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).

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).

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.

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.

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.

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.

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

OBJECTIVES: To determine the effectiveness of radical radiotherapy in medically inoperable stage I/II non-small cell lung cancer (NSCLC) and the extent of treatment related morbidity. METHODS: Randomised trials were sought by electronically searching the Cochrane Clinical Trials Register, and both randomised and non-randomised trials were sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. The studies included were those of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose of >40 Gy in 20 fractions over 4 weeks or its radiobiological equivalent. RESULTS: Two randomised and 35 non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria, leaving one randomised and 26 non-randomised studies for analysis. In the randomised trial 2 year survival was higher following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) than following 60 Gy in 30 fractions over 6 weeks (24%). An estimated 2003 patients were included in the 26 non-randomised studies; overall survival was 22-72% at 2 years, 17-55% at 3 years, and 0-42% at 5 years. Following treatment, 11-43% of patients died from causes other than cancer. Cancer specific survival was 54-93% at 2 years, 22-56% at 3 years, and 13-39% at 5 years. Complete response rates were 33-61% and local failure rates were 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 although the reasons for prescribing higher doses were not clearly stated. The outcome was worse 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. CONCLUSIONS: No randomised trials 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.

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.

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.

Quantitative single-photon emission tomography for tumour blood flow measurement in bronchial carcinoma.

A single-photon emission tomography (SPET) technique for the absolute measurement of tumour perfusion is described. Phantom studies have shown that source-background ratios are dependent upon source size and radial position within the phantom. A means of correcting source-background count ratios for these variables has been developed and used to correct tumour-lung ratios obtained in 28 patients with bronchial carcinomas who underwent technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) SPET. On SPET images, the normal lung appears as a relatively homogeneous background. The relationship between 99mTc background concentration (kBq/ml) and counts/pixel was determined from phantom studies and the tumour 99mTc concentration from the background 99mTc concentration and corrected tumour-lung ratio. The total activity of the lipophilic 99mTc-HMPAO species injected was measured. The activity reaching the systemic circulation (Asys) was obtained by subtracting the activity trapped in the pulmonary circulation (obtained from background 99mTc concentration and lung volume). Tumour blood flow may then be calculated from fraction of Asys contained in the tumour provided cardiac output and extraction fraction are known. Blood flow through the central region of tumours ranged from zero to 59.0 (mean 14.1) ml min-1 100 g-1 and through the whole tumour from 0.6 to 68.0 (mean 20.6) ml min-1 100 g-1.

Anatomically derived attenuation coefficients for use in quantitative single photon emission tomography studies of the thorax.

Elimination of errors due to poor attenuation correction is an essential part of any quantitative single photon emission tomography (SPET) technique. Attenuation coefficients (mu Tc) for use in attenuation correction of SPET data were determined using technetium 99m and cobalt 57 flood sources and using topographical information obtained from computed tomography (CT) scans and magnetic resonance (MR) images. In patients with carcinoma of the bronchus, the mean attenuation coefficient for 99mTc was 0.096 cm-1 when determined across a transverse section of the thorax at the level of the tumour by means of a 57Co flood source (13 patients) and 0.093 and 0.074 cm-1 as determined from CT scans for points in the centre of the tumour and contralateral normal lung, respectively (21 patients). In 18 patients with breast tumours, the mean attenuation coefficient for 99mTc was 0.110 and 0.076 cm-1 when determined from MRI cross-sections for points in the centre of the tumour and normal contralateral lung, respectively. This indicates significant overcorrection for attenuation when the conventional value of 0.12 cm-1 is used. A value in the range 0.08-0.09 cm-1 would be more appropriate for SPET studies of the thorax. An alternative approach to quantitative region of interest (ROI) analysis is to perform attenuation correction appropriate to the centre of each ROI (using topographical information derived from CT or MRI) on non-attenuation-corrected reconstructions.