Palliative radiotherapy regimens for non-small cell lung cancer.

BACKGROUND: Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. OBJECTIVES: To discover the most effective and least toxic regimens of palliative radiotherapy for non-small cell lung cancer, and whether higher doses increase survival. SEARCH STRATEGY: The electronic databases MEDLINE, EMBASE, Cancerlit and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished. SELECTION CRITERIA: Randomised controlled clinical trials comparing different regimens of palliative radiotherapy in patients with non-small cell lung cancer. DATA COLLECTION AND ANALYSIS: Fourteen randomised trials were reviewed. There were important differences in the doses of radiotherapy investigated, the patient characteristics and the outcome measures. Because of this heterogeneity no meta-analysis was attempted. MAIN RESULTS: There is no strong evidence that any regimen gives greater palliation. Higher dose regimens give more acute toxicity, especially oesophagitis. There is evidence for a modest increase in survival (5% at 1 year and 3% at 2 years) in patients with better performance status (PS) given higher dose radiotherapy. Some regimens are associated with an increased risk of radiation myelitis. AUTHORS' CONCLUSIONS: The majority of patients should be treated with short courses of palliative radiotherapy, of 1 or 2 fractions. Care should be taken with the dose to the spinal cord. The use of high dose palliative regimens should be considered for and discussed with selected patients with good performance status. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), there is a relatively high incidence of brain metastases following radical treatment. At present, the role of prophylactic cranial irradiation (PCI) in this group of patients is not clear. OBJECTIVES: To investigate whether PCI has a role in the management of patients with NSCLC treated with radical intent. SEARCH STRATEGY: The electronic databases MEDLINE, EMBASE and Cancerlit, along with handsearching of journals, relevant books, and review articles used to identify potentially eligible trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing PCI with no PCI in NSCLC patients treated with radical intent. DATA COLLECTION AND ANALYSIS: Four RCTs were reviewed. Due to the small patient numbers, and variations in radiotherapy (RT) dose, no meta-analysis was attempted. MAIN RESULTS: PCI may reduce the incidence of brain metastases, but there is no evidence of a survival benefit. There is no evidence that any regimen is superior, and the effect of PCI on quality of life (QOL) is not known. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of PCI in clinical practice. Where possible, patients should be offered entry into a clinical trial.

Outpatient intensive chemotherapy for small cell lung cancer: five years experience of modified 'ICE' ifosfamide carboplatin and etoposide.

INTRODUCTION: Small Cell Lung Cancer (SCLC) is increasingly being treated in the district general hospital setting. The search for an active regimen which can be given with the least toxicity and best outcomes led us to use a modified ICE (Ifosfamide, Carboplatin and Etoposide) regimen and modify it further by using oral mesna instead of intravenous mesna. METHOD: All patients selected to receive the modified ICE regime over a 5-year period were included in our study. All patients were assessed for performance status and prognostic factors. Only those with WHO performance status 0-1 and Manchester prognostic score 0-3 were considered for ICE chemotherapy. All patients were followed up for 1 year after recruitment was completed. RESULTS: Median survival for all 32 patients was 18.4 months (CI 12.2-24.6) and for the 28 patients with limited disease the median survival was 19.9 months (CI 8.2-31.6). Toxicity levels were low with no neutropenic deaths. One patient died three days after treatment was started due to disease progression. A total of 6 patients remained alive one year after recruitment was completed. Five out of the 6 were followed up for at least 2 years. CONCLUSION: Using this out-patient modified ICE regime we have achieved a median survival comparable to other active chemotherapy regimes for SCLC with no significant increase in toxicity.

Acute changes in peak expiratory flow rate following palliative radiotherapy for bronchial carcinoma.

PURPOSE: Changes in respiratory function occurring in the months and years following radiotherapy have been well documented. The changes that occur in the hours after treatment are less clear, we report a study that recorded peak expiratory flow rate (PEFR) in the 72 h following radiotherapy to the mediastinum and large airways. METHODS: Fifty-six patients with carcinoma affecting the major bronchii were recruited; 39 were male, with a median age of 66 years; 49 had histologically confirmed lung cancer. The median baseline PEFR was 300 1/s (range: 120-600). Patients were asked to record home PEFR readings in the 72 h that followed the first fraction of radiotherapy. Doses ranges from an 8-Gy single fraction to 60 Gy in 30 fractions. RESULTS: Forty-nine patients recorded a fall in PEFR (3%-60% of the baseline value) in the 24 h after radiotherapy, the mean for all 56 patients was a fall of 20.3% (95% confidence interval -15.8% to -24.8%). These lowest values occurred a median time of 6 h after treatment (range: 2-24 h). By 72 h the mean PEFR had returned to the baseline. Tumour site (central or lobar bronchus) and fraction size (<3 GY or >3 Gy) had no significant effect on the fall in PEFR (Mann-Whitney U-test P = 0.15 and P = 0.06, respectively). CONCLUSION: We conclude that a fall in PEFR can occur after radiotherapy treatment to the mediastinum. This is of concern in patients being treated for bronchial carcinoma whose respiratory function may already be compromised.

