A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG.

BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

Economic evaluation of a randomized clinical trial of hospital versus telephone follow-up after treatment for breast cancer.

BACKGROUND: This was an economic evaluation of hospital versus telephone follow-up by specialist nurses after treatment for breast cancer. METHODS: A cost minimization analysis was carried out from a National Health Service (NHS) perspective using data from a trial in which 374 women were randomized to telephone or hospital follow-up. Primary analysis compared NHS resource use for routine follow-up over a mean of 24 months. Secondary analyses included patient and carer travel and productivity costs, and NHS and personal social services costs of care in patients with recurrent breast cancer. RESULTS: Patients who had telephone follow-up had approximately 20 per cent more consultations (634 versus 524). The longer duration of telephone consultations and the frequent use of junior medical staff in hospital clinics resulted in higher routine costs for telephone follow-up (mean difference pound 55 (bias-corrected 95 per cent confidence interval (b.c.i.) pound 29 to pound 77)). There were no significant differences in the costs of treating recurrence, but patients who had hospital-based follow-up had significantly higher travel and productivity costs (mean difference pound 47 (95 per cent b.c.i. pound 40 to pound 55)). CONCLUSION: Telephone follow-up for breast cancer may reduce the burden on busy hospital clinics but will not necessarily lead to cost or salary savings.

TN/TN glottic carcinoma: a comparison of two fractionation schedules.

The aim of this paper is the retrospective comparison of accelerated/hypofractionated radiotherapy regimen (AHFX) with standard fractionation regimen (SFX) for patients with early glottic carcinoma. One hundred and forty-five patients with T(1)-T(2) glottic cancer between 1986 and 1998 were eligible. Before 1992, patients received 60-66 Gy in 30-33 fractions over 6-6.5 weeks (SFX) with (60)Co and 6-MV beams. After 1992, patients received 52.5-55 Gy in 20 fractions over 4 weeks (AHFX) using 6-MV beams. The end-points were overall survival, laryngectomy-free survival (LFS), loco-regional control and toxicity. One hundred and two were stage T(1)N(0); 43 were stage T(2)N(0). Median follow up was 4.9 years. The 5-year overall survival was 78%. Five-year loco-regional control in T(1)N(0) patients was higher in AHFX than in SFX group (95 vs 75%, P = 0.002). Loco-regional control in T(2)N(0) patients was similar for AHFX and SFX (81 vs 80%, P = 0.813). Overall LFS was 88%. T(1)N(0) AHFX patients had 5-year LFS of 95% compared with 75% for SFX (P = 0.003). For T(2)N(0) AHFX patients, overall LFS was 92% compared with 80% for the SFX group (P = 0.291). No grade 4 or 5 late toxicity occurred. One AHFX patient developed grade 3 toxicity; two of 51 SFX patients developed grade 2 toxicity versus five of 94 AHFX patients. AHFX using 6-MV beams for treatment of early glottic cancer resulted in equivalent LFS and toxicity when compared with SFX.

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer.

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study.

PURPOSE: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. PATIENTS AND METHODS: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. RESULTS: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P=0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P=0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P=0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P<0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P<0.05), except for the mucous membrane where late effects were similar in both arms. CONCLUSIONS: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy.

The ex vivo effect of high concentrations of doxorubicin on recurrent ovarian carcinoma.

The cardiotoxicity of anthracyclines has largely prevented dose intensification, but the use of liposomal preparations (e.g. Caelyx/Doxil) allows much higher intra-tumoral concentrations to be achieved without cardiotoxicity. However, it is uncertain how much this will improve response rates over standard anthracycline therapy. The ATP-based chemosensitivity assay (ATP-TCA) has been used to develop new regimens for several tumor types, to investigate the molecular basis of chemosensitivity and shows considerable promise as a clinical method for individualizing chemotherapy. In this study, we have used the ATP-TCA to determine the concentration responsiveness of tumor-derived cells to concentrations of doxorubicin. The 22 tumor samples included were obtained from 20 heavily pretreated patients with recurrent ovarian cancer. Eight had previous anthracycline exposure, four as part of the CAP regimen. The results show more than 95% inhibition at clinically achievable concentrations in 11 of 22 tumors tested. Of the rest, seven showed a plateau effect between 80 and 95% inhibition, suggesting that there might be a subset of resistant cells present that is not inhibited by high concentrations of doxorubicin. Two tumors showed complete resistance and neither of these had previously received anthracycline therapy. As it has been suggested that gemcitabine might enhance anthracycline sensitivity in combination and we have had good results with gemcitabine modulation of alkylating agents in the assay, we have tested the combination of doxorubicin+gemcitabine under assay conditions in 11 tumors with little indication of improvement. In conclusion, doxorubicin at concentrations achievable with liposomal preparations shows strong ex vivo activity against pretreated recurrent ovarian cancer in just over half of the cases tested.

