Acute toxicity and cost analysis of a phase III randomized trial of accelerated and conventional radiotherapy for squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group study

The primary purpose of the present analysis was to assess the feasibility and acute toxicity of a pure accelerated fractionation regimen in a cooperative group setting. This analysis included the first 320 patients entered on to the Trans-Tasman Radiation Oncology Group (TROG) randomized controlled trial which compared accelerated radiotherapy (ART) with conventional radiotherapy (CRT) in stage III and IV squamous cell carcinoma (SCC) of the head and neck. Patients were randomized to either 59.4 Gy in 33 fractions over 24 days (ART) or to 70 Gy 35 fractions over 49 days (CRT) after being stratified for site and stage. Accrual began in 1991 and the trial was closed on 3 April 1998 with the targeted 350 patients. The 3-year survival for the whole group was 54%, and the 3-year disease-free survival was 41%. Toxicity data were available on 303 patients (148 ART; 155 CRT). Mucosal toxicity was worse in the accelerated arm, and it peaked approximately 3 weeks earlier than the conventional arm. Skin toxicity was equivalent but occurred approximately 7 days earlier in the accelerated arm. Acute effects in both arms healed completely. Hospitalization was more common in the ART arm (71 vs 52 patients; P = 0.01) but the total bed days in hospital was not greatly different (1707 bed days for ART and 1607 bed days for CRT). Patients were more likely to require nasogastric (NG) feeding in the ART arm (49 vs 33 patients; P = 0.02). There were 1157 NG feeding days for ART and 1154 NG feeding days for CRT. The average cost of radiation treatment per patient including hospitalization, NG feeding and accommodation was $11,750 in the ART arm and $11,587 in the CRT arm. The accelerated arm has been shown to be a tolerable, practical and cost-equivalent regimen. The assessment of the therapeutic ratio of this accelerated protocol (ART) will be determined when the analysis of late effects and loco-regional control is made when the data are more mature.     

A quality assurance audit: phase III trial of maximal androgen deprivation in prostate cancer (TROG 96.01)

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme.     

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer

Objective

A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 10⁸ cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment.

Method

Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment.

Results

The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15–25% (8–20 Gy for 5×2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered.

Conclusion

Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods.     

A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer

Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a randomised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival. The overall primary control (P = 0.016) and survival (P = 0.075) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone. The improvement in primary control (P = 0.0019) and survival (P = 0.0089) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy is statistically significant. The treatment was well tolerated and there has been no increase of late morbidity.     

Comparative trial of large and small fractions in the radiotherapy of head and neck cancer.

A random controlled trial was performed to compare long and short fractionation of radiotherapy in patients with head and neck cancer with a poor prognosis. Ninety-eight matched pairs were treated, one member of each pair received 10 fractions in 22 days, the other 30 fractions in 42 days. The same nominal standard dosages were used in each arm of the trial. Mucosal reactions were more severe with 10 fractions, skin reactions more severe with 30 fractions. No difference in survival, local tumour control rates or late normal tissue effects could be demonstrated. It is suggested that any possible therapeutic advantage of prolonged fractionation is minimal and that it is justified to use a small number of large fractions in clinical trials involving hyperbaric oxygen or electron-affinic sensitizers.     

Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer

Purpose

In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated.

Patients and methods

From 2000–2002, 38 patients with stage III (5.3?%) and stage IV (94.7?%) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m² on days 1–5 and 6 cycles of weekly cisplatin (30 mg/m²). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial.

Results

Median follow-up was 11.4 years (95?% CI 8.6–14.2) and mean dose 71.6 Gy. Of the patients, 82?% had 6 (n?=?15) or 5 (n?=?16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6?%, respectively. Grade 3 mucositis in 50?%, grade 3 and 4 dysphagia in 55 and 13?%. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2?%, the MFS was 77.5, 66.7, and 57.2?% and the OS 59.6, 29.2, and 15?%, respectively.

Conclusion

Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups.     