Immediate side effects of large fraction radiotherapy.

The use of hypofractionated radiotherapy regimens is becoming more widely recognized in the palliation of non-small cell lung carcinoma (NSCLC). Anecdotal reports of chest pain, rigors and fevers in the hours that follow radiotherapy led us to perform a survey estimating the frequency and severity of these symptoms following treatment to the thorax. One hundred and eighteen patients completed questionnaires 24 hours after palliative radiotherapy treatment; 84 were male. The median age was 67 years. One hundred and seven had histologically confirmed NSCLC. A parallel opposed technique was used in 113 patients. Doses ranged from 8 Gy in a single fraction to 60 Gy in 30 fractions. Chest pain was reported by 54 (45.8%) patients after the first radiotherapy fraction; in 42 it commenced within 12 hours of treatment. The pain varied in site, nature and duration; on 23 occasions, it lasted under 2 hours. Systemic symptoms (rigors, sweating, fevers) were documented on 43 questionnaires, starting within 12 hours of treatment in 33 patients and on 30 occasions lasting less than 2 hours. Chest pain and systemic symptoms occurred together in 28 patients. Only 49 (41.5%) patients reported no immediate side effects. We conclude that patients receiving palliative radiotherapy for bronchial carcinoma often develop significant symptoms in the hours following treatment. The timing and duration suggest a relationship with the radiotherapy, and we feel that patients should be warned of the possible occurrence of these symptoms.

Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC)

Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung cancer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with limited-stage SCLC who had had a complete response to induction therapy. Initially, patients were randomised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regimen versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29-0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58-0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66-1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fractionation and to clarify the effect on survival. Patients with SCLC achieving a complete response to induction therapy should be offered PCI.

Understanding patients: let's talk about it. A study of cancer communication.

As part of a project on quality of life in patients with lung cancer, an investigation was carried out to examine how patients reacted to the study. A group of 82 patients attending a chest clinic were interviewed by means of a short questionnaire. They were asked to indicate whether an interview was preferable to filling in a questionnaire and whether a home visit was preferable to a clinic interview, and their feelings about interviews. In addition, we documented our observations during the study period. All patients agreed to participate in the study, of whom, 56 patients (68%) preferred to be interviewed, 8 (10%) preferred to fill in a questionnaire by themselves, and the remaining 18 (22%) expressed no preference. Forty-one patients (50%) preferred to be interviewed at their homes, 13 (16%) in the clinic, and 28 (34%) expressed no preference. Nearly all patients (96%) indicated that they found being interviewed very or quite comfortable. Our observations indicated that patients were pleased to talk about and discuss their perceived cultural and social values or daily life experiences. The findings suggest that, despite the strenuous attempts by clinicians to deliver effective health care, proper communication with patients remains limited. The finding has some implications for community care.

Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party.

In patients with non-metastatic but inoperable non-small cell lung cancer that is locally too extensive for radical radiotherapy (RT), but who have good performance status, it is important to determine whether thoracic RT should be the minimum that is required to palliate thoracic symptoms or whether treatment should be more intensive, with the aim of prolonging survival. A total of 509 such patients from 11 centres in the UK between November 1989 and October 1992 were admitted to a trial comparing palliative versus more intensive RT with respect to survival and quality of life. They were allocated at random to receive thoracic RT with either 17 Gy in two fractions (F2) 1 week apart (255 patients) or 39 Gy in 13 fractions (F13) 5 days per week (254 patients). Survival was better in the F13 group, the median survival periods being 7 months in the F2 group compared with 9 months in the F13 group, and the survival rates 31% and 36% at one year and 9% and 12% at 2 years, respectively (hazard ratio = 0.82; 95% CI0.69-0.99). There was a suggestion of a trend towards greater benefit in fitter patients. Metastases appeared earlier in the F2 group. As recorded by patients using the Rotterdam Symptom Checklist, the commonest symptoms on admission were cough, shortness of breath, tiredness, lack of energy, worrying and chest pain. These were more rapidly palliated by the F2 regimen. Psychological distress was generally lower in the F13 group. Three patients (two F13, one F2) exhibited evidence of myelopathy. As recorded by patients using a diary card, 76% of the F2 compared with 81% of the F13 patients had dysphagia associated with their RT. This was transient, lasting for a median of 6.5 days in the F2 group compared with 14 days in the F13 group. In conclusion, the F2 regimen had a more rapid palliative effect. In the F13 group, although treatment-related dysphagia was worse, survival was longer.

Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party.

Radiation myelopathy (RM) is an uncommon but serious late effect of thoracic radiotherapy (RT), which oncologists try to avoid by careful planning and dose selection. Five patients with RM are described from among 1048 with inoperable non-small cell lung cancer treated with palliative RT in three randomized trials conducted by the Medical Research Council Lung Cancer Working Party. Seven RT regimens were used in these trials: 10 Gy in a single fraction on one day (10/1/1) (114 patients), 17/2/8 (524 patients), 27/6/11 (47 patients), 30/6/11 (36 patients), 30/10/12 (88 patients), 36/12/16 (86 patients) and 39/13/17 (153 patients). Of the five instances of RM, three occurred in the 524 patients treated with 17 Gy in two fractions, and two in the 153 treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17 Gy group, 2.5% for the 39 Gy group, and 0% for the remainder, but the annual risks had wide 95% confidence intervals, indicating that the distribution of episodes among the seven regimens could have been random. Nevertheless, calculation of cord doses in terms of the total doses that would have an equivalent biological effect if given in 2 Gy fractions (LQED2 values) from our data for different values of the ratio of the linear quadratic parameters of the cell survival curve (alpha/beta), suggest that the best estimate of alpha/beta is less than 3 Gy, and possibly close to 2 Gy. This emphasizes the sensitivity of human spinal cord to changes in fraction size. We recommend that, when the computed LQED2 for a schedule of treatment that includes the thoracic spinal cord (assuming alpha/beta = 2 for cord) exceeds 48 Gy, oncologists should consider reducing the dose to the cord.

An audit of travel and waiting times for outpatient radiotherapy.

The object of this study was to assess the non-medical factors which detract from the quality of outpatient receiving service to a population of 2.7 million in a wide geographical area. We conducted a survey by patient questionnaire of all outpatients receiving radiotherapy in the West of Scotland on a single day in 1990. A total of 216 outpatients attended for radiotherapy with a 92% response rate to the questionnaire being achieved. Median values (and ranges) were: age 58 (4-85) years, number of daily treatments 20 (4-33), distance travelled in one direction 10 (1-60) miles, travelling time 45 (5-130) minutes, waiting time in the unit for treatment 60 (0-200) minutes, and a time away from home of 2 hours 50 minutes (35 minutes-7 hours). Sixteen per cent of patients had a relative who lost time from work by transporting the patient and only 12 of 60 patients who were away from home over a meal time were offered a hospital meal. Sixteen per cent of patients came by ambulance and 73% by motor car. Of 146 travelling by car 27% used a charity service and 20% a volunteer driver ambulance service car. It is concluded that long travelling distances, travelling times and treatment waiting times for many patients require revision of transport provision, a strict appointment system, more treatment machines and hostel accommodation.

The role of palliative radiotherapy in malignant mesothelioma.

Chest pain is often a major problem in patients with malignant pleural mesothelioma but there are few data regarding the usefulness of radiotherapy (RT) in its palliation. Following a recent retrospective report which suggested that wide-field RT frequently affords pain relief in this disease, we prospectively assessed the effect of hemithorax irradiation on pain control. Twenty-two patients with chest pain due to mesothelioma received 30 Gy in 10 daily fractions to the involved hemithorax. The patients' symptoms were assessed before RT, 1 month after RT, and then 2 monthly. Symptoms were graded by the clinician and the patient, and analgesic requirements were noted at each assessment. Performance status and respiratory status were recorded by WHO and MRC criteria respectively. Nineteen assessable patients have been followed for at least 3 months after RT. The treatment was well tolerated, with nausea and vomiting in only 1 patient. Pain control improved in 13/19 patients at 1 month, but 9/12 patients had worsening chest pain at 3 months, and at 5 months pain control had deteriorated in 6/7 patients. Although partial regression of chest wall masses was seen in 5/9 patients, RT did not appear to delay the progression of respiratory symptoms or radiological changes. The median duration of survival after RT was 4 months. Radiotherapy can relieve pain due to malignant pleural mesothelioma but its effect at this dose is short-lived.

Total abdominal and pelvic radiotherapy in the management of early stage ovarian carcinoma.

