P. O'Brien

Phase II Multicenter Study of Brief Single-Agent Methotrexate Followed by Irradiation in Primary CNS Lymphoma

PURPOSE To assess, in a multi-institutional setting, the impact on relapse, survival, and toxicity of adding two cycles of intravenous methotrexate to cranial irradiation for immunocompetent patients with primary CNS lymphoma. PATIENTS AND METHODS Forty-six patients with a median age of 58 years and Eastern Cooperative Oncology Group performance status 0 to 3 were entered onto this phase II study. The protocol consisted of methotrexate 1 g/m(2) on days 1 and 8 followed by cranial irradiation on day 15. A whole-brain dose of 45 Gy was followed by a boost of 5.4 Gy. Intrathecal chemotherapy and spinal irradiation were given only to patients for whom cytologic examination of CSF was positive for CNS lymphoma. The median follow-up time was 36 months, with a minimum potential follow-up of 12 months. RESULTS Median survival was 33 months, with 2-year probability of survival 62% +/- 15% (95% confidence interval). Twenty patients have relapsed. The predominant site of relapse was the brain. Neither performance status nor age was found to influence survival. Six patients developed a dementing illness at a median of 16 months after treatment, and three of these died as a consequence. CONCLUSION A brief course of intravenous methotrexate before cranial irradiation is associated with 2-year and median survival rates superior to those reported for radiotherapy alone and similar to more intensive combined-modality regimens. Neurotoxicity remains an important competing risk for these patients.

Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer

BACKGROUND AND PURPOSE The relationship between acute and late mucosal reactions remains ill defined but is of considerable relevance to efforts to produce therapeutic gains through the use of altered fractionation schemes and concurrent chemotherapy. We therefore investigated whether acute mucosal reactions in patients treated with an accelerated and a conventionally fractionated radiotherapy regime predicted the severity of late mucosal reactions. PATIENTS AND METHODS The study population consisted of 191 patients randomised on a prospective trial comparing conventional fractionation at 2 Gy/fraction per day, 70 Gy over 47 days with an accelerated regimen of 59.4 Gy, 1.8 Gy b.i.d over 24 days for Stage III-IV carcinoma of the head and neck. Acute and late mucosal reactions were scored according to RTOG/EORTC criteria and analyzed using multiple regression techniques. RESULTS The duration of time spent by patients at the acute confluent mucositis grade 3 level was inversely related to the time to onset of the reaction for both fractionation schedules. Time to onset was more rapid for patients treated on the accelerated schedule but time spent at the reaction grade did not differ significantly between the schedules. After correction for treatment and patient related factors, anatomical site (oral cavity/oropharynx versus hypopharynx/larynx) and increasing duration of confluent mucositis emerged as independent predictors of the hazard of late mucosal reactions with the latter effect being more pronounced in the accelerated treatment arm. The expected reduction in late mucosal effects in the accelerated fractionation arm, predicted by the LQ model for late effects was identified only in patients whose acute confluent mucosal reactions lasted less than 20 days. CONCLUSIONS The presence of individual patient susceptibility factors that determine the severity of acute mucosal reactions is suggested. A link between severe and prolonged acute reactions and the risk of developing late mucosal reactions that is independent of biological dose, has also been found. Purpose designed prospective studies of these issues are necessary.

A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial.

PURPOSE To investigate the effects separately and together of (a) shortening overall treatment time and (b) giving concurrent carboplatin in patients having radical radiotherapy for inoperable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Between April 1989 and May 1995, 204 patients with medically inoperable or technically unresectable NSCLC localised to the primary site and regional lymph nodes were randomised to receive one of four treatments using a 2 x 2 factorial design: standard radiotherapy, 60 Gy in 30 fractions in 6 weeks (R6); accelerated radiotherapy, 60 Gy in 30 fractions in 3 weeks (R3); standard radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and 5 of radiotherapy (R6C); accelerated radiotherapy as in R3 with carboplatin 70 mg/m2/day for 5 days during week 1 of radiotherapy (R3C). RESULTS The estimated median survival of all randomised patients was 15.7 months and estimated 2-year survival was 31%. The longest survival was seen in patients randomised to R6C (median 20.3 months, 41% surviving at 2 years) but there were no statistically significant differences between treatment arms or treatment factors (carboplatin versus no carboplatin, accelerated versus conventional radiotherapy). Haematological toxicity was significantly greater in patients treated with carboplatin and oesophageal toxicity was significantly greater and more protracted in patients treated with accelerated radiotherapy. CONCLUSIONS This study failed to show a significant survival advantage for any of the treatment arms or factors. Halving overall treatment time resulted in significantly greater oesophageal toxicity with no suggestion of a survival advantage.

