Concurrent chemoradiotherapy in non-small cell lung cancer.

BACKGROUND: In a previous meta-analysis of adjuvant chemotherapy in NSCLC there was a 13% reduction in the risk of death in patients receiving radical radiotherapy. This overview specifically excluded trials in which chemotherapy and radiotherapy were given concurrently (NSCLCCG 1995). The use of concurrent chemotherapy and radiotherapy might be seen as a way of increasing the effectiveness of radiotherapy at the same time as reducing the risks of metastatic disease by using chemotherapy. OBJECTIVES: To determine the effectiveness of concurrent chemoradiotherapy as compared to radiotherapy alone with regard to local control and overall survival; and to determine whether the addition of concurrent chemotherapy results in an altered risk of treatment-related morbidity. To compare concurrent with sequential chemoradiotherapy. SEARCH STRATEGY: Electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE with identification of further studies from references cited in the initial identified studies. SELECTION CRITERIA: Randomised trials of patients with stage I-III non-small cell lung cancer (NSCLC) undergoing radical radiotherapy and randomised to receive concurrent chemoradiotherapy versus radiotherapy alone, or concurrent versus sequential chemoradiotherapy. DATA COLLECTION AND ANALYSIS: Identified trials were reviewed independently by both reviewers. Relative risks (calculated according to a random-effects model) were determined with respect to overall survival, progression-free survival and treatment morbidity. MAIN RESULTS: Fourteen randomised studies (including 2393 patients) of concurrent chemoradiotherapy versus radiotherapy alone met the inclusion criteria. In a meta-analysis there was a reduction in risk of death at two years (relative risk (RR) 0.93; 95% CI 0.88 to 0.98; P = 0.01). Similar improvements in two-year locoregional progression-free survival (RR 0.84; 95% CI 0.72 to 0.98; P = 0.03) and progression-free survival at any site (RR 0.90; 95% CI 0.84 to 0.97; P = 0.005) were also seen in those receiving concurrent chemoradiotherapy. Subgroup analysis suggested the possibility of a greater benefit from regimens which incorporated once daily fractionation of radiotherapy or a higher total chemotherapy dose. The incidence of acute oesophagitis, neutropenia and anaemia were significantly increased by concurrent chemoradiotherapy. In a meta-analysis of three trials of concurrent versus sequential chemoradiotherapy there was a significant reduction in the risk of death at two years with concurrent treatment (RR 0.86; 95% CI 0.78 to 0.95; P = 0.003) but potentially at the expense of toxicity, although data was incomplete. REVIEWERS' CONCLUSIONS: With concurrent chemoradiotherapy there was a 14% reduction in risk of death at two years compared to sequential chemoradiotherapy, and a 7% reduction compared to radiotherapy alone. In both cases there was some increase in acute oesophagitis. Caution is advised in adopting concurrent chemoradiotherapy as the standard of care because of uncertainties about the true magnitude of benefit in comparison with sequential chemoradiotherapy. With short follow up and uncertainties about toxicity in the identified studies, the optimal chemotherapy regimen remains uncertain. The confounding effects of treatment-related anaemia and gaps in treatment due to toxicity require further investigation.

Treatment of malignant hypercalcaemia with aminohexane bisphosphonate (neridronate).

Twenty patients with hypercalcaemia due to malignancy, which persisted following rehydration, were treated with the bisphosphonate, aminohexane bisphosphonate (AHBP), which is structurally similar to pamidronate. The treatment given was a single infusion of 125 mg of AHBP in 500 ml of normal saline infused over 4 h. Serum and urine biochemistry were measured before and after treatment. Acute toxicity was evaluated with particular attention to gastrointestinal symptoms, acute-phase reaction and change in renal function, as judged by serum creatinine. The infusion of AHBP induced a rapid fall apparent by day 3 (P < 0.001), with a nadir at day 7. The serum calcium remained lower at days 14 and 28 than at day 0, but the numbers followed up were low (n = 5 and n = 4). In all 20 patients there was a fall in serum calcium after treatment, and in 13 (65%) normocalcaemia was achieved. Failure to respond completely to AHBP appeared to be associated with a renal mechanism of hypercalcaemia. Treatment was associated with a significant decrease in fasting urinary calcium excretion (P < 0.05). There was no change in white cell count or renal function following AHBP and only two cases of mild pyrexia after infusion. We conclude that aminohexane bisphosphonate is an effective agent in the treatment of tumour-induced hypercalcaemia, with rapid onset of effect and low toxicity.

Tumour induced hypercalcaemia: a case for active treatment.

This paper reports a retrospective survey of the diagnosis, management and outcome of hypercalcaemia in patients admitted to a regional oncology centre over a 12-month period; 168 cases of tumour induced hypercalcaemia were identified. In 69 patients (41%) the presence of hypercalcaemia was not noted in the case records; in a further 15 patients (9%) a positive decision was made not to treat the condition, although some of these patients continued to receive other forms of active treatment. Of the remaining patients, 20 (12%) received intravenous fluids alone and 64 (38%) received bisphosphonate therapy. Of those patients with initial serum calcium > 3 mmol/l 71% were treated with bisphosphonates. Median survival from onset of hypercalcaemia was only 2 months, but in the bisphosphonate treated group, 98% experienced a fall in serum calcium within a week of treatment. We believe that the symptomatic relief associated with a fall in serum calcium justifies active management even in the face of a poor prognosis. A large proportion of cases of tumour induced hypercalcaemia remain undiagnosed or untreated and we believe that this deserves further attention.

Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate.

Thirty patients with hypercalcaemia due to malignancy that persisted following rehydration, were treated with a single dose of the bisphosphonate, clodronate. Clodronate (1.5 g) was administered intravenously in 500 ml normal saline over 4 h. Serum and urine biochemistry were measured before and after treatment and the results were compared with data from 15 patients given the recommended regimen 300 mg intravenous clodronate daily for 5 consecutive days. The single infusion induced a rapid and significant fall in serum calcium, apparent at day 3 (P < 0.0001) that persisted to the end of follow-up at day 10 (P < 0.001). Eighty per cent (24/30) of patients became normocalcaemic. The response was associated with a significant decrease in fasting urinary calcium excretion, and no change in renal function, as judged by serum creatinine. The same dose of clodronate, given as 5 daily infusions, induced a comparable decrease in serum calcium, but was less rapid in onset so that at day 3 the serum calcium was significantly lower with the single infusion (P = 0.02). The calcium lowering effect of both regimens depended on the tumour type. We conclude that the single infusion of 1500 mg clodronate is as effective in reducing serum calcium as the same dose given over 5 days. The single infusion has a more rapid onset of effect, is more convenient than multiple infusions, and has no adverse effect on renal function.

Thiamine status of healthy and institutionalized elderly subjects: analysis of dietary intake and biochemical indices.

Thiamine status was assessed in healthy young and elderly subjects and institutionalized elderly patients by measuring dietary intake, erythrocyte levels of thiamine and the activity of the thiamine-dependent enzyme, erythrocyte transketolase, with and without the addition of excess thiamine pyrophosphate (the TPP effect). Healthy elderly subjects had a reduced intake of thiamine compared with the younger subjects but erythrocyte levels of thiamine and the TPP effect were comparable, suggesting adequate thiamine status. The institutionalized elderly patients had a low intake of thiamine compared with the healthy elderly as well as abnormal biochemical indices suggestive of suboptimal thiamine status. Thiamine deficiency does not appear to be a problem in healthy elderly people but those in institutions are at risk of deficiency which might adversely affect their clinical state.