Dose and volume de-escalation of radiotherapy in head and neck cancer.

Radiotherapy plays a key role in the treatment of head and neck cancer. However, irradiation of the head and neck region is associated with high rates of acute and chronic toxicity. Technological advances have led to better visualisation of target volumes and critical structures and improved dose conformality in the treatment volume. Despite this, acute toxicity has not been substantially reduced and late toxicity has a significant impact on patients' quality of life. The greater radiosensitivity of tumours associated with the HPV and the development of new imaging techniques have encouraged research into new deintensified strategies to reduce the side effects of radiotherapy. The aim of this paper is to review the literature on the strategies of de-escalated treatment in dose and/or volume in head and neck cancer.

Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment

Purpose The objective of this trial was to evaluate the safety and efficacy of melatonin oral gel mouthwashes in the prevention and treatment of oral mucositis (OM) in patients treated with concurrent radiation and systemic treatment for head and neck cancer. Methods Randomized, phase II, double-blind, placebo-controlled trial (1:1 ratio) of 3% melatonin oral gel mouthwashes vs. placebo, during IMRT (total dose ≥ 66 Gy) plus concurrent Q3W cisplatin or cetuximab. Primary endpoint: grade 3–4 OM or Severe Oral Mucositis (SOM) incidence by RTOG, NCI, and a composite RTOG-NCI scales. Secondary endpoints: SOM duration and grade 2–4 OM or Ulcerative Oral Mucositis (UOM) incidence and duration. Results Eighty-four patients were included in the study. Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Compared with the placebo arm, RTOG-defined SOM incidence was numerically lower in the 3% melatonin oral gel arm (53 vs. 64%, P = 0.36). In patients treated with cisplatin, assessed by the RTOG-NCI composite scale, both SOM incidence (44 vs. 78%; P = 0.02) and median SOM duration (0 vs. 22 days; P = 0.022) were significantly reduced in the melatonin arm. Median UOM duration assessed by the RTOG-NCI scale was also significantly shorter in the melatonin arm (49 vs. 73 days; P = 0.014). Rate of adverse events and overall response rate were similar between the two arms. Conclusions Treatment with melatonin oral gel showed a consistent trend to lower incidence and shorter SOM duration and shorter duration of UOM. These results warrant further investigation in phase III clinical trial (AU)

Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment.

PURPOSE: The objective of this trial was to evaluate the safety and efficacy of melatonin oral gel mouthwashes in the prevention and treatment of oral mucositis (OM) in patients treated with concurrent radiation and systemic treatment for head and neck cancer. METHODS: Randomized, phase II, double-blind, placebo-controlled trial (1:1 ratio) of 3% melatonin oral gel mouthwashes vs. placebo, during IMRT (total dose ≥ 66 Gy) plus concurrent Q3W cisplatin or cetuximab. Primary endpoint: grade 3-4 OM or Severe Oral Mucositis (SOM) incidence by RTOG, NCI, and a composite RTOG-NCI scales. Secondary endpoints: SOM duration and grade 2-4 OM or Ulcerative Oral Mucositis (UOM) incidence and duration. RESULTS: Eighty-four patients were included in the study. Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Compared with the placebo arm, RTOG-defined SOM incidence was numerically lower in the 3% melatonin oral gel arm (53 vs. 64%, P = 0.36). In patients treated with cisplatin, assessed by the RTOG-NCI composite scale, both SOM incidence (44 vs. 78%; P = 0.02) and median SOM duration (0 vs. 22 days; P = 0.022) were significantly reduced in the melatonin arm. Median UOM duration assessed by the RTOG-NCI scale was also significantly shorter in the melatonin arm (49 vs. 73 days; P = 0.014). Rate of adverse events and overall response rate were similar between the two arms. CONCLUSIONS: Treatment with melatonin oral gel showed a consistent trend to lower incidence and shorter SOM duration and shorter duration of UOM. These results warrant further investigation in phase III clinical trial.