Radiation induced sarcomas of the head and neck following radiotherapy for nasopharyngeal carcinoma

AIM: To report the radiological findings of radiation induced sarcomas (RIS) in the head and neck following radiotherapy for nasopharyngeal carcinoma. MATERIALS AND METHODS: The clinical notes and radiological studies (MR n = 3, CT n = 4) of four patients were reviewed retrospectively. RESULTS: RIS developed 5 to 10 years following radiotherapy. Two patients had tumours arising from the alveolar process of the maxilla, one from the nasal cavity, and one patient had a tumour at two sites, involving the external auditory canal and the uvula. Three of the four patients had large tumours at diagnosis with a 3.5-6 cm predominately homogeneous soft tissue mass, complete destruction of bone and extensive local invasion. One was small and localized to the nasal turbinate. Radiation osteitis was identified in two of the four (50%) patients. CONCLUSION: The site of RIS following radiotherapy for NPC is variable but is invariably within the high dose zone of the radiotherapy. These sarcomas tend to present late with a large soft tissue mass. Radiation osteitis is not a constant feature. As surgery provides the only chance of cure, imaging has an important role in the pre-operative mapping of the extent of tumour. et al.     

头颈部肿瘤放疗中转化医学相关机制的研究进展

头颈部肿瘤是目前世界上最常见的肿瘤之一,超过90%的头颈部肿瘤为鳞状细胞癌。放疗在头颈部肿瘤的治疗中显得尤为重要,目前国内治疗早期肿瘤可以单纯放疗为主,晚期肿瘤则选择综合性治疗。转化医学是近些年来新的研究重点,将科研过程及其成果与临床紧密结合,尤其体现在通过检测患者肿瘤组织中的基因突变靶点及基因单核苷酸多态性分型、mRNA基因定量表达,为临床提供靶向及个体化放疗的依据,能显著提高治疗的有效率。     

An original accelerated radiotherapy schedule in stage III to IV head and neck cancers. Results in a multicenter setting.

BACKGROUND: Accelerated radiotherapy delivery has recently been shown to be effective in overcoming repopulation during fractionated radiotherapy. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the feasibility and results of a particular accelerated schedule in Stage III to IV head and neck carcinomas used in a multicenter setting. PATIENTS AND METHODS: Seventy-four patients with Stage III (26 patients) or IV (48 patients) head and neck carcinomas were treated with a 5-week accelerated schedule (69.6 to 69.8 Gy in 41 to 40 fractions over a period of 35 to 36 days). Treatment began with 20 Gy in 10 daily fractions to initial involved sites, followed by bi-fractionated radiotherapy (2 x 1.6 Gy to 1.66 Gy/day) to a larger head and neck volume. Thirty-six (49%) patients received induction chemotherapy (median 3 cycles, range 1 to 4 cycles). RESULTS: Grade 3 or 4 (RTOG) confluent mucositis was observed in 57 patients (77%) and Grade 3 dysphagia in 33 patients (44%). Grade 3 or 4 (RTOG-EORTC) late complications were scored in 10.5% of cases. The 5-year actuarial locoregional control rate was 56% (95% CI: 42 to 71). The 5-year overall actuarial survival was 32% (95% CI: 18 to 46). Induction chemotherapy was not associated with a more favorable outcome. CONCLUSIONS: This study demonstrates the feasibility of this schedule in a multicenter setting. The oncologic results appear similar to those obtained by other accelerated regimens, while the rate of late complications seems acceptable. Five-week accelerated regimens warrant further evaluation, particularly in conjunction with concomitant chemotherapy, in the framework of prospective trials.     

