Radiation-induced angiosarcoma of the breast: retrospective analysis at a regional treatment centre.

BACKGROUND: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer. METHODS: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England. RESULTS: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41-78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4-16.0)-this interval has decreased over the last 24 years (r2 = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342-14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646-30.88]; P = 0.0086). CONCLUSION: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted.

Lorlatinib for the treatment of inflammatory myofibroblastic tumour with TPM4-ALK fusion following failure of entrectinib.

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

Pazopanib, a promising option for the treatment of aggressive fibromatosis.

Desmoid tumour/aggressive fibromatosis (DT/AF) is a rare soft-tissue neoplasm that is locally aggressive but does not metastasize. There is no standard systemic treatment for symptomatic patients, although a number of agents are used. Tyrosine kinase inhibitors have recently been reported to show useful activity. We reviewed our bi-institutional (Royal Marsden Hospital, Cambridge University Hospitals) experience with the tyrosine kinase inhibitor pazopanib in the treatment of progressing DT/AF. Eight patients with DT/AF were treated with pazopanib at Royal Marsden Hospital and Cambridge University Hospitals between June 2012 and June 2016. The median age of the patients was 37.5 (range: 27-60) years. The median duration of pazopanib treatment was 12 (range: 5-22) months and for three patients the treatment is ongoing. Three patients discontinued treatment early (patient preference, intolerable toxicity and logistical reasons, respectively). None of the patients showed radiological progression while on treatment, best responses according to Response Evaluation Criteria In Solid Tumors 1.1 were partial response in 3/8 and stable disease in 5/8 cases. Six patients derived clinical benefit from treatment in terms of improved function and/or pain reduction. Median progression-free survival was 13.5 (5-36) months. Only one patient experienced intolerable toxicity (grade 3 hypertension) leading to early treatment discontinuation. In our series of patients with DT/AF, pazopanib demonstrated important activity both in terms of symptom control (75%) and absence of radiological progression (100%). Results of ongoing confirmatory trials are eagerly awaited.

Trends in the characteristics, dose-limiting toxicities and efficacy of phase I oncology trials: The Cancer Research UK experience.

INTRODUCTION: Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients. METHODS: Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n = 603) and 2004-2013 (25 trials, n = 750) for comparative purposes. RESULTS: From 1995-2003 to 2004-2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004-2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995-2003) to 36.0% (2004-2013; P = 0.0033) due to higher rates of disease stabilisation. CONCLUSION: Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable.

A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task?

Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes. Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway. Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were <5 cm, 34% in the 5-10 cm range, and 51% >10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years. Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the "real world" impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists.

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience.

OBJECTIVES: The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m2, irinotecan 135 mg/m2, folinic acid 400 mg/m2 and 5-FU infusion 2,400 mg/m2 over 46 h, with routine subcutaneous filgrastim on a 14-day cycle. METHODS: Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death. RESULTS: Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively. CONCLUSION: Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings.

Presentation and management of pulmonary artery sarcoma.

BACKGROUND: Pulmonary artery sarcoma (PAS) is a rare but aggressive malignancy that leads to heart failure and death without treatment. Here we reviewed the presentation and management of patients treated at a national centre for pulmonary endarterectomy (PEA) and its associated hospital in Cambridge, UK. METHODS: Details of PAS patients treated at Papworth and Addenbrooke's Hospitals between 2000 and 2014 were reviewed. RESULTS: Twenty patients were diagnosed with PAS (11 males, 9 females), with a median age of presentation of 57 years (range 27-77). Presenting symptoms include dyspnoea (20), chest pain/tightness (7), oedema (5), constitutional symptoms (5), cough (3) and haemoptysis (3). Twelve patients were in group III/IV of the NYHA functional classification of symptoms. Initial CT scans were suggestive of thromboembolism in seven patients. Histological findings were of intimal sarcoma (13) and high grade sarcoma NOS (6). Median overall survival (OS) was 17 months. Fourteen patients underwent PEA to relieve vascular obstruction, while six had inoperable and/or metastatic disease. There were three peri-operative deaths. Although there was no difference in median OS between patients who had PEA and those who did not (20 vs 17 months, P = 0.2488), surgery provided significant symptomatic improvement and some with long-term survival. Five patients received post-surgical chemotherapy (anthracycline +/- ifosfamide), and after completion four also had radiotherapy. Patients who received post-operative chemo- and radio-therapy showed a trend towards better survival compared to those who had surgery alone (24 vs 8 months, P = 0.3417). For palliative chemotherapy, partial responses were observed with the VID regimen and pegylated liposomal doxorubicin. Stable disease was achieved in a patient with intimal sarcoma with rhabdomyosarcomatous differentiation on third-line cisplatin and topotecan. The longest surviving patient (102 months) has had PEA, adjuvant epirubicin and radiotherapy. She developed lung metastases 7 years later, which were treated with radiofrequency ablation. CONCLUSIONS: PAS often presents with symptoms mimicking pulmonary hypertension, heart failure or thromboembolic disease. PEA provides good symptomatic relief and in some cases, offers a chance of long-term survival. Although outcome appears to be better when PEA is combined with post-operative chemo- and radio-therapy, further studies are warranted.

Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare but frequently fatal sarcoma, and many of its characteristics still require further clarification. METHODS: We retrospectively analysed 41 patients treated at or referred to two regional referral centres in the UK between 1991 and 2012. A review of the current literature was also performed. RESULTS: The median age of presentation was 27 years (range 16 to 45 years), with a male-to-female ratio of 3:1. Ninety percent of patients had disease in the abdomen. The median size of the presenting tumour was 13 cm (range 3.5 to 23 cm), and 80% had metastatic disease at diagnosis, mainly in the liver (33%) and lungs (21%). Time-to-progression (TTP) was 3.9, 2.3 and 1.1 months after first-, second- and third-line chemotherapy, respectively. First-line treatment with VIDE chemotherapy appeared to confer the longest TTP (median 14.6 months). Ifosfamide and doxorubicin resulted in TTP of >3.8 months when used in any-line setting. Eleven patients received targeted agents as part of a clinical trial. After a median follow-up of 14 months, the overall median survival (MS) was 16 months. There was no difference in MS with regards to age, gender, or size of the presenting tumour. Patients with extra-abdominal disease survived longer compared to those with tumours in the abdomen (all still alive vs MS of 15 months; P = 0.0246). Patients with non-metastatic intra-abdominal disease who underwent surgery had an MS of 47 months (16 months for those who did not have surgery; P = 0.0235). Radiotherapy for locoregional control in patients with metastatic intra-abdominal DSRCT was associated with longer survival (MS of 47 vs 14 months; P = 0.0147). CONCLUSIONS: DSRCT is a rare but often fatal disease that mainly affects younger male patients. Those with intra-abdominal DSRCT have a poorer prognosis, although surgical resection for localised disease and radiotherapy in the metastatic setting are associated with improved survival. A patient's age, gender and size of presenting tumour do not have prognostic significance.

Tivozanib for the treatment of metastatic renal cancer.

Tyrosine kinase inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (RCC). Drugs such as sorafenib, sunitinib and pazopanib act on the VEGF receptor pathway, but they can also inhibit other kinases, resulting in off-target toxicities. Tivozanib was developed due to its potency and selectivity against VEGF receptors 1-3. It has a favorable pharmacokinetic profile after oral administration and a long plasma half-life. In the Phase III TIVO-1 trial, it demonstrated a higher response rate and longer progression-free survival than sorafenib with a better side-effect profile. It is currently awaiting approval to be used in the first-line treatment of metastatic RCC. An early-phase trial has also shown its tolerability at full dose when given with the mTOR inhibitor temsirolimus, suggesting its potential in combination treatment. This article examines tivozanib from its laboratory to clinical development, as well as its relevance and future role in the treatment of RCC in the era of the tyrosine kinase inhibitors.

Modification of the early gene enhancer-promoter improves the oncolytic potency of adenovirus 11.

Oncolytic adenoviruses based on serotype 5 (Ad5) have several shortcomings, including the downregulation of its receptor in cancer cells, high prevalence of neutralizing antibodies and hepatotoxicity. Another adenoviral serotype, Ad11, could overcome these obstacles. Here, we show that human cancer cell lines express higher levels of the Ad11 receptor CD46, resulting in much better infectivity than Ad5. Surprisingly, only 36% (9/25) of the cell lines were more sensitive to Ad11- than to Ad5-mediated cytotoxicity. Investigations revealed that it was the transcription of Ad11 E1A, not CD46 expression or virus infectivity, which determined the cell's sensitivity to Ad11 killing. Ad11 E1A mRNA levels have an effect on viral DNA replication, structural protein synthesis and infectious particle production. To test the hypothesis that increased E1A transcription would lead to improved Ad11 replication in Ad5-sensitive (but Ad11-less sensitive) cells, two Ad11 mutants (Ad11-Ad5-P and Ad11-Ad5-EP) were constructed where either the E1A promoter or enhancer-promoter, respectively, was replaced by that of Ad5. Ad11-Ad5-EP demonstrated increased E1A mRNA levels and replication, together with enhanced oncolytic potency in vitro and in vivo. This effect was found in both the Ad5-sensitive and Ad11-sensitive cancer cells, broadening the range of tumors that could be effectively killed by Ad11-Ad5-EP.

Prolonged response of relapsed high grade serous ovarian carcinoma to the oral angiokinase inhibitor nintedanib in a patient with a germline BRCA1 mutation.

► Nintedanib is an anti-angiogenic agent that has demonstrated activity in relapsed ovarian cancer. ► Our patient had prolonged response to nintedanib, allowing her to have potentially curative surgery 6 years after her diagnosis. ► The relationship between angiogenesis and BRCA mutation is worth exploring in ovarian cancer.

PRSS3 promotes tumour growth and metastasis of human pancreatic cancer.

BACKGROUND AND AIMS: Metastasis accounts for the poor outcome of patients with pancreatic cancer. We recently discovered PRSS3 to be over-expressed in metastatic human pancreatic cancer cells. This study aimed to elucidate the role of PRSS3 in the growth and metastasis of human pancreatic cancer. METHODS: PRSS3 expression in human pancreatic cancer cell lines was detected by qPCR and immunoblotting. The effect of PRSS3 on cancer cell proliferation, migration and invasion in vitro, tumour growth and metastasis in vivo were investigated by manipulation of PRSS3 expression in human pancreatic cancer cell lines. VEGF expression was detected by ELISA, and the pathway through which PRSS3 regulates VEGF expression was investigated. The therapeutic effect of targeting this pathway on metastasis was assessed in vivo. Immunohistochemistry was employed to detect PRSS3 expression in human pancreatic cancer tissues. RESULTS: PRSS3 was over-expressed in the metastatic PaTu8988s cell line, but not in the non-metastatic PaTu8988t cell line. Over-expression of PRSS3 promoted pancreatic cancer cell proliferation as well as invasion in vitro, and tumour progression and metastasis in vivo. Stepwise investigations demonstrated that PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway. ERK inhibitor significantly delayed the progression of metastases of pancreatic cancer and prolonged the survival of animals bearing metastatic pancreatic cancer (p<0.05). 40.54% of human pancreatic cancers (n=74) were positive for PRSS3 protein. A significant correlation was observed between PRSS3 expression and metastasis (p<0.01). Multivariate Cox regression analysis indicated that patients with PRSS3 expression in their tumours had a shorter survival time compared to those without PRSS3 expression (p<0.05). CONCLUSION: PRSS3 plays an important role in the progression, metastasis and prognosis of human pancreatic cancer. Targeting the PRSS3 signalling pathway may be an effective and feasible approach for treatment of this lethal cancer.

Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles.

Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.

Biological approaches to therapy of pancreatic cancer.

Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials.