Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors

Purpose

To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors.

Methods

Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient.

Results

The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively.

Conclusions

The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM.     

Advantage of combining NLCQ-1 (NSC 709257) with radiation in treatment of human head and neck xenografts

NLCQ-1 (NSC 709257), a hypoxia-selective cytotoxin that targets DNA through weak intercalation, was investigated for efficacy in combination with single or fractionated radiotherapy of human head and neck xenografts. A staged tumor experiment was performed in tumor-bearing female athymic nude mice that were locally irradiated with or without NLCQ-1. Tumor hypoxia was assessed by immunohistochemistry for pimonidazole adducts in tumors of varying weight. Fractionated radiation, depending on the dose, was administered either once daily for 4 days or once daily for 4 days followed by a 7-day rest and repeat. NLCQ-1 was administered i.p. at 15 mg/kg alone or 45 min before each radiation dose. Hypoxia (1-52%) was detected in all tumors and was positively correlated with tumor size. NLCQ-1 alone resulted in about 10 days of tumor growth delay, measured at sixfold the tumor's original size, without causing toxicity. All combination treatments with NLCQ-1 were more effective than treatments with radiation alone. Radiation at 1 Gy given once daily for 4 days on days 20 and 30 caused 3.5 days of tumor growth delay, whereas in combination with NLCQ-1 it caused 14.5 days of growth delay. Radiation at 5 Gy given in two doses 10 days apart resulted in 3.5 days of tumor growth delay, whereas more than 20 additional days of delay were observed in combination with NLCQ-1. Radiation given as a single dose of 10 Gy resulted in about 7 days of tumor growth delay, whereas in combination with NLCQ-1 about 30 additional days of delay were seen. These results suggest a significant advantage in combining radiation with NLCQ-1 in treatment of human head and neck tumors, which are known to have hypoxic areas.     

Definitive,intensity modulated tomotherapy with a simultaneous integrated boost for prostate cancer patients – Long term data on toxicity and biochemical control

AimTo report long-term data regarding biochemical control and late toxicity of simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) with tomotherapy in patients with localized prostate cancer.BackgroundDose escalation improves cancer control after curative intended radiation therapy (RT) to patients with localized prostate cancer, without increasing toxicity, if IMRT is used.Materials and methodsIn this retrospective analysis, we evaluated long-term toxicity and biochemical control of the first 40 patients with intermediate risk prostate cancer receiving SIB-IMRT. Primary target volume (PTV) 1 including the prostate and proximal third of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. PTV 2 containing the prostate with smaller safety margins was treated as SIB to a total dose of 76 Gy with 2.17 Gy per fraction. Toxicity was evaluated using an adapted CTCAE-Score (Version 3).ResultsMedian follow-up of living patients was 66 (20–78) months. No late genitourinary toxicity higher than grade 2 has been reported. Grade 2 genitourinary toxicity rates decreased from 58% at the end of the treatment to 10% at 60 months. Late gastrointestinal (GI) toxicity was also moderate, though the prescribed PTV Dose of 76 Gy was accepted at the anterior rectal wall. 74% of patients reported any GI toxicity during follow up and no toxicity rates higher than grade 2 were observed. Grade 2 side effects were reported by 13% of the patients at 60 months. 5-year freedom from biochemical failure was 95% at our last follow up.ConclusionSIB-IMRT using daily MV-CT guidance showed excellent long-term biochemical control and low toxicity rates.     

Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients

Background

although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up.

Methods

patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3–4/anyN, or anyT/N1–2; ECOG Performance Status 0–2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 ± 2 days after RT completion, adopting the total mesorectal excision technique.

Results

24 men and 23 women were enrolled; median age was 55 years (r.: 39–77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18–84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence.

Conclusion

bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT.

