• Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.

      Sherwood Forest Hospitals NHS Foundation Trust (2013-05)
      Summary Background Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. Findings 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35–57), 2-year OS was 82·7% (79·5–85·9) in the R-CHOP-14 group and 80·8% (77·5–84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70–1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8–79·1, and R-CHOP-21 74·8%, 71·0–78·4; 0·94, 0·76–1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. Interpretation R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study.
    • Neuromuscular electrical stimulation of the quadriceps in patients with non-small cell lung cancer receiving palliative chemotherapy: a randomized phase II study

      Chauhan, Alpna (2013-12)
      BACKGROUND: A reduced exercise capacity is associated with increased morbidity and mortality in patients with advanced non-small cell lung cancer (NSCLC). Therapeutic exercise can be beneficial and neuromuscular electrical stimulation (NMES) of the quadriceps muscles may represent a practical approach. The primary aim of this study was to determine the acceptability of NMES of the quadriceps to patients with NSCLC used alongside palliative chemotherapy. Secondary aims explored aspects of safety and efficacy of NMES in this setting. METHODS: Patients with advanced NSCLC due to receive first-line palliative chemotherapy were randomized to usual care with or without NMES. They were asked to undertake 30 minute sessions of NMES, ideally daily, but as a minimum, three times weekly. For NMES to be considered acceptable, it was predetermined that ≥80% of patients should achieve this minimum level of adherence. Qualitative interviews were held with a subset of patients to explore factors influencing adherence. Safety was assessed according to the Common Terminology Criteria for Adverse Events. Quadriceps muscle strength, thigh lean mass, and physical activity level were assessed at baseline and after three cycles of chemotherapy. RESULTS: 49 patients (28 male, median (IQR) age 69 (64-75) years) participated. Of 30 randomized to NMES, 18 were eligible for the primary endpoint, of whom 9 (50% [90% CI, 29 to 71]) met the minimum level of adherence. Adherence was enhanced by incorporating sessions into a daily routine and hindered by undesirable effects of chemotherapy. There were no serious adverse events related to NMES, nor significant differences in quadriceps muscle strength, thigh lean mass or physical activity level between groups. CONCLUSIONS: NMES is not acceptable in this setting, nor was there a suggestion of benefit. The need remains to explore NMES in patients with cancer in other settings.
    • Education and Training Needs in Radiation Oncology in India: Opportunities for Indo-US Collaborations.

      Morgan, David (2015-12)
      Purpose: To conduct a survey of radiation oncologists in India, to better understand specific educational needs of radiation oncology in India and define areas of collaboration with US institutions. Methods and Materials: A 20-question survey was distributed to members of the Association of Indian Radiation Oncologists and the Indian Brachytherapy Society between November 2013 and May 2014. Results: We received a total of 132 responses. Over 50% of the physicians treat more than 200 patients per day, use 2-dimensional or 3-dimensional treatment planning techniques, and approximately 50% use image guided techniques. For education needs, most respondents agreed that further education in intensity modulated radiation therapy, image guided radiation therapy, stereotactic radiation therapy, biostatistics, and research methods for medical residents would be useful areas of collaboration with institutions in the United States. Other areas of collaboration include developing a structured training module for nursing, physics training, and developing a second-opinion clinic for difficult cases with faculty in the United States. Conclusion: Various areas of potential collaboration in radiation oncology education were identified through this survey. These include the following: establishing education programs focused on current technology, facilitating exchange programs for trainees in India to the United States, promoting training in research methods, establishing training modules for physicists and oncology nurses, and creating an Indo-US. Tumor Board. It would require collaboration between the Association of Indian Radiation Oncologists and the American Society for Radiation Oncology to develop these educational initiatives.
    • Modelling the radiobiological effect of intraoperative X-ray brachytherapy for breast cancer using an air-filled spherical applicator