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.

Quality assurance audit in an Australasian phase III trial of accelerated radiotherapy for head and neck cancer (TROG 91.01). Trans-Tasman Radiation Oncology Group.

The Trans-Tasman Radiation Oncology Group (TROG) initiated a randomized trial, testing accelerated (twice daily) radiotherapy against conventional radiotherapy for stage III and stage IV squamous cell carcinoma of the head and neck in 1991. In 1996, the Trial Management Committee arranged for a technical audit of 76 cases from 11 institutions, conducted by investigators from interstate institutions. A 10% unacceptable protocol violation rate was detected, which compares favourably with initial Radiation Therapy Oncology Group (RTOG) experience in the late 1970s. Infrastructural deficits with poor quality of documentation, incomplete retrieval of films and document return have been demonstrated in some cases. The Trans-Tasman Radiation Oncology Group is actively pursuing procedural and resourcing issues in order to redress this and is actively expanding its Quality Assurance (QA) Programme with an intercentre dosimetry study. Ultimately, comprehensive clinical and technical QA site visits are planned.

Audit in the management of T3 fixed-cord laryngeal cancer.

PURPOSE: To determine results of various treatments for T3 fixed-cord lesions and the subset T3 glottic cancer in Auckland from 1979 to 1995. PATIENTS AND METHODS: Data were collected retrospectively from a departmental database, and the notes were reviewed. Because of the difficulty in determining the subsite of some fixed-cord lesions, the entire group of T3 fixed-cord lesions was examined, and those tumors that were considered to be definitely arising from the glottis were then analyzed as a specific subset. RESULTS: Fixed-cord lesions were diagnosed in 75 patients (21 supraglottic, 54 glottic). Primary surgery (total laryngectomy) was performed on 46 patients, primary radical dose radiotherapy was undertaken on 25 patients, and four patients were treated palliatively. For T3 fixed-cord lesions, disease-specific survival for radiotherapy and surgery was 36% and 66%, respectively, and 32% and 67%, respectively, for T3 glottic lesions. For both T3 fixed-cord and T3 glottic lesions, surgery produced significantly better survival than did radiotherapy (<60 Gy; P = .0157). With radiotherapy greater than 60 Gy, cancer of the larynx has been controlled in seven of 13 patients, although only five patients are alive, with a median follow-up of 24 months (range, 12-49 months). CONCLUSION: Radiotherapy less than 60 Gy produced markedly inferior results to surgery for T3 fixed-cord lesions and T3 glottis in Auckland. Radiotherapy at more than 60 Gy shows promise, but an ongoing audit is essential to ensure that survival is similar to surgery and to that reported by those promoting organ-preservation protocols.

A simple percutaneous inserter for radiopaque gold seeds used in radiotherapy treatment planning.

Percutaneous insertion of a radiopaque marker is an important technique used in radiotherapy planning for both external-beam and brachytherapy. It is of particular importance in the oral cavity. We describe the construction and use of a simple inserter for 'cold' gold seeds manufactured from a commercially available Becton Dickinson Brand 5-mL disposable syringe and a Becton Dickinson Brand 18 G 1 1/2 TW (1.25 x 38 mm) hypodermic needle.

Mucosal regeneration during radiotherapy. Trans Tasman Radiation Oncology Group (TROG).