Dynamic contrast enhanced magnetic resonance scanning as a predictor of response to accelerated radiotherapy for advanced head and neck cancer

Tumour perfusion has been assessed in patients with advanced head and neck cancer using dynamic contrast enhanced MRI prior to and at completion of accelerated radiotherapy, and related to local tumour control. Sequential MRI scans, at 3 s intervals after intravenous injection of gadolinium using a dynamic scan sequence through a tumour region of interest (ROI), were performed in 13 patients with advanced head and neck cancer before and on completion of radiotherapy. The scans have been analysed in terms of maximum tumour enhancement (E), slope of the enhancement versus time curve and the time taken to reach maximum tumour enhancement (Tmax), and these parameters related to tumour outcome after radiotherapy. Local tumour control was related to the value of E on a post-radiotherapy scan and the difference in Tmax between a pre- and post-radiotherapy scan. Durable local control was seen in those tumours with a post-radiotherapy value for E of less than 8 and a mean fall in Tmax of 27.3 s. These results imply that tumours with diminished tumour perfusion at the end of radiotherapy are those most sensitive to treatment and that those tumours which show greater tumour enhancement after accelerated radiotherapy are likely to fail locally. This may reflect the persistence of viable perfused tumour at completion of radiotherapy.     

Cytogenetic damage of radiotherapy in long-term head and neck cancer survivors

Purpose: To evaluate cytogenetic damage of radiotherapy (RT) and chemoradiotherapy (CRT) in long-term head and neck cancer survivors.

Materials and methods: This study included 20 patients treated with RT (10 patients) or CRT (10 patients) for head and neck cancer. Nine healthy volunteers were included as control subjects. Cytochalasin B-blocked micronucleus (CBMN) assay was used to evaluate cytogenetic damage. To evaluate micronucleus (MN) by CBMN, the venous blood samples were drawn median 68 months (range 60–239 months) after the completion of treatment (RT or CRT) for head and neck cancer.

Results: Nuclear division index (NDI) and number of MN in mononuclear and binuclear lymphocytes were significantly higher in patients with head and neck cancer than in control subjects [1.19 (1.08–1.47) vs. 1.07 (1.04–1.14), p?p?p?=?0.020, respectively]. NDI and number of MN in mononuclear lymphocytes were significantly lower in control subjects compared patients received CRT and those received only RT, but there was no significant difference between patients received CRT and those received only RT. Number of MN in binuclear lymphocytes was significantly lower in control subjects compared to patients received CRT, but there was no significant difference between control subjects and those received only RT. Also there was no significant difference between patients received CRT and those received only RT in terms of number of MN in binuclear lymphocytes.

Conclusions: MN frequency of mononuclear and binuclear lymphocytes in medical follow-up of patients with head and neck cancer after RT could be important in evaluating cytogenetic damage of RT. However, further investigations are needed to provide quantitative correlations between MN yields and the clinical features in post-radiotherapy period.     

MR imaging of head and neck lesions using high-dose gadodiamide injection: a phase III clinical trial

In order to evaluate the safety and efficacy of a high-dose gadodiamide injection a phase-III trial was conducted using a dose of 0.3 mmol Gd/kg bw in patients with known or suspected tumors in the head and neck region. A total of 90 in- and outpatients referred to MR examination for tumor in the head and neck area were included. Precontrast images consisted of T₁- and T₂-weighted sequences. A FATSAT sequence was also applied. After i. v. contrast administration T₁-weighted scans were obtained. Efficacy was evaluated by means of a comparison of the pre- and postcontrast images. Postcontrast images gave more diagnostic information compared with precontrast images, which facilitated diagnosis in all patients. In 8 patients T₁-weighted postcontrast images revealed abnormal structures not seen on precontrast images and no lesion was obscured by the contrast medium. Gadodiamide injection at a dose of 0.3 mmol Gd/kg bw was judged as safe and effective for the examination of tumors in the head and neck region. Use of the contrast medium increased the diagnostic information in the images and increased the confidence in making the diagnosis.     

Prospective feasibility trial of radiotherapy target definition for head and neck cancer using 3-dimensional PET and CT imaging.

