Deciding when to return to sport after injury is complex and multifactorial—an exercise in risk management. Return to sport decisions are made every day by clinicians, athletes and coaches, ideally ...in a collaborative way. The purpose of this consensus statement was to present and synthesise current evidence to make recommendations for return to sport decision-making, clinical practice and future research directions related to returning athletes to sport. A half day meeting was held in Bern, Switzerland, after the First World Congress in Sports Physical Therapy. 17 expert clinicians participated. 4 main sections were initially agreed upon, then participants elected to join 1 of the 4 groups—each group focused on 1 section of the consensus statement. Participants in each group discussed and summarised the key issues for their section before the 17-member group met again for discussion to reach consensus on the content of the 4 sections. Return to sport is not a decision taken in isolation at the end of the recovery and rehabilitation process. Instead, return to sport should be viewed as a continuum, paralleled with recovery and rehabilitation. Biopsychosocial models may help the clinician make sense of individual factors that may influence the athlete's return to sport, and the Strategic Assessment of Risk and Risk Tolerance framework may help decision-makers synthesise information to make an optimal return to sport decision. Research evidence to support return to sport decisions in clinical practice is scarce. Future research should focus on a standardised approach to defining, measuring and reporting return to sport outcomes, and identifying valuable prognostic factors for returning to sport.
Objectives
To compare the results of Gleason Grade Group (GGG) classification following central pathology review with previous local pathology assessment, and to examine the difference between using ...overall and worst GGG in a large patient cohort treated with radiotherapy and short‐course hormone therapy.
Patients and Methods
Patients with low‐ to high‐risk localized prostate cancer were randomized into the multicentre CHHiP fractionation trial between 2002 and 2011. Patients received short‐course hormone therapy (≤6 month) and radical intensity‐modulated radiotherapy (IMRT). Of 2749 consented patients, 1875 had adequate diagnostic biopsy tissue for blinded central pathology review. The median follow‐up was 9.3 years. Agreement between local pathology and central pathology‐derived GGG and between central pathology‐derived overall and worst GGG was assessed using kappa (κ) statistics. Multivariate Cox regression and Kaplan–Meier methods were used to compare the biochemical/clinical failure (BCF) and distant metastases (DM) outcomes of patients with GGG 1–5.
Results
There was poor agreement between local pathology‐ and central pathology‐derived GGG (κ = 0.19) but good agreement between overall and worst GGG on central pathology review (κ = 0.89). Central pathology‐derived GGG stratified BCF and DM outcomes better than local pathology, while overall and worst GGG on central pathology review performed similarly. GGG 3 segregated with GGG 4 for BCF, with BCF‐free rates of 90%, 82%, 74%, 71% and 58% for GGGs 1–5, respectively, at 8 years when assessed using overall GGG. There was a progressive decrease in DM‐free rates from 98%, 96%, 92%, 88% and 83% for GGGs 1–5, respectively, at 8 years with overall GGG. Patients (n = 57) who were upgraded from GGG 2–3 using worst GS had BCF‐free and DM‐free rates of 74% and 92% at 8 years. CHHiP eligibility criteria limit the interpretation of these results.
Conclusion
Contemporary review of International Society of Urological Pathology GGG successfully stratified patients treated with short‐course hormone therapy and IMRT with regard to both BCF‐free and DM‐free outcomes. Patients upgraded from GGG 2 to GGG 3 using worst biopsy GS segregate with GGG 3 on long‐term follow‐up. We recommend that both overall and worst GS be used to derive GGG.
Summary Background Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed ...to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. Methods Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. Findings 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4–81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80–1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0–27·9) for patients on early treatment and 27·1 months (22·8–30·9) for those on delayed treatment. Interpretation Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. Funding UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We ...hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy.
IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1–3, with a tumour size of 3 cm or less (pT1–2), none to three positive axillary nodes (pN0–1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase non-inferiority margin at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio HR was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634.
Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7–83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5–2·3) of patients in the control group, 0·2% (0·02–1·2) in the reduced-dose group, and 0·5% (0·2–1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were −0·73% (−0·99 to 0·22) for the reduced-dose and −0·38% (−0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance p=0·007 for partial-breast and breast harder or firmer p=0·002 for reduced-dose and p<0·0001 for partial-breast) compared with whole-breast radiotherapy.
We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide.
Cancer Research UK.
