Dr Diana Tait
Honorary Faculty: Gastrointestinal Clinical Oncology
Biography
Dr Diana Tait is a Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust and Honorary Clinical Senior Lecturer at The Institute of Cancer Research. She has a specialist interest in upper gastrointestinal (GI) and lower GI (colorectal) tumours, and hepatobiliary, anal and breast cancers. She has a particular interest in the use of combinations of chemotherapy and radiotherapy to treat GI tumours, and the use of modern radiotherapy techniques for optimising treatment, including intensity-modulated radiotherapy (IMRT) and stereotactic radiotherapy.
She was Vice-President and Dean of the Faculty of Clinical Oncology at the Royal College of Radiologists from September 2012 to September 2014, sitting on numerous national committees looking into developing, setting and maintaining national standards to continue and implement modern radiotherapy techniques to improve quality of care for cancer patients.
Dr Tait was Chair of the Radiotherapy Awareness Programme (2014-2018), in conjunction with Cancer Research UK. This cross-sector group seeks to raise public awareness of radiotherapy and its benefits to patients.
She pursues her interest in late consequences of treatment and survivorship issues as a member Macmillan Clinical Advisory Board and is a Trustee for Bowel Cancer UK (2017-present).
MD, FRCR, FRCP, UNIVERSITY OF EDINBURGH.
OFFICER, Vice President & Dean, Faculty of Clinical Oncology, Royal College of Radiologists, September 2012.
Committee Member, International Advisory Board Member, International Journal of Radiation Oncology,Biology,Physics, January 2013.
Radiotherapy Clinical Reference Group, RCR Affiliated Organisation Member, UK Government - NHS Commissioning Board, March 2013.
Related pages
Types of Publications
Journal articles
AIMS: Serial photographs have been collected prospectively to evaluate the effect of radiotherapy on normal tissues in the breast. The aim of this study was to compare two methods of scoring radiation-induced changes. MATERIALS AND METHODS: Five-year photographs of 400 patients randomised to receive either 42.9 or 39 Gy in 13 fractions to the whole breast after tumour excision of early breast cancer were compared with a post-surgery baseline and scored for change in breast appearance on a three-point graded scale. Two alternative methods of scoring using three observers were compared: (a) scores allocated independently, with independent resolution of discrepancies, and (b) scores allocated by consensus. RESULTS: Treatment effects estimated from the consensus and independent scores were very similar (odds ratio 1.89, 95% confidence interval 1.21-2.96 vs 2.28, 95% confidence interval 1.50-3.47, respectively). Agreement between the scores obtained from each method was reasonable, and the repeatability of the consensus method was good. CONCLUSIONS: The consensus method of scoring photographic change in breast appearance seems to be no less sensitive to randomised dose as the independent method of assessment, but is much quicker to administer. The consensus method has been used to score over 3000 sets of photographs in the National Cancer Research Institute Standardisation of Breast Radiotherapy trial.
PURPOSE: To investigate the potential for intensity-modulated radiotherapy (IMRT) to spare the bowel in rectal tumors. METHODS AND MATERIALS: The targets (pelvic nodal and rectal volumes), bowel, and bladder were outlined in 5 patients. All had conventional, three-dimensional conformal RT and forward-planned multisegment three-field IMRT plans compared with inverse-planned simultaneous integrated boost nine-field equally spaced IMRT plans. Equally spaced seven-field and five-field and five-field, customized, segmented IMRT plans were also evaluated. RESULTS: Ninety-five percent of the prescribed dose covered at least 95% of both planning target volumes using all but the conventional plan (mean primary and pelvic planning target volume receiving 95% of the prescribed dose was 32.8 +/- 13.7 Gy and 23.7 +/- 4.87 Gy, respectively), reflecting a significant lack of coverage. The three-field forward planned IMRT plans reduced the volume of bowel irradiated to 45 Gy and 50 Gy by 26% +/- 16% and 42% +/- 27% compared with three-dimensional conformal RT. Additional reductions to 69 +/- 51 cm(3) to 45 Gy and 20 +/- 21 cm(3) to 50 Gy were obtained with the nine-field equally spaced IMRT plans-64% +/- 11% and 64% +/- 20% reductions compared with three-dimensional conformal RT. Reducing the number of beams and customizing the angles for the five-field equally spaced IMRT plan did not significantly reduce bowel sparing. CONCLUSION: The bowel volume irradiated to 45 Gy and 50 Gy was significantly reduced with IMRT, which could potentially lead to less bowel toxicity. Reducing the number of beams did not reduce bowel sparing and the five-field customized segmented IMRT plan is a reasonable technique to be tested in clinical trials.
A single large dose of megavoltage x-rays delivered through a grid is currently being utilized by some centres for palliative radiotherapy treatments of large tumours. In this note, we investigate the dosimetry of grid therapy using two-dimensional film dosimetry and three-dimensional gel dosimetry. It is shown that the radiation dose is attenuated more rapidly with depth in a grid field than an open field, and that even shielded regions receive approximately 25% of the dose to the unshielded areas.
Global gene expression profiling has potential for elucidating the complex cellular effects and mechanisms of action of novel targeted anticancer agents or existing chemotherapeutics for which the precise molecular mechanism of action may be unclear. In this study, decreased expression of genes required for RNA and protein synthesis, and for metabolism were detected in rectal cancer biopsies taken from patients during a 5-fluorouracil infusion. Our observations demonstrate that this approach is feasible and can detect responses that may have otherwise been missed by conventional methods. The results suggested new mechanism-based combination treatments for colorectal cancer and demonstrated that expression profiling could provide valuable information on the molecular pharmacology of established and novel drugs.
BACKGROUND AND PURPOSE: To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy. MATERIALS AND METHODS: A treatment planning study was performed to compare two-phase conformal radiotherapy (CFRT) with IMRT in five patients. The CFRT plans consisted of anterior, posterior and bilateral posterior oblique fields, while the IMRT plans consisted of either nine equispaced fields (9F), or four fields (4F) with orientations equal to the CFRT plans. IMRT plans with seven, five or three equispaced fields were also investigated in one patient. Treatment plans were compared using dose-volume histograms and normal tissue complication probabilities. RESULTS: The 9F IMRT plan was unable to improve on the homogeneity of dose to the planning target volume (PTV), compared with the CFRT plan (dose range, 16.9+/-4.5 (1 SD) vs. 12.4+/-3.9%; P=0.06). Similarly, the 9F IMRT plan was unable to reduce the mean lung dose (11.7+/-3.2 vs. 11.0+/-2.9 Gy; P=0.2). Similar results were obtained for seven, five and three equispaced fields in the single patient studied. The 4F IMRT plan provided comparable PTV dose homogeneity with the CFRT plan (11.8+/-3.3 vs. 12.4+/-3.9%; P=0.6), with reduced mean lung dose (9.5+/-2.3 vs 11.0+/-2.9 Gy; P=0.001). CONCLUSIONS: IMRT using nine equispaced fields provided no improvement over CFRT. This was because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the CFRT fields offered an improvement in lung sparing. Thus, IMRT with a few carefully chosen field directions may lead to a modest reduction in pneumonitis, or allow tumour dose escalation within the currently accepted lung toxicity.
BACKGROUND AND PURPOSE: This study aims to evaluate the reduction in radiation dose to normal thoracic structures through the use of conformal radiotherapy techniques in the treatment of oesophageal cancer, and to quantify the resultant potential for dose escalation. MATERIALS AND METHODS: Three different CT-derived treatment plans were created and compared for each of ten patients. A two-phase treatment with conventional straight-edged fields and standard blocks (CV2), a two-phase conformal plan (CF2), and a three-phase conformal plan where the third phase was delivered to the gross tumour only (CF3), were considered for each patient. Escalated dose levels were determined for techniques CF2 and CF3, which by virtue of the conformal field shaping, did not increase the mean lung dose. The resulting increase in tumour control probability (TCP) was estimated. RESULTS: A two-phase conformal technique (CF2) reduced the volume of lung irradiated to 18 Gy from 19.7+/-11.8 (1 SD) to 17.1+/-12.3% (P=0.004), and reduced the normal tissue complication probability (NTCP) from 2.4+/-4.0 to 0.7+/-1.6% (P=0.02) for a standard prescribed dose of 55 Gy. Consequently, technique CF2 permitted a target dose of 59.1+/-3.2 Gy without increasing the mean lung dose. Technique CF3 facilitated a prescribed dose of 60.7+/-4.3 Gy to the target, the additional 5 Gy increasing the TCP from 53. 1+/-5.5 to 68.9+/-4.1%. When the spinal cord tolerance was raised from 45 to 48 Gy, technique CF3 allowed 63.6+/-4.l Gy to be delivered to the target, thereby increasing the TCP to 78.1+/-3.2%. CONCLUSIONS: Conformal radiotherapy techniques offer the potential for a 5-10 Gy escalation in dose delivered to the oesophagus, without increasing the mean lung dose. This is expected to increase local tumour control by 15-25%.
