J.Michael Henk

Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions

PURPOSE To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per days extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each days extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil: Patterns of fractionation study of radiobiology

PURPOSE To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil. METHODS AND MATERIALS A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed. RESULTS With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa. CONCLUSION The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

Optimisation of radiotherapy for carcinoma of the parotid gland: a comparison of conventional, three-dimensional conformal, and intensity-modulated techniques

BACKGROUND AND PURPOSE To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution. MATERIALS AND METHODS The planning target volume (PTV), contra-lateral parotid gland, oral cavity, brain-stem, brain and cochlea were outlined on CT planning scans of six patients with parotid gland tumours. Optimised conventional RT and 3DCRT plans were created and compared with inverse-planned IMRT dose distributions using dose-volume histograms. The aim was to reduce the radiation dose to organs at risk and improve the PTV dose distribution. A beam-direction optimisation algorithm was used to improve the dose distribution of the IMRT plans, and a class solution for parotid gland IMRT was investigated. RESULTS 3DCRT plans produced an equivalent PTV irradiation and reduced the dose to the cochlea, oral cavity, brain, and other normal tissues compared with conventional RT. IMRT further reduced the radiation dose to the cochlea and oral cavity compared with 3DCRT. For nine- and seven-field IMRT techniques, there was an increase in low-dose radiation to non-target tissue and the contra-lateral parotid gland. IMRT plans produced using three to five optimised intensity-modulated beam directions maintained the advantages of the more complex IMRT plans, and reduced the contra-lateral parotid gland dose to acceptable levels. Three- and four-field non-coplanar beam arrangements increased the volume of brain irradiated, and increased PTV dose inhomogeneity. A four-field class solution consisting of paired ipsilateral coplanar anterior and posterior oblique beams (15, 45, 145 and 170 degrees from the anterior plane) was developed which maintained the benefits without the complexity of individual patient optimisation. CONCLUSIONS For patients with parotid gland tumours, reduction in the radiation dose to critical normal tissues was demonstrated with 3DCRT compared with conventional RT. IMRT produced a further reduction in the dose to the cochlea and oral cavity. With nine and seven fields, the dose to the contra-lateral parotid gland was increased, but this was avoided by optimisation of the beam directions. The benefits of IMRT were maintained with three or four fields when the beam angles were optimised, but were also achieved using a four-field class solution. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.

POTENTIAL ROLE OF INTENSITY-MODULATED RADIOTHERAPY IN THE TREATMENT OF TUMORS OF THE MAXILLARY SINUS

PURPOSE To assess 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques to see whether doses to critical structures could be reduced while maintaining planning target volume (PTV) coverage in patients receiving conventional radiotherapy (RT) for carcinoma of the maxillary sinus because of the risk of radiation-induced complications, particularly visual loss. METHODS AND MATERIALS Six patients who had recently received conventional RT for carcinoma of the maxillary sinus were studied. Conventional RT, 3D-CRT, and step-and-shoot IMRT plans were prepared using the same 2-field arrangement. The effect of reducing the number of segments in the IMRT beams was investigated. RESULTS 3D-CRT and IMRT reduced the brain and ipsilateral parotid gland doses compared with the conventional plans. IMRT reduced doses to both optic nerves; for the contralateral optic nerve, 15-segment IMRT plans delivered an average maximal dose of 56.4 Gy (range 53.9-59.3) compared with 65.7 Gy (range 65.3-65.9) and 64.2 Gy (range 61.4-65.6) for conventional RT and 3D-CRT, respectively. IMRT also gave improved PTV homogeneity and improved coverage, with an average of 8.5% (range 7.0-11.7%) of the volume receiving <95% of the prescription dose (64 Gy) compared with 14.7% (range 14.1-15.9%) and 15.1% (range 14.4-16.1%) with conventional RT and 3D-CRT, respectively. Little difference was found between the 15 and 7-segment plans, but 5 segments resulted in a reduced minimal PTV dose. CONCLUSIONS IMRT offers significant advantages over conventional RT and 3D-CRT techniques for treatment of maxillary sinus tumors. Good results can be obtained from 7 segments per beam without compromising the PTV coverage. This number of segments is practical for implementation in a busy RT department.

Three weeks radiotherapy for T1 glottic cancer: the Christie and Royal Marsden Hospital Experience

BACKGROUND AND PURPOSE Radiotherapy for laryngeal carcinoma is conventionally given over a 6-7-week period. However, in a number of UK centres early lesions are treated over 3 weeks. We review recent results of this policy and discuss the reasons why short treatment times may be advantageous. MATERIALS AND METHODS Two hundred patients (100 from each centre) with T1 glottic invasive squamous cell carcinoma treated with definitive radiotherapy between 1989 and 1997 were analysed. The median age was 68 years. All patients received once daily fractionation, 5 days a week to a total tumour dose of 50.0-52.5 Gy in 16 fractions over 21 days; the fraction size ranged from 3.12 to 3.28 Gy. The median follow-up period was 5 years and 10 months. RESULTS The 5-year local control rates with radiotherapy for the whole group was 93%; there were 14 recurrences of which seven were salvaged by laryngectomy giving an ultimate local control of 96%. The 5-year overall survival was 80% and cause specific survival at 5 years was 97%. Univariate analysis revealed that T1 substaging (P=0.82) and anterior commissure involvement (P=0.47) did not significantly influence local control. A severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment. There were no severe acute complications. CONCLUSIONS Once daily radiotherapy over 3 weeks gives excellent local control in patients with T1 glottic squamous-cell carcinoma and has a low rate of severe complications. The short overall treatment time and large fraction size may be advantageous in radiotherapy of these well-differentiated tumours.