Abstract Background and purpose FAST-Forward is a phase 3 clinical trial testing a 1-week course of whole breast radiotherapy against the UK standard 3-week regimen after primary surgery for early ...breast cancer. Two acute skin toxicity substudies were undertaken to test the safety of the test schedules with respect to early skin reactions. Material and methods Patients were randomly allocated to 40 Gy/15 fractions (F)/3-weeks, 27 Gy/5F/1-week or 26 Gy/5F/1-week. Acute breast skin reactions were graded using RTOG (first substudy) and CTCAE criteria v4.03 (second substudy) weekly during treatment and for 4 weeks after treatment ended. Primary endpoint was the proportion of patients within each treatment group with grade ⩾3 toxicity (RTOG and CTCAE, respectively) at any time from the start of radiotherapy to 4 weeks after completion. Results 190 and 162 patients were recruited. In the first substudy, evaluable patients with grade 3 RTOG toxicity were: 40 Gy/15F 6/44 (13.6%); 27 Gy/5F 5/51 (9.8%); 26 Gy/5F 3/52 (5.8%). In the second substudy, evaluable patients with grade 3 CTCAE toxicity were: 40 Gy/15F 0/43; 27 Gy/5F 1/41 (2.4%); 26 Gy/5F 0/53. Conclusions Acute breast skin reactions with two 1-week schedules of whole breast radiotherapy under test in FAST-Forward were mild.
To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.
In this phase 2 ...noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.
One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range IQR, 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval CI, 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.
PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.
A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous ...integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity.
IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1–3pN0–3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants.
Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (–0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group).
In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits.
Cancer Research UK.
The purpose of this UK study was to evaluate interfraction reproducibility and body image score when using ultraviolet (UV) tattoos (not visible in ambient lighting) for external references during ...breast/chest wall radiotherapy and compare with conventional dark ink.
In this non-blinded, single-centre, parallel group, randomized control trial, patients were allocated to receive either conventional dark ink or UV ink tattoos using computer-generated random blocks. Participant assignment was not masked. Systematic (∑) and random (σ) setup errors were determined using electronic portal images. Body image questionnaires were completed at pre-treatment, 1 month and 6 months to determine the impact of tattoo type on body image. The primary end point was to determine that UV tattoo random error (σ
) was no less accurate than with conventional dark ink tattoos, i.e. <2.8 mm.
46 patients were randomized to receive conventional dark or UV ink tattoos. 45 patients completed treatment (UV: n = 23, dark: n = 22). σ
for the UV tattoo group was <2.8 mm in the u and v directions (p = 0.001 and p = 0.009, respectively). A larger proportion of patients reported improvement in body image score in the UV tattoo group compared with the dark ink group at 1 month 56% (13/23) vs 14% (3/22), respectively and 6 months 52% (11/21) vs 38% (8/21), respectively.
UV tattoos were associated with interfraction setup reproducibility comparable with conventional dark ink. Patients reported a more favourable change in body image score up to 6 months following treatment. Advances in knowledge: This study is the first to evaluate UV tattoo external references in a randomized control trial.
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and ...survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
Summary Background In metastatic renal cell carcinoma combinations of interferon alfa-2a, interleukin-2, and fluorouracil produce higher response rates and longer progression-free survival than do ...single agents. We aimed to compare overall survival in patients receiving combination treatment or interferon alfa-2a. Methods RE04/30012 was an open-label randomised trial undertaken in 50 centres across eight countries. 1006 treatment-naive patients diagnosed with advanced metastatic renal cell carcinoma were randomly allocated (1 to 1) by minimisation to receive interferon alfa-2a alone or combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil. Treatment was not masked. The primary endpoint was overall survival. Treatment groups were compared with a non-stratified log-rank test. Analysis was by intention to treat. This study is registered, number ISRCTN 46518965. Findings 502 patients were randomly assigned to receive interferon alfa-2a and 504 to receive combined treatment. Median follow-up was 37·2 months (24·8–52·3). Median overall survival was 18·8 months (17·0–23·2) for patients receiving interferon alfa-2a versus 18·6 months (16·5–20·6) for those receiving combination therapy. Overall survival did not differ between the two groups (hazard ratio 1·05 95% CI 0·90–1·21, p=0·55; absolute difference 0·3% (−5·1 to 5·6) at 1 year and 2·7% (−8·2 to 2·9) at 3 years). Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and 131 (26%) of those receiving combined treatment. Interpretation Although combination therapy does not improve overall or progression-free survival compared with interferon alfa-2a alone, immunotherapy might still have a role because it can produce remissions that are of clinically relevant length in some patients. Identification of patients who will benefit from immunotherapy is crucial. Funding UK Medical Research Council.
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