This study compares the performance of one proton and four conformal X-ray planning techniques in treating non-small cell lung cancer (NSCLC). The treatment volumes for 13 NSCLC patients undergoing radical radiotherapy were planned using the five different techniques and dose-volume histograms (DVH) were used extensively in the comparative analysis. The minimum dose to the phase 2 target volume was escalated to 90 Gy, or until the point at which pre-set tolerance limits of spinal cord or lung were exceeded. The proton plan could treat nine of the 13 patients up to a dose of 90 Gy. Among the four X-ray techniques, performance varied enormously. One of them could not treat any of the patients, even to the conventional 60 Gy level, without failing to meet one or more of the criteria, whilst another one could treat 10 out of the 13 patients, although with this technique only four were permitted to have the dose escalated to 90 Gy. It was also found that two of the 13 patients could not be treated by any of the proton or X-ray plans to the conventional level, and were therefore considered unsuitable for radical radiotherapy. Various issues in conformal NSCLC radiotherapy including organ movement, tumour control, other possible organs at risk etc., are also discussed.
BACKGROUND: Radical radiotherapy is commonly used to treat localised prostate cancer. Late chronic side-effects limit the dose that can be given, and may be linked to the volume of normal tissues irradiated. Conformal radiotherapy allows a smaller amount of rectum and bladder to be treated, by shaping the high-dose volume to the prostate. We assessed the ability of this new technology to lessen the risk of radiation-related effects in a randomised controlled trial of conformal versus conventional radiotherapy. METHODS: We recruited men with prostate cancer for treatment with a standard dose of 64 Gy in daily 2 Gy fractions. The men were randomly assigned conformal or conventional radiotherapy treatment. The primary endpoint was the development of late radiation complications (> 3 months after treatment) measured with the Radiation Therapy and Oncology Group (RTOG) score. Indicators of disease (cancer) control were also recorded. FINDINGS: In the 225 men treated, significantly fewer men developed radiation-induced proctitis and bleeding in the conformal group than in the conventional group (37 vs 56% > or = RTOG grade 1, p=0.004; 5 vs 15% > or = RTOG grade 2, p=0.01). There were no differences between groups in bladder function after treatment (53 vs 59% > or = grade 1, p=0.34; 20 vs 23% > or = grade 2, p=0.61). After median follow-up of 3.6 years there was no significant difference between groups in local tumour control (conformal 78% [95% CI 66-86], conventional 83% [69-90]). INTERPRETATION: Conformal techniques significantly lowered the risk of late radiation-induced proctitis after radiotherapy for prostate cancer. Widespread introduction of these radiotherapy treatment methods is appropriate. Our results are the basis for dose-escalation studies to improve local tumour control.
BACKGROUND: A prospective, randomized clinical trial to assess the effect of reducing the volume of irradiated normal tissue on acute reactions in pelvic radiotherapy accured 266 evaluable patients between 1988 and 1993. PURPOSE: This is the definitive analysis to assess the differences between the conformal and conventional arms of the trial. MATERIALS AND METHODS: In both arms, patients were treated with 6 MV X-rays using a 3-field technique (in all but 5 cases) consisting of an anterior and two wedged lateral or posterior oblique fields; in the conventional arm, rectangular fields were employed, whereas in the conformal arm, the fields were shaped with customized blocks drawn according to the beam's-eye-view of the target volume. The most common dosage was 64 Gy in 2-Gy fractions 5 times a week, although a subgroup (of ca. bladder patients) were treated with 30-36 Gy in once-a-week 6 Gy fractions. Each patients completed a comprehensive acute toxicity scoring questionnaire concentrating on bowel and bladder problems, tiredness and nausea, before the start of treatment, weekly during and for 3 weeks after the end of treatment and then monthly for a further 2 months. compliance was excellent. RESULTS: There were no differences between the patients in the two arms with respect to age, gender, tumour type (52% prostate, 41% bladder, 5% rectum, 2% other) fractionation/dosage, anterior field size, weight, or baseline symptoms. Substantial differences in normal-tissue volumes (rectum, bladder, etc.) were achieved: median high-dose volume (HDV) of 689 cm3 for the conformal technique versus 792 cm3 for the conventional. A clear pattern of an increase in symptoms during RT, followed by a decrease after RT, was observed for the patient group as a whole. However, a very extensive analysis has not revealed any (statistically) significant differences between the two arms in level of symptoms, nor in medication prescribed. The disparity between our findings and those of other, non-randomized studies is discussed. CONCLUSIONS: The data on late effects must be collected and analyzed before any definite conclusions can be drawn on the benefits of conformal therapy in the pelvis.
Measurements of MR spin-lattice (T1), and spin-spin (T2) relaxation times in lumbar vertebrae have been performed in a pilot study on six adult patients, treated for acute myeloid leukaemia (AML). All patients were treated with initial chemotherapy and then proceeded to bone marrow transplantation (BMT), conditioned with Melphalan and total body irradiation (TBI). MR measurements were made between 21 and 89 months after TBI. The relaxation times in the six patients were compared with those in six healthy age-matched volunteers to establish whether there were differences between the two groups. Average T1 values in the vertebrae of the treated patients are significantly shorter (p < 0.01) than in the healthy volunteers. This is consistent with the observation of a relatively hyperintense vertebral bone marrow in the T1 weighted images and is likely to be a consequence of treatment induced fatty replacement of marrow. Shorter T1 values tend to be distributed within the centre of the lumbar vertebrae compatible with observations, made by others, which suggest that the peripheral zone of the vertebral body has been repopulated with bone marrow cells whereas the central zone, around the basivertebral vein, is predominantly fat. Histogram displays of vertebral body relaxation time distributions (T1, T2) for both patients and healthy age-matched volunteers are similar in that both patients and volunteers give histograms that are only slightly skewed. This similarity is probably a reflection of the fact that the patients have been in remission for over a year and have generally healthy bone marrow.
The aim of this study was to assess the accuracy of pelvic radiotherapy during a trial of blocked radiotherapy at the Royal Marsden Hospital, UK. Prospective evaluation was performed on 90 patients receiving CT planned pelvic radiotherapy using weekly anterior-posterior and lateral portal films. Field placement errors (FPEs) were calculated by comparing field centres of each film with a designated point of interest. Data was evaluated to calculate the overall treatment simulator differences, the number of error free treatments, and mean treatment-simulator position and to evaluate the role of systematic versus random errors. Age, weight, disease site, position of treatment, fractionation, blocked versus conventional techniques were assessed for their effect on treatment accuracy. The mean absolute error between treatment and simulator films was anterior right-left (ARL) 0.25 cm, anterior superior-inferior (ASI) 0.32 cm, lateral anterior-posterior (LAP) 0.42 cm, and lateral superior-inferior (LSI) 0.28 cm. On average the field centre was displaced by 0.66 cm (standard deviation, S.D. = 0.34) from that intended. On each treatment day 29% of anterior films and 45% of lateral films had at least one 0.5 cm error. Overall 59% of treatments had at least one 0.5 cm error and 9% a 1.0 cm error. The field centre was more than 0.5 cm from the position intended in 66% of treatments and over 1 cm for 14% of treatments. Analysis of variance showed that both random and systematic errors occurred in all directions. Though random errors were of similar magnitude in all direction (variance sigma 2 = 0.06-0.09 cm2); systematic errors showed a 4-fold variation being greatest in the LAP direction (sigma 2 = 0.19 cm2) and least the ARL direction (sigma 2 = 0.048 cm2). No factor consistently predicted for worse outcome in all directions. Hypofractionated treatments were less accurate in the LSI direction (P > 0.05). Systematic errors were associated in the ARL direction with hypofractionation (P < 0.01) and, in the LSI direction with weight (P < 0.03) and age (P < 0.05). We conclude that significant random and systematic errors can occur during pelvic radiotherapy especially in the LAP direction. These results suggest that in the absence of a customised immobilisation device, to cover 95% of errors, margins of 0.6 cm for RL and SI directions and 0.9 cm for AP direction should be allowed between the planning and clinical target volumes. However, ideally, each centre should determine their own margin requirements according to local clinical practice.
