The role of external beam radiotherapy in the management of medullary carcinoma of the thyroid: A systematic review.

OBJECTIVE: In order to clarify the role of external beam radiotherapy in the management of medullary thyroid cancer (MTC), a systematic review was undertaken. PATIENTS AND INTERVENTIONS: Patients with MTC of any stage receiving radiotherapy, either as adjuvant postoperative treatment or as primary treatment for unresectable disease. DESIGN: Electronic searching Medline and ProQuest databases for randomised or non-randomised studies. A risk of bias assessment (ROBINS-I) was carried out for each study. MAIN OUTCOME MEASURES: Overall survival, rates of locoregional recurrence, locoregional relapse-free survival. RESULTS: There were no randomised studies. Twenty-seven non-randomised studies were identified. Within four cohort studies, radiotherapy had no significant effect on overall survival. Within one prospective and 22 retrospective studies (of approximately 1200 patients), radiotherapy similarly had no consistent effect on overall survival but there was evidence that radiotherapy reduces the risk of locoregional relapse, particularly in those with nodal involvement, extrathyroidal extension or residual disease. In a meta-analysis of patients within four studies, radiotherapy reduced the risk of locoregional relapse by at least 38%. Evidence supports the use of doses of 60 Gy or greater and an interval between surgery and radiotherapy of less than two months. Thirteen of 63 patients (21%) treated for unresectable disease achieved a complete response. Acute morbidity was observed in relation to difficulty swallowing, xerostomia and skin reactions. Late morbidity was infrequent with a low incidence of xerostomia. CONCLUSIONS: Radiotherapy should be considered for those at high risk of locoregional relapse, in particular those with nodal involvement, extrathyroidal extension or residual disease (microscopic or macroscopic).

Quantitative in vivo measurements of tumor perfusion using rubidium-81 and positron emission tomography.

Rubidium-81 (t1/2 = 4.58 hr) was investigated as a tumor perfusion tracer in the VX2 carcinoma implanted into rabbit thigh muscle using a large-area, multiwire proportional chamber positron emission tomography (PET) system. Perfusion was determined using the arterial reference sample method, and the results from PET imaging were compared with postmortem tissue sampling. Absolute quantitation of tumor perfusion was achieved using external probes to estimate local extraction fraction. Redistribution of rubidium-81 (81Rb) was investigated using a dual-tracer technique. Average perfusion was found to be 13.5 and 3.7 ml/min/100 g in tumor and normal muscle, respectively. The extraction fraction as estimated from a two-compartment model ranged from 0.94 to 1.00. No significant redistribution of 81Rb was observed in these tissues. Nine patients with malignancies were studied using 81Rb and PET. Tumor perfusion in four patients with carcinoma of the breast was elevated by a factor of 1.8 (range 1.2-2.3) compared to contralateral normal breast.

The effects of oral hydralazine on blood pressure, cardiac output and peripheral resistance with respect to dose, age and acetylator status.

Cardiovascular responses are reported in 21 patients with carcinoma of the bronchus taking part in a study of tumour perfusion. There were eight slow and 12 fast acetylators; acetylator status was not determined in one patient with a history of sulphonamide allergy. Hydralazine dose ranged from 25 to 150 mg orally (equivalent to 0.37 to 2.86 mg/kg). Mean arterial blood pressure fell from 98 mmHg before hydralazine to 90 mmHg 60 min after hydralazine (p = 0.002) and mean cardiac output rose from 5.53 l/min to 7.75 l/min (p = 0.00005). Calculated total peripheral resistance fell by 30% (p = 0.0002). Falls in peripheral resistance per milligram hydralazine administered were greater in patients over 70 years of age. Acetylator status was a poor predictor of response. Side-effects were reported by eight patients and were related to the magnitude of fall in peripheral resistance (p = 0.0005) but not to falls in blood pressure (p = 0.12).

The effects of single dose oral hydralazine on blood flow through human lung tumours.