      Morgan, David (2016)
      PURPOSE: We present a framework, in which we compare a conventional standard dose of 50 Gy in 25 fractions with accelerated partial breast irradiation (APBI) using electronic brachytherapy (eBT). We discuss how radiobiological modelling enables us to establish a framework, within which we can compare external beam radiotherapy (EBRT). This leads to a determination of the shell of isoeffect in breast tissue, at which very low kV eBT can be considered to be clinically equivalent to standard EBRT. MATERIAL AND METHODS: To estimate relative biological effectiveness (RBE) values as a function of dose and irradiation time, we used a modified linear quadratic (LQ) approach, taking into account the ability of this new device, to deliver 20 Gy at the surface of a 40 mm diameter rigid, hollow spherical applicator in less than 2 minutes. In this study, we considered the radiobiological effectiveness of the Papillon + X-ray brachytherapy device operating at 30 kV, 0.3 mA producing dose rates in excess of 14 Gy/min. RESULTS: Calculated clinical RBEs ranged from 1.154 at the surface of a 40 mm diameter applicator to 1.100 at 35 mm from the applicator surface for the Papillon+ device. The absolute physical dose D (abs) 30 kV ranged from 20.00 Gy at the applicator surface to 1.20 at 35 mm distant. The product of the isoeffective single dose of (60)Co reference radiation - (RBE)(60)Co, and the RBE corrected standard 2 Gy equivalent dose fractions (EQD2) doses, EQD2(30 kV) * (RBE)(60)Co ranged from 98.62 Gy at the applicator surface to 1.13 at 35 mm. The 'shell of isoeffect', the value on the X-axis where the EQD2(30 kV) * (RBE)(60)Co line crosses the 50 Gy mark on the Y-axis, was found to be approximately 3.5 mm beyond the applicator surface. CONCLUSIONS: The 'shell of isoeffect' can serve as a useful metric with which to compare the radiobiological effectiveness of low kV eBT with various regimes of conventional EBRT.
    • Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis.

      Haynes, Andrew (2016-04)
      The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP-like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN-IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R-CHOP have excellent outcomes and may merit reduced follow up frequency.
    • Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT.

      Morgan, David (2016-06)
      Objective To quantify the journeys and CO2 emissions if women with breast cancer are treated with risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT) rather than several weeks' course of external beam whole breast radiotherapy (EBRT) treatment. Setting (1) TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy, (2) 2 additional UK centres offering TARGIT. Participants 485 UK patients (249 TARGIT, 236 EBRT) in the prepathology stratum of TARGIT-A trial (where randomisation occurred before lumpectomy and TARGIT was delivered simultaneously with lumpectomy) for whom geographical data were available and 22 patients treated with TARGIT after completion of the TARGIT-A trial in 2 additional UK breast centres. Outcome measures The shortest total journey distance, time and CO2 emissions from home to hospital to receive all the fractions of radiotherapy. Methods Distances, time and CO2 emissions were calculated using Google Maps and assuming a fuel efficiency of 40mpg. The groups were compared using the Student t test with unequal variance and the non-parametric Wilcoxon rank-sum (Mann-Whitney) test. Results TARGIT patients travelled significantly fewer miles: TARGIT 21681, mean 87.1 (SE 19.1) versus EBRT 92591, mean 392.3 (SE 30.2); had lower CO2 emissions 24.7kg (SE 5.4) vs 111kg (SE 8.6) and spent less time travelling: 3h (SE 0.53) vs 14h (SE 0.76), all p<0.0001. Patients treated with TARGIT in 2 hospitals in semirural locations were spared much longer journeys (753 miles, 30h, 215kg CO2 per patient). Conclusions The use of TARGIT intraoperative radiotherapy for eligible patients with breast cancer significantly reduces their journeys for treatment and has environmental benefits. If widely available, 5 million miles (8000000km) of travel, 170000 woman-hours and 1200 tonnes of CO2 (a forest of 100hectares) will be saved annually in the UK.
    • Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer.

      Sherwood Forest Hospitals NHS Foundation Trust (2017-01)
      Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.
    • Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study.