During the last 3 years the Royal Marsden Hospital (RMH) has conducted a prospective randomised trial of conformal pelvic radiotherapy in which dose/volume data and acute toxicity scores have been determined prospectively. Pending completion of the trial, a preliminary analysis has been undertaken of the volume reductions achieved, and of some of the symptom scores. The average symptom score increased during radiotherapy, more markedly for bowel than bladder symptoms. In comparing total doses of 30-38 Gy with 56-65 Gy, watery bowel motions were more frequent with the higher doses (p = 0.013) but in the high-dose group neither this symptom nor tenesmus correlated with volume of rectum treated to at least 90% of the prescribed dose. We conclude that the assessment of the impact of volume on the level of acute symptoms in pelvic radiotherapy is complex, and requires analysis of a range of symptoms, dose levels and normal-tissue volumes. The degree of symptom reduction from conformal radiotherapy will emerge from the RMH randomised trial within the next 12 months.
We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.
Paraffin sections from 32 patients with primary medulloblastoma were analysed by flow cytometry for DNA ploidy and proliferative index to assess the value of these measurements in determining prognosis. Twenty-seven samples were informative. Of these 27 patients, 8 had had a total resection. The tumors were diploid in 13 patients and aneuploid in 14. Neither ploidy nor S-phase fraction were prognostic factors for survival, even when considered in conjunction with the type of surgery performed. This is in contrast to other published data, emphasising the need for large multicentre studies of biological prognostic factors in this rare tumour.
In view of the morbidity and potential mortality associated with routine post-operative lymph node radiotherapy in women with early stage breast cancer, an attempt has been made to select patients in whom radiotherapy can be withheld. Three hundred and forty-seven consecutive patients treated wide local excision plus or minus axillary surgery have been evaluated. Only 20% were subsequently given radiotherapy to regional nodes. Relapse in the axilla, the supraclavicular fossa or at both these sites have occurred in 16 patients so far, 12 of whom were successfully treated. Systemic relapse was seen in eight of these patients occurring with one exception before or within 3 months of node relapse. Only four have persisting symptoms as a result of nodal relapse. So far, a policy involving selective lymphatic radiotherapy in women treated for early breast cancer appears justified.
In 20 patients with invasive bladder cancer suitable for radical radiotherapy, a simple conformal planning technique has been compared with conventional beam arrangements in terms of normal tissue sparing. The median treatment volume for the group was reduced from 2275 to 1416 cm3 by the introduction of conformal planning. More specifically, in 13/20 patients (65%) the percentage volume of rectum irradiated to 90% of the isocentric dose was reduced by more than 30%, although the extent of rectal sparing varied greatly between patients. Overall, conformal planning appeared to be less successful at reducing the volume of large and small bowel irradiated to high dose. However, the data suggest that considerable benefit can be expected for those patients most at risk of morbidity by virtue of high bowel volumes included within the treatment length. A randomised trial is now being set up to determine the clinical impact of this planning technique in terms of reduced bowel morbidity.
In order to assess the blood flow patterns through human lung tumours, 20 patients received 400-750 MBq 99TcmHMPAO intravenously 10 min before single photon emission computed tomography (SPECT). Ratios of uptake in the whole tumour relative to normal lung ranged from 0.35 to 1.53 (mean 1.01) with eight tumours showing less uptake than normal lung and ten showing greater uptake. In one patient the tumour was not distinguishable from surrounding lung and in another a large pleural effusion prevented evaluation. Tumour: lung ratios for central tumour regions ranged from 0 to 1.83 (mean 0.80) with 13 showing lower uptake than normal lung and five showing greater uptake. Duplicate scans were performed in eight patients demonstrating satisfactory reproducibility. This technique provides a simple and reproducible method for the assessment of tumour blood flow.
BACKGROUND: Rectal bleeding after pelvic radiotherapy is often attributed to radiation proctitis and patients do not routinely undergo flexible endoscopy. AIMS: To assess the significance of bleeding after radiotherapy. METHODS: We maintained a prospective register of all such patients referred to our endoscopy unit. RESULTS: One hundred and thirty-nine men (median age 70 years; range 31-82), and 32 women (median age 61 years; range 30-81) were referred with rectal bleeding (median 2 years; range 0-21) after pelvic radiotherapy. Primary tumour sites were urological (n = 139), gastrointestinal (n = 7) and gynaecological (n = 25). Ninety patients had bleeding alone; 81 had other symptoms. One hundred and forty-one had typical radiation proctitis; in 65 this was the sole diagnosis; eight had cancer, nine had high-risk adenomas, and six had three or more small adenomas. Ninety-five other diagnoses were made. Eleven (73%) patients with advanced polyps or cancer required only flexible sigmoidoscopy to make the diagnosis, while four (27%) diagnoses were made only after colonoscopy; 47% of these patients had no other symptoms apart from rectal bleeding. CONCLUSIONS: After pelvic radiotherapy, clinical symptoms are not reliable in differentiating between radiation proctitis alone or more significant pathology. It is mandatory that all patients with new onset rectal bleeding are investigated with, at least, flexible sigmoidoscopy.
After radiotherapy for pelvic cancer, chronic gastrointestinal problems may affect quality of life (QOL) in 6-78% of patients. This variation may be due to true differences in outcome in different diseases, and may also represent the inadequacy of the scales used to measure radiotherapy-induced gastrointestinal side effects. The aim of this study was to assess whether outcome measures used for nonmalignant gastrointestinal disease are useful to detect gastrointestinal morbidity after radiotherapy. Results obtained from a Vaizey Incontinence questionnaire and a modified Inflammatory Bowel Disease questionnaire (IBDQ)--both patient completed--were compared to those from a staff administered Late Effects on Normal Tissue (LENT)--Subjective, Objective, Management and Analytic (SOMA) questionnaire in patients who had completed radiotherapy for a pelvic tumour at least 3 months previously. In all, 142 consecutive patients were recruited, 72 male and 70 female, median age 66 years (range 26-90 years), a median of 27 (range 3-258) months after radiotherapy. In total, 62 had been treated for a gynaecological, 58, a urological and 22, a gastrointestinal tract tumour. Of these, 21 had undergone previous gastrointestinal surgery and seven suffered chronic gastrointestinal disorders preceding their diagnosis of cancer. The Vaizey questionnaire suggested that 27% patients were incontinent for solid stools, 35% for liquid stools and 37% could not defer defaecation for 15 min. The IBDQ suggested that 89% had developed a chronic change in bowel habit and this change significantly affected 49% patients: 44% had more frequent or looser bowel movements, 30% were troubled by abdominal pain, 30% were troubled by bloating, 28% complained of tenesmus, 27% were troubled by their accidental soiling and 20% had rectal bleeding. At least 34% suffered emotional distress and 22% impairment of social function because of their bowels. The small intestine/colon SOMA median score was 0.1538 (range 0-1) and the rectal SOMA median score was 0.1428 (range 0-1). Pearson's correlations for the IBDQ score and small intestine/colon SOMA score was -0.630 (P<0.001), IBDQ and rectum SOMA -0.616 (P<0.001), IBDQ and Vaizey scores -0.599 (P<0.001), Vaizey and small intestine/colon SOMA 0.452 (P<0.001) and Vaizey and rectum SOMA 0.760 (P<0.001). After radiotherapy for a tumour in the pelvis, half of all patients develop gastrointestinal morbidity, which affects their QOL. A modified IBDQ and Vaizey questionnaire are reliable in assessing new gastrointestinal symptoms as well as overall QOL and are much easier to use than LENT SOMA.