In a prospective study, 57 women with early stage ovarian carcinoma received total abdominal and pelvic radiotherapy (TAPR) following radical surgery. The whole abdomen received 22.5 Gy m.p.d. by large opposed fields in 18 fractions over 4 1/2 weeks, with 8 MeV X rays, followed by a further 22.5 Gy in 10 fractions over 2 weeks to the pelvis alone, using a dosage and technique similar to that described from the Princess Margaret Hospital, Toronto. The actuarial 5-year relapse-free and overall survival figures were 49 and 57% respectively, which appear to be significantly worse than those reported from Toronto (73% and 75%). The incidence of severe bowel toxicity (7%) was higher. There was no correlation between survival and FIGO stage at laparotomy, but a significant correlation with histological grade. These data do not seem to support the idea of a "curative" role for post-operative irradiation at this dosage in these patients.

Involvement of the central nervous system by non-Hodgkin's lymphoma in adults. A review of 36 cases.

Thirty-six (10.1 per cent) of a total of 355 adult patients with non-Hodgkin's lymphoma seen over a seven and a half year period developed compression or infiltration of the central nervous system (CNS). In nine patients (2.5 per cent) extradural tumour masses compressed the spinal cord or brain. Five of these patients, all previously untreated, responded well to treatment, with excellent recovery of CNS function and survival in the long term. The prognosis for the four patients with advancing drug-resistant systemic disease at the time of CNS compression was poor. In 27 patients (7.6 per cent) a clinical or cytological diagnosis of meningeal infiltration was made (on cerebrospinal fluid). Meningeal disease was seen most frequently in patients with high-grade lymphoma, either at presentation or during subsequent progression of systemic disease. All of these patients have died of systemic and/or CNS disease less than 20 (median 3) months from diagnosis of meningeal disease. Meningeal infiltration represents a significant clinical problem for which new approaches to prophylaxis and treatment are required.

Cisplatin combination chemotherapy versus chlorambucil in advanced ovarian carcinoma: mature results of a randomized trial.

A randomized study to compare the efficacy of combination chemotherapy (cisplatin, doxorubicin, cyclophosphamide: PACe) with chlorambucil (CB) in International Federation of Gynecology and Obstetrics (FIGO) stage III and IV ovarian carcinoma was conducted between May 1979 and October 1983. Patients failing initial CB were subsequently eligible for treatment with PACe. Eighty-nine patients were randomized and 85 were eligible for analysis; as of date, 72 of these patients have died. The majority of patients in this study had bulky residual disease after their initial laparotomy (76%). Complete response (CR) was documented by a second laparotomy after five cycles of combination therapy or 6 to 12 months alkylating agent therapy. The overall response rate (CR plus partial response [PR]) for the combination (PACe, 68%) was significantly higher (P = .0004) than that for the chlorambucil (CB, 26%). However, the median survival was not improved (PACe, 13 months; CB, 11 months) and the survival curves were not significantly different (log rank test P = .25). The results of this study are comparable to preliminary data reported from other similar randomized studies. PACe, as administered in this study, is not indicated as routine therapy in patients with bulky residual ovarian carcinoma.

Second look laparotomy in the management of epithelial cell carcinoma of the ovary.

Case histories from 20 patients undergoing postchemotherapy "second look" laparotomy for metastatic epithelial cell carcinoma of the ovary were reviewed in an attempt to evaluate the usefulness of this procedure and its likely impact on patient survival. The patient population comprised 18 patients treated with a combination of cisplatin, adriamycin and cyclophosphamide (PACe) and 2 patients treated with chlorambucil. The findings at second look were often predictable, and related to the adequacy of initial surgery. Complete tumour regression identified a group of patients with a relatively good prognosis. However in most patients residual tumour was found which rarely proved resectable. Second line chemotherapy was poorly tolerated, and appeared to have little impact on the disease particularly after combination chemotherapy had been used initially. There was little evidence that second look surgery itself positively contributed to survival. This procedure and its timing should be regarded as experimental and a suitable subject for randomised clinical trials.

A report on a prospective trial of no initial therapy in patients with initial therapy in patients with asymptomatic favourable prognosis non-Hodgkin's lymphoma.

Thirty-one (58 per cent) of a group of fifty-three unselected patients with stage II-IV favourable prognosis non-Hodgkin's lymphoma were regarded as being eligible for a prospective study of no initial therapy. Seventeen of these patients (55 per cent) have required no treatment for periods from 6 + -47 + months, (median 18 months) and fourteen patients have been treated with chemotherapy for progressive disease after a period varying from 3-40 months (median 9.5 months). Selected asymptomatic patients with non-bulky disease may be suitable for no initial therapy. Randomized prospective trials will be needed to test whether survival is affected by delaying therapy.

Late recurrence in Hodgkin's disease: a report of two cases.

Two cases of Hodgkin's disease are described who relapsed 22 and 19 years after regional radiation therapy. One of the patients also developed a carcinoma of the large bowel soon after first relapse. The importance of long follow-up and documentation of cause of death in Hodgkin's disease is stressed.