Radiation injury of the rectum.

Any clinician involved in the treatment of pelvic malignancies with radiation is aware of the potential for rectal injury. Although severe effects have been well described for many years, it is only more recently that lesser degrees of rectal injury have been considered important. Patients are not always forthcoming in describing symptoms they find socially embarrassing; clinicians perhaps reticent in pursuing symptoms that may be resistant to intervention; and preclinical and clinical researchers handicapped by difficulty accessing the organ. Endpoints used in animal models may not reflect those of importance in humans. Interest in rectal injury has been stimulated by advances in brachytherapy technology and the advent of conformal therapy for prostate cancer. More sophisticated clinical assessments of late toxicity have evolved and greater efforts made to understand the pathophysiology of patients symptoms. This review aims to draw together pre-clinical and clinical information pertaining to rectal injury due to radiation. It is not intended as an exhaustive review of the incidence of rectal injury, but more detail has been provided on the impact of treatment of prostate and cervix cancer, particularly when patient-derived endpoints have been used.

Spontaneous improvement in late rectal mucosal changes after radiotherapy for prostate cancer

PURPOSE To describe the natural history of mucosal changes, in particular the development of telangiectases in the rectum, after radiotherapy (RT) for prostate cancer. METHODS AND MATERIALS Twenty patients undergoing local-field, nonconformal RT for prostate cancer underwent flexible sigmoidoscopy every 6 months for up to 3 years after RT completion. Telangiectasis was scored as absent, single, multiple, or multiple confluent. The site and circumferential extent were also documented. The patients filled in a diary to document the symptoms they were experiencing, including rectal bleeding. RESULTS Of the 20 patients, 12 developed multiple telangiectases, and 10 of these had rectal bleeding, which in all cases was mild. Telangiectasis was most commonly seen between 4 (anorectal junction) and 8 cm from the anal verge. In 5 patients, 4 of whom had multiple telangiectases, spontaneous resolution occurred. CONCLUSION Late radiation effects in the rectum do not appear to be permanent in all cases. This first prospective prolonged evaluation may provide an explanation for the observation that rectal bleeding resolves in a large proportion of patients with mild symptoms after RT. The reasons for improvement in the late radiation changes in the rectum compared with the permanent changes seen in organs such as the skin are unknown.

Optimism and survival in lung carcinoma patients

It is popular belief that the psychologic response to a diagnosis of cancer influences survival in patients with cancer; however, research has produced contradictory results. In this prospective study, the authors investigated the relation between pretreatment levels of optimism and survival in patients with nonsmall cell lung carcinoma (NSCLC).

A phase III study of accelerated radiotherapy with and without carboplatin in nonsmall cell lung cancer : an interim toxicity analysis of the first 100 patients

PURPOSE In 1989 we initiated a multicenter randomized trial to determine if accelerated radiotherapy with or without concurrent carboplatin improves local control and survival in patients with limited nonsmall cell lung cancer. This interim analysis was performed on the first 100 patients to determine whether the toxicity of the four treatment arms is acceptable. METHODS AND MATERIALS One hundred patients with limited nonsmall cell lung cancer have been randomized to receive one of four treatments: arm I, radiotherapy 60 Gray (Gy) in 30 fractions in 6 weeks; arm II, accelerated radiotherapy 60 Gy in 30 fractions in 3 weeks; arm III, radiotherapy as in arm I plus carboplatin 350 mg/m2 during weeks 1 and 5 of radiotherapy; arm IV, radiotherapy as in arm II plus carboplatin 350 mg/m2 during week 1. Survival was measured for the group as a whole and treatment-related toxicities in the four arms were compared. RESULTS The estimated median survival for all 100 patients was 17.1 months with 33% estimated survival at 2 years. The major toxicities were hematologic and esophageal. Patients receiving carboplatin had more neutropenia (p < 0.0001) and thrombocytopenia (p = 0.002) than patients receiving radiotherapy alone, and this was most marked in patients on arm III. Both carboplatin and accelerated radiotherapy separately caused more severe esophagitis when compared to conventional radiotherapy alone (p = 0.011 and p = 0.0017, respectively). Esophagitis was more prolonged in patients having accelerated radiotherapy (p < 0.0001, median duration 3.2 months compared with 1.4 months for patients receiving conventional fractionation). Six patients (23%) treated on arm II have required dilatation of esophageal stricture, one dying with a laryngo-esophageal fistula. CONCLUSION In patients receiving radiotherapy for unresectable lung cancer, overall treatment time can be halved and carboplatin administered concurrently with increased but acceptable esophageal and hematologic toxicity.