     

Low-dose Taxol radiosensitization in locally advanced head and neck cancers

INTRODUCTION: Combined modality treatment with chemotherapy and radiotherapy in locally advanced head and neck cancers is an effective and often the only treatment with a chance of cure. An alternative is to use chemotherapeutic agents at low doses as radiosensitizers. In this study we examined the radiosensitizing effect of low dose Taxol in locally advanced head and neck cancer. Patients and methods: 26 patients with locally advanced squamous cell carcinoma of the oral cavity and the oropharynx were treated with external beam radiotherapy up to doses of 66-70 Gy and received concomitantly 2 mg/m(2) Taxol intravenously three times a week. Response rates according to WHO criteria, side effects according to the National Cancer Institute Common Toxicity Criteria, overall and progression-free survival were evaluated. RESULTS: All patients completed the therapy. Median radiation dose was 66 Gy, Taxol dose 40 mg/m(2) and treatment duration 54 days. 8 weeks after completion of therapy complete response was 30.8%, partial response 34.6%, stable disease 11.5% and progressive disease 23.1%. The median follow-up time was 25 months (9-36). At the cloes- out date 12 (46,1%) of the patients were alive, 9 without evidence of disease. The estimated median overall survival was 22 months (CI 14.2-34.6), the median progression-free survival 12 months (CI 5.2-18.8). We observed four grade 4, fourteen grade 3 and numerous grade 1-2 side effects. There was no treatment related death. DISCUSSION: Our regimen resulted in a worse response rate than the aggressive chemoradiation protocols treating the same disease. However, the two-year survival was comparable with the results of other studies. The advantages of our schedule are that it is well tolerated, easy to perform on an outpatient basis, resource effective and does not deteriorate the general condition of the patients, therefore successive therapy can be carried out immediately if necessary. We intend to evaluate the effectivity of this treatment in a study comparing radiotherapy with Taxol sensitization versus radiotherapy alone.     

Proton re-irradiation of unresectable recurrent head and neck cancers

BackgroundThis study presents a retrospective analysis (efficacy and toxicity) of outcomes in patients with unresectable recurrence of previously irradiated head and neck (H&N) cancers treated with proton therapy. Locoregional recurrence is the main pattern of failure in the treatment of H&N cancers. Proton re-irradiation in patients with relapse after prior radiotherapy might be valid as promising as a challenging treatment option.Materials and methodsFrom November 2015 to January 2020, 30 patients with in-field recurrence of head and neck cancer, who were not suitable for surgery due to medical contraindications, tumor localization, or extent, received re-irradiation with intensity-modulated proton therapy (IMPT). Sites of retreatment included the aerodigestive tract (60%) and the base of skull (40%). The median total dose of prior radiotherapy was 55.0 Gy. The median time to the second course was 38 months. The median re-irradiated tumor volume was 158.1 cm³. Patients were treated with 2.0, 2.4, and 3.0 GyRBE per fraction, with a median equivalent dose (EQD₂) of 57.6 Gy (α/β = 10). Radiation-induced toxicity was recorded according to the RTOG/EORTC criteria.ResultsThe 1- and 2-year local control (LC), progression-free survival (PFS), and overall survival (OS) were 52.6/21.0, 21.9/10.9, and 73.4/8.4%, respectively, with a median follow-up time of 21 months. The median overall survival was 16 months. Acute grade 3 toxicity was observed in one patient (3.3%). There were five late severe side effects (16.6%), with one death associated with re-irradiation.ConclusionRe-irradiation with a proton beam can be considered a safe and efficient treatment even for a group of patients with unresectable recurrent H&N cancers.     

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancer

BackgroundThe aim of the study was to investigate the safety of combining preoperative stereotactic body radiotherapy (SBRT) with robotic radical prostatectomy (RP) for high risk prostate cancer (HRCaP). Many patients with HRCaP will require adjuvant or salvage radiotherapy after RP. The addition of preoperative SBRT before RP may spare patients from subsequent prolonged courses of RT.Materials and methodsEligible patients had NCC N HRCaP and received a total of 25 Gy or 30 Gy in five daily fractions of SBRT to the prostate and seminal vesicles followed by robotic RP with pelvic lymphadenectomy 31–45 days later. The primary endpoint was prevalence of acute genitourinary (GU) and gastrointestinal (GI) toxicity. Secondary endpoints were patient-reported quality of life (QOL) and biochemical recurrence (BcR).ResultsThree patients received preoperative SBRT to 25 Gy and four received 30 Gy. Median follow-up was 18 months. Highest toxicity was grade 2 and 3 in six (85.7%) and one (14.3%) patients, respectively. All patients developed grade 2 erectile dysfunction and 4 of 7 (57%) developed grade 2 urinary incontinence (UI) within a month after surgery. One patient developed acute grade 3 UI, but there was no grade ≥ 4 toxicity. One patient experienced acute grade 2 hemorrhoidal bleeding. On QOL, acute GU complaints were common and peaked within 3 months. Bowel symptoms were mild. Two patients with pN+ experienced BcR.ConclusionsPreoperative SBRT before robotic RP in HRCaP is feasible and safe. The severity of acute GU toxicity with preoperative SBRT may be worse than RP alone, while bowel toxicity was mild.     

The efficiency of the radiobiological and clinical of the intraoperative radiation therapy in combination with distant gamma-radiation therapy of malignant tumors

The efficiency of the radiobiological and the clinical planning of the combination of the intraoperative radiation therapy (IORT) and the external beam radiation therapy (EBRT) was assessed according to the incidence of local recurrences and to the level of radiation-induced damages during 5 years for patients with malignant tumors of head and neck, lung and soft tissues. Criteria of radiobiological planning for performing IORT + EBRT using the modified model of TDF (time-dose-fractionation) for calculating a single IORT dose and total radiation doses was defined among 169 patients of the studied group. The control group included 115 patients who were treated with surgery followed by photon radiation therapy at the total dose of 40-45 Gy. The Clinical critetia for performing the combined treatment with IORT and EBRT were such like: locally-advanced tumors, multicentrical location of tumor sites and the necessity of the increasing of the total doses of the combination of IORT and EBRT. The Average rates of total doses of IORT and EBRT were 67 +/- 2.1 Gy for patients with cancer of nasal cavity and of accessory nasal sinus, 50 +/- 1.8 Gy for patients with oral cavity cancer, 60 +/- 0.7 Gy for patients with lung cancer and 75 +/- 2.0 Gy for patients with sarcomas of soft tissues. Radiation-induced damages for normal tissues such as mandible osteomyelitis, neuritis and pathological bone fracture occurred among 16.8% of patients from the studied group if the TDF factor was exceeded over 100 conventional units. The combined treatment with IORT and EBRT resulted the significant reduction of recurrence rate among 5-year as compared with the combined treatment fot the control group: 37.5 +/- 5.3% and 65 +/- 5.1% of patients with cancer of nasal cavity and accessory nasal sinus; 55.8 +/- 6.3% and 80 +/- 5.9% of patients with oral cavity cancer; 57.8 +/- 6.7% and 75 +/- 5.8% of patients with non-small cell lung cancer and 32.7 +/- 6.1% and 72 +/- 6.7% of patients with sarcomas of soft tissues, respectively. The use of criteria for radiobiological and clinical planning of the combined treatment with IORT and EBRT promotes the improvement of long-term treatment results.     

Clinical Trial of Prophylactic Extended-Field Carbon-Ion Radiotherapy for Locally Advanced Uterine Cervical Cancer (Protocol 0508)

To evaluate the efficacy and the toxicity of prophylactic extended-field carbon-ion radiotherapy (C-ion RT, Protocol 0508) for locally advanced squamous cell carcinoma of the uterine cervix in phase I / II clinical trial. Between May 2006 and January 2012, 26 patients of Protocol 0508 were treated with C-ion RT. The numbers of patients with stage IIB, IIIB, and IVA disease were 13, 11, and 2, respectively. Twenty patients had pelvic lymph node metastases. Median tumor size was 6.1 cm (range, 4.0–10.0 cm). The treatment consisted of extended-field irradiation of 39.0 gray equivalents (GyE) in 13 fractions, and additional 15.0 GyE in 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, 18.0 GyE in 2 fractions was given to GTV only. Total dose to the cervical tumor was 72.0 GyE over 20 fractions. The median follow-up period was 37 months. Twenty-one patients had grade 1 or 2 acute gastrointestinal toxicity, but all patients completed the treatment on schedule. There were no grade 3 or higher late complications, with 8 patients having grade 1 or 2 toxicities, 1 had grade 2 gastrointestinal toxicity and 2 had grade 2 genitourinary toxicity. Four patients (15.4%) developed local recurrence, and 8 patients (30.8%) had distant metastases. The 2-year local control rate, progression-free survival rate and overall survival rate were 83.6%, 61.5% and 73.1%, respectively. There were no severe acute or late complications in this trial. Prophylactic extended-field C-ion RT for locally advanced squamous cell carcinoma of the uterine cervix was a safe treatment. Although the number of patients in this study was small, the results support further investigations to confirm the therapeutic efficacy and to avoid or reduce toxicity.

