The purpose of this article is two-fold: to help statisticians confronted with the design, implementation and analysis of clinical trials and new to the field of head and neck cancer; but also to ...sensitize research physicians with the role, the tasks and the challenges faced by the medical statisticians. These two purposes altogether will hopefully encourage and enable fluid communication between the research physician and the medical statistician and the understanding of each other's field and concerns. In particular, the methodological challenges resulting from the heterogeneity of the head and neck cancer, the complexity of the treatments and the associated comorbidities are presented with examples borrowed from medical literature and from the practical experience of the authors in this field.
Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined.
We ...identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results.
In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD.
The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.
We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development ...strategies for this class of compounds.
We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013.
A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion.
This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
In many recurrent and/or metastatic cancers, the advent of immunotherapy opens up new scenarios of treatment response, with new phenomena, such as pseudoprogression and hyperprogression. Because of ...this, different immune-related response criteria have been developed, and new therapeutic strategies adopted, such as treatment beyond progression. Moreover, the role of progression-free survival as a surrogate has been questioned, and new surrogate endpoint hypotheses have arisen. A proper understanding of radiological imaging, an assessment of the biological events triggered by therapy, and the clinical evolution of the lesions and of the patient performance status are all factors that should be considered to guide the oncologist’s treatment choice. The primary aim of this article is to discuss how all these concepts apply to recurrent/metastatic head and neck squamous cell carcinoma patients when treated with immunotherapy.
PurposeRare cancers are defined by an incidence of <6 out of 100 000 cases per year. They are under-represented in clinical research including tumour molecular analysis. The aim of Arcagen is to ...generate a multinational database integrating clinical and molecular information of patients with rare cancers.Patients and methodsWe present the retrospective feasibility cohort of patients with rare cancers, with previously collected tumour samples available from any stage. Molecular analysis was performed using FoundationOne CDx for all histologies except for sarcoma where FoundationOne Heme was used. Clinical data including demographic data, medical history, malignant history, treatment and survival data were collected.ResultsEighty-seven patients from three centres were screened; molecular data were obtained for 77 patients (41 sarcomas, 9 yolk sac tumours, 14 rare head and neck cancers, 13 thymomas). The median age at the time of diagnosis was 48 (range 28–85). Most patients had reportable genomic alterations (89%). The most common alterations were linked to cell cycle regulation (TP53, RB1, CDKN2A/B deletions and MDM2 amplification). Multiple activating single-nucleotide variants (SNVs) could be detected in the RAS/RAF family. The tumour mutational burden status was globally low across all samples with a median of 3 Muts/MB (range 0–52). Only 4 cases (ie, 4.7% of tumours) had direct actionable mutations for a treatment approved in Europe within the patient’s tumour type.ConclusionThe Arcagen project aims to bridge the gap and improve knowledge of the molecular landscape of rare cancers by prospectively recruiting up to 1000 patients.
Treatment of locally advanced head and neck carcinoma not amenable for surgical resection or resected with high-risk features is usually based on (chemo-)radiation treatment. Oral mucositis ...represents one of the main side effects of (chemo-)radiation, with an important impact on quality of life and causing approximately 20% of early interruption of treatment, leading to a suboptimal dose administered. Treatment and prevention of oral mucositis have a central role in the therapeutic pathways of head and neck cancer patients but remains quite challenging. Although extensive research is conducted to identify interventions for the management of mucositis, very few interventions had sufficient evidence to generate an international expert consensus. This may be partially explained by confounding factors that could influence the development and assessment of oral mucositis. Little is known about the confounding factors of oral mucositis, which, if not well balanced in an experimental study, could lead to non-solid results. The current paper aims to review the main oral mucositis confounding factors related to head and neck cancer patients.
Reply to Caccialanza et al Boisselier, Pierre; Thézénas, Simon; Flori, Nicolas ...
The American journal of clinical nutrition,
04/2021, Letnik:
113, Številka:
4
Journal Article
Recenzirano
Odprti dostop
A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX. Boisselier P, Kaminsky MC, Thézenas S, Gallocher O, ...Lavau-Denes S, Garcia-Ramirez M, Alfonsi M, Cupissol D, de Forges H, Janiszewski C, Geoffrois L, Sire C, Senesse P; Head and Neck Oncology and Radiotherapy Group (GORTEC). Am J Clin Nutr. 2020 Dec 10;112(6):1523-1531. doi: 10.1093/ajcn/nqaa227. PMID: 32936874 Clinical Trial. Immunonutrition in head and neck cancer patients undergoing chemoradiotherapy: an alternative approach for overcoming potential bias. Caccialanza R, Cereda E, Orlandi E, Filippi AR, Comoli P, Alberti A, Imarisio I, Pedrazzoli P, Bossi P. Am J Clin Nutr. 2021 Apr 6;113(4):1053-1054. doi: 10.1093/ajcn/nqaa421. PMID: 33822867 No abstract available.
Recent recommendations on cachexia highlight, in head and neck cancers, the heterogeneity of studies, focusing on weight loss and sequelae including swallowing disorders. The current national ...guidelines emphasize that, in cases of concurrent chemoradiotherapy (cCRT) involving the oral cavity and oropharynx, prophylactic gastrostomy placement should be carried out systematically. We review why this technique is particularly relevant in this specific location for the feasibility of cCRT.
A randomized trial is underway on swallowing disorders and the quality of life of patients after prophylactic vs. reactive gastrostomy in advanced oropharyngeal cancer patients treated with CRT. Concurrently, recent literature reviews emphasize the importance of the cumulative dose of chemotherapy for local control and survival. In cases of cCRT involving the oral cavity or the oropharynx, nutritional support could have a beneficial or detrimental impact on chemotherapy.
Specifically for patients treated with cCRT involving the oral cavity and oropharynx, prophylactic gastrostomy would be able to fulfill the three objectives of local control, survival, and quality of life, minimizing complications related to nutritional support. Studies need to be more homogeneous. In clinical practice, nutrition should primarily assist in carrying out cancer treatment when survival is the main goal.
A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. ...Fluorodeoxyglucose (18FFDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by 18FFDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.
This prospective multicenter study evaluated the prognostic value of circulating tumor cells (CTCs) in relapsing nonoperable or metastatic head and neck squamous cell carcinoma (rHNSCC) treated by ...chemotherapy and cetuximab.
In 65 patients suitable for analyses, peripheral blood was taken at day 0 (D
) D
, and D
of treatment for CTC detection by CellSearch
, EPISPOT, and flow cytometry (FCM). Progression-free survival (PFS) was assessed with the Kaplan-Meier method and compared with the log-rank test (
< 0.05).
At D
, CTCs were detected with EPISPOT, CellSearch, and FCM in 69% (45/65), 21% (12/58), and 11% (7/61) of patients, respectively. In the patients tested with all 3 methods, EPISPOT identified 92% (36/39), 92% (35/38), and 90% (25/28) of all positive samples at D
, D
, and D
, respectively. Median PFS time was significantly lower in (
) patients with increasing or stable CTC counts (36/54) from D
to D
with EPISPOT
(3.9 vs 6.2 months; 95% CI, 5.0-6.9;
= 0.0103) and (
) patients with ≥1 CTC detected with EPISPOT or CellSearch
(37/51) (
= 0.0311), EPISPOT or FCM (38/54) (
= 0.0480), and CellSearch or FCM (11/51) (
= 0.0005) at D
.
CTCs can be detected before and during chemotherapy in patients with rHNSCC. D
-D
CTC kinetics evaluated with EPISPOT
are associated with the response to treatment. This study indicates that CTCs can be used as a real-time liquid biopsy to monitor the early response to chemotherapy in rHNSCC.
NCT02119559.
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