A role for radiotherapy in neuropathic bone pain : Preliminary response rates from a prospective trial (Trans-Tasman Radiation Oncology Group, Trog 96.05)

PURPOSE Radiotherapy (RT) has a proven role in palliation of pain from bone metastases with numerous randomized trials obtaining response rates (RRs) of typically 70-80% regardless of the fractionation employed. However RT for neuropathic bone pain (NBP), i.e., pain with a radiating cutaneous component due to compression/irritation of nerves by tumor has not previously been studied, and its role is thus uncertain. METHODS AND MATERIALS In February 1996, the Trans-Tasman Radiation Oncology Group (TROG) initiated a multicenter randomized trial comparing a single 8 Gy fraction with 20 Gy in 5 fractions for NBP with an accrual target of 270. Formal interim analyses were planned at 90 and 180 patients. The 90th patient was accrued in June 1998, and data from the first interim analysis with both arms combined form the basis of this report. RESULTS Forty-four patients were randomized to a single 8 Gy, 46 to 20 Gy in 5 fractions. The commonest primary sites were prostate (34%), lung (28%) and breast (10%). Median age was 68 years (range 37-89). The index site was spine (86%), rib (13%), base of skull (1%). On an intention-to-treat basis, the overall RR was 53/90 = 59% (95% CI = 48-69%), with 27% achieving a complete response and 32% a partial response. The overall RR for eligible patients was 49/81 = 60% (95% CI = 49-71%) with 27% and 33% achieving complete and partial responses respectively. Estimated median time to treatment failure was 3.2 months (95% CI = 2.1-5.1 months), with estimated median survival of 5.1 months (95% CI = 4.2-7.2 months). To date, six spinal cord/cauda equina compressions and four new or progressive pathological fractures have been detected at the index site after randomization, although one cord compression occurred before radiotherapy was planned to commence. In February 1999, the Independent Data Monitoring Committee strongly recommended continuation of the trial. CONCLUSION Although these results are preliminary, it seems clear that there is indeed a role for RT in the treatment of NBP. Analysis of outcome by treatment arm awaits completion of the randomized trial.

Tumour recurrence or treatment sequelae following radiotherapy for larynx cancer

Differentiating between recurrent carcinoma and significant sequelae of radiotherapy after treatment of laryngeal carcinoma is an uncommon but difficult clinical problem. Head and neck surgeons can be faced with deciding on the necessity for salvage laryngectomy without prior histological confirmation of recurrence. This paper reviews the literature pertaining to this topic to provide a better overall estimate of the risk of recurrence in these cases. Approximately 50% of patients with severe oedema or necrosis following radiotherapy for larynx cancer will have recurrence. Less than 10% of all larynges removed will be histologically negative when persistent or recurrent tumour is suspected clinically or indicated by biopsy following radiotherapy.

An independent check of treatment plan, prescription and dose calculation as a QA procedure

In many radiotherapy centres where planning for external beam treatments is performed by radiation therapists, the treatment sheet and its calculations are independently checked by staff from a different educational background, typically a radiotherapy physicist. The benefits of this practice were evaluated in a radiotherapy department with two linear accelerators, one combined superficial-orthovoltage unit and one telecaesium unit. Within the 19 months of the investigation period, 2328 checks were performed on the treatment sheets of 1579 patients. In six cases, errors in excess of 5% were detected, which if uncorrected, could potentially have affected local tumour control or caused normal tissue complications. It was found that an independent check of treatment sheets assists in keeping these errors as low as can be achievable in clinical practice, and suggests that treatment sheet checking and in vivo dosimetry play a complementary role in this aim. Independent treatment sheet checking is an important quality assurance (QA) activity, with additional advantages such as improved communication in the department, education of staff and in vivo dosimetry targeting. Therefore the advantages of the procedure seem to outweigh the additional workload of approximately 0.3 full-time staff per 1000 patients per year.