The aim of this investigation was to evaluate the influence and accuracy of (18)F-FDG PET in target volume definition as a complementary modality to CT for patients with head and neck cancer (HNC) using dedicated PET and CT scanners. METHODS: Six HNC patients were custom fitted with head and neck and upper body immobilization devices, and conventional radiotherapy CT simulation was performed together with (18)F-FDG PET imaging. Gross target volume (GTV) and pathologic nodal volumes were first defined in the conventional manner based on CT. A segmentation and surface-rendering registration technique was then used to coregister the (18)F-FDG PET and CT planning image datasets. (18)F-FDG PET GTVs were determined and displayed simultaneously with the CT contours. CT GTVs were then modified based on the PET data to form final PET/CT treatment volumes. Five-field intensity-modulated radiation therapy (IMRT) was then used to demonstrate dose targeting to the CT GTV or the PET/CT GTV. RESULTS: One patient was PET-negative after induction chemotherapy. The CT GTV was modified in all remaining patients based on (18)F-FDG PET data. The resulting PET/CT GTV was larger than the original CT volume by an average of 15%. In 5 cases, (18)F-FDG PET identified active lymph nodes that corresponded to lymph nodes contoured on CT. The pathologically enlarged CT lymph nodes were modified to create final lymph node volumes in 3 of 5 cases. In 1 of 6 patients, (18)F-FDG-avid lymph nodes were not identified as pathologic on CT. In 2 of 6 patients, registration of the independently acquired PET and CT data using segmentation and surface rendering resulted in a suboptimal alignment and, therefore, had to be repeated. Radiotherapy planning using IMRT demonstrated the capability of this technique to target anatomic or anatomic/physiologic target volumes. In this manner, metabolically active sites can be intensified to greater daily doses. CONCLUSION: Inclusion of (18)F-FDG PET data resulted in modified target volumes in radiotherapy planning for HNC. PET and CT data acquired on separate, dedicated scanners may be coregistered for therapy planning; however, dual-acquisition PET/CT systems may be considered to reduce the need for reregistrations. It is possible to use IMRT to target dose to metabolically active sites based on coregistered PET/CT data.     

Intensity-modulated radiotherapy: examples of its utility in head and neck cancer

Intensity-modulated radiotherapy (IMRT) has been available at Peter MaCallum Cancer Centre (PMCC) since November 2000. The present report illustrates two cases of our early experience with IMRT. Case 1 is a 66-year-old man with a T(1)N(2)M(0) nasopharyngeal carcinoma treated with chemo-radiotherapy using parotid-sparing IMRT. Fourteen months following treatment he remains in complete remission, with salivary function assessed using a xerostomia-specific quality of life questionnaire, having returned to near pretreatment levels by 12 months. Case 2 is a 70-year-old man with a T(4)N(0)M(0) base of tongue squamous cell carcinoma treated with chemo-radiotherapy after refusing radical surgery. He had received subtotal nodal irradiation to 36 Gy in 1994 for Hodgkins disease stage IIA. A radical dose was still achievable despite previous irradiation without exceeding unacceptable spinal cord dose with IMRT. He remains in complete remission 14 months from his initial presentation without evidence of neurological toxicity. Intensity-modulated radiotherapy allows sparing of critical normal structures in the head and neck without compromising dose to the tumour. It is, therefore, desirable for several clinical applications and essential in some, if unacceptable compromises are not to be made.     

Dosimetry and use of an immobilization system for head and neck radiotherapy treatments

The day-to-day reproducibility of planned radiotherapy treatment is an important precondition for achieving good clinical results and reducing toxic effects. This reproducibility is difficult to achieve in the irradiation of head and neck malignancies because of the mobility of this anatomical area. This paper presents a dosimetric study and analysis of the utility of a facial mask immobilization system prepared from an orthopedic glass-fiber bandage. The dosimetric study conducted on a lucite phantom shows that the interposition of one, two, or three layers of the bandage reduces the deep absorbed dose by about 1% at 0.5 cm2, while increasing the absorbed surface dose by 12% (for a field of 15 X 15 cm2 and one layer of bandage) to 46% (for a field of 5 X 5 cm and three layers of bandage). The dosimetric study conducted on a Rando Anderson manikin shows an average increase in the skin dose of about 8% and a maximum increase of about 20%. The good dosimetric results and the practicality of this system of immobilization have persuaded us to propose it as an alternative to the systems currently on the market, which, although rather more sophisticated, are also more expensive.