BACKGROUND: Acute gastrointestinal symptoms affect 90% of patients during pelvic radiotherapy. Elemental diet is protective in animal models. A nonrandomized study suggested benefit from a partial elemental diet. A pilot study suggested that radiotherapy patients only tolerate oral elemental diet comprising one-third of total calories for 3 weeks. AIM: To assess the feasibility and efficacy of replacing one-third of normal diet with elemental diet during the first 3 weeks of pelvic radiotherapy in reducing acute gastrointestinal toxicity. METHODS: Patients were randomized to elemental diet or no intervention. Toxicity was assessed using the Inflammatory Bowel Disease Questionnaire, Vaizey Incontinence scale and Radiation Therapy Oncology Group tool. Faecal calprotectin measured intestinal mucosal inflammation. RESULTS: Twenty-nine women and 21 men, median age 61.5 years were randomized. Patients taking elemental diet did not have lower gastrointestinal toxicity ratings or inflammatory markers (P > 0.2). The mean dose taken was 21% (2-36%) of total caloric requirements. CONCLUSIONS: Patients cannot tolerate large volumes of oral elemental diet. The quantities consumed in this study produced no therapeutic benefit. Future studies should aim to replace a higher proportion of nutritional intake for a longer duration of radiotherapy treatment.
BACKGROUND: Reliable, non-invasive biological markers of the severity of radiotherapy-induced damage to the gastrointestinal tract are not available. Clinicians continue to use symptom scores as surrogate indicators of toxicity. AIM: To determine whether levels of potential biochemical markers of mucosal toxicity change during pelvic radiotherapy. METHODS: Fifty-nine patients (30:29 males:females) with mixed pelvic malignancies, receiving 45-70 Gy were recruited. At baseline and weeks 4 or 5 of radiotherapy, blood samples for citrulline, C-reactive protein, eosinophil cationic protein and stool samples for faecal calprotectin were obtained. Symptoms were measured using the Inflammatory Bowel Disease Questionnaire - Bowel Subset, Radiation Therapy Oncology Group and Vaizey Incontinence Questionnaires. Paired t-tests of change in marker values were calculated. RESULTS: Citrulline (P = 0.02) and faecal calprotectin (P = 0.01) values changed significantly between baseline and 4/5 weeks. Inflammatory Bowel Disease Questionnaire - Bowel Subset fell significantly (mean fall = 10 points, s.d.: 8.9). Changes in markers did not correlate with symptoms. CONCLUSIONS: Some biochemical markers of mucosal toxicity change significantly during treatment. Further studies must investigate the timing of changes of these biochemical markers, their relationship to gastrointestinal physiological change and the radiotherapy dose delivered to the gastrointestinal tract and whether changes in markers acutely can predict the degree of long-term gastrointestinal dysfunction.
BACKGROUND: Radiation dose distributions created by two dimensional (2D) treatment planning are responsible for partial volumes receiving >107% of the prescribed dose in a proportion of patients prescribed whole breast radiotherapy after tumour excision of early breast cancer. These may contribute to clinically significant late radiation adverse effects. AIM: To test three dimensional (3D) intensity modulated radiotherapy (IMRT) against 2D dosimetry using standard wedge compensators in terms of late adverse effects after whole breast radiotherapy. METHODS: Three hundred and six women prescribed whole breast radiotherapy after tumour excision for early stage cancer were randomised to 3D IMRT (test arm) or 2D radiotherapy delivered using standard wedge compensators (control arm). All patients were treated with 6 or 10MV photons to a dose of 50Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumour bed of 11.1Gy in 5 fractions to 100%. The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2 and 5 years follow up. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life and physician assessments of breast induration. Analysis was by intention to treat. RESULTS: 240 (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71/122 (58%) allocated standard 2D treatment compared to only 47/118 (40%) patients allocated 3D IMRT. The control arm patients were 1.7 times more likely to have a change in breast appearance than the IMRT arm patients after adjustment for year of photographic assessment (95% confidence interval 1.2-2.5, p=0.008). Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the centre of the breast, pectoral fold, infra-mammary fold and at the boost site. No significant differences between treatment groups were found in patient reported breast discomfort, breast hardness or quality of life. CONCLUSION: This analysis suggests that minimisation of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. Incidence of change in breast appearance was statistically significantly higher in patients in the standard 2D treatment arm compared with the IMRT arm. A beneficial effect on quality of life remains to be demonstrated.
BACKGROUND & AIMS: No data exists about the effect of pelvic radiotherapy on taste preference for oral nutrition supplements, including elemental diet, which may prevent gastrointestinal symptoms if taken during pelvic radiotherapy. This double blind study aimed to: (1) examine the palatability of elemental, peptide and polymeric oral nutrition supplements in patients with pelvic malignancies compared with healthy controls (2) assess changes in taste preference following pelvic radiotherapy (3) develop a reliable scale to measure taste preference. METHODS: Subjects blind tasted six 30ml oral nutrition supplement samples, one duplicated, before and after 5 weeks of treatment (or the same time interval for controls). A Likert scale was used to score preference. RESULTS: Fifty patients and 50 controls were recruited. Before radiotherapy, patients had a lower mean preference for the peptide formulation than the other oral nutrition supplements (P<0.001). There were no significant differences in preferences between patients and controls (P>0.2 all supplements). Radiotherapy did not affect supplement preference. CONCLUSIONS: Patients with pelvic malignancy and healthy controls rate elemental nutritional supplements as highly as polymeric supplements and significantly better than peptide supplements. This trend continues even after pelvic radiotherapy. A Likert scale is a reliable tool in this scenario.
PURPOSE: Simple scales with greater sensitivity than Radiation Therapy Oncology Group (RTOG) grading to detect acute gastrointestinal toxicity during pelvic radiotherapy, could be clinically useful. METHODS AND MATERIALS: Do questionnaires used in benign gastrointestinal diseases detect toxicity in patients undergoing radiotherapy? The patient-completed Inflammatory Bowel Disease (IBDQ) and Vaizey Incontinence questionnaires were compared prospectively at baseline and at Week 5 to physician-completed RTOG grading. RESULTS: A total of 107 patients, median age 63 years, were recruited. After 5 weeks of treatment, patients with gynecologic and gastrointestinal cancer were more symptomatic than urologic patients (p = 0.012; p = 0.014). Overall, 94% had altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60% pain, >48% distress, 44% tenesmus, >40% restrictions in daily activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal medication. The median RTOG score was 1 (range, 0-2), median IBDQ score 204.5 (range, 74-224), and median Vaizey score 5 (range, 0-20). Chemotherapy preceding radiotherapy increased fecal incontinence (p = 0.002). RTOG scores stabilized after 3 weeks, IBDQ scores peaked at Week 4, and Vaizey scores worsened throughout treatment. IBDQ and Vaizey scores distinguished between groups with different RTOG scores. CONCLUSION: The IBDQ and Vaizey questionnaires are reliable and sensitive, offering greater insight into the severity and range of symptoms compared with RTOG grading.
We report the case history of a woman with a germ line mutation in the TP53 gene who developed 17 separate primary tumours. The incidence of new tumours rose steeply after adjuvant tamoxifen treatment for breast cancer and adjuvant vaginal vault radiotherapy for endometrial cancer. This increase could be due to cumulative genetic damage from environmental agents and the fact that the patient lived to the relatively late age of 60 years, or to a high inherent deleterious somatic mutation rate, which could represent the inability of cells from patients with TP53 mutations to repair therapy-induced genetic damage.
BACKGROUND: To avoid the late sequelae associated with cranial radiation therapy in childhood, intermediate- or high-dose intravenous methotrexate (HDMTX) has found increasing application as a means of preventing the development of overt central nervous system disease in childhood acute leukaemia. However, acute and chronic neurotoxicity has been described following HDMTX therapy, and the long-term intellectual outcome in children treated in this way is inadequately documented. Proton magnetic resonance spectroscopy ((1)H-MRS) of the brain is a noninvasive, quantitative way of assessing aspects of cerebral metabolism, which has not previously been applied to the study of children undergoing central nervous system directed therapy. PROCEDURE: To evaluate the potential role of (1)H-MRS in the investigation of related neurotoxicity, 11 children who had received HDMTX (cumulative dose 6-96 g/m(2)) underwent localised (1)H-MRS, magnetic resonance imaging. Neuropsychological assessments were performed on the children who had more than 1 year of follow-up time since last methotrexate treatment. Control (1)H-MRS studies on 11 adult and 6 young volunteers were undertaken. Eight patients had spectra of adequate quality. Comparisons between (1)H-MRS metabolite ratios and normal controls were made. RESULTS: Patients had a low choline/water ratio compared to controls (P < 0.01). No differences between patient and control NAA/water, Cr/water, Naa/Cr, and Cho/Cr ratios were seen. Overall, 3 patients had abnormal white matter changes on MRI. The mean IQ of the patients (104.1) was in the normal range. CONCLUSIONS: It is postulated that choline depletion in the brains of these patients may reflect subclinical disturbances of myelin metabolism as a result of methotrexate therapy and may represent a possible avenue of treatment in patients with clinical chronic methotrexate-related neurotoxicity.
A patient with a malignant, functioning, aortico-sympathetic paraganglioma and a solitary bone metastasis causing paraplegia was treated by spinal decompression, irradiation of the metastasis, surgical excision of the primary tumour and systemic I-131 meta-iodobenzyl-guanidine (mIBG). Sixteen months after treatment there was no clinical, radiological or biochemical evidence of residual disease and neurological function was restored. The case supports the use of combined treatment incorporating mIBG in patients with metastatic neuroendocrine tumours which demonstrate mIBG uptake.
PURPOSE: To analyze the cause of GI symptoms after pelvic radiotherapy (RT) in a consecutive series of patients with symptoms beginning after RT. A striking lack of evidence is available concerning the optimal treatment for the 50% of patients who develop permanent changes in bowel habits affecting their quality of life after pelvic RT. As a result, in the UK, most such patients are never referred to a gastroenterologist. METHODS AND MATERIALS: All diagnoses were prospectively recorded from a consecutive series of patients with symptoms that started after RT and who were referred during a 32-month period to a gastroenterology clinic. Patients either underwent direct access flexible sigmoidoscopy or were investigated in a standard manner by one gastroenterologist after first being seen in the clinic. RESULTS: A total of 265 patients referred from 15 institutions were investigated. They included 90 women (median age, 61.5 years; range, 22-84 years) and 175 men (median age, 70 years; range, 31-85 years). RT had been completed a median of 3 years (range, 0.1-34 years) before the study in the women and 2 years (range, 0-21 years) before in the men. Of the 265 patients, 171 had primary urologic, 78 gynecologic, and 16 GI tumors. The GI symptoms included rectal bleeding in 171, urgency in 82, frequency in 80, tenesmus, discomfort, or pain in 79, fecal incontinence in 79, change in bowel habit in 42, weight loss in 19, vomiting without other obstructive symptoms in 18, steatorrhea in 7, nocturnal defecation in 8, obstructive symptoms in 4, and other in 24. After investigation, significant neoplasia was found in 12%. One-third of all diagnoses were unrelated to the previous RT. More than one-half of the patients had at least two diagnoses. Many of the abnormalities diagnosed were readily treatable. The symptoms were generally unhelpful in predicting the diagnosis, with the exception of pain, which was associated with neoplasia (p < 0.001). CONCLUSION: The results of our study have shown that radiation enteritis is not a single disease entity. More than one-half of the patients had more than one GI diagnosis contributing to their symptoms. After pelvic RT, specific GI symptoms were not a reliable measure of the underlying diagnoses, and the evaluation of new GI symptoms is worthwhile. An algorithm for this purpose is proposed.
BACKGROUND: Approximately 13,000 patients undergo pelvic radiotherapy annually in the UK. It is not clear how frequently patients develop a permanent change in bowel habit after pelvic radiotherapy that affects their quality of life because the measures of gastrointestinal toxicity used in trials in the past have generally been inadequate. It has been suggested that patients who are symptomatic are only rarely referred to a gastroenterologist and it is not known how patients manage their symptoms. METHODS: Patients who had completed radiotherapy for pelvic cancer at least 1 year previously were invited to answer 30 structured questions in a face-to-face interview to determine the frequency of gastrointestinal symptoms and what orthodox, dietary and complementary therapies they used to deal with them. They were also asked to score the effectiveness of the measures they had taken. RESULTS: One hundred and seven patients were recruited [35 males; median age, 65 years (range, 35-80 years); 72 females; median age, 67.5 years (range, 31-87 years)]. Eight had been treated for a gastrointestinal primary tumour, 34 for a urological tumour and 65 for gynaecological tumours. Eighty-seven patients (81%) described new-onset gastrointestinal problems starting after radiotherapy. These symptoms affected the quality of life in 56 patients (52%). Significant effects on the quality of life were caused by diarrhoea or constipation (n = 53), faecal leakage (n = 19), abdominal, rectal or perineal pain (n = 14) and rectal bleeding (n = 6). Fifty-nine patients had seen a doctor for their symptoms (86% found this helpful), 12 had seen a dietician or nurse (50% found this helpful) and 14 had seen alternative practitioners (88% found this helpful). Dietary manipulation generally did not improve symptoms, except in a small group of patients (14/15) who avoided raw vegetables to great benefit. CONCLUSIONS: At least 1 year after pelvic radiotherapy, gastrointestinal symptoms which have an adverse effect on the quality of life may be more common than generally reported. Patients found that advice from doctors and alternative practitioners was equally valuable. Dietary manipulation was generally unhelpful for gastrointestinal symptoms after pelvic radiotherapy, although the role of eliminating raw vegetables may benefit from further evaluation.
BACKGROUND: Inflammatory responses to pelvic radiotherapy can result in severe changes to normal gastrointestinal function with potentially severe long-term effects. Reduced or modified fat diets may confer benefit. METHODS: This randomised controlled trial recruited patients with gynaecological, urological or lower gastrointestinal malignancy due to receive radical radiotherapy. Patients were randomised to a low fat (20% total energy from long chain triglycerides), modified fat (20% from long chain triglycerides and 20% from medium chain triglycerides) or normal fat diet (40% total energy from long chain triglycerides). The primary outcome was a difference in change in Inflammatory Bowel Disease Questionnaire--Bowel (IBDQ-B) score, from the start to end of radiotherapy. RESULTS: A total of 117 patients with pelvic tumours (48% urological; 32% gastrointestinal; 20% gynaecological), with mean (SD) age: 65 (11.0) years, male:female ratio: 79:38, were randomised. The mean (SE) fall in paired IBDQ-B score was -7.3 (0.9) points, indicating a worsening toxicity. Differences between groups were not significant: P = 0.914 (low versus modified fat), P = 0.793 (low versus normal fat) and P = 0.890 (modified versus normal fat). The difference in fat intake between low and normal fat groups was 29.5 g [1109 kJ (265 kcal)] amounting to 11% (of total energy intake) compared to the planned 20% differential. Full compliance with fat prescription was only 9% in the normal fat group compared to 93% in the low fat group. CONCLUSIONS: A low or modified fat diet during pelvic radiotherapy did not improve gastrointestinal symptom scores compared to a normal fat intake. An inadequate differential in fat intake between the groups may have confounded the results.
PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.
INTRODUCTION: 3-Hydroxy-methylglutaryl coenzyme-a reductase inhibitors (statins) improve survival following pelvic irradiation for cancer. Large studies suggest that patients with hypertension may have reduced gastrointestinal (GI) toxicity. Animal data suggest that statins and ACE inhibitors (ACEi) may protect against normal tissue injury. Their efficacy in humans has not been reported. AIMS/METHODS: To evaluate the impact of statins and ACEi on normal tissue toxicity during radical pelvic radiotherapy. GI symptomatology was recorded prospectively before radiotherapy, weekly during treatment and 1 year later using the inflammatory bowel disease questionnaire-bowel (IBDQ-B) subset. Cumulative acute toxicity (IBDQ-B AUC) and worst score were determined. Dose, brand and duration of statin and/or ACEi usage were obtained from General Practitioners. RESULTS: Of 308 patients recruited, 237 had evaluable acute drug and toxicity data and 164 had data at 1year. Acutely, 38 patients (16%) were taking statins, 39 patients (16.5%) were taking ACEi and 18 patients (7.6%) were taking statin+ACEi. Mean changes in acute scores were 7.3 points (non-statin users), 7.3 (non-ACEi users) and 7.0 (non-statin+ACEi users) compared to 4.8 points (statin users), 5.0 points (ACEi users) and 4.9 points (statin+ACEi users). Statin use (p=0.04) and combined statin+ACEi use (p=0.008) were associated with reduced acute IBDQ-B AUC after controlling for baseline scores (ANOVA). At 1 year, users maintained higher IBDQ-B scores than non-users in all user subgroups. CONCLUSION: Use of statin or statin+ACEi medication during radical pelvic radiotherapy significantly reduces acute gastrointestinal symptoms scores and also appears to provide longer-term sustained protection.