Influence of the technique and comorbidities in hypofractionated radiotherapy for prostate cancer.

PURPOSE: To analyze the differences in toxicity and biochemical relapse-free survival with hypofractionated radiotherapy with three-dimensional radiotherapy (3D-CRT) or volumetric arc therapy (VMAT) for prostate cancer taking into account comorbidity measured using the Charlson Comorbidity Index (CCI). METHODS: From January 2011 to June 2016, 451 patients with prostate cancer were treated with 60 Gy (20 daily fractions). VMAT or 3D-CRT was used. Distribution by stage: 17% low-risk, 27.2% intermediate-risk; 39.2% high-risk, 16.6% very high-risk. Mean CCI was 3.4. RESULTS: With a median follow up of 51 months, most patients did not experience any degree of acute GI toxicity (80.9%) compared to 19.1%, who experienced some degree, mainly G-I /II. In the multivariate analysis, only technique was associated with acute GI toxicity ≥ G2. Patients treated with VMAT had greater acute GI toxicity compared with those who received 3D-CRT (23.9% vs. 13.5%, p = 0.005). With respect to acute GU toxicity, 72.7% of patients experienced some degree, fundamentally G-I/II. Neither age, CCI, nor androgen deprivation therapy (ADT) were associated with greater toxicity. Overall survival at 2, 5 and 7 years was 97%, 88% and 83% respectively. The only factor with statistical significance was CCI, with a greater number of events in individuals with a CCI ≥ 4 (p < 0.03). CONCLUSIONS: Hypofractionated radiotherapy for prostate cancer is an effective, well-tolerated treatment even for elderly patients with no associated comorbidity. Longer follow up is needed in order to report data on late toxicity.

Efficacy and safety of a simplified SBRT regimen for central and peripheral lung tumours.

BACKGROUND: Evaluate the safety, toxicity and efficacy of an institutional-simplified SBRT protocol with two short SBRT regimens (three or five fractions) for the treatment of lung cancer and oligometastases, according to the volume and localization of tumours. METHODS: Patients with stage I (T1 or T2) non-small cell lung cancer or lung oligometastases were treated from August 2011 to October 2015. Patients were required to be considered medically inoperable and were discussed in a multidisciplinary team. RESULTS: 100 patients were analysed, 59 had a peripheral location (P), and 41 a central location (C).All patients finished their SBRT course without interruptions related to acute toxicity. The most frequent acute toxicity was grade 1 asthenia, only one patient developed grade 3 toxicity (pneumonitis) and there were no grade 4 or 5 acute toxicities. Three asymptomatic radiation-induced rib fractures were identified, the 1 and 2-year rib fracture-free survival were 97% and 94%, respectively. Two-year progression-free survival and 2-year overall survival of all patients were 52% and 70%, respectively, with a median PFS and OS of 26 and 43 months. Survival free of local progression (SFLP) at 2 years was 89%. A higher PFS in primary lung cancer compared with metastatic tumours was observed, with a median of 35 months with 19 months (p = 0.01). However, no statistical difference was observed in terms of OS between both diseases. CONCLUSIONS: SBRT in lung cancer with three sessions for peripheral tumours and five sessions for central tumours may be safely delivered, with low morbidity.

Causes of death in patients with locally advanced head and neck cancer treated with radiotherapy and systemic therapy.

BACKGROUND: To investigate the incidence of non-cancer mortalities and prognostic factors associated with competitive causes of death in a homogeneous cohort of patients with locally advanced head and neck cancer treated with radiotherapy and systemic treatment. METHODS: This study included 284 patients with locally advanced head and neck cancer treated with radiotherapy and systemic treatment between 2005 and 2017. The cumulative incidence of death associated with tumour, second tumours, treatment, side effects and comorbidity was calculated. A Fine and Gray regression model was used to investigate factors associated with cancer and competitive mortality. RESULTS: The cumulative incidence of tumoral death at 5 and 10 years were 35 and 47% respectively, whereas the cumulative incidence of competitive mortality were 10 and 12% respectively. In the multivariate analysis, age and comorbidity were independent factors for non-cancer mortality. Patients with a high risk of non-cancer mortality presented a cumulative incidence of 17.3% at 5 years and 18.4% at 10 years. CONCLUSIONS: This study demonstrated a high incidence of competing mortality in older patients with comorbidities. Non-cancer deaths should be considered when selecting patients for combination therapies and in the study design ofclinical trials.

Radiotherapy in soft-tissue sarcoma of the extremities

Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease

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Radiotherapy in soft-tissue sarcoma of the extremities.

Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease.

The role of stereotactic body radiotherapy in reirradiation of head and neck cancer recurrence.

INTRODUCTION: Head and neck cancer recurrence is a therapeutic challenge due to the anatomical and functional constraints of the head and neck area. Stereotactic body radiotherapy (SBRT) is a high-precision technique of radiotherapy that consists of delivering a high ablative biological dose in 1-5 high-dose fractions, requiring a very high precision of the radiotherapy process with potential application in this clinical setting METHODS: Different studies that investigate the role of SBRT in the treatment of recurrent head and neck cancer have been reviewed. Indications to properly select patients for this treatment are presented. RESULTS: Retrospective studies and phase I-II trials with selected patients have shown low to moderate toxicity, with an efficacy at least similar to that of treatment with combinations of radiotherapy and chemotherapy. In selected patients, SBRT is a treatment option for recurrent head and neck cancer with low toxicity. DISCUSSION: New prospective studies should clarify data regarding the efficacy and toxicity of SBRT in head and neck cancer recurrence.

Improving efficacy and efficiency through the implementation of a new organisational model in a Radiation Oncology Department

Background. To evaluate a new organisational model, "process management" (PM), implemented in the Hospital Universitario Virgen de la Victoria (HUVV) compared with traditional models used in other Radiation Oncology Departments (RODs), in terms of efficacy and efficiency. Methods. The study period ranged from September 2011 to August 2012. Efficacy was assessed, comparing the number of patients attended in first consultation and treated per month, average waiting time from referral to first visit and average waiting time from first visit to treatment. Data were collected from two public hospitals in Andalusia: the HUVV and another Public Hospital in Andalusia (PHA1). Efficiency was assessed comparing the costs per patient attended in first visit and treated at HUVV in 2012 compared with those of a second Public Hospital in Andalusia (PHA2) for 2008. The number of sessions saved using hypofractionation versus classical schemes during the year 2012 in HUVV was estimated, and the money saved was calculated. Results. In the efficacy analysis, we found significant differences in the average waiting time for first visit, start of treatment, and the number of patients seen and treated annually. After calculating the total cost generated in the ROD, the efficiency analysis showed a lower cost per patient attended in first visit (EUR 599.17) and per patient treated (EUR 783.50), with a saving of 6035 sessions using hypofractionated schemes. Conclusions. Process management in an ROD reduces time, both to first medical visit and to treatment initiation, allowing an optimisation of linear accelerator (LINAC) capacity (AU)

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Improving efficacy and efficiency through the implementation of a new organisational model in a Radiation Oncology Department.

BACKGROUND: To evaluate a new organisational model, "process management" (PM), implemented in the Hospital Universitario Virgen de la Victoria (HUVV) compared with traditional models used in other Radiation Oncology Departments (RODs), in terms of efficacy and efficiency. METHODS: The study period ranged from September 2011 to August 2012. Efficacy was assessed, comparing the number of patients attended in first consultation and treated per month, average waiting time from referral to first visit and average waiting time from first visit to treatment. Data were collected from two public hospitals in Andalusia: the HUVV and another Public Hospital in Andalusia (PHA1). Efficiency was assessed comparing the costs per patient attended in first visit and treated at HUVV in 2012 compared with those of a second Public Hospital in Andalusia (PHA2) for 2008. The number of sessions saved using hypofractionation versus classical schemes during the year 2012 in HUVV was estimated, and the money saved was calculated. RESULTS: In the efficacy analysis, we found significant differences in the average waiting time for first visit, start of treatment, and the number of patients seen and treated annually. After calculating the total cost generated in the ROD, the efficiency analysis showed a lower cost per patient attended in first visit (EUR 599.17) and per patient treated (EUR 783.50), with a saving of 6035 sessions using hypofractionated schemes. CONCLUSIONS: Process management in an ROD reduces time, both to first medical visit and to treatment initiation, allowing an optimisation of linear accelerator (LINAC) capacity.

Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy.

BACKGROUND: MEK1 (MAP2K1) and MEK2 (MAP2K2) are closely related dual-specificity protein kinases which function by phosphorylating both serine/threonine and tyrosine residues of their substrates ERK1 and ERK2, controlling fundamental cellular processes that include cell growth and proliferation. To investigate the prognostic significance of pMEK expression in the nucleus and cytoplasm among patients with locally advanced head and neck cancer treated with concurrent radiochemotherapy. METHODS: Immunohistochemistry was performed on the retrieved archival tissue of 96 patients to detect pMEK, p53 and Ki-67. RESULTS: Sixty-six percent of patients were positive for pMEK expression in the nucleus and 41 % in cytoplasm. On univariate analysis, high nuclear pMEK was predictive of worse 5y-DFS and 5y-OS, with a trend to significance (26 % vs. 41 %, p = 0.09; 36 % vs. 47 %, p = 0.07). High cytoplasmic pMEK was predictive of better 5-y OS and 5-y DFS outcomes (61 % vs. 27 %, p = 0.01; 46 % vs. 22 %, p = 0.02). On multivariate analysis, low cytoplasmic pMEK and high nuclear pMEK predicted worse DFS and OS (p = 0.01; p = 0.04 and p = 0.02; p = 0.02 respectively). CONCLUSIONS: Subcellular localisation of pMEK has different prognosis in locally advanced head and neck cancer treated with radiochemotherapy.

Multicenter phase II clinical trial of operative capecitabine with concurrent radiotherapy in patients with locally advanced rectal cancer

INTRODUCTION: To assess pathologic complete response, sphincter preservation rates and toxicity profile of preoperative chemoradiation with capecitabine in resectable locally advanced rectal cancer. MATERIALS AND METHODS: Fifty-eight patients from six Spanish centers were included (March 2004 to June 2005) with histological/cytological diagnosis of locally advanced rectal cancer, age between 18 and 80 years, ECOG 0-2, adequate bone marrow, renal and hepatic functions. Prior chemotherapy/radiotherapy was not allowed. Preoperative treatment was capecitabine 825 mg/m(2) bid concomitant to radiotherapy (45 + 5.4 Gy boost over 5.5 weeks). Surgery was performed 4-8 weeks after completion of chemoradiotherapy. RESULTS: Fifty-eight patients were enrolled in this study: 60.3 % males, median age of 64.5 (30.9-78.7) years, 28.6 % with ECOG 0 and 71.4 % with ECOG 1. Median distance of tumor from the anal verge was 7 (1-12) cm. Fifty-two (89.6. %) patients completed preoperative chemoradiotherapy. Primary tumor and node downstaging occurred in 61.1 and 69.6 % of patients, respectively. Surgery was performed in 55 patients (94.8 %): 80 % had negative lymph nodes and 72.7 % underwent sphincter-preserving procedures. A pathologic complete response was observed in 10.5 % (95 % CI 2.5-18.5) of the patients. Main grade I-II toxicities were leucopenia (43.1 %), neutropenia (24.1 %), anemia (36.2 %), diarrhea (32.8 %) and skin disorders (5.1 %), from which diarrhea (6.9 %), leucopenia (1.7 %) and skin disorders (1.7 %) reached grade III. There were no grade IV toxicities. CONCLUSIONS: Preoperative capecitabine-based chemoradiation is a well-tolerated and effective neoadjuvant treatment for locally advanced rectal cancer that achieves encouraging rates of tumor downstaging (AU)

Competing causes of death in patients with locoregionally advanced head and neck cancer treated with concomitant boost radiation plus concurrent weekly cisplatin

BACKGROUND: This study analyzes the morbidity and the contribution of different causes of death to the outcome of patients with locally advanced head and- neck cancer after weekly cisplatin plus concomitant boost accelerated radiation treated in our center. MATERIALS AND METHODS: Ninety-four patients with locally advanced head and neck carcinoma were included in this phase II trial consisting of concomitant boost radiation plus concurrent weekly cisplatin. The 43 patients treated in our centered with long-term follow-up were analyzed. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (93 %) received both radiation and complete chemotherapy according to protocol. Severe late toxicity presented were subcutaneous (5 %), larynx (2 %) and esophagous (5 %). Grade I-II late toxicity included mainly xerostomy (30 %), skin (16 %) and mucosal (16 %) toxicity. With a median follow-up of 95 months (9-135), the median overall survival and progression-free survival were 26 and 19 months, respectively (95 % CI 1-52; and 95 % CI 0-45); 60 % of the patients died because of head and neck cancer and 12 % of a second neoplasm, while 27 % of non-cancer patients died. CONCLUSIONS: Patients with locoregionally advanced head and neck cancer treated with concomitant boost accelerated radiation plus chemotherapy show significant risks of mortality from causes other than disease progression (AU)

Gammagrafía salival cuantitativa en pacientes con cáncer de cabeza y cuello tratados con radioterapia / Quantitative salivary gland scintigraphy in head and neck cancer patients following radiotherapy

Objetivo. Determinar el papel de la gammagrafía salival (GS) cuantitativa en la detección de alteraciones funcionales de las glándulas salivales en pacientes con cáncer de cabeza y cuello tratados con radioterapia (RT). Material y métodos. Se estudió a 19 pacientes (17 varones) con edad media de 62,4 años (44–75). Se realizaron tres estudios a cada paciente: basal, a los 3 y a los 18 meses tras la RT. La gammagrafía salival se realizó con 3,7MBq/kg de 99mTc-pertecnetato durante 25 minutos y zumo de limón al final del minuto 15. Se calculó la fracción de excreción (FE), las cuentas máximas/minuto/píxel/MBq (CMPM), el porcentaje de captación a partir de las curvas actividad/tiempo de áreas de interés sobre ambas glándulas parótidas (GP) y glándulas submaxilares (GSM) y la influencia de las dosis recibidas por las parótidas. Resultados. La FE mostró una disminución significativa del estudio basal a los 3 meses (p<0,001), tanto en las GP como en las GSM, y a los 18 meses en las GSM (p<0,001). Se observó un aumento significativo de la FE del estudio a los 3 meses al de los 18 meses (p<0,05). Resultados. La CMPM no cambió significativamente en las GP desde el estudio basal a los de 3 y 18 meses, pero sí en las GSM con disminución significativa (p<0,01) desde el estudio basal al de 18 meses. El porcentaje de captación no cambió significativamente. Se observó correlación moderada entre la dosis a parótidas y los parámetros a los 3 meses post-RT (p<0,05). Conclusiones. La FE presentó mayor sensibilidad que la captación al efecto de la RT sobre la función salival, mostrando, además, recuperación funcional a lo largo del tiempo en las GP(AU)

Objective. To assess the role of quantitative salivary gland scintigraphy (SGS) in the detection of functional impairment of salivary glands in patients with head and neck cancer treated with radiotherapy (RT). Material and methods. We studied 19 patients (17 men), mean age 62.4 years (44–75). Three studies were performed to each patient: baseline, 3 and 18 months after RT. SGS was acquired for 25 minutes following injection of 3.7MBq/kg of 99mTc-pertechnetate with lemon juice at the end of minute 15. Material and methods. Excretion fraction (EF), counts per minute/pixel/MBq (CMPM) and uptake percentage were obtained from time-activity curves from ROIs placed over parotid (PG) and submandibular glands (SMG) and related to the doses received by the PG. Results. EF showed a significant reduction from the baseline to the 3 months study (p<0.001) for the PG and SMG and from the baseline to the 18 months study for the SMG (p<0.001). A significant improvement of EF was seen from the 3 months to the 18 months study for the PG (p<0.05). Results. CMPM did not change significantly from the baseline to the 3 months and 18 months studies for the PG and showed a significant reduction (p<0.01) for the SMG from the baseline to 18 months study. The uptake percentage did not change significantly between studies. A moderate association was observed between the doses to PG and the 3m study parameters. Conclusions. EF was more sensitive than uptake in assessing post-RT impairment of salivary function. In addition, it reflected functional recovery of parotid glands over time(AU)

[Quantitative salivary gland scintigraphy in head and neck cancer patients following radiotherapy]. / Gammagrafía salival cuantitativa en pacientes con cáncer de cabeza y cuello tratados con radioterapia.

OBJECTIVE: To assess the role of quantitative salivary gland scintigraphy (SGS) in the detection of functional impairment of salivary glands in patients with head and neck cancer treated with radiotherapy (RT). MATERIAL AND METHODS: We studied 19 patients (17 men), mean age 62.4 years (44-75). Three studies were performed to each patient: baseline, 3 and 18 months after RT. SGS was acquired for 25 minutes following injection of 3.7 MBq/kg of (99m)Tc-pertechnetate with lemon juice at the end of minute 15. Excretion fraction (EF), counts per minute/pixel/MBq (CMPM) and uptake percentage were obtained from time-activity curves from ROIs placed over parotid (PG) and submandibular glands (SMG) and related to the doses received by the PG. RESULTS: EF showed a significant reduction from the baseline to the 3 months study (p<0.001) for the PG and SMG and from the baseline to the 18 months study for the SMG (p<0.001). A significant improvement of EF was seen from the 3 months to the 18 months study for the PG (p<0.05). CMPM did not change significantly from the baseline to the 3 months and 18 months studies for the PG and showed a significant reduction (p<0.01) for the SMG from the baseline to 18 months study. The uptake percentage did not change significantly between studies. A moderate association was observed between the doses to PG and the 3m study parameters. CONCLUSIONS: EF was more sensitive than uptake in assessing post-RT impairment of salivary function. In addition, it reflected functional recovery of parotid glands over time.

Nuevas perspectivas en el tratamiento paliativo del glioblastoma multiforme y astrocitoma anaplásico recidivado con implantes de carmustina / New prospects of the paliative treatment of relapsing glioblastoma multiforme and anaplastic astrocytoma with carmustine implants

Analizamos el tratamiento de las recidivas de glioblastoma multiforme y astrocitoma anaplásico con cirugíamás la implantación de polímeros de carmustina (BCNU) en el lecho de la recidiva, con el objetivo de mejorarla calidad de vida, los síntomas neurológicos y generales, y aumentar el control tumoral. Reflejamos la experienciay datos clínicos de 4 pacientes intervenidos.El empleo de carmustina implantes puede realizarse de forma factible sin objetivarse efectos adversos queinterfieran la calidad de vida, además de observar un enlentecimiento en la progresión del deterioro neurológicode los pacientes.La selección de pacientes jóvenes, con un buen performance estatus, en los que se prevea la mejor resecciónde la recidiva posible, garantizará el éxito en el tratamiento paliativo con implantes de carmostina

In recurrent glioblastoma multiforme and anaplastic astrocytoma, surgery and carmustine (NCNU) polymersimplants over the surgical area of the removed recidivation is a promising way to improve the quality of life,the neurologic and general symptoms, and the tumor control. We report our data and experience in fourpatients. The resection was optimized because the patients were young and showed a performance statusbetween 0 and 2