Hydralazine has been shown to reduce tumour blood flow and to potentiate the cytotoxicity of melphalan and bioreductive agents in mice. In order to determine whether such a strategy might have clinical potential, a study was undertaken to investigate the effects of hydralazine on blood flow through human tumours. Twenty-two patients with carcinoma of the bronchus received a single oral dose of hydralazine in the range 25 to 150 mg (0.37-2.86 mg/kg) according to age and acetylator status. Tumour blood flow was assessed by single photon emission computed tomography (SPECT) performed 10 min following intravenous 99Tcm-HMPAO on two occasions 2-8 days apart, the second being performed 60 min after hydralazine administration. In 20 evaluable patients, hydralazine caused a 38% increase in blood flow through the whole tumour (p = 0.007) and a 28% increase in flow through the tumour centre (p = 0.03) with greater increases occurring in patients sustaining greater falls in peripheral resistance. Tumour vascular resistance fell indicating active vasodilation in arterioles supplying tumours. Side-effects due to hydralazine were reported by eight patients.

The pathway study: results of a pilot feasibility study in patients suspected of having lung carcinoma investigated in a conventional chest clinic setting compared to a centralised two-stop pathway.

UNLABELLED: The best chance of cure in non-small cell lung cancer (NSCLC) is surgical resection, but UK rates of 8% compare poorly to 25% in the USA and Europe. Delays in diagnosis in the current UK system may be one reason for such discrepancy. To address this problem we set up a rapid diagnostic system and compared it to the conventional method of investigations in a pilot randomised trial. METHODS: Eighty-eight patients were prospectively enrolled from three District General Hospitals and randomised to either investigation locally or to the rapid system at The Royal Marsden Hospital. The pilot end-points were feasibility and audit of radical treatment rates to enable estimates for patient numbers for the full study. RESULTS: Forty-five and 43 patients were in the central and conventional arms, respectively (65% male, median age 69 years). There was a 4-week improvement in time to first treatment in those in the central arm (P=0.0025) with 13/30 (43%) and 9/27 (33%) patients having radical treatment in the central and conventional arms, respectively. Patients in the conventional arm felt the diagnostic process was too slow (P=0.02) while those in the central arm seemed to have a better care experience (P=0.01). There were significantly less visits to the general practitioner (GP) in the central arm (P=0.02). CONCLUSIONS: This pilot study demonstrates that the full study is feasible but would require the commitment and involvement of a large number of patients and physicians. The results show several advantages to investigations and diagnosis in the central arm, particularly in time to treatment initiation, patient satisfaction and rate of radical treatments. The improved rate of radical treatment could lead to an improved survival rate.

Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable).

BACKGROUND: In general, surgery is believed to offer the best prospects for cure for early stage non-small cell lung cancer (NSCLC). In spite of the intention to consider all patients with stage I-II disease for surgery, there are those who, although technically operable, either refuse surgery or are considered inoperable because of insufficient respiratory reserve, cardiovascular disease or general frailty. This group may therefore be considered "medically inoperable". Some respiratory physicians refer these patients for radical radiotherapy whilst others believe that radiotherapy has little to offer and adopt a watch policy, referring patients for palliative radiotherapy only when they become symptomatic. Although there is little evidence from randomised trials to support the use of radical radiotherapy for stage I/II NSCLC, it is the perception of most clinical oncologists (radiotherapists) that patients should receive radical, as opposed to palliative, treatment (COIN 1999). OBJECTIVES: To determine the effectiveness and the morbidity of radical radiotherapy for medically inoperable NSCLC. SEARCH STRATEGY: Randomised trials were sought by electronic searching the Cochrane Clinical Trials Register and both randomised and non-randomised trials sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. SELECTION CRITERIA: Studies of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose greater than 40Gy in 20 fractions over four weeks or its radiobiological equivalent. DATA COLLECTION AND ANALYSIS: Two randomised and thirty-five non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria and were not included in the review. MAIN RESULTS: In the randomised trial comparing two radiotherapy schedules, two-year survival was superior following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) compared to 60Gy in 30 fractions over six weeks (24%). There were 26 non-randomised retrospective studies including an estimated 2003 patients, in which overall survival results varied between 33-72% at two years, 17-55% at three years and 0-42% at five years. The proportion of deaths not due to cancer was 11-43%. Cancer-specific survival was between 54-93% at two years, 22-56% at three years and 13-39% at five years. Complete response rates were 33-61% and local failure rates between 6-70%. Distant metastases developed in approximately 25% of patients. Better response rates and survival were seen in those with smaller tumours and in those receiving higher doses though the reasons for prescribing higher doses were not clearly stated. Worse outcome was seen in those with prior weight loss or poor performance status. Assessment of treatment-related morbidity and effects on quality of life and symptom control were inconclusive because of the lack of prospective evaluation and paucity of data. REVIEWER'S CONCLUSIONS: There were no randomised trials that compared a policy of immediate radical radiotherapy with palliative radiotherapy given when patients develop symptoms. In the absence of such trials, radical radiotherapy appears to result in a better survival than might be expected had treatment not been given. A substantial, though variable, proportion of patients died during follow-up from causes other than cancer. The optimal radiation dose and treatment technique (particularly with respect to mediastinal irradiation) remain uncertain.

Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable).

BACKGROUND: In general, surgery is believed to offer the best prospects for cure for early stage non-small cell lung cancer (NSCLC). In spite of the intention to consider all patients with stage I-II disease for surgery, there are those who, although technically operable, either refuse surgery or are considered inoperable because of insufficient respiratory reserve, cardiovascular disease or general frailty. This group may therefore be considered "medically inoperable". Some respiratory physicians refer these patients for radical radiotherapy whilst others believe that radiotherapy has little to offer and adopt a watch policy, referring patients for palliative radiotherapy only when they become symptomatic. Although there is little evidence from randomised trials to support the use of radical radiotherapy for stage I/II NSCLC, it is the perception of most clinical oncologists (radiotherapists) that patients should receive radical, as opposed to palliative, treatment (COIN 1999). OBJECTIVES: To determine the effectiveness and the morbidity of radical radiotherapy for medically inoperable NSCLC. SEARCH STRATEGY: Randomised trials were sought by electronic searching the Cochrane Clinical Trials Register and both randomised and non-randomised trials sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. SELECTION CRITERIA: Studies of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose greater than 40Gy in 20 fractions over four weeks or its radiobiological equivalent. DATA COLLECTION AND ANALYSIS: Two randomised and thirty-five non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria and were not included in the review. MAIN RESULTS: In the randomised trial comparing two radiotherapy schedules, two-year survival was superior following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) compared to 60Gy in 30 fractions over six weeks (24%). There were 26 non-randomised retrospective studies including an estimated 2003 patients, in which overall survival results varied between 33-72% at two years, 17-55% at three years and 0-42% at five years. The proportion of deaths not due to cancer was 11-43%. Cancer-specific survival was between 54-93% at two years, 22-56% at three years and 13-39% at five years. Complete response rates were 33-61% and local failure rates between 6-70%. Distant metastases developed in approximately 25% of patients. Better response rates and survival were seen in those with smaller tumours and in those receiving higher doses though the reasons for prescribing higher doses were not clearly stated. Worse outcome was seen in those with prior weight loss or poor performance status. Assessment of treatment-related morbidity and effects on quality of life and symptom control were inconclusive because of the lack of prospective evaluation and paucity of data. REVIEWER'S CONCLUSIONS: There were no randomised trials that compared a policy of immediate radical radiotherapy with palliative radiotherapy given when patients develop symptoms. In the absence of such trials, radical radiotherapy appears to result in a better survival than might be expected had treatment not been given. A substantial, though variable, proportion of patients died during follow-up from causes other than cancer. The optimal radiation dose and treatment technique (particularly with respect to mediastinal irradiation) remain uncertain.

Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus.