BACKGROUND: In rectal cancer, the standard of care after the completion of radiotherapy is surgery at 6 to 8 weeks. However, there is variation regarding the timing of surgery. OBJECTIVE: This investigation aimed to audit the timing of surgery following radiotherapy and to compare perioperative morbidity and tumor downstaging in patients operated on, before and after the 6- to 8-week window. DESIGN: A retrospective review of rectal cancers treated preoperatively in our cancer network over a 27-month period. The effect of "time till surgery" of 6 to 8 weeks, <6 weeks, and >8 weeks on T downstaging and nodal downstaging was calculated by univariate and multivariate logistic regression analyses. SETTING: This study was conducted in an oncology tertiary referral center in the Southwest London Cancer Network. PATIENTS: Patients receiving preoperative radiotherapy for primary locally advanced rectal cancer undergoing subsequent surgical resection were eligible. MAIN OUTCOME MEASURES: The primary outcome measurement was time to surgery following the completion of (chemo) radiotherapy. Thirty-day perioperative morbidity and mortality and tumor and nodal downstaging were examined according to the timing of surgery. LIMITATIONS: This study was limited by its nonrandomized retrospective design and the lack of standardization of preoperative chemotherapy. RESULTS: Thirty-two (34%) patients underwent surgery at 6 to 8 weeks, 45 (47%) at >8 weeks, and 18 (19%) at <6 weeks after radiotherapy. Delay was attributed to scheduling in 87% of cases and to comorbidities in the remainder. T downstaging occurred in 6 (33.3%) patients in the <6 weeks group, in 12 (37.5%) in the 6 to 8 weeks group, and in 28 (62.2%) in >8 weeks group with no significant differences in perioperative morbidity. On multivariate analysis, T downstaging was significantly greater for the >8 weeks group (OR, 3.79; 95% CI: 1.11-12.99; P = .03). More patients were staged ypT0-T2, 19 of 45 (42%) in the >8 weeks group vs other groups, 14 of 50 (28%, P < .05). CONCLUSIONS: Following radiotherapy, surgery frequently occurs at >8 weeks and is associated with increased downstaging. The consequences on survival and perioperative morbidity warrant further investigation.
BACKGROUND: The benefit of induction chemotherapy (IC) before chemoradiotherapy (CRT) for inoperable esophageal adenocarcinoma has not been established. To clarify toxicities and outcomes of combined modality treatment, we performed a retrospective review. MATERIALS AND METHODS: Sixty-eight consecutive patients were identified. Fifty-one patients had CRT, 17 had radiotherapy (RT). Fifty-eight received IC before RT. IC consisted of 4 cycles of platinum and fluoropyrimidines followed by CRT 54 Gy with concurrent infusional 5-fluorouracil (5-FU) or capecitabine. Response to IC was assessed at 3 months and response to CRT at 3 months. Time to progression (TTP) and overall survival (OS) are reported. RESULTS: Fifty-four patients were men and 14 were women, with median age 72 years (range, 42-87 years). There were 29 stage II, 33 stage III, 4 stage IVa, and 2 stage IVb tumors. The response 3 months after completion of treatment was 39.6%. No grade 4 toxicity was reported, but 10/58 patients had grade 3 toxicity from IC. The median TTP and OS from RT for the entire cohort was 12 months (95% confidence interval [CI], 7-18) and 16 months (95% CI, 5-27), respectively. The 1- and 2-year survival rates from diagnosis were 73% and 47%, respectively. There was no statistically significant difference in TTP or OS in patients who responded to IC compared with those who did not (median TTP 11 vs. 12 months, respectively; P = .8; median OS 15 vs. 14 months, respectively; P = .8). CONCLUSION: The outcome in patients with adenocarcinoma of the esophagus after CRT is comparable to unselected surgical series. Response to IC is not always an indicator of eventual outcome.
Current management of early-stage rectal cancer comprises combinations of surgery, radiotherapy, and chemotherapy, with the presence or absence of several validated high-risk features determining which treatment modalities will be used and the order of administration. In high-risk individuals, most centers have adopted neoadjuvant combined chemotherapy and radiotherapy followed by surgery as the initial approach. However, long-term toxicity, limited survival gains, and high rates of distant failure have called this approach into question, with early data suggesting that neoadjuvant chemotherapy alone may be feasible in selected patient groups. This review discusses the current data and feasibility of managing early stage rectal cancer with neoadjuvant chemotherapy before surgical resection.
PURPOSE: Significant chronic symptoms following pelvic radiotherapy occur more frequently than commonly realized. Predictive factors for the development of late symptoms are poorly defined. Moderate sustained acute (cumulative) toxicity might predict severe late effects better than peak reaction. METHODS AND MATERIALS: To determine prospectively whether peak or cumulative gastrointestinal (GI) acute symptoms better predict late symptoms in patients receiving pelvic radiotherapy. Symptom scores were measured weekly from the start of radiotherapy, and at 1 year using the Modified Inflammatory Bowel Disease Questionnaire-Bowel subset. The possible prognostic impact of patient-related factors was explored. RESULTS: Three hundred and eight patients were recruited. 100 were excluded due to lack of follow-up data at one year resulting from death, too ill, stoma, relapsed, non-response or withdrawal. A further 15 were excluded for incomplete data, leaving 193 patients with evaluable data. Of these, 28 had GI, 101 urological, and 64 gynecological cancers. Patients' median age was 65 years (range, 23-82), and they were treated with median 60 Gy dose for a median of 6 weeks. Univariate analysis revealed a significant association between cumulative acute symptom scores and scores at 1 year (p < 0.001), which was dose-independent (p < 0.001). Acute peak and 1-year scores were not associated (p = 0.431). The correlation coefficient between cumulative acute symptoms and symptoms at 1 year was 0.367 and for peak acute symptoms was weaker at 0.057. Patients with an abnormal body mass index and current smokers were more likely to experience worse symptoms at 1 year. CONCLUSION: Cumulative acute symptoms are more predictive of late symptoms than peak acute changes in score. This association is independent of the radiotherapy dose delivered and is suggestive of a consequential late effect.
BACKGROUND: Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. METHODS: Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. FINDINGS: 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). INTERPRETATION: Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. FUNDING: UK National Health Service, Sanofi-Aventis.
Modern three-dimentional radiotherapy is based upon CT. For rectal cancer, this relies upon target definition on CT, which is not the optimal imaging modality. The major limitation of CT is its low inherent contrast resolution. Targets defined by MRI could facilitate smaller, more accurate, tumour volumes than CT. Our study reviewed imaging and planning data for 10 patients with locally advanced low rectal cancer (defined as < 6 cm from the anal verge on digital examination). Tumour volume and location were compared for sagittal pre-treatment MRI and planning CT. CT consistently overestimated all tumour radiological parameters. Estimates of tumour volume, tumour length and height of proximal tumour from the anal verge were larger on planning CT than on MRI (p < 0.05). Tumour volumes defined on MRI are smaller, shorter and more distal from the anal sphincter than CT-based volumes. For radiotherapy planning, this may result in smaller treatment volumes, which could lead to a reduction in dose to organs at risk and facilitate dose escalation.
The aim of this study was to evaluate the MR findings of anal carcinoma using an external pelvic phased-array coil before and after chemoradiation treatment. 15 patients with carcinoma of the anal canal underwent T(2) weighted and short-tau inversion recovery (STIR) imaging before and after chemoradiation. Images were reviewed in consensus by two radiologists. At pre-treatment imaging, the tumour size and stage, signal intensity and infiltration of adjacent structures were recorded. MR imaging was repeated immediately after chemoradiation, every 6 months for the first year and then yearly. Tumour response was assessed by recording change in tumour size and signal intensity. Prior to treatment, the mean tumour size was 3.9 cm (range, 1.8-6.4 cm). Tumours appeared mildly hyperintense at T(2) weighted and STIR imaging. There was good agreement in T staging between clinical examination and MR imaging (kappa = 0.68). In 12 responders with long disease remission, a greater percentage reduction in the size of MR signal abnormality in the tumour area was observed at 6 months (mean 54.7%; 46-62%) than immediately after treatment (mean 38.6%; 30-46%) (p = 0.002, t-test). 7/12 showed stabilization of T(2) signal reduction in the tumour area after 1 year, and 5/12 showed complete resolution of signal alterations at 2 years. Pelvic phased-array MR imaging is useful for local staging of anal carcinoma and assessing treatment response. After treatment, a decrease in tumour size accompanied by reduction and stability of the MR T(2) signal characteristics at 1 year after chemoradiation treatment was associated with favourable outcome.