      Sherwood Forest Hospitals NHS Foundation Trust (2017-02-10)
      Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20(+) DLBCL age >/= 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m(2) was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age >/= 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL.
    • Faecal occult blood testing screening for colorectal cancer and 'missed' interval cancers: are we ignoring the elephant in the room? Results of a multicentre study.

      Aggarwal, Smeer; Dharmavaram, Sridhar; Menon, Achyuth; Dube, Mukul; George, Anil Thomas (2017-05)
      AIM: Biennial faecal occult testing (FOBT) is used to screen for colorectal cancer throughout the United Kingdom (UK). Interval cancers are tumours that develop in patients between screening rounds who have had a negative FOBT. Through a multicentre study, we compared demographics of patients with interval cancers, FOBT screen detected cancers and cancers that developed in patients who chose not to participate in the screening programme. METHOD: Five hundred and sixteen colorectal cancers were detected in the screening age group (60-74 years) population in three United Kingdom NHS Hospitals over two years. 127 (25%) were interval cancers, 161 (31%) were screen-detected and 228 (44%) were cancers that developed in patients who had declined FOBT. The interval cancer group had a higher incidence of right sided cancers (38% vs 29% and 24%), a higher proportion of high tumour stages (Dukes C&D) (70% vs 53% and 33%) and a shorter time from diagnosis to death (10 months vs 13 months and 24 months) compared to patients who had declined the FOBT and the FOBT screen detected cancers. Of all the patients studied, those with right sided interval cancers had the worst outcome. A quarter of the colorectal cancers diagnosed in our study were interval cancers. Patients with right-sided interval cancers had the highest proportion of Dukes C and D tumours coupled with the shortest survival time after diagnosis when compared with all the other groups. This article is protected by copyright. All rights reserved.
    • Glove Port Transanal Excision of Rectal Tumors an Alternative Method for Rectal Tumor Excision: Single Center Experience.

      Dharmavaram, Sridhar (2017-08)
      Aim: Transanal minimal invasive surgery has been practiced for several years for excision of rectal tumors however there is no standard consensus about its applications. This minimally invasive approach helps in avoiding major rectal resections and its associated risk of mortality and morbidity.The aim of this study is to describe a single center experience with transanal glove port excision of rectal tumors which are not amenable to colonoscopic excision. Materials and Methods: Between the years 2011 and 2014, 9 patients underwent glove port excision of rectal tumors located within 15 cm from the anal verge. Glove port was constructed using circular anal dilator, standard surgical glove and a wound protector retractor; regular laparoscopic instruments were used. The median follow-up period was for 18 months (range, 9 to 27 mo) and all patients had flexible sigmoidoscopy for follow-up to look for any recurrence of the tumors. Results: All patients underwent transanal excision of rectal tumors successfully using glove port device and laparoscopic instruments. Full thickness excision of the tumor was performed in all patients and there was no significant postoperative morbidity. The final histology of 6 patients was benign and the remaining 3 patients had malignancy reported in the specimen. During the follow-up period between 12 and 18 months 3 patients had a recurrence of the polyp which was removed endoscopically without the need for any further surgical intervention. Conclusions: Glove port excision of rectal tumors is a feasible alternative to conventional surgical treatment for large benign rectal tumors.What does this paper add to the literature?This article demonstrates that performing local excision of rectal tumors can be achieved safely at a lower cost using simple platforms that are constructed locally like the glove ports. It also highlights the benefits of using the available laparoscopic kits to perform the procedure while making use of the previously acquired skills.
    • Impact of MRI on high grade Ductal Carcinoma Insitu (HG DCIS) management, are we using the full scope of MRI?

      Dakka, Mahmoud (2017-10)
      Introduction: Preoperative assessment of pure Ductal Carcinoma Insitu (DCIS) is essential in the surgical planning. The role of Magnetic resonance imaging (MRI) has long been debated. The impact of MRI on the management of High Grade (HG) DCIS was assessed, whether it accurately captures the true size of this entity in comparison to conventional imaging, and, if MRI use would reduce the number of re-excision surgery.Method: Ninety-one consecutive patients with HG DCIS, who were identified from a prospectively collected data at Kettering General Hospital between April 2011 and December 2015. All patients had preoperative MRI scan in addition to the standard breast imaging. This was compared to a control group of consecutive patients (n=52) which was obtained from a period just before 2011. Impact on surgical planning and number of surgeries for each patient was compared. The size of HG DCIS estimated by MRI was compared to the final histological size. Secondary outcomes included change of initial surgical plan and detection of occult contralateral breast cancer.Results: MRI group had 91 patients with median age of 63. Seventy percent of which presented through the screening program. The overall sensitivity of MRI to detect HG DCIS was 77% (70/91) with a false negative rate FNR of 23% (21/91). Therefore, 70 patients only were included in the data analysis. The control group included 52 screening patients with comparable baseline characteristics. Re-excision (or completion mastectomy) rates were higher in the control group 26% compared to 8% in the MRI group (P-value 0.012). MRI use correctly converted the initial plan of breast conservation to mastectomy in 9 patients (13%). Five patients had additional ipsilateral malignant features (7%).Occult contra lateral disease, was diagnosed in 2 patients (3%).Conclusion: This study suggests that MRI could be an important tool in reducing the re-excision rates in the surgical management of HG DCIS. Although still controversial, selective MRI imaging can be useful in the preoperative diagnosis and evaluation of HG DCIS. Case by case discussion at MDT is crucial. Wider adaptation of MRI when indicated in the assessment of breast lesions with proper correlation to histology postoperatively is a key in improving our MRI interpretation skills, helping us to exploit the full scope of this useful tool.
    • Who Should Be Investigated for Haematuria? Results of a Contemporary Prospective Observational Study of 3556 Patients

      Smith, Kerry; Lovegrove, Wayne (2018-03-07)
      Abstract: There remains a lack of consensus among guideline relating to which patients require investigation for haematuria. We determined the incidence of urinary tract cancer in a prospective observational study of 3556 patients referred for investigation of haematuria across 40 hospitals between March 2016 and June 2017 (DETECT 1; ClinicalTrials.gov: NCT02676180) and the appropriateness of age at presentation in cases with visible (VH) and nonvisible (NVH) haematuria. The overall incidence of urinary tract cancer was 10.0% (bladder cancer 8.0%, renal parenchymal cancer 1.0%, upper tract transitional cell carcinoma 0.7%, and prostate cancer 0.3%). Patients with VH were more likely to have a diagnosis of urinary tract cancer compared with NVH patients (13.8% vs 3.1%). Older patients, male gender, and smoking history were independently associated with urinary tract cancer diagnosis. Of bladder cancers diagnosed following NVH, 59.4% were high-risk cancers, with 31.3% being muscle invasive. The incidence of cancer in VH patients <45 yr of age was 3.5% (n = 7) and 1.0% (n = 4) in NVH patients <60 yr old. Our results suggest that patients with VH should be investigated regardless of age. Although the risk of urinary tract cancer in NVH patients is low, clinically significant cancers are detected below the age threshold for referral for investigation.
    • Regional variations in UK colorectal cancer screening and mortality.

      George, Anil Thomas; Aggarwal, Smeer; Dharmavaram, Sridhar; Menon, Achyuth; Dube, Mukul (2018-07)
      The article reports on the regional variations of colorectal cancer screening and mortality in Great Britain. Topics mention including the National Bowel Cancer Screening Programme (NBCSP), reduction of colorectal cancer mortality through biennial screening for faecal occult blood and patient survival and survival patterns.
    • Acute presentation of a partially obstructing laryngeal tumour: adjuvant agents to gaseous induction of anaesthesia.