BACKGROUND: Superior vena caval obstruction (SVCO) is an uncommon manifestation of carcinoma of the bronchus characterised by neck swelling and distended veins over the chest. In recent years, the majority of patients with small cell lung cancer (SCLC) with SVCO at diagnosis have tended to receive chemotherapy whilst the majority of patients presenting with non-small cell lung cancer (NSCLC) and SVCO have tended to receive radiotherapy. Steroids may also be prescribed. Stenting now provides a further treatment option which may be combined with radiotherapy and chemotherapy or used on its own. The optimal timing of stenting at present is unclear. OBJECTIVES: To determine the relative effectiveness of treatments currently employed in the management of SVCO. SEARCH STRATEGY: Electronic searching of Cochrane Clinical Trials register, Medline and Embase. Identification of further studies from references cited in trials identified by electronic searching. SELECTION CRITERIA: Both randomised and non-randomised controlled trials in which patients with carcinoma of the bronchus and a diagnosis of SVCO had been treated with any combination of the following treatment modalities: steroids, chemotherapy, radiotherapy or insertion of an expandable metal stent. DATA COLLECTION AND ANALYSIS: There were 3 randomised and 98 non-randomised studies of which 2 and 44 respectively met the inclusion criteria. MAIN RESULTS: SVCO was present at diagnosis in 10.0% of patients with SCLC and 1.7% of patients with NSCLC. In one randomised trial in SCLC, the rate of SVCO relapse was not significantly reduced by giving radiotherapy on completion of chemotherapy. In the other, in NSCLC, the addition of induction chemotherapy to a course of synchronous chemo-radiotherapy did not increase the rates of relief of SVCO. In SCLC, chemotherapy and/or radiotherapy relieved SVCO in 77%; 17% of those treated had a recurrence of SVCO. In NSCLC, 60% had relief of SVCO following chemotherapy and/or radiotherapy; 19% of those treated had a recurrence of SVCO. Insertion of an SVC stent relieved SVCO in 95%; 11% of those treated had further SVCO but recanalisation was possible in the majority resulting in a long-term patency rate of 92%. Morbidity following stent insertion was greatest if thrombolytics were administered. No study described the effectiveness of steroids in SVCO. REVIEWER'S CONCLUSIONS: Chemotherapy and radiotherapy are effective in relieving SVCO in a proportion of patients whilst stent insertion appears to provide relief in a higher proportion and more rapidly. The optimal timing of stent insertion (whether at diagnosis or following failure of other modalities) is currently uncertain. The effectiveness of steroids in SVCO remains uncertain.

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.

Survey of attitudes of UK clinical oncologists towards radionuclide therapy.

A survey of UK consultants in clinical oncology was carried out in November 1997. The aim of this was to explore their attitudes towards radionuclide therapy and to determine the proportion of clinical oncologists involved in this modality. Three hundred and twenty-eight questionnaires were sent out and 227 (69.2%) were returned. Approximately one-half of those responding treat thyroid cancer or benign thyroid disease with radioactive iodine ((131)I) or prostate cancer with strontium ((89)Sr). The median number of patients treated per year with (131)I for benign thyroid disease was 12, with evidence of increasing subspecialization. Treatment with radioactive phosphorus ((32)P) for haematological disorders and yttrium ((90)Y) for intra-articular conditions was carried out by 31% (median number treated per year, two) and 6% (median number per year, five) respectively. There was strong support for the continuing involvement of clinical oncologists in radionuclide therapy for thyroid and prostate cancer. There was significant support for patients with benign thyroid disease or requiring intra-articular (90)Y to be treated by a specialist in nuclear medicine. However, this support was less strong amongst those currently involved in treatment compared with those not involved. There was support for the continued involvement of clinical oncologists in the use of (32)P. Attitudes appeared not to vary in different parts of the UK.

Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review.