PURPOSE: To apply thin-section T2-weighted magnetic resoance imaging (MRI) to evaluate the number, size, distribution, and morphology of benign and malignant mesorectal lymph nodes before and after chemoradiation treatment compared with histopathologic findings. METHODS AND MATERIALS: Twenty-five patients with poor-risk adenocarcinoma of the rectum treated with neoadjuvant chemoradiation were evaluated prospectively. Thin-section T2-weighted MR images obtained before and after chemoradiation treatment were independently reviewed in consensus by 2 expert radiologists to determine the tumor stage, nodal size, nodal distribution, and nodal stage. Total mesorectal excision surgery after chemoradiation allowed MR nodal stage to be compared with histopathology using kappa statistics. Nodal downstaging was compared using the Chi-square test. RESULTS: Before chemoradiation, 152 mesorectal nodes were visible (mean, 6.2 mm; 100 benign, 52 malignant) and 4 of 52 malignant nodes were in contact with the mesorectal fascia. The nodal staging was 7/25 N0, 10/25 N1, and 7/25 N2. After chemoradiation, only 29 nodes (mean, 4.1 mm; 24 benign, 5 malignant) were visible, and none were in contact with the mesorectal fascia. Nodal downstaging was observed: 20/25 N0 and 5/25 N1 (p < 0.01, Chi-square test). There was good agreement between MRI and pathologic T-staging (kappa = 0.64) and N-staging (kappa = 0.65) after chemoradiation. CONCLUSIONS: Neoadjuvant chemoradiation treatment resulted in a decrease in size and number of malignant- and benign-appearing mesorectal nodes on MRI. Nodal downstaging and nodal regression from the mesorectal fascia were observed after treatment. MRI is a useful tool for assessing nodal response to neoadjuvant treatment.
The past decade has seen pronounced changes in the treatment of locally advanced rectal cancer. Historically, the standard of care involved surgery followed by adjuvant radiotherapy or chemoradiotherapy. More recently, the emergence of neo-adjuvant chemoradiotherapy has fundamentally changed the management of patients with locally advanced disease. In clinical trials, pathological complete responses of up to 25% have raised the question as to whether surgery can be avoided in a select cohort of patients. A trial of omission of surgery for selected patients with complete response after preoperative chemoradiotherapy has shown favourable long-term results. In this article, we outline emerging factors for achieving pathological complete response, non-operative strategies to date, methods for prediction of response to chemoradiotherapy, and future directions with the addition of MRI as a radiological guide to complete response.
PURPOSE: To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) -defined poor-risk rectal cancer. PATIENTS AND METHODS: MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending > or = 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. RESULTS: Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION: Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.
Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.
BACKGROUND: We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m(2) intravenously (i.v.) and LV 20 mg/m(2) i.v. bolus days 1-5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m(2)/day for 12 weeks). RESULTS: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62-1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61-1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU. CONCLUSIONS: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.
The combination of protracted venous infusion (PVI) fluorouracil (5-FU) and mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms of response rate and failure-free survival. This study explores the effect of dose intensification by circadian timing of 5-FU in this combination on response, toxicity, and survival. Patients with advanced colorectal carcinoma were randomized to receive PVI 5-FU 300 mg/m2 daily or circadian-timed infusion (CTI) of 5-FU, beginning at 600 mg/m2 and subsequently reduced to 450 mg/m2, delivered as a flat-rate infusion from 10:15 PM to 9:45 AM. Both groups received mitomycin-C at a dose of 7 mg/m2 given every 6 weeks. From April 1996 to August 1998, 320 patients were randomized, including 263 with metastatic disease and 21 with circumferential margin involvement. The overall response rate for the PVI 5-FU group was 38%, compared with 30.3% for the CTI group (P = 0.176). There was no statistically significant difference in terms of failure-free survival (8.0 months vs. 9.9 months; P = 0.131) or overall survival (15.8 months vs. 16.3 months; P = 0.275) between the treatment groups. There were no differences in global quality of life. Grade 3/4 diarrhea occurred significantly more frequently with CTI 5-FU (6.5% vs. 19.8%; P < 0.001); a nonsignificant trend toward increased incidences of grade 3/4 infection and palmar plantar erythema were observed with CTI 5-FU. This study confirms the high response rate and overall survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal cancer. However, dose intensification of 5-FU using a circadian-timed, flat-rate infusion did not lead to improved response or survival.
PURPOSE: This analysis aims to evaluate routine carcino-embryonic antigen (CEA) and computed tomography (CT) of thorax, abdomen, and pelvis as part of protocol-specified follow-up policy for colorectal cancer (CRC). PATIENTS AND METHODS: Patients with resected stage II and III CRC were randomly assigned to bolus fluorouracil/leucovorin or protracted venous infusion fluorouracil. Following completion of chemotherapy, patients were seen in clinic at regular intervals for 5 years. CEA was measured at each clinic visit, and CT of thorax, abdomen, and pelvis was performed at 12 and 24 months after commencement of chemotherapy. RESULTS: Between 1993 and 1999, 530 patients were recruited. The median follow-up was 5.6 years. Disease relapses were observed in 154 patients. Relapses were detected by symptoms (n = 65), CEA (n = 45), CT (n = 49), and others (n = 9). Fourteen patients, whose relapses were detected by CT, had a concomitant elevation of CEA and were included in both groups. The CT-detected group had a better survival compared with the symptomatic group from the time of relapse (P =.0046). Thirty-three patients (21%) proceeded to potentially curative surgery for relapse and enjoyed a better survival than those who did not (P <.00001). For patients who underwent hepatic or pulmonary metastatic resection, 13 (26.5%) were in the CT group, eight (17.8%) in the CEA group, and only two (3.1%) in the symptomatic group (CT v symptomatic, P <.001; CEA v symptomatic, P =.015). CONCLUSION: Surveillance CT and CEA are valuable components of postoperative follow-up in stage II and III colorectal cancer.
We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of 5-fluorouracil (5-FU) delivered by protracted intravenous infusion (PVI 5-FU) against the standard bolus regimen of 5-FU and folinic acid (5-FU/FA) given for 6 months as adjuvant treatment in colorectal cancer. A total of 716 patients with curatively resected Dukes' B or C colorectal cancer were randomised to 5-FU/FA (5-FU 425 mg m(-2) i.v. and FA 20 mg m(-2) i.v. bolus days 1-5 every 28 days for 6 months) or to PVI 5-FU alone (300 mg m(-2) day for 12 weeks). With a median follow-up of 19.8 months, 133 relapses and 77 deaths have been observed. Overall survival did not differ significantly (log rank P=0.764) between patients receiving 5-FU/FA and PVI 5-FU (3-year survival 83.2 vs 87.9%, respectively). Patients in the 5-FU/FA group had significantly worse relapse-free survival (RFS, log rank P=0.023) compared to those receiving PVI 5-FU (3-year RFS, 68.6 vs 80%, respectively). Grades 3-4 neutropenia, diarrhoea, stomatitis and severe alopecia were significantly less (P<0.0001) and global quality of life scores significantly better (P&<0.001) for patients in the PVI 5-FU treatment arm. In conclusion, infused 5-FU given over 12 weeks resulted in similar survival to bolus 5-FU and FA over a 6 month period, but with significantly less toxicity.
