity of intensity-modulated and three-dimensional radiotherapy in patients with cervix carcinoma: A randomized prospective study

PurposeThe use of intensity-modulated radiotherapy (IMRT) to treat cervix carcinoma has increased, however prospective randomized trials are still lacking.AimTo compare the dosimetric parameters and associated acute toxicity in patients with cervix carcinoma treated with three-dimensional (3D) conformal radiotherapy and IMRT.Patients and methodsForty patients were randomized in two arms each consisting of 20 patients. Patients in both arms received concurrent chemoradiation (cisplatin 40 mg/m² weekly; 50 Gy/25 fractions). Patients were treated with 3D conformal radiotherapy in one arm and with IMRT in another arm. After external beam radiotherapy, all patients received brachytherapy (21 Gy/3 fractions at weekly interval). For dosimetric comparison, both kinds of the plans were done for all the patients. All patients were assessed throughout and until 90 days after completion of treatment for acute gastrointestinal, genitourinary and hematologic toxicities.ResultsBoth plans achieved adequate planning target volume coverage, while mean conformity index was found significantly better in IMRT plans (P-value = 0.001). D₃₅ (dose to 35% volume) and D₅₀ for bladder was reduced by 14.62 and 32.57% and for rectum by 23.82 and 43.68% in IMRT. For IMRT, V₄₅ (volume receiving 45 Gy) of bowel were found significantly lesser (P-value = 0.0001), non-tumour integral dose was found significantly higher (P-value = 0.0240) and V₂₀ of bone marrow was found significantly reduced (P-value = 0.019) in comparison to that in 3D conformal radiotherapy. Significant reduction of grade 2 or more (20 vs 45%; P-value = 0.058) and grade ≥ 3 (5 vs 15%, P-value = 0.004) acute genitourinary toxicity and grade 2 or more (20 vs 45%, P-value = 0.003) and grade 3 or more (5 vs. 20%, P-value = 0.004) acute gastrointestinal toxicity while no significant difference for grade 2 and 3 or more haematological toxicity was noted in patients treated with IMRT compared to 3D conformal radiotherapy.ConclusionIMRT provide a good alternative for treatment of cervix carcinoma with lower acute gastrointestinal and acute genitourinary toxicity with similar target coverage compared to 3D conformal radiotherapy.     

An Assessment of Action Levels in Imaging Strategies in Head and Neck Cancer using TomoTherapy. Are Our Margins Adequate in the Absence of Image Guidance?

AimsTo assess the effectiveness of different on-treatment correction strategies on set-up accuracy in patients with head and neck cancer (HNC) treated on a TomoTherapy HiArt? system. To assess the adequacy of clinical target volume (CTV) to planning target volume (PTV) treatment planning margins when treating with intensity-modulated radiotherapy without daily image guidance.Materials and methodsThe set-up accuracy measured by daily online volumetric imaging was retrospectively reviewed for the first 15 patients with HNC treated on the TomoTherapy unit at Addenbrooke's Hospital. For each fraction, megavoltage computed tomography was carried out, any discrepancy from the planning scan was noted, and corrected, before treatment. These data were used to evaluate imaging correction protocols using three different action levels. The first three fractions were imaged and used to correct for systematic error, using a 5 mm action level (5 mmAL), a 3 mm action level (3 mmAL), and no action level (NAL). All imaging strategies were applied, to assess the number of fractions that would potentially have exceeded a 5 and 3 mm margin. Systematic and random errors were calculated for the population, assuming the NAL protocol had been applied, and minimum CTV–PTV margins, required to allow for errors attributable only to set-up, were calculated using van Herk's formula.ResultsIn total, 490 fractions were analysed. Using a 5 mmAL imaging protocol, potentially 198/490 fractions (40%) were outside a 5 mm CTV–PTV margin and 400/490 (82%) were outside a 3 mm margin. Using a 3 mmAL imaging protocol, potentially 67/490 fractions (14%) were outside a 5 mm CTV–PTV margin and 253/490 (52%) were outside a 3 mm margin. A small systematic error was identified in the system; once corrected this would improve these results. Using the NAL imaging protocol, potentially 31/490 fractions (6%) were outside a 5 mm CTV–PTV margin and 143/490 fractions (29%) were outside a 3 mm margin. Estimated minimum CTV–PTV margins to account only for set-up errors, with three-fraction image-guided radiotherapy and a NAL protocol, were 2.8, 3.1 and 4.1 mm in the mediolateral, superior–inferior and anterior–posterior directions, respectively.ConclusionReducing the action level at which the systematic error is corrected improves the probability of treatment delivery accuracy. Using the NAL correction protocol reduces the number of fractions that have set-up displacements outside a 5 mm CTV–PTV margin. Although a 5 mm margin is probably sufficient for standard HNC radiotherapy, change to a 3 mm margin is not favoured at our centre without access to daily image-guided radiotherapy.     

RAS mutations and cetuximab in locally advanced rectal cancer: Results of the EXPERT-C trial

BackgroundRAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial.MethodsNinety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed.ResultsEleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n = 40; CAPOX-C, n = 38). In this population, after a median follow-up of 63.8 months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p = 0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p = 0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p = 0.20).ConclusionsRAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.     

Phase II trial of combination treatment with paclitaxel,carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02)

BackgroundThe standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.Patients and methodsEligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m² on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m², followed by 250 mg/m² weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.ResultsForty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.ConclusionsThe PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.Registered clinical trial numberUMIN000010507.     

Analyse des contraintes dosimétriques obtenues par trois techniques d’irradiation de tumeurs pulmonaires

PurposeComparison of three dosimetric techniques of lung tumor delineation to integrate tumor motion during breathing.Patients and methodsNineteen patients with T1-3N0M0 malignant lung tumor were treated with definitive chemoradiotherapy (14 cases) or pre-surgery chemoradiation. Doses were, respectively, 66 and 46 Gy. CT-scan for delineation was performed during three phases of breathing: free breathing and deep breath-hold inspiration and expiration. GTV (gross tumor volume) was delineated on the three sequences. The classic technique included GTV from the free-breathing sequence plus a CTV (clinical target volume) margin of 5 to 8 mm plus a PTV (planning target volume) margin of 7 to 10 mm (including ITV [internal target volume] margin and set-up margin). The gating-like technique included GTV from the deep breath-hold inspiration sequence plus a CTV margin of 5 to 8 mm plus a PTV margin of 2 mm. The three-volume technique, included GTV as a result of the fusion of GTVs from the three sequences plus a CTV margin of 5 to 8 mm plus a PTV margin of 2 mm. Dosimetry was calculated for the three PTVs, if possible, with the same fields number and position. Dose constraints and rules were imposed to accept dosimetries: firstly spinal cord maximal dose less than 45 Gy, followed by V95 % for PTV greater than or equal to 95 %, and V20 GY_Gy for lung less than or equal to 30 %, V30 GY_Gy for lung less than or equal to 20 %.ResultsGTVs were not statistically different between the three methods of delineation. PTVs were significantly lower with the gating-like technique. V95% of the PTV were not different between the three techniques. With the classic-, the gating-like- and the 3-volume techniques, dosimetry was considered as acceptable, respectively in 15, 18 and 15 cases. Comparisons of constraint values showed that the gating-like method gave the best results. In the case of pre-operative management, the gating-like method allowed the best results even for the V95% values. However, in the absence of gating device or without the possibility to use it, the 3-volume method allowed to take into account more precisely the organ motion than the classical technique.ConclusionThe 3-volume method can be done. It is a good method to take into account the organ motions. However, the gating-like method gives the best results leading to propose its use even for pre-operative patients with upper tumors.