Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Treatment Outcomes of Stereotactic Ablative Body Radiotherapy on Extra-cranial Oligometastatic and Oligoprogressive Breast Cancer: Mature Results from a Single Institution Experience.

AIMS: Evidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. MATERIALS AND METHODS: A retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients' age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. RESULTS: 56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0-132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3-28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5-158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. CONCLUSION: There are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities.

Single-Dose Focal Salvage High Dose Rate Brachytherapy for Locally Recurrent Prostate Cancer.

AIMS: To evaluate focal high dose rate (HDR) brachytherapy in locally recurrent prostate cancer. MATERIALS AND METHODS: Patients with biochemical relapse after non-surgical primary treatment for localised prostate cancer were selected after a negative screen for metastatic disease. Template mapping biopsies combined with multiparametric magnetic resonance imaging were used to identify the location of the tumour and the focal clinical target volume. The planning aim dose prescription was 19 Gy. Outcome measures were biochemical relapse-free survival and toxicity using International Prostate Symptom Score and Common Terminology Criteria for Adverse Events (version 4.0) scores. RESULTS: Between March 2013 and December 2018, 50 patients underwent salvage HDR brachytherapy. The median follow-up was 21 months (range 1-53). Biochemical progression-free survival at 2 and 3 years was 63% and 46%, respectively. On multivariate analysis, only prostate-specific antigen nadir ≤0.5 ng/ml post-salvage (P = 0.03, hazard ratio 0.04) was associated with biochemical progression-free survival. Relapse was associated with distant metastases in 11/13 patients in whom this was investigated. Late grade 3 genitourinary toxicities were gross haematuria (three patients), severe lower urinary tract symptoms (two patients), erectile dysfunction (one patient) and urethral stricture requiring surgery (four patients). No acute and late grade 4 or 5 genitourinary and no grade 3 or higher gastrointestinal toxicities were recorded. CONCLUSIONS: Focal salvage HDR monotherapy achieves biochemical control in 46% of patients at 3 years with acceptable toxicity rates in selected patients. Biochemical relapse was related to a post-salvage prostate-specific antigen nadir of ≥0.5 ng/ml. Long-term outcomes are needed to assess the impact on the natural history of prostate cancer in these patients.

Stereotactic body radiotherapy (SBRT) in the management of extracranial oligometastatic (OM) disease.

OBJECTIVE: A review of stereotactic body radiotherapy (SBRT) for oligometastases defined as three or fewer sites of isolated metastatic disease. The aim was to identify local control, overall survival (OS) and progression-free survival (PFS) of patients receiving SBRT for oligometastatic (OM) disease. METHODS: Data were analysed for SBRT delivered between 01 September 2010 and 31 March 2014. End points included local control, PFS, OS and toxicity. RESULTS: 76 patients received SBRT. The median age was 60 years (31-89 years). 44 were male. Median follow-up was 12.3 months (0.2-36.9 months). Major primary tumour sites included colorectal (38%), the breast (18%) and the prostate (12%). The treatment sites included lymph nodes (42%), the bone and spine (29%) and soft tissue (29%). 42% were previously treated with conventional radiotherapy. 45% were disease free after SBRT. 4% had local relapse, 45% had distant relapse, and 6% had local and distant relapse. Local control was 89%. The OS was 84.4% at 1 year and 63.2% at 2 years. PFS was 49.1% at 1 year and 26.2% at 2 years. Toxicities included duodenal ulcer and biliary stricture formation. CONCLUSION: SBRT can achieve durable control of OM lesions and results in minimal radiation-induced morbidity. ADVANCES IN KNOWLEDGE: This cohort is one of the largest reported to date and contributes to the field of SBRT in oligometastases that is emerging as an important research area. It is the only study reported from the UK and uses a uniform technique throughout. The efficacy and low toxicity with durable control of local disease with this approach is shown, setting the foundations for future randomized studies.

Prostate stereotactic body radiotherapy­first UK experience.