This study was designed to evaluate the benefits of neoadjuvant chemotherapy prior to chemoradiation and surgery in patients with locally advanced rectal cancer. Patients with previously untreated primary rectal cancer, reviewed in a multidisciplinary meeting and considered to have locally advanced disease on the basis of physical examination and imaging (MRI+CT n=30, CT alone n=6), were recruited. Patients received protracted venous infusion 5-FU (300 mg m(-2) day(-1) for 12 weeks) with mitomycin C (MMC) (7 mg m(-2) i.v. bolus every 6 weeks). Starting on week 13, 5-FU was reduced to 200 mg m(-2) day(-1) and concomitant pelvic radiotherapy 45 Gy in 25 fractions was commenced followed by 5.4-9 Gy boost to tumour bed. Surgery was planned 6 weeks after chemoradiation. Postoperatively, patients received 12 weeks of MMC and 5-FU at the same preoperative doses. Between January 99 and August 01, 36 eligible patients were recruited. Median age was 63 years (range=40-85). Following neoadjuvant chemotherapy, radiological tumour response was 27.8% (one CR and nine PRs) and no patient had progressive disease. In addition, 65% of patients had a symptomatic response including improvement in diarrhoea/constipation (59%), reduced rectal bleeding (60%) and diminished pelvic pain/tenesmus (78%). Following chemoradiation, tumour regression occurred in 80.6% (six CRs and 23 PRs; 95% CI=64-91.8%) and only one patient still had an inoperable tumour. R0 resection was achieved in 28 patients (82%). When compared with initial clinical staging, the pathological downstaging rate in T and/or N stage was 73.5% and pathological CR was found in one patient. Neoadjuvant systemic chemotherapy as a prelude to synchronous chemoradiation can be administered with negligible risk of disease progression and produces considerable symptomatic response with associated tumour regression.
BACKGROUND: The role of palliative resection of the primary tumour in patients who present with metastatic colorectal cancer is unclear. AIMS: This study compared the incidence of major intestinal complications in such patients who received chemotherapy treatment with or without prior palliative resection of the primary tumour. PATIENTS: The incidence of intestinal obstruction, perforation, fistula formation, and gastrointestinal haemorrhage, and the requirement for abdominal radiotherapy in patients with metastatic colorectal cancer treated at a single institution over a 10 year period was determined. RESULTS: Eighty two patients received initial treatment with chemotherapy without resection of the primary tumour (unresected group) and 280 patients had undergone prior resection (resected group). In the unresected group, the incidence of peritonitis, fistula formation, and intestinal haemorrhage was 2.4% (95% confidence interval (CI) 0.3-8.5%), 3.7% (95% CI 0.8-10.3%), and 3.7% (95% CI 0.8-10.3%), respectively, and was not significantly different from the resected group. Intestinal obstruction affected 13.4% (95% CI 6.9-22.7%) of patients in the unresected group and 13.2% (95% CI 9.2-17.2%) of patients in the resected group. More patients in the unresected group required >/=3 blood transfusions (14.6% v 7.5%; p=0.048) and abdominal radiotherapy (18.3% v 9.6%; p=0.03) than the resected group. CONCLUSIONS: The incidence of major intestinal complications in patients with unresected colorectal cancer and synchronous metastases who receive initial treatment with chemotherapy is low. Chemotherapy may be successfully used as initial treatment for such patients with no increased risk of most major intestinal complications compared with patients who have undergone initial resection of the primary tumour.
BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS: Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle. RESULTS: The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.
Total body irradiation (TBI) is a highly emetogenic component of the majority of conditioning regimens in use for bone marrow transplantation. Conventional antiemetic therapy fails to control nausea and vomiting induced by single fraction TBI in as many as 50% of patients. In a double blind study of 20 patients undergoing marrow transplantation, a single 8 mg ondansetron dose was compared with placebo given immediately prior to TBI. Our routine premedication of phenobarbitone and corticosteroid was also administered to all patients. All patients had received high dose melphalan the previous evening. Only 1 of the 10 patients in the ondansetron group experienced an emetic event compared with 5 of the 10 in the comparison group (p = 0.029). No significant adverse events were observed. Ondansetron appears to have extremely useful antiemetic activity during single fraction low dose rate TBI.
PURPOSE: There has been no previously published data related to the quantification of rectal motion using cone-beam computed tomography (CBCT) during standard conformal long-course chemoradiotherapy. The purpose of the present study was to quantify the interfractional changes in rectal movement and dimensions and rectal and bladder volume using CBCT and to quantify the bony anatomy displacements to calculate the margins required to account for systematic (Σ) and random (σ) setup errors. METHODS AND MATERIALS: CBCT images were acquired from 16 patients on the first 3 days of treatment and weekly thereafter. The rectum and bladder were outlined on all CBCT images. The interfraction movement was measured using fixed bony landmarks as references to define the rectal location (upper, mid, and low), The maximal rectal diameter at the three rectal locations was also measured. The bony anatomy displacements were quantified, allowing the calculation of systematic (Σ) and random (σ) setup errors. RESULTS: A total of 123 CBCT data sets were analyzed. Analysis of variance for standard deviation from planning scans showed that rectal anterior and lateral wall movement differed significantly by rectal location. Anterior and lateral rectal wall movements were larger in the mid and upper rectum compared with the low rectum. The posterior rectal wall movement did not change significantly with the rectal location. The rectal diameter changed more in the mid and upper than in the low rectum. No consistent relationship was found between the rectal and bladder volume and time, nor was a significant relationship found between the rectal volume and bladder volume. CONCLUSIONS: In the present study, the anterior and lateral rectal movement and rectal diameter were found to change most in the upper rectum, followed by the mid rectum, with the smallest changes seen in the low rectum. Asymmetric margins are warranted to ensure phase 2 coverage.
It is generally assumed that femoral head osteonecrosis (FHO) is a serious but rare complication of pelvic radiotherapy. A review of the literature carried out by the authors indicates a prevalence of 4/763 (95% confidence interval 0.1%-1.3%). A recent publication has suggested that the prevalence of symptomatic FHO may be much greater than previously assumed as a result of sensitization of bone to radiation by concomitant treatment with chemotherapy. Magnetic resonance imaging (MRI) is currently the most sensitive modality for detecting and confirming symptomatic or asymptomatic FHO of any aetiology. The aim of this study therefore was to assess the prevalence of symptomatic and asymptomatic FHO in patients previously treated for anal cancer by chemoradiation (CRT). The hips of 34 currently disease-free individuals (11 men and 23 women; median age 67 years, range 32-86) were scanned using a coronal T1-weighted sequence. The images were assessed for evidence of FHO. The median time of scanning after the end of CRT was 35 months (range 6-107). No cases (0/34) of symptomatic or asymptomatic FHO were detected in these patients. Given the established sensitivity of MRI in the detection of FHO, it is concluded that changes indicative of osteonecrosis were uncommon after CRT in the current cohort of patients. Recent evidence from the literature suggests, however, that elderly females are at greatest risk of developing FHO after CRT.
Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4-35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1-12). The median total serum bilirubin level was 116 mmol/l (range 63-194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in nonresponders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.
PURPOSE: We reviewed the outcome of children with medulloblastoma treated from 1970 to 1985 with combined radiotherapy and chemotherapy. PATIENTS AND METHODS: Fifty-seven children with a median age of 8 years (range 1 to 16 years) at diagnosis were analyzed regarding survival, site and time of recurrence, treatment toxicity, prognostic factors and performance status. RESULTS: The overall 5- and 10-year-survival was 66% and 54%, respectively. Patients with subarachnoid metastases or positive cerebrospinal fluid cytology (M1-3) had a shorter survival compared with those without it (p < 0.1). Furthermore, survival appeared to improve with the addition of lomustine (CCNU) to vincristine chemotherapy with a 5-year-survival of 70% versus 31% (relative risk 3.4, 95% confidence interval 1.4 to 8.1) although it should be noted that these were consecutive not randomized patients treated. Of the 52 patients achieving remission, 17 relapsed either in primary (2), spine (5) or a combination of these (10). Two patients developed bone metastases without central nervous system recurrence. Performance status measured crudely appeared to be good in long-term survivors. Of 31 patients that survived for long-term follow-up and had their performance evaluated, 28 had no or minor residual neurological signs and the remaining 3 were disabled. CONCLUSION: Combined modality treatment for medulloblastoma in childhood was able to cure 54% of patients with a good performance status in the majority of survivors.
The perils of radiotherapy in pediatric oncology are well advertised and, justifiably, alternative treatment strategies have been sought. However, radiotherapy can be a highly effective antitumor agent and results with alternative therapies, in terms of survival and quality of life, need to be carefully scrutinized. In addition, biologic and technical innovations in radiotherapy are increasing its versatility and providing means of more adequately protecting adjacent normal tissues.