Locoregional control and toxicity following high-dose hypofractionated and accelerated palliative radiotherapy regimens in breast cancer.

AIMS: For patients with locally advanced primary/recurrent breast cancer, radiotherapy is an effective treatment for locoregional control. 36 Gy in 6 Gy once-weekly fractions is a commonly used schedule, but there are no data comparing local control and toxicity between 36 Gy delivered once-weekly versus accelerated schedules of multiple 6 Gy fractions per week. This retrospective study compared local control rates and acute and late toxicity in patients undergoing 30-36 Gy in 6 Gy fractions over 6 weeks versus more accelerated schedules over 2-3 weeks for an unresected breast cancer. MATERIALS AND METHODS: Patients who received 30-36 Gy in 6 Gy fractions to an unresected breast cancer ± involved lymph nodes between December 2011 and August 2020 were identified. Patients were grouped into once-weekly versus accelerated fractionation schedules. Response rates, local control and toxicity data were analysed. RESULTS: In total, 109 patients were identified. The median follow-up duration was 46 months. Forty-seven patients (43%) received once-weekly fractions and 62 patients (57%) received accelerated fractionation schedules. There were no significant differences in baseline tumour characteristics between the groups. Eighty-seven per cent of patients had an objective (complete or partial) response (81% in the once-weekly group; 91% in the accelerated group). The median time to local progression was 23.5 months overall (95% confidence interval 17.8-29.2); 23.5 months (95% confidence interval 18.8-28.1) in the once-weekly group and 19.0 months (95% confidence interval 7.0-31.1) in the accelerated group (P = 0.99). Acute toxicity of any grade occurred in 75% of patients (76% in the once-weekly group; 74% in the accelerated group) and grade 3 toxicity occurred in 7% of patients (7% in the once-weekly group; 8% in the accelerated group). There were no associations between the groups and acute or late toxicity grade (P = 0.78 and P = 0.26, respectively), although one grade 4 late toxicity (skin radionecrosis) occurred in a patient who received five fractions a week and therefore this regimen is not recommended. Study limitations included a lack of statistical power analysis, the necessary grouping of all accelerated patients for analysis and a high rate of censored data. CONCLUSION: There were no apparent differences in response rate, time to local progression or toxicity between patients who received 30-36 Gy in 6 Gy fractions once-weekly compared with twice-weekly as palliative treatment for locally advanced breast cancer. This regimen appears to be a safe alternative and may be preferred by patients.

Systemic treatment of advanced clear cell sarcoma: results from a retrospective international series from the World Sarcoma Network.

BACKGROUND: Clear cell sarcoma (CCS) is a translocated aggressive malignancy with a high incidence of metastases and poor prognosis. There are few studies describing the activity of systemic therapy in CCS. We report a multi-institutional retrospective study of the outcomes of patients with advanced CCS treated with systemic therapy within the World Sarcoma Network (WSN). MATERIALS AND METHODS: Patients with molecularly confirmed locally advanced or metastatic CCS treated with systemic therapy from June 1985 to May 2021 were included. Baseline demographic and treatment information, including response by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, was retrospectively collected by local investigators. Descriptive statistics were carried out. RESULTS: Fifty-five patients from 10 institutions were included. At diagnosis, the median age was 30 (15-73) years and 24% (n = 13/55) had metastatic disease. The median age at diagnosis was 30 (15-73) years. Most primary tumours were at aponeurosis (n = 9/55, 16%) or non-aponeurosis limb sites (n = 17/55, 31%). The most common fusion was EWSR1-ATF1 (n = 24/55, 44%). The median number of systemic therapies was 1 (range 1-7). The best response rate was seen for patients treated with sunitinib (30%, n = 3/10), with a median progression-free survival of 4 [95% confidence interval (CI) 1-7] months. The median overall survival for patients with advanced/metastatic disease was 15 months (95% CI 3-27 months). CONCLUSIONS: Soft tissue sarcoma-type systemic therapies have limited benefit in advanced CCS and response rate was poor. International, multicentre prospective translational studies are required to identify new treatments for this ultra-rare subtype, and access to early clinical trial enrolment remains key for patients with CCS.

From 25 Fractions to Five: How Hypofractionation has Revolutionised Adjuvant Breast Radiotherapy.

There is a sound empirical basis for hypofractionation in radiotherapy for breast cancer. This article reviews the radiobiological implications of hypofractionation in breast cancer derived from a series of clinical trials that began when 50 Gy in 25 fractions over 5 weeks was commonplace. These trials led first to 40 Gy in 15 fractions over 3 weeks and, subsequently, to 26 Gy in five fractions over 1 week being adopted as standards of care for many patients prescribed whole- or partial-breast radiotherapy after primary surgery.

How Low Can You Go? The Radiobiology of Hypofractionation.

Hypofractionated radical radiotherapy is now an accepted standard of care for tumour sites such as prostate and breast cancer. Much research effort is being directed towards more profoundly hypofractionated (ultrahypofractionated) schedules, with some reaching UK standard of care (e.g. adjuvant breast). Hypofractionation exerts varying influences on each of the major clinical end points of radiotherapy studies: acute toxicity, late toxicity and local control. This review will discuss these effects from the viewpoint of the traditional 5 Rs of radiobiology, before considering non-canonical radiobiological effects that may be relevant to ultrahypofractionated radiotherapy. The principles outlined here may assist the reader in their interpretation of the wealth of clinical data presented in the tumour site-specific articles in this special issue.

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation.

INTRODUCTION: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. IPSILATERAL BREAST TUMOUR RELAPSE (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4-3.1), 1.7% (1.2-1.6) after 27 Gy and 1.4% (0.2-2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. NORMAL TISSUE EFFECTS: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. RADIOBIOLOGICAL CONSIDERATIONS: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/ß estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. CONCLUSION: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard.

Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24-40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.

Preoperative breast radiation therapy: Indications and perspectives.

Preoperative breast radiation therapy (RT) is not a new concept, but older studies failed to change practice. More recently, there has been interest in revisiting preoperative RT using modern techniques. This current perspective discusses the indications, summarises the published literature and then highlights current clinical trials, with particular attention to combining with novel drugs and optimising associated translational research.

Where Do We Look for Markers of Radiotherapy Fraction Size Sensitivity?

The response of human normal tissues to radiotherapy fraction size is often described in terms of cellular recovery, but the causal links between cellular and tissue responses to ionising radiation are not necessarily straightforward. This article reviews the evidence for a cellular basis to clinical fractionation sensitivity in normal tissues and discusses the significance of a long-established inverse association between fractionation sensitivity and proliferative indices. Molecular mechanisms of fractionation sensitivity involving DNA damage repair and cell cycle control are proposed that will probably require modification before being applicable to human cancer. The article concludes by discussing the kind of correlative research needed to test for and validate predictive biomarkers of tumour fractionation sensitivity.

Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib.

PURPOSE: Patients with advanced GIST following standard imatinib and sunitinib often have good performance status and need additional therapy. This study tested nilotinib, a second-generation tyrosine kinase inhibitor, in patients with advanced GIST refractory to standard therapies. METHODS: This single-center open-label phase II study has a primary objective to determine progression-free survival at 6 months. Using a novel statistical design, 17 patients were to be enrolled; if ≥ 10 were progression free (PF) at 2 months, 19 additional patients would be enrolled. The therapy was considered of benefit if ≥ 13 of 36 patients were PF at 6 months. All patients signed informed consent and entry criteria included normal cardiac function. Exploratory analyses correlating genotype with response were also performed. RESULTS: Thirteen patients were treated; 2 had received agents after imatinib and sunitinib. Treatment was well tolerated with one grade 4 anemia attributed to nilotinib. No measurable responses were observed; median time to progression was 2 months. One patient remained on study with stable disease for 12 months. Mutation testing is available from 10 primary tumors with 7 exon 11 mutations, 1 exon 9 mutation, and 2 without KIT/PDGFR mutations. Two samples from recurrent disease had 2 mutations, both primary exon 11 mutations with an additional exon 17 mutation, including the patient with prolonged stable disease. CONCLUSIONS: Nilotinib was well tolerated in these patients with advanced GIST. Accrual was halted due to insufficient clinical benefit. However, nilotinib may provide benefit to specific subsets of advanced GIST with exon 17 mutations.

A retrospective review of the histopathology and clinicopathologic correlates of appendices removed from patients of acute appendicitis.

AIM: Appendicitis is the most common intra-abdominal condition requiring emergency surgery, with a life time risk of about 6%. Although considerable data are available in the literature regarding the histopathology of appendicectomy specimens, such information from the Indian subcontinent remains unreported. METHODS: A total of 348 consecutive appendices removed because of clinical suspicion of acute appendicitis were selected. Three sections from each specimen were submitted for histopathology. Histopathologic acute appendicitis if present was further classified into 3 subcategories. A retrospective analysis was performed on all these specimens. RESULTS: The male female ratio was 2.6:1 with highest number of cases in the age group 21-30 years; 282 specimens out of 348 showed features consistent with acute appendicitis with an overall higher occurrence in males. Statistically significant association was obtained between perforation and male sex, older age and acute suppurative appendicitis. CONCLUSIONS: Present study shows that acute appendicitis in India is a disease of young males. The negative appendicectomy rate is about 10.9%. On further subclassification of acute appendicitis, uncomplicated acute appendicitis seems to be the most common followed by acute suppurative appendicitis.

Phase II study of oral capecitabine in patients with hormone-refractory prostate cancer.

BACKGROUND: Currently available treatment for hormone refractory prostate cancer is limited in efficacy and associated with significant toxicity. This phase II study was performed to assess the efficacy of the oral fluoropyrimidine capecitabine in advanced prostate cancer. PATIENTS AND METHODS: Patients who had a rising prostate-specific antigen (PSA) despite androgen withdrawal, but who remained free from cancer-related symptoms. In total, 14 patients received oral capecitabine 1250 mg/m2 twice daily for two weeks of a three-week cycle. Tumour response was assessed using serum PSA measurement at 3-weekly intervals and, where present, imaging of soft tissue metastases. RESULTS: One of 14 patients experienced a partial response as assessed by both PSA and imaging of liver metastases. In seven other patients (50%), treatment decreased the rate of PSA rise. The duration of PSA stabilisation was generally short, but in 5/14 patients (36%) was sustained beyond 18 weeks, and in one patient to 24 weeks. Toxicity was significant but manageable, the most common adverse events being nausea, mucositis and hand-foot syndrome, each occurring in 50% of patients. Other common side effects were diarrhoea and lymphopenia. All toxicities were grade 1 or 2, except for grade 3 hand-foot syndrome occurring in one patient, and no dose reduction was required because of toxicity. CONCLUSION: Capecitabine has limited activity as a single agent in prostate cancer, but appears to modulate tumour biology. Considering the added convenience of oral administration, these results support further evaluation of combinations containing capecitabine in hormone-refractory prostate cancer.

The hyfrecator: a treatment for radiation induced telangiectasia in breast cancer patients.

Radiation induced telangiectasia is a common problem in breast cancer survivors. By interfering with choice of clothing and acting as an unpleasant visible reminder of their disease, it negatively affects quality of life. The hyfrecator, based on the principles of electrosurgery, is a standard treatment modality for facial telangiectasia. This study aims to demonstrate the efficacy and tolerability of the hyfrecator as a treatment for radiation induced telangiectasia. Patients with radiation induced telangiectasia of breast or chest wall were prospectively identified from the breast cancer follow up clinic and offered treatment with the hyfrecator (sessions at 8 weekly intervals). Pre- and post-treatment photographs were obtained in a standardized manner and two blinded physician observers evaluated response. A linear analogue scale (LAS) was used by the patients to evaluate treatment response and any discomfort. At the end of treatment, patients completed a quality of life questionnaire. Of 16 patients enrolled, 15 completed the study. Treatment benefited all patients with severe or marked telangiectasia. Complete disappearance of telangiectasia was achieved in the majority (88%) of patients by the end of treatment. A median of six sessions (range 3-9) was required. All but one (93%) considered the treatment worthwhile. The majority (69%) judged the treatment to be painless or only mildly painful. 73% reported an improvement in self-confidence. The treatment was well tolerated by all the patients. All patients showed a remarkable clearance of vessels with a high degree of satisfaction with the results. Treatment with the hyfrecator is very effective for radiation induced telangiectasia. Three to four sessions achieve a substantial objective and subjective reduction in telangiectasia with a concomitant improvement in quality of life. It is a cost effective, ambulant out patient procedure requiring no local anaesthesia.