Trial Registration

UMIN-CTR UMIN000016169     

Neck emphysema in a HNSCC cancer patient undergoing concurrent radiotherapy and cetuximab

BackgroundLung toxicity in patients undergoing cetuximab and radiotherapy (Cetux-RT) for head and neck squamous cell carcinoma (HNSCC) has been reported in literature and represents a serious side effect of concurrent therapies.MethodsWe report a case of a HNSCC patient that developed neck emphysema during the course of Cetux-RT. The patient was an old male (80 years old) in a good performance status, with an oropharyngeal cancer (T4aN3a).ResultsDuring RT, cone-beam computed tomography (CBCT) showed bilateral neck emphysema that was confirmed at restaging CT. We decided to stop the treatment and to treat the neck emphysema with conservative strategies. After one week CT was repeated and the neck emphysema had improved, so we decided to complete the RT treatment.ConclusionsPatients undergoing Cetux-RT must be properly selected, whereas IGRT imaging must be viewed carefully in order to permit an early diagnosis and careful management of the patients.     

Toxicity outcome in patients treated with modulated arc radiotherapy for localized prostate cancer

Aim

This study evaluates the acute toxicity outcome in patients treated with RapidArc for localized prostate cancer.

Background

Modern technologies allow the delivery of high doses to the prostate while lowering the dose to the neighbouring organs at risk. Whether this dosimetric advantage translates into clinical benefit is not well known.

Materials and methods

Between December 2009 and May 2012, 45 patients with primary prostate adenocarcinoma were treated using RapidArc. All patients received 1.8 Gy per fraction, the median dose to the prostate gland, seminal vesicles, pelvic lymph nodes and surgical bed was 80 Gy (range, 77.4–81 Gy), 50.4 Gy, 50.4 Gy and 77.4 Gy (range, 75.6–79.2 Gy), respectively.

Results

The time between the last session and the last treatment follow up was a median of 10 months (range, 3–24 months). The incidence of grade 3 acute gastrointestinal (GI) and genitourinary (GU) toxicity was 2.2% and 15.5%, respectively. Grade 2 acute GI and GU toxicity occurred in 30% and 27% of patients, respectively. No grade 4 acute GI and GU toxicity were observed. Older patients (>median) or patients with V60 higher than 35% had significantly higher rates of grade ≥2 acute GI toxicity compared with the younger ones.

Conclusions

RapidArc in the treatment of localized prostate cancer is tolerated well with no Grade >3 GI and GU toxicities. Older patients or patients with higher V60 had significantly higher rates of grade ≥2 acute GI toxicity. Further research is necessary to assess definitive late toxicity and tumour control outcome.     

Oral Mucosa Dose Parameters Predicting Grade ≥3 Acute Toxicity in Locally Advanced Nasopharyngeal Carcinoma Patients Treated With Concurrent Intensity-Modulated Radiation Therapy and Chemotherapy: An Independent Validation Study Comparing Oral Cavity versus Mucosal Surface Contouring Techniques

PURPOSE: To determine whether volumes based on the contours of the mucosal surface instead of the oral cavity can be used to predict grade ≥3 acute oral mucosa toxicity in patients with locally advanced nasopharyngeal carcinoma (LANPC) treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. METHODS AND MATERIALS: A standardized method for the oral cavity (oral cavity contours, OCC) and a novel method for the mucosal surface (mucosal surface contours, MSC) were developed for the oral mucosa and prospectively applied to the radiation treatment plans of 92 patients treated with concurrent IMRT and chemotherapy for LANPC. Dose–volume histogram (DVH) data were extracted and then toxicity was analyzed. Receiver operating characteristic analysis and logistic regression were carried out for both contouring methods. RESULTS: Grade ≥3 acute oral mucosa toxicity occurred to 20.7% (19/92) of patients in the study. A highly significant dose–volume relationship between oral mucosa irradiation and acute oral mucosa toxicity was supported by using both oral cavity and mucosal surface contouring techniques. In logistic regression, body weight loss was an independent factor related to grade ≥3 acute toxicity for OCC and MSC (P = .017 and 0.005, respectively), and the independent factor of dosimetric parameters for OCC and MSC were V30Gy (P = .003) and V50Gy (P = .003) respectively. In the receiver operating characteristics curve, the areas under V30Gy of the OCC curves was 0.753 (P = .001), while the areas under V50Gy of MSC curves was 0.714 (P = .004); the cut-off value was 73.155% (sensitivity, 0.842; specificity, 0.671) and 14.32% (sensitivity, 0.842; specificity, 0.575), respectively. CONCLUSION: DVH analysis of mucosal surface volumes accurately predicts grade ≥3 acute oral mucosa toxicity in patients with LANPC receiving concurrent IMRT and chemotherapy, but in clinical practice the MSC method appears no better than the OCC one.     