OBJECTIVE: To conduct a systematic review to determine the relative effectiveness of treatments currently employed in the management of superior vena caval obstruction (SVCO). SEARCH STRATEGY: Electronic searching of the Cochrane Clinical Trials Register, Medline and Embase with identification of further studies from references cited in trials identified by electronic searching. SELECTION CRITERIA: Both randomized and non-randomized controlled trials in which patients with carcinoma of the bronchus and SVCO had been treated with any combination of steroids, chemotherapy, radiotherapy or insertion of an expandable metal stent. DATA COLLECTION AND ANALYSIS: There were three randomized and 98 non-randomized studies of which two and 44 respectively met the inclusion criteria. MAIN RESULTS: Superior vena caval obstruction was present at diagnosis in 10.0% of patients with small cell lung cancer (SCLC) and 1.7% of patients with non-small cell lung cancer (NSCLC). In one small randomized trial in SCLC, the rate of SVCO relapse was not significantly reduced by giving radiotherapy on completion of chemotherapy. In another, in NSCLC, the addition of induction chemotherapy to a course of synchronous chemo-radiotherapy did not provide greater relief of SVCO. In SCLC chemotherapy and/or radiotherapy relieved SVCO in 77%; 17% of those treated had a recurrence of SVCO. In NSCLC, 60% had relief of SVCO following chemotherapy and/or radiotherapy; 19% of those treated had a recurrence of SVCO. Insertion of an SVC stent relieved SVCO in 95%; 11% of those treated had further SVCO but recanalization was possible in the majority resulting in a long-term patency rate of 92%. Morbidity following stent insertion was greater if thrombolytics were administered. REVIEWERS' CONCLUSIONS: Chemotherapy and radiotherapy are effective in relieving SVCO in a proportion of patients whilst stent insertion may provide relief in a higher proportion and more rapidly. The effectiveness of steroids and the optimal timing of stent insertion (whether at diagnosis or following failure of other modalities) remain uncertain.

99Tcm-labelled meso-HMPAO and glutathione content of human lung tumours.

Levels of reduced glutathione (GSH) are increased in some types of malignant tumours and are known to influence the response to radio- and chemotherapy. In vitro studies suggest a correlation between cellular GSH concentration and retention of the meso form of hexamethyl propyleneamineoxime (HMPAO). This study investigates the relationship between in vivo tissue retention of 99Tcm-labelled HMPAO and GSH concentration in ten patients referred for thoracotomy for possible lung cancer. Retention of 99Tcm-HMPAO was measured using single photon emission computed tomography (SPECT). The tumour and normal lung concentration of reduced glutathione (GSH) was measured in tissue specimens collected peroperatively. Malignancy was confirmed in eight patients. Of seven patients undergoing curative resection for carcinoma, tumour GSH concentration was higher (mean 2.76 mM) than normal lung (mean 1.04 mM). In one neurofibroma, the GSH concentration was 1.80 mM. No correlation was found between 99Tcm meso-HMPAO retention and either the tumour GSH concentration or the tumour:lung GSH ratio. The results from this small series demonstrate that the intracellular GSH concentration of malignant lung tumours is generally higher than that in normal lung but that meso-HMPAO retention could not be used to predict these levels.

Are mastectomy resection margins of clinical relevance? A systematic review.

Although some guidelines support the use of post-mastectomy radiotherapy where the resection margin is involved or close, the scientific basis of this practice is not established. This systematic review explores the relationship between margin status and subsequent relapse. Pooled data from 22 studies (18,863 women) identified an involved post-mastectomy margin in 2.5%, a close margin in 8.0% and muscle or fascia invasion in 7.2% of patients. In a meta-analysis of five studies of non-inflammatory breast cancer without radiotherapy, local recurrence was increased by an involved or close margin (relative risk 2.6; P<0.00001). The effect of muscle or fascia invasion was of borderline significance (relative risk 1.7; P=0.04). In two separate meta-analyses, risk of relapse was related to margin status in women with inflammatory breast cancer (relative risk 3.1; P<0.0001) but not in those undergoing skin-sparing mastectomy (relative risk 2.1; P=0.16).