BACKGROUND AND PURPOSE: Regeneration of the aerodigestive mucosa is known to occur during conventionally fractionated radiotherapy. The circumstances surrounding its time of onset and magnitude are not well understood, however. MATERIAL AND METHODS: Mucosal reactions were observed in 100 patients undergoing conventionally fractionated treatment at 2 Gy/day over 7 weeks and 88 receiving accelerated treatment at 1.8 Gy twice daily over 3 1/2 weeks on the Trans Tasman Radiation Oncology Group head and neck cancer trials. Similar observations in 61 patients treated palliatively at dose rates between 0.8 and 240 Gy/h using ten 3.0-4.2 Gy fractions over 2 weeks are compared. RESULTS: Several findings emerged from these studies: 1. Reactions evolved more quickly at oropharyngeal sites than in the hypopharynx. 2. Reactions at both sites evolved more rapidly at greater rates of dose accumulation. 3. The timing of reactions suggested the presence of a strong regenerative mucosal response that started before the manifestation of "patchy' (grade II) mucosal reactions. 4. The regenerative response was strong enough to "make good' damage accumulated at a rate of 2 Gy/day in over a third of cases. 5. The linear quadratic model without time correction failed to provide an adequate prediction of the frequency or intensity of mucosal reactions produced by any of the regimes. A simple model of the regenerative response is presented. CONCLUSIONS: This study suggests that the timing and magnitude of the regenerative response vary between sites and individuals but are linked to the amount of epithelial cellular depletion occurring during treatment.

Use of peritoneal insufflation to displace the small bowel during pelvic and abdominal radiotherapy in carcinoma of the cervix.

Peritoneal insufflation is a technique which reliably displaces small bowel from pelvic and abdominal radiotherapy fields with the aim of reducing bowel reactions which limit the dose of radiation applied to these sites. Use of this technique in five patients undergoing radiotherapy for advanced carcinoma of the cervix, and the degree of bowel displacement resulting, dosimetry, acute reactions and tolerability of the technique are presented, with discussion of the possibility of future escalation in radiotherapy dose.

'Watch policy' in patients with suspected stage I testicular seminoma: CT as a sole staging and surveillance technique.

A study was undertaken to assess the role of computed tomography (CT) as the sole imaging technique for the staging and surveillance of patients with stage I testicular seminoma. Of the 15 patients studied, five (33%) relapsed. This relapse rate differs from other studies. The reasons for this are discussed.

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone.

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.

Trilostane in the treatment of advanced breast cancer.

The combination of trilostane 960 mg daily and either dexamethasone 0.5 mg b.d. or hydrocortisone 10 mg b.d. has been used to treat advanced metastatic breast cancer in post-menopausal women. Twenty-three patients had assessable disease and received treatment for a minimum of 8 weeks. Six (26%) showed an objective response and three (13%), stabilisation of previously progressive disease, sustained for at least 3 months. Side-effects were mainly gastrointestinal. Biochemical studies suggest that the mechanism of action may be inhibition of conversion of androstenedione to oestrone.

A double-blind controlled trial of salmon calcitonin in pain due to malignancy.

Thirty-two patients with established malignancy and associated pain participated in a randomised double-blind controlled trial. They received salmon calcitonin SC 200 UI or matching placebo 6-hourly for 48 h and were assessed by using a combination of a 20-point visual analogue scale (VAS), a 4-point physician's global pain scale, and ranking of the co-administered analgesics into 20 grades of potency. Twenty-five patients (13 calcitonin, 12 placebo) were evaluated. Seven patients (4 calcitonin, 3 placebo) were excluded either because the initial pain score was less than or equal to 5 on the VAS, or because there were insufficient data (due to death occurring within the first week of the study or, in one patient, blindness preventing completion of the VAS). One week after commencing therapy there was improvement or marked improvement of pain in significantly more patients in the calcitonin group (5/13) than in the placebo group (0/12) (Fisher's exact two-tailed probability test, P = 0.0484). At the end of the second week three patients in the calcitonin group were still showing marked improvement.

Electroencephalographic changes in epileptics while viewing television.

Ten consecutive epileptic patients who showed abnormal electroencephalographic (E.E.G.) responses to intermittent photic stimulation have been studied while watching television. Though only two gave a history of television epilepsy nine exhibited spike-wave discharges in the E.E.G. during viewing. This effect occurred when the set was functioning normally but was increased in five subjects when the screen was deliberately caused to flicker.