Late toxicity for prostate cancer patients treated with hypofractionated helical tomotherapy

AimThe purpose of this study is to evaluate the long term tolerability of hypofractionated helical tomotherapy (HT) in localized prostate cancer patients.BackgroundPrevious hypofractionated schedules with conventional RT were associated with excessive toxicity, likely due to inadequate sophistication of treatment delivery. There are few data about late toxicity after HT.Materials and methodsWe evaluated 38 patients with primary adenocarcinoma of the prostate. There were 9 (24%), 15 (39%), and 14 (37%) patients with high, intermediate, and low risk, respectively. Patients were treated with hypofractionated HT from May 2008 to February 2011. Hypofractionation regimens included: 68.04 Gy at 2.52 Gy/fraction (N = 25; 66%), 70 Gy at 2.5 Gy/fraction (N = 4; 11%) and 70.2 Gy at 2.6 Gy/fraction (N = 9; 23%). Late genitourinary (GU) and gastrointestinal (GI) toxicity was scored using the Radiation Therapy Oncology Group scoring system.ResultsMedian age at diagnosis was 70 years (range 49–80) and median follow-up, 5.8 years. Late grade 1, 2 and 3 GI toxicity were 13%, 24%, and 2.6%, respectively. Late grade 1, 2, 3 GU toxicity were 29%, 21%, and 8%, respectively. Sexual toxicity was evaluated in 19 patients to be grade 1, 2 in 11% and grade 3 in 16%. Multivariate analysis showed that patients with higher values of rectum V50 associated with late GI toxicity (P = 0.025). Patients with PSA ≤8 (P = 0.048) or comorbidities (P = 0.013) at diagnosis were associated with higher late GU toxicity. Additionally, PSA ≤8 also associated with moderate (grade ≥2) late GU toxicity in the multivariate analysis (P = 0.028).ConclusionsHypofractionated HT can be delivered safely with limited rates of moderate and severe late toxicity. The proportion of the rectum that receives a moderate and high dose, having comorbidities, and PSA at diagnosis seem to associate with long term toxicity.     

草酸铂联合FL三周方案二线治疗晚期肠癌25例疗效分析

目的评价草酸铂（L-OHP）联合氟脲嘧啶（5-FU）、甲酰四氢叶酸钙（CF）二线治疗晚期复发大肠癌的疗效和不良反应。方法L-OHP 130 mg/m^2,静脉滴入,2 h,d1;CF 100 mg/m^2,5-FU前2小时静脉滴入,d1-d5;5-FU 500 mg/m^2,静脉滴入,6-8 h,d1-d5,21 d为1个周期。结果全组CR 1例,PR 3例,SD 17例,PD 4例,总有效率为16%,疾病控制率为84%。主要不良反应为中性粒细胞减少、消化道反应及外周神经毒性。结论L-OHP联合5-FU、CF方案（OFL）二线治疗晚期复发大肠癌安全、有效,毒性反应可耐受。     

Concomitant chemo-radiotherapy for unresectable oesophageal cancer: A mono-institutional study on 40 patients

Background/AimTo analyse clinical response, overall (OS) and disease free survival (DFS) and toxicity in patients with unresectable oesophageal cancer treated by concomitant chemo-radiotherapy (CRT).Materials and methodsForty patients with stage IIa–IVa biopsy proven oesophageal carcinoma were treated with CRT. All patients were studied with endoscopy and CT and judged unresectable after multidisciplinary discussion. CRT consisted of 3 cycles of cisplatin 100 mg/m² or carboplatin 300 mg/m² on day 1 and 5-fluorouracil 1000 mg/m² as a continuous infusion of 96 h associated with concurrent 3D-conformal RT. By using 15 MeV X-rays, a total dose of 60–66 Gy was delivered with daily fractions of 1.8–2.0 Gy.ResultsComplete response (CR), partial response (PR) and no response (NR) were observed in 50%, 20% and 20% of cases, respectively. Of the 20 patients with CR, 15 developed loco-regional recurrent disease. OS and DFS rates at 3 and 5 years were 38%, 8%, 49% and 10%, respectively. Total radiation dose ≥60 Gy improved loco-regional control and complete response (CR vs. PR + NR; p = 0.004) influenced both DFS and loco-regional control. Grade 3 gastrointestinal and haematological acute toxicity occurred in 3/40 patients (7.5%). One patient developed grade 4 renal failure. Late toxicity was reported in 2/40 patients (5.0%), consisting of grade 3 radiation pneumonitis.ConclusionsConcomitant CRT for unresectable oesophageal cancer can result in an acceptable loco-regional control with limited toxicity. Response after treatment and total radiation dose influenced the outcome.     

Clinical applications of palifermin: amelioration of oral mucositis and other potential indications

Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health economics. Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parentral nutrition, suboptimal delivery of anti‐neoplastic treatment, and morbidity and mortality. Palifermin, a recombinant derivative of human keratinocyte growth factor, is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing haematopoietic stem cell transplantation (HSCT). Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high‐risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer. The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient‐reported outcome in multiple studies. The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening. Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft‐versus‐host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT. Palifermin is generally well tolerated with mild‐to‐moderate skin and oral adverse events. Future studies may expand the use of palifermin into other areas that would benefit from its cytoprotective and regenerative effects.     

Phase I Trial of Radiotherapy Concurrent with Twice-Weekly Gemcitabine for Head and Neck Cancer: Translation From Preclinical Investigations Aiming to Improve the Therapeutic Ratio

BACKGROUND: Once-weekly gemcitabine concurrent with radiotherapy was highly effective in the treatment of head and neck cancer (HNC) but limited by high mucosal toxicity. Pre-clinical investigations suggested that delivering gemcitabine at substantially lower doses twice weekly during radiotherapy improved the therapeutic ratio. We sought to translated these preclinical findings to a phase I trial. METHODS: Twenty-five patients with non-resectable HNC were scheduled to receive gemcitabine twice weekly during the last 2 weeks (total 5 infusions) of hyperfractionated radiotherapy delivering 1.2 Gy twice daily to total 76.8 Gy. Tumor biopsies to measure active intracellular (phosphorylated) gemcitabine were planned after the first drug delivery. Patients were assigned to escalating dose cohorts using the Continuous Reassessment Method. RESULTS: Twenty-one patients evaluable for toxicity were divided into cohorts receiving twice weekly treatment with 10, 20, 33, or 50 mg/m² gemcitabine. Dose-limiting toxicity was grade 3-4 confluent mucositis/pharyngitis, and the maximally tolerated dose (MTD) was 20 mg/m². Median survival was 20 months, with no difference between cohorts receiving lower (10, 20 mg/m²) or higher (33, 50 mg/m²) gemcitabine doses. Tumor biopsies after the first drug delivery showed only a minority of tumor cells in the specimens. CONCLUSION: These findings validate preclinical models that show that gemcitabine is radiation sensitizer at doses far below those used for systemic chemotherapy. However, the improvement in the therapeutic ratio predicted from the preclinical study did not translate into a substantial relative increase in the MTD of the drug in the clinical phase I trial.     

