Influence of stem-cell cycle time on accelerated re-population during radiotherapy in head and neck cancer

Objectives

Tumour re‐population during radiotherapy was identified as an important reason for treatment failure in head and neck cancers. The process of re‐population is suggested to be caused by various mechanisms, one of the most plausible one being accelerated division of stem‐cells (i.e. drastic shortening of cell cycle duration). However, the literature lacks quantitative data regarding the length of tumour stem‐cell cycle time during irradiation.

Materials and methods

The presented work suggests that if accelerated stem‐cell division is indeed a key mechanism behind tumour re‐population, the stem‐cell cycle time can drop below 10 h during radiotherapy. To illustrate the possible implications, the mechanism of accelerated division was implemented into a Monte Carlo model of tumour growth and response to radiotherapy. Tumour response to radiotherapy was simulated with different stem‐cell cycle times (between 2 and 10 h) after the initiation of radiotherapy.

Results

It was found that very short stem‐cell cycle times lead to tumour re‐population during treatment, which cannot be overcome by radiation‐induced cell kill. Increasing the number of radiation dose fractions per week might be effective, but only for longer cell cycle times.

Conclusion

It is of crucial importance to quantitatively assess the mechanisms responsible for tumour re‐population, given that conventional treatment regimens are not efficient in delivering lethal doses to advanced head and neck tumours.     

Stochastic modelling of the role of cisplatin in altered fractionation schedules for head and neck cancer

Advanced head and neck cancers are one of the most challenging cancers facing the oncologists due to their aggressiveness attributable to the high hypoxic content and the tumour's ability to repopulate during radiotherapy. Alterations of radiotherapy fractionation schedules are possible ways to improve tumour control. Clinical trials have shown that both hyperfractionated radiotherapy (multiple fractions a day, over the same treatment time), and accelerated radiotherapy (higher doses per fraction, six days a week, over 5 weeks or less) are more effective than conventional radiotherapy in the management of head and neck cancer. However, the treatment choice between hyperfractionated and accelerated radiotherapy is still debated, due to very similar results obtained regarding tumour control. Furthermore, while radiotherapy alone has an impact on the short-term prognosis of advanced head and neck cancer, the long-term benefits have been moderate. Cisplatin is a chemotherapeutic agent which combined with conventional radiotherapy has shown to improve patient survival. The present paper employs a Monte Carlo modelling approach in assessing the effect of combined cisplatin-altered fractionation schedule on tumour response. The growth of a head and neck carcinoma has been modelled using probabilistic functions sampled by computer generated random number sequences, maintaining the biological constitution of a tumour. The tumour growth model has been built to simulate the in vivo processes taking place before and after radiotherapy/chemotherapy. The model has shown that adding cisplatin to radiotherapy improves tumour control in both hyperfractionated and accelerated radiotherapy.     

First results of a randomized clinical trial of fast neutrons compared with X or gamma rays in treatment of advanced tumours of the head and neck. Report to the Medical Research Council.

Results of the first randomized clinical trial to compare the effects of fast neutrons and those of x or gamma rays (photons) in treating patients with advanced tumours of the head and neck are reported. In 37 out of 52 patients treated with neutrons and 16 out of 50 treated with photons the local tumour completely regressed; the tumour later recurred in nine of the 16 photon patients but in none of the 37 neutron patients. The advantages to the neutron-treated patients were seen in tumours of well and poorly differentiated histology and in each site. Complications after treatment did not differ significantly between the groups. Despite these substantial differences in local control of the tumour there were no significant differences in mortality between the series. A detailed study of the effective doses and the response of tumours and normal tissue in each series indicated that the improved results from neutron therapy were due to differences in the biological quality of the beam and not to the rather higher average effective dose in the neutron series. To assess the long-term effects of neutron treatment patients in earlier stages of disease and with smaller tumours should be included in the next phase of the trial.     

The Evolution of Tumour Composition During Fractionated Radiotherapy: Implications for Outcome

Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially resolved mathematical model of tumour growth, first proposed by Greenspan (Stud Appl Math 51:317–340, 1972), to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intratumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon regrowth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.     

Omni-wedge technique for increased dose homogeneity in head and neck radiotherapy

Dose homogeneity in head and neck tumour irradiation is a challenging task for conventional radiotherapy due to large anatomic contour irregularities and tissue heterogeneities in irradiation volumes. We present a simple technique based on the omni-wedge concept which uses superimposed fields, orthogonally wedged, to improve target-volumes homogeneity in head and neck tumour irradiation. The routine implementation of this technique is straightforward and easy to achieve with standard radiotherapy equipment and treatment planning software. Our five-year experience in the clinical implementation of this technique is presented.     

Increased prevalence of tumour infiltrating immune cells in oropharyngeal tumours in comparison to other subsites: relationship to peripheral immunity

Background

The nature of the tumour microenvironment immune response in head and neck cancer patients has an important role in tumour development and metastasis, but it is unknown if this differs between cancer subsites or whether it is related to the peripheral immune response.

Methods

Immune cells (CD4, CD8, Foxp3) in head and neck squamous cell carcinoma tissue (HNSCC; n = 66), detected by immunohistochemistry, have been correlated with tumour subsite and immune cells in the peripheral circulation (CD4⁺CD25^HighFoxp3⁺ Treg and CD4⁺ T cells), identified using flow cytometry.

Results

Oropharyngeal tumours had a greater number of infiltrating immune cells in both tumour and stroma compared with other subsites, but no difference was observed in the circulating levels. Immune cells in the stroma were positively related to those in the tumour with consistently higher levels in stroma. A strong relationship was found between the number of CD4⁺ and Foxp3⁺ cells but not between the number of CD8⁺ and Foxp3⁺ cells in the tumour. The number of Foxp3⁺ cells within the tumour was positively correlated with the percentage of circulating CD4⁺CD25^High cells positive for Foxp3. Late stage laryngeal tumours showed a higher number of Foxp3⁺ lymphocytes compared with early stage malignancies, and oropharyngeal tumours had more CD4⁺ cells in node negative tumours compared with node positive ones.

Conclusion

The level of immune cell infiltration in head and neck squamous cell carcinoma appears to be subsite dependent residing primarily in the stroma and is likely to be dependent on the peripheral immune response.     

Palliative brachytherapy to axilla and hypopharynx in elderly patient with hypopharyngeal squamous cell carcinoma — case report

Brachytherapy (BT) is an important local treatment of tumor and it can be applied to different anatomical sites either in a curative or palliative setting. BT can deliver large dose of radiation to the tumor while sparing the surrounding normal tissue which translates into a better therapeutic ratio compared to external beam radiotherapy. However, the evidence for the use of brachytherapy in the palliative setting is lacking in the literature. In this case report, we describe the brachytherapy technique and outcome of a patient with squamous cell carcinoma of the hypopharynx who underwent palliative brachytherapy to the hypopharynx and metastatic tumor at the right axilla.     

On the eptihermal neutron energy limit for Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT): Study and impact of new energy limits

Background and purpose: Accelerator-Based Boron Neutron Capture Therapy is a radiotherapy based on compact accelerator neutron sources requiring an epithermal neutron field for tumour irradiations. Neutrons of 10 keV are considered as the maximum optimised energy to treat deep-seated tumours. We investigated, by means of Monte Carlo simulations, the epithermal range from 10 eV to 10 keV in order to optimise the maximum epithermal neutron energy as a function of the tumour depth.Methods: A Snyder head phantom was simulated and mono-energetic neutrons with 4 different incident energies were used: 10 eV, 100 eV, 1 keV and 10 keV. ¹⁰B capture rates and absorbed dose composition on every tissue were calculated to describe and compare the effects of lowering the maximum epithermal energy. The Therapeutic Gain (TG) was estimated considering the whole brain volume.Results: For tumours seated at 4 cm depth, 10 eV, 100 eV and 1 keV neutrons provided respectively 54%, 36% and 18% increase on the TG compared to 10 keV neutrons. Neutrons with energies between 10 eV and 1 keV provided higher TG than 10 keV neutrons for tumours seated up to 6.4 cm depth inside the head. The size of the tumour does not change these results.Conclusions: Using lower epithermal energy neutrons for AB-BNCT tumour irradiation could improve treatment efficacy, delivering more therapeutic dose while reducing the dose in healthy tissues. This could lead to new Beam Shape Assembly designs in order to optimise the BNCT irradiation.     

Neoadjuvant cisplatin for head and neck cancer: Simulation of a novel schedule for improved therapeutic ratio

Current clinical studies support the role of neoadjuvant cisplatin administration prior to curative radiotherapy or radio-chemotherapy for advanced head and neck cancer. Nevertheless, based on locoregional control rates the studies indicate that there is need to redesign cisplatin-based schedules for induction chemotherapy, thus the ideal treatment regimen is yet to be established. While the pharmacokinetics/dynamics of daily cisplatin regimens correspond better with the cell cycle properties of head and neck cancers, weekly regimens are more commonly employed in clinics due to lower complications. Yet, the high rates of adverse events induced by current cisplatin schedules often represent a limiting factor in the overall success of the treatment.The aim of the present paper was to model the pharmacodynamic properties of cisplatin and to simulate and compare various neoadjuvant treatment regimens in regards to their effect on tumour control. Treatment simulation was undertaken on a virtual squamous cell carcinoma of the head and neck, previously grown by computer-based probabilistic methods.The model suggests that a novel cisplatin treatment, given every three days is comparable, in regards to tumour control, with the daily administration and more effective than the weekly regimen in neoadjuvant settings. Endpoints were assessed in terms of cell population regrowth after treatment cessation followed by two weeks of unperturbed growth. Simulation of two weeks low-dose daily cisplatin followed by two weeks ‘free growth’ lead to 15% population regrowth, while weekly high-dose cisplatin over three weeks, followed by two weeks unperturbed growth resulted in 52% tumour cell regrowth. The proposed novel schedule of low-dose third-daily cisplatin gives closer tumour regrowth to daily administration (27% versus 15%) than to the weekly regimen (52%) and also similar cell distribution along the cell cycle as the daily one, suggesting therefore comparable response to subsequent treatment.The advantage of using a third-daily drug regimen would be a decrease in normal tissue complication rates compared to daily administration and possibly an increase in tumour control when compared to the ‘conventional’ weekly cisplatin delivery.     

Feasibility of Tomotherapy-Based Image-Guided Radiotherapy to Reduce Aspiration Risk in Patients with Non-Laryngeal and Non-Pharyngeal Head and Neck Cancer

Purpose

The study aims to assess the feasibility of Tomotherapy-based image-guided radiotherapy (IGRT) to reduce the aspiration risk in patients with non-laryngeal and non-hypopharyngeal cancer. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers was conducted. All patients had a modified barium swallow (MBS) prior to treatment, which was repeated one month following radiotherapy. Mean middle and inferior pharyngeal dose was recorded and correlated with the MBS results to determine aspiration risk.

Results

Mean pharyngeal dose was 23.2 Gy for the whole group. Two patients (4.2%) developed trace aspiration following radiotherapy which resolved with swallowing therapy. At a median follow-up of 19 months (1–48 months), all patients were able to resume normal oral feeding without aspiration.

Conclusion and Clinical Relevance

IGRT may reduce the aspiration risk by decreasing the mean pharyngeal dose in the presence of large cervical lymph nodes. Further prospective studies with IGRT should be performed in patients with non-laryngeal and non-hypopharyngeal head and neck cancers to verify this hypothesis.     

Escalated hyperfractionation in radiotherapy for head and neck cancer – 5-year results

PurposeTo evaluate 5-year results of escalated hyperfractionation schedule in aspect of local tumour control (LTC) and late radiation toxicity.Material and methodsForty eight patients with squamous cell carcinoma of oral cavity (34 pts), oropharynx (11 pts) and larynx (3) in stage T1-4N0-1 have been treated at Centre of Oncology in Gliwice, between the years 1988–92. There were four patients with T1 primary tumour, 27 with T2, 11 with T3 and 2 with T4; in 4 patients the tumour stage remains unknown (TX). All the patients were treated by radiation therapy alone, using the technique of two opposed parallel fields and hyperfractionation with escalation of the dose per fraction during the second part of the treatment schedule. The total dose ranged between 62,2 and 74 Gy. The median follow-up was 62 months.ResultsDespite of the relative high proportion of complete local regressions (75%), the 5-year LTC rate of 54% was noted in the whole group of patients. Stage-related LTC rates were as follows: 100% for TX tumours, 50% for T1, 55% for T2, 45% for T3 and 0% for T4. Acute radiation reactions were more intensive than those usually observed during conventional radiotherapy; all patients experienced a confluent mucositis and two waves of acute mucosal reaction because of treatment gap were observed during the radiation course. Severe late radiation toxicity (grade IV) was noted in two patients (4%).ConclusionsLong-term tumour control results of escalated hyperfractionation radiotherapy may suggest that there is no benefit of a such regimen. However, in the majority of patients the treatment course differed markedly from protocol assumptions.     

Radiation therapy after radical prostatectomy: strike early, strike hard! The case for adjuvant radiation therapy

With a large local tumor, when surgical extirpation results in a positive surgical margin, adjuvant radiotherapy is the routine approach for a variety of solid tumors, such as head and neck cancers, rectal cancer, lung cancer, and breast cancer. With prostate cancer, however, surgery and radiotherapy are considered as alternative single-modality treatments, and their combination is far less enthusiastically embraced. Despite a trend toward earlier clinical diagnosis of prostate cancer since the introduction of prostate-specific antigen (PSA) screening, modern surgical series continue to show a 15%-25% incidence of positive surgical margins. Postoperative radiotherapy, whether delivered as "adjuvant therapy" shortly after surgery or as "salvage therapy" when serum PSA becomes detectable, effectively improves local control and prolongs disease-free survival.     

Stereotactic radiation therapy for skull base recurrences: Is a salvage approach still possible?

AimA literature review was performed to analyse the role of stereotactic radiotherapy given in a single shot or in a fractionated fashion for recurrent skull base tumours in order to ascertain if it can be a real salvage approach.BackgroundThe management of recurrent skull base tumours can have a curative or palliative intent and mainly includes surgery and RT.Materials and methodsOne-thousand-ninety-one articles were found in the search databases and the most relevant of them were analysed and briefly described.ResultsData on recurrences of meningioma, pituitary adenoma, craniopharyngioma, chordoma and chondrosarcoma, vestibular schwannoma, glomus jugulare tumours, olfactory neuroblastoma and recurrences from head and neck tumours invading the base of skull are reported highlighting the most relevant results in terms of local control, survival, side effects and complications.ConclusionsIn conclusion, it emerges that SRS and FSRT are effective and safe radiation modalities of realize real salvage treatment for recurrent skull base tumours.     

Effect of radiotherapy delay in overall treatment time on local control and survival in head and neck cancer: Review of the literature

Treatment delays in completing radiotherapy (RT) for many neoplasms are a major problem affecting treatment outcome, as increasingly shown in the literature. Overall treatment time (OTT) could be a critical predictor of local tumor control and/or survival. In an attempt to establish a protocol for managing delays during RT, especially for heavily overloaded units, we have extensively reviewed the available literature on head and neck cancer. We confirmed a large deleterious effect of prolonged OTT on both local control and survival of these patients.     

Radiosensitization of Hypoxic Cells <Emphasis Type="Italic">in vitro</Emphasis>: a Water-soluble Derivative of Paranitroacetophenone

IT is believed that, in radiotherapy, the local control of some tumours is limited by radioresistant hypoxic regions in the tumour. Drugs which will sensitize these hypoxic tumour cells to radiation without increasing damage to surrounding well-oxygenated normal tissue, have, therefore, been demanded.     

Modern radiotherapy techniques in the treatment of tumour of the base of tongue

AIM: To demonstrate the role, the execution and the importance of the computed tomography (CT) based three-dimensional brachytherapy and conformal percutan radiotherapy in the treatment of the advanced tumour of the base of tongue. METHODS: Between January 1993 and June 2000, 27 patients with stage III-IV squamous cell cancers of the base of tongue were treated after 60 Gy percutan irradiation with interstitial, high dose rate brachytherapy (23 patients) or conformal, multi-fields radiotherapy (4 patients) as a boost. The dose of the boost irradiation varied between 12 and 24 Gy. RESULTS: Boost irradiation was well tolerated by the patients. The local tumour control at the mean follow-up period (39 months) was 52%. Using this two treatment methods in case of percutan conformal irradiation 6%, in case of brachytherapy 1.5% of the mandible received the prescribed boost dose. The spinal cord received a maximum of 15%, and 8% of the boost dose, respectively, depending on the two treatment types. CONCLUSION: With the help of these two radiotherapeutic modalities locally higher cumulative dose and better tumour control can be achieved without the higher risk of radiation injury of the surrounding normal tissues and the two most critical organs (medulla, mandible).     

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with ¹⁰B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells.The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced.Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments.The optimal neutron energy is within [500 eV−3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases.Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235–238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options.