AIMS: Stereotactic body radiotherapy (SBRT) combines image-guided radiotherapy with hypofractionation, both of which will probably result in improvements in patient outcomes in prostate cancer. Most clinical experience with this technique resides in North America. Here we present the first UK cohort to receive SBRT for prostate cancer. MATERIALS AND METHODS: Fifty-one prostate cancer patients (10 low risk, 35 intermediate risk and 6 high risk) were treated with 36.25 Gy in five fractions over 1-2 weeks and gold seed image guidance. All patients had toxicity International Prostate Symptom score (IPSS) and Radiation Therapy Oncology Group recorded prospectively and prostate-specific antigen was measured 3-6 monthly during follow-up. RESULTS: The median IPSS was 6, 11, 8 and 5 at baseline, 1-3 weeks, 4-6 weeks and 7-12 weeks after treatment. Radiation Therapy Oncology Group genitourinary and gastrointestinal toxicity of grade 2 was seen in 22% and 14%, respectively, at 1-3 weeks after treatment; no patient had grade 3+ toxicity at this time point, although two patients had grade 3 urinary frequency recorded during treatment. The median follow-up for the 42 patients who did not receive androgen deprivation was 14.5 months. Prostate-specific antigen at 13-18 months after treatment was 1.3 ng/ml. CONCLUSION: Prostate SBRT is a promising treatment for organ-confined prostate cancer and is currently being investigated in a UK-led phase III trial.

Quality of life after radical radiotherapy for prostate cancer: longitudinal study from a randomised trial of external beam radiotherapy alone or in combination with high dose rate brachytherapy.

AIM: To compare prospective, long-term quality of life in patients randomised to external beam radiotherapy (EBRT) alone or with a boost of high dose rate (HDR) brachytherapy. MATERIALS AND METHODS: In total, 216 patients participating in the UK randomised trial of EBRT ± HDR brachytherapy were included in this analysis. EBRT delivering 55 Gy in 20 fractions was compared with EBRT followed by HDR brachytherapy of 2 × 8.5 Gy. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and FACT-G (General) questionnaires, administered before radiotherapy, at 6 months and bi-annually thereafter. Differences in mean FACT global scores and erectile function between treatment arms were compared using chi-squared tests. RESULTS: Over a 10.5 year follow-up, no difference in FACT-G, FACT-P or Trial Outcome Index (TOI) scores was seen between treatments and means were similar to their pretreatment values. Mean erectile function scores in arm 2 were similar to arm 1, but were significantly lower than the pretreatment mean (P ≤ 0.002). There was no evidence that quality of life deteriorated with increasing follow-up time in any of the four FACT domains. CONCLUSIONS: The improved biochemical control of disease seen in these patients with EBRT + HDR brachytherapy coupled with equitoxic early and late urinary and bowel morbidity, indicate a therapeutic advantage, which has now been confirmed by the results for general and prostate-related quality of life changes, despite a decline in erectile function.

Report on the early efficacy and tolerability of I(125) permanent prostate brachytherapy from a UK multi-institutional database.

AIMS: To report the results of I(125) prostate brachytherapy from a central, prospectively collected database of three UK institutions. MATERIALS AND METHODS: All patients treated with I(125) permanent prostate brachytherapy at the Christie Hospital, Manchester (CHM), Cookridge Hospital, Leeds (CKL) and Mount Vernon Hospital, Northwood, London (MVL) since 2003 have been prospectively registered on a detailed central database. Patient, tumour, pre- and post-implant dosimetry data have been recorded. Urinary toxicity as assessed by the International Prostate Symptom Score, catheterisation and urinary stricture rates after implant have been documented and biochemical failure determined, using both the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and the Phoenix (nadir + 2 ng/ml) definition. RESULTS: In total, 1535 patients were registered on the database between January 2003 and October 2006, including 432 from CHM, 926 from CKL and 177 from MVL, with a median follow-up of 21 months (range 1-56). Patient and tumour characteristics were similar at all centres. Pre-implant dose indices were comparable between centres, except for the V150, with median values of 51.9, 64.3 and 69.8% at CHM, CKL and MVL, respectively. Median post-implant dose parameters were lower than pre-planned constraints by up to 33.0% at each centre for all values, except at CKL where the V200 was 23.9% higher. The International Prostate Symptom Score increased from a median of 5 at baseline to 18, 6 weeks after implant, but was not significantly different to baseline values by 12 months. Nine per cent of men required catheterisation after implant for a median duration of 53 days, but urinary stricture rates remained low at 1%. Neoadjuvant hormonal manipulation was used in 228 men (15%) for downsizing and 159 (10%) for intermediate/high-risk disease. Collated biochemical failure rates were low at this point of follow-up, with actuarial 2-year ASTRO and Phoenix biochemical failure-free survival rates of 94.4 and 94.5%, respectively, consistent with other large single centre reports. When post-implant dosimetric factors were assessed for a relationship to biochemical failure, no indices consistently predicted for improved ASTRO and Phoenix biochemical failure-free survival rates. CONCLUSIONS: This ongoing collaboration shows that with limited infrastructure (a single industry-sponsored data manager), a large multi-institutional database estimated to represent one-third of implants carried out in the UK during this time can be developed. Patient selection was similar across all centres and adhered to published guidelines. Early biochemical and toxicity outcomes confirm the efficacy and tolerability of I(125) prostate brachytherapy in a large cohort of patients. A further analysis is planned.

High dose rate iridium-192 brachytherapy as a component of radical radiotherapy for the treatment of localised prostate cancer.

AIMS: To assess the treatment outcomes and toxicity of conformal high dose rate (HDR) brachytherapy boost as a means of radiation dose escalation in patients with localised prostate cancer. MATERIALS AND METHODS: Between December 1998 and July 2004, 65 consecutive patients with localised prostate cancer (magnetic resonance imaging-staged T1-3 N0 M0) were treated with external beam radiation therapy (EBRT) followed by two fractions of HDR iridium-192 brachytherapy. The patients selected this treatment modality in preference to entering an ongoing randomised phase 3 trial. Any pre-treatment serum prostate-specific antigen (PSA) and Gleason score were included. The primary end point was biochemical disease-free progression. Late treatment-related morbidity was graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer criteria. RESULTS: The median patient age was 67.3 years (range 47.9-80). Sixty patients (92.3%) had intermediate- to high-risk disease defined by clinical stage, presenting PSA and Gleason score/World Health Organisation (WHO) grade. With a median follow-up of 3.5 years (range 0.6-5.8), two patients had died of metastatic disease and another four patients had PSA relapse, giving a 3-year actuarial biochemical disease-free progression of 90.8%. Three patients (4.6%) had acute grade 3 genitourinary toxicity, in the form of urinary retention. Late grade 3 and 4 genitourinary toxicities occurred in four patients (6.2%) and one patient (1.5%), respectively. No late gastrointestinal toxicities were observed. CONCLUSIONS: These results suggest that the combined modality of conformal HDR brachytherapy and EBRT is a feasible treatment modality with acceptable acute and late toxicities, comparable with those of EBRT alone. It offers an attractive conformal treatment modality with the potential of further dose escalation in the treatment of localised prostate cancer.

Can I look at my list? An evaluation of a 'prompt sheet' within an oncology outpatient clinic.

AIMS: We introduced a patient 'prompt sheet' into our clinic between January 2004 and January 2005. The aim was to determine whether it would facilitate communication and help patients in obtaining their desired level of information about their illness, and assist with decision making. We conducted an audit survey to investigate the way follow-up takes place in our oncology clinic, to determine what works and what does not work in the clinic, and to examine how patients access the most useful information and to assess the utility of, and patient satisfaction with, a locally developed pilot prompt sheet. MATERIALS AND METHODS: A single questionnaire was designed to elicit information on patients' information needs, overall satisfaction with the oncology clinic, and uptake and perceived usefulness of the prompt sheet. We carried out an audit survey in the form of a Likert-scale questionnaire (33 questions), followed immediately afterwards by a semi-structured interview. A specialist nurse asked a range of open questions about what was good and bad about the clinic and the prompt sheets. RESULTS: Despite efforts to ensure that all patients received the prompt-sheet leaflets, only 254 out of 300 (85%) received them. Of these, 195 (65%) felt that they were 'very helpful', and 30 (10%) found them 'fairly helpful'. However, 15 (5%) had no strong feelings and only three found them either fairly or completely unhelpful. One-third of the patients were able to ask more questions about their disease as a result of the prompt sheet, although they felt the doctor was busy and did not want to take up too much of their time. Men with prostate cancer found the prompt sheet particularly helpful to ask questions. CONCLUSION: This satisfaction audit suggests that our pilot prompt sheet is helpful to patients attending oncology outpatient appointments, particularly for men with prostate cancer. We aim to adapt the present prompt sheet on the basis of the replies obtained, and re-audit in the future.

Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or radiotherapy, has been extended with the introduction of more effective combinations of chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced colorectal cancer show high response rates to combination cytotoxic therapy. This evidence of efficacy coupled with the introduction of novel molecular targeted therapies (such as Bevacizumab and Cetuximab), and long waiting times for radiotherapy have rekindled an interest in delivering NACT in locally advanced rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and nasopharynx cancer where traditionally NACT has been used. So, is NACT in rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and consolidation chemotherapy in locally advanced rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in rectal cancer and other disease sites. Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative adjuvant chemotherapy. In particular, there is insufficient data in rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to induction chemotherapy can predict response to subsequent radiotherapy. The observation that spectacular responses to chemotherapy before radical radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in head and neck cancer, nasopharyngeal cancer, non-small-cell lung cancer, small-cell lung cancer and cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or radiotherapy alone. Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of radiotherapy appears the best option for patients with locally advanced rectal cancer and in all disease sites where radiation is the primary local therapy.

A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer.

PURPOSE: Our aim was to evaluate the efficacy, toxicity, and pharmacokinetic behavior of single-agent paclitaxel given weekly to elderly patients with lung cancer. EXPERIMENTAL DESIGN: Previously untreated patients with stage IIIB/IV non-small cell lung cancer were eligible for the study if they were at least 70 years of age and had preserved organ function. Paclitaxel was administered over 1 h at a dose of 90 mg/m(2) for 6 consecutive weeks on an 8-week cycle. The pharmacokinetics of paclitaxel were assessed during the first and sixth week of therapy in a subgroup of eight patients. RESULTS: A total of 35 patients (median age, 76 years; range, 70-85) were enrolled. The overall response rate was 23%. Median time to failure was 5.2 months, whereas the median survival time was 10.3 months. Survival rates after 1 and 2 years were 45 and 22%, respectively. Grade 3/4 toxicities included neutropenia (5.8%), hyperglycemia (17.6%), neuropathy (5.8%), and infection (8.8%). Two patients died from treatment-related toxicity. There was no significant difference (P = 0.18) between the total body clearance of paclitaxel on the first (17.4 +/- 2.9 liters/h/m(2), mean +/- SD) and sixth (15.8 +/- 4.1 liters/h/m(2)) week of therapy. CONCLUSION: Paclitaxel administered as a weekly 1-h infusion at a dose of 90 mg/m(2) is a safe and effective therapy for elderly patients with advanced non-small cell lung cancer. Its pharmacokinetics in elderly patients do not appear to differ from historical data for younger patients, and there was no suggestion of a change in drug clearance after repeated weekly dosing.

The role of staging CT scans in the treatment of prostate cancer: a retrospective audit.

A retrospective audit was performed to review the use of diagnostic and planning computed tomographic (CT) scans in the management of patients treated with radical radiotherapy for prostate cancer at Mount Vernon Hospital. All 97 patients had a planning CT scan. In addition, 85 also underwent a diagnostic scan for staging purposes. Fifty-one (60%) had both pelvic and abdominal imaging. Twenty abnormalities were detected in 19 patients. Although 13 of these were 'malignant' abnormalities considered to represent metastatic disease, only four altered the treatment intent. Overall, only 4% of patients were denied radical treatment on the basis of CT findings. Malignant intra-abdominal disease was not identified in the absence of metastatic disease in the pelvis. This study confirms that abdominal CT scans contribute very little useful prognostic information in men with prostate cancer, and are not necessary for routine staging prior to radiotherapy. We propose that a single CT scan of the pelvis in patients who are suitable for radical radiotherapy can provide adequate information for both staging and planning purposes, resulting in significant reductions in cost, radiation exposure and scanner time.

Syringomyelia after chemotherapy and radiotherapy for advanced oropharyngeal carcinoma: cause or coincidence?

A patient presented with syringomyelia 18 months after the completion of treatment with both chemotherapy and radiotherapy for an advanced oropharyngeal carcinoma. The link with therapy is discussed.

Superior vena cava obstruction: a modern management strategy.

Superior vena cava obstruction (SVCO) is a distressing syndrome. The condition may present to specialists in many branches of medicine, but patients have traditionally been referred on to clinical oncologists for management, as malignancy is the main aetiological factor. Treatment without a histological diagnosis is no longer justified, because management needs to be tailored to the underlying disease. This article reviews the causes, symptoms, methods of diagnosis and therapy options. The role of stenting in SVCO is discussed and a management algorithm is proposed.