Prognostic value of p53 overexpression in head and neck carcinomas: a pilot study

OBJECTIVE: To correlate p53 overexpression in squamous cell carcinoma of the head and neck region with the outcome of treatment. STUDY DESIGN: Twenty-five biopsy-proven squamous cell carcinomas of the head and neck region, locally advanced and untreated, were studied. Before treatment, all patients underwent fine needle aspiration from primary and/or metastatic lesions. Smears were prepared from the aspirate for immunostaining, and p53 overexpression was measured semiquantitatively. All patients received a radical dosage of radiation equivalent to 60 Gy for 6 weeks in 30 fractions from a 6-MV linear accelerator. Local-regional disease control was studied, and the mean follow-up duration was one year. The pretreatment values of p53 overexpression were correlated with the outcome of treatment. RESULTS: Overexpression of p53 was found in 36% patients. At the end of 1 year, 6/9 patients showing overexpression were disease free as compared to 5/16 patients without overexpression. The difference was not significant (chi2 test, P>.05). CONCLUSION: Response to radiation therapy is not dependent on p53 overexpression in squamous cell carcinoma of the head and neck region. However, this was only a pilot study, and a large number of cases are needed to establish the prognostic value of p53 overexpression in locally advanced head and neck squamous cell carcinoma.     

Gemcitabine-cisplatin combination in the first line treatment of non-small cell lung cancer. Our experience and analysis of safety

In our Department we have studied the first line treatment of 90 stage IIIA-IV non-small cell lung cancer patients using gemcitabine/cisplatin combination. Thirteen cases have been unevaluable for various reasons. At the time of evaluation the planned 4 cycles have been delivered to 38% of patients (34/90). The PR was 39% (30/77), the CR was 2.6% (2/77) while the ORR was found to be 41% (32/77). 226 treatment cycles have been evaluated for side effects. There was no treatment-induced death in this series. CTC grade 3-4 neutropenia occurred in 5.7% of the cycles and only in 2 cases combined with fever. CTC grade 3-4 thrombocytopenia occurred in 4.4% of the cycles but only one patient required platelet suspension administration. Grade 3-4 anaemia developed in 3.5% of the cycles where 5 cases have been treated with RBC concentrate while 3 cases with erythropoietin. Complete alopecia occurred in 6 patients but 3 of them received brain irradiation as well. CTC grade 3-4 nausea and vomiting occurred in 4.4 and 3% of the cycles, respectively, but rehydration was only necessary in 3% of the cycles. Delay of the therapy due to hematological toxicity or vomiting occurred in 8% of the cycles but did not last longer than 2 weeks. Severe CTC grade 3-4 nephrotoxicity did not occur in this study while grade 1-2 elevation of serum creatinine level was found in 1.7% of the cycles. We have concluded that the gemcitabine/cisplatin combination is a safe outpatient modality for the first line treatment of advanced non-small cell lung cancer patients.     

Feasibility and safety of definite volumetric modulated arc therapy with simultaneous integrated boost to the dominant intraprostatic lesion in patients with unfavorable intermediate to high-risk prostate cancer

BackgroundThe most common site of recurrence of prostate cancer after definite radiation therapy is the dominant intraprostatic lesion (DIL). This study aimed to investigate the feasibility and safety of definite volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) to the DIL in patients with unfavorable intermediate to high-risk prostate cancer.Materials and methodsIn this prospective uncontrolled clinical trial, patients were delivered VMAT at a dose of 87.75 Gy in 39 fractions or 70 Gy in 20 fractions to the DIL in combination with androgen deprivation therapy. Genitourinary (GU) and rectal toxicity, International Prostate Symptom Score (IPSS) and IPSS quality of life (IPSS-QOL) score were collected.ResultsForty-five patients with a median follow-up of 20 months were analyzed. The cumulative incidence of acute grade ≥ 2 GU and rectal toxicity was 33.1% and 9.5%, respectively. Regarding late toxicity, the cumulative incidence of grade ≥ 2 GU and rectal toxicity was 12.6% and 2.8%, respectively. During treatment, the mean increase of IPSS was +7.4 ± 4.2 and the mean increase of IPSS-QOL was +1.7 ± 1.3. However, both IPSS and IPSS-QOL scores returned to their baseline levels by 3-months post-treatment. No significant correlation between baseline characteristics and grade ≥ 2 GU or rectal toxicity was found.ConclusionFocal SIB to the DIL of ≥ 90 Gy EQD2 in unfavorable intermediate to high-risk prostate cancer patients resulted in tolerable toxicity profiles. The mean IPSS and IPSS-QOL scores both worsened during treatment; however, both scores returned to baseline level by 3 months after treatment.