      Thomas, Carolyn (2018-07)
      We present the case of a 53-year-old man who attended our emergency department with stridor. He had recently undergone investigation for possible glottic cancer. We discuss the airway management of such a case. We believe this to be the first description of propofol target controlled infusion and clonidine to supplement a sevoflurane gas induction, in order to obtund response to intubation while maintaining spontaneous ventilation. We also consider how airway interventions may impact prognosis and need to be considered.
    • 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

      Sherwood Forest Hospitals NHS Foundation Trust; PERSEPHONE Steering Committee and Trial Investigators (2019-06-06)
      BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5.4 years (IQR 3.6-6.7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89.4% (95% CI 87.9-90.7) in the 6-month group and 89.8% (88.3-91.1) in the 12-month group (hazard ratio 1.07 [90% CI 0.93-1.24], non-inferiority p=0.011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0.0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0.0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.
    • Understanding primary parotid squamous cell carcinoma - A systematic review.

      Tsirevelou, Paraskevi (2020-02)
      Introduction The true incidence of primary parotid squamous cell carcinoma (SCC) is unknown and likely overestimated in the literature. The aim of this systematic review is to examine the diagnosis, aetiology and incidence of parotid SCC by analysing studies evaluating primary parotid SCC. Results A total of 14 observational retrospective studies on primary parotid SCC were included. There are currently no standard criteria for ascertainment of primary parotid SCC. Primary parotid SCC is thought to be due to squamous metaplasia within the ductal epithelium and subsequent invasive squamous carcinoma. Histological features that favour primary disease includes SCC confined to parotid parenchyma with no direct communication to the skin and the absence of mucin. Incidence of primary parotid SCC varied from 1.54 to 2.8 cases per million person-years. Around 30%–86% of patients recorded to have primary parotid SCC on clinical records, when scrutinised, were in fact secondary to parotid lymph node involvement following regional advancement from skin or upper aerodigestive tract SCC. Conclusion Primary parotid SCC is rare and it is currently a diagnosis of exclusion. Thorough clinical assessment including endoscopy, preoperative imaging and the scrutiny of histopathological findings allow for differentiation between primary and secondary SCC within the parotid. This thus affects both initial treatment and subsequent follow-up. Highlights •Primary parotid SCC is currently a diagnosis of exclusion.•Criteria for ascertainment of primary parotid SCC varies in the literature.•Combination of detailed clinical assessment, endoscopic assessment, cross-sectional imaging and histological assessment is required to differentiate between primary and metastatic parotid SCC.•30%–86% of patients recorded to have primary parotid SCC on clinical records were actually metastatic SCC.
    • Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT).

      Jahan, Ali (Clinical Cancer Research https://clincancerres.aacrjournals.org/content/26/7/1574.long, 2020-04)
      Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER + invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. ( n = 17) produced significant decreases from baseline versus placebo ( n = 11) in pGSK3β (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. ( n = 5) and 240 mg b.i.d. ( n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
    • Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed.

      Sherwood Forest Hospitals NHS Foundation Trust (2020-05)
      Aim: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the 5-year survival of these patients would be near zero without metastasectomy. We tested the clinical effectiveness of this practice in Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), a randomized, controlled noninferiority trial. Method: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomization was remote and stratified according to site, with minimization for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases and carcinoembryonic antigen level. The trial management group was blind to patient allocation until after intention-to-treat analysis. Results: From 2010 to 2016, 93 participants were randomized. These patients were 35-86 years of age and had between one and six lung metastases at a median of 2.7 years after colorectal cancer resection; 29% had prior liver metastasectomy. The patient groups were well matched and the characteristics of these groups were similar to those of observational studies. The median survival after metastasectomy was 3.5 (95% CI: 3.1-6.6) years compared with 3.8 (95% CI: 3.1-4.6) years for controls. The estimated unadjusted hazard ratio for death within 5 years, comparing the metastasectomy group with the control group, was 0.93 (95% CI: 0.56-1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. Conclusion: Patients in the control group (who did not undergo lung metastasectomy) have better survival than is assumed. Survival in the metastasectomy group is comparable with the many single-arm follow-up studies. The groups were well matched with features similar to those reported in case series.
    • A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

      Jahan, Ali (2020-08)
      Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. Patients and methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. Results: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. Conclusions: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.