Treatment of head and neck cancer with CHART and nimorazole: phase II study.

BACKGROUND AND PURPOSE Causes of failure of radiotherapy in squamous cell carcinoma of the head and neck probably include repopulation and hypoxia. Very accelerated schedules such as continuous hyperfractionated accelerated radiation therapy (CHART) overcome the repopulation problem but allow limited time for reoxygenation, so a hypoxic-cell sensitizer may be especially beneficial. Nimorazole is the only such agent to have shown a significant effect in a randomized controlled trial in head and neck cancer. Accordingly we studied the combination of CHART and nimorazole. METHODS Sixty-one patients with advanced stage III (21) or IV (40) squamous cell carcinoma of the head and neck unsuitable for surgery were treated in a phase II study of the combination. The radiation dose was 56.75 Gy in 36 fractions in 12 consecutive days. Nimorazole was administered orally or enterally 90 min before radiotherapy at a dose of 1.2, 0.9, and 0.6 g/m(2) with the first, second and third daily fractions, respectively. This dosage consistently yielded plasma concentrations above 30 microg/ml. RESULTS All the patients have been followed for a minimum of 2 years since treatment. Loco-regional control at 2 years is 55%, stage III 62% and stage IV 50%. Normal tissue effects were the same as those previously seen with CHART, except for a possible slight increase in acute skin reaction. Nimorazole toxicity was somewhat greater than with once daily administration in previous studies. Grade 3 nausea or vomiting occurred in 22% of patients. Two patients developed grade 1 peripheral neuropathy, and one patient died during treatment of encephalopathy, which was probably an idiosyncratic reaction to the drug. CONCLUSIONS Local control rates are higher than those previously seen with CHART, suggesting a positive effect of nimorazole. Further studies of hypoxia-modifying agents with accelerated radiotherapy are warranted, and nimorazole is the simplest of these.

Pilot study of nimorazole as A hypoxic-cell sensitizer with the chart regimen in head and neck cancer

PURPOSE A potential disadvantage of accelerated fractionation in radiotherapy is the lack of time for reoxygenation, so that hypoxia becomes a more potent cause of failure. Accordingly, we have combined nimorazole, the only hypoxic radiosensitizer shown to significantly improve local control in head and neck cancer, with continuous hyperfractionated accelerated radiation therapy (CHART). METHODS AND MATERIALS Twenty-two patients with locally advanced (stage IV) squamous cell carcinoma of the head and neck were treated with escalating doses of nimorazole given concomitantly with CHART (three fractions of 1.5 Gy per day, spaced 5 1/2 hours apart, on 12 consecutive days). All patients received 1.2 g/m2 nimorazole 90 minutes before each first daily fraction. Seventeen patients received a further 0.6 g/m2 before each second daily fraction and six of these patients received an additional dose of 0.6 g/m2 before each third fraction. RESULTS The three times daily schedule yielded mean plasma drug concentrations at the time of irradiation of 37.7 microg/ml with the morning fractions, 31.2 microg/ml with the afternoon fractions, and 30.4 microg/ml with the evening fractions. In view of these results the midday dose was increased to 0.9 microg/m2 in an ongoing Phase II study. Drug toxicity was limited to nausea and vomiting apart from two cases of mild paraesthesia at the highest dose level. CONCLUSIONS Comparison with a historical group of patients, treated with the CHART regimen alone and matched for irradiation volume and technique, showed that nimorazole did not increase the severity of acute normal tissue radiation effects. Encouraging tumor responses have been seen in the patients receiving nimorazole with every radiotherapy fraction.

Le Fort I osteotomy and low-dose rate Ir192 brachytherapy for treatment of recurrent nasopharyngeal tumours

BACKGROUND Treatment of recurrent nasopharyngeal carcinoma is a difficult clinical problem. External beam re-irradiation is associated with a long-term cure in a proportion of cases but this may be associated with severe radiation injury. METHODS Eighteen patients with post-nasal space tumours were treated between 1986 and 2001 with surgical excision and nasopharyngeal brachytherapy via a Le Fort I osteotomy approach. Low-dose rate (LDR) and high-dose rate (HDR) brachytherapy was used. Data was prospectively collected. Local control and overall survival were measured. Acute and late complications were assessed using the RTOG system. RESULTS The overall survival was 67% at 2 years and 33.5% at 5 years. The corresponding local control rates were 42 and 31.5%, respectively. The T stage at relapse was a significant prognostic factor for local control (P=0.004) but not overall survival. Acute toxicity was mild. RTOG grade >/=3 late complications occurred in 40% of patients treated with the HDR, and 0% treated with LDR. CONCLUSIONS The results of the Le Fort osteotomy, tumour debulking and post-operative brachytherapy gives local control rates similar to those achieved with wide-field re-irradiation. Complication rates are acceptable and are lower than that reported with other methods of radiation therapy. The surgical technique was well tolerated. HDR brachytherapy with this technique had a high complication rate. This approach is a viable option in the treatment of recurrent nasopharyngeal tumours.

Misonidazole in patients receiving radical radiotherapy: Pharmac-okinetic effects of phenytoin tumor response and neurotoxicity

In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed a initial peripheral neuropathy rate of 55%, despite a dose limitation of 12g/m2 of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970s. Neuropathy was a serious side effect but the drug phenytoin has been shown to shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed.