Activity of eribulin mesylate in heavily pretreated breast cancer granted accessvia the Cancer Drugs Fund

Aim: Eribulin mesylate is a synthetic analog of halichondrin B and is licensed for the treatment of patients with locally advanced or metastatic breast cancer that has progressed following treatment with anthracyclines and taxanes. It was not deemed to be cost effective based on a cost analysis by the National Institute for Health and Care Excellence in England and therefore it is not funded routinely by the National Health Service. The establishment of the Cancer Drugs Fund in England subsequently enabled access. As with any new chemotherapy drug that enters clinical practice for metastatic breast cancer (MBC) it is often used in heavily pretreated patients and the experience in a routine clinical setting can differ from that in a clinical study. We therefore present the experience of the first 25 cases treated at our institution via the Cancer Drugs Fund. Materials & methods: A total of 25 patients were treated and in the 22 assessable cases the objective response rate was 18% (four out of 22), with a clinical benefit rate of 41.0% (9 out of 22). Results: The median time-to-progression and overall survival were 4.08 months and 5.89 months, respectively. There was a significant difference in clinical benefit rate (odds ratio: 0.065; 95% CI: 0–0.529; p = 0.0055), as well as time-to-progression (hazard ratio: 9.18; 95% CI: 2.26–37.38; p = 0.002 adjusted for age at diagnosis and interval between initial MBC diagnosis and commencing eribulin) favoring those patients who had not been rechallenged. There was no significant difference in overall survival (hazard ratio: 1.16; 95% CI: 0.44–3.05; p = 0.770 adjusted for age at diagnosis and interval between initial diagnosis of MBC and commencing eribulin). Conclusion: Eribulin mesylate shows clinical activity; however, there appears to be differences in terms of benefit in patients based on whether patients have been rechallenged with an anthracycline and/or a taxane. These data require confirmation in larger patient groups

Activity of eribulin mesylate in heavily pretreated breast cancer granted accessvia the Cancer Drugs Fund

Aim: Eribulin mesylate is a synthetic analog of halichondrin B and is licensed for the treatment of patients with locally advanced or metastatic breast cancer that has progressed following treatment with anthracyclines and taxanes. It was not deemed to be cost effective based on a cost analysis by the National Institute for Health and Care Excellence in England and therefore it is not funded routinely by the National Health Service. The establishment of the Cancer Drugs Fund in England subsequently enabled access. As with any new chemotherapy drug that enters clinical practice for metastatic breast cancer (MBC) it is often used in heavily pretreated patients and the experience in a routine clinical setting can differ from that in a clinical study. We therefore present the experience of the first 25 cases treated at our institution via the Cancer Drugs Fund. Materials & methods: A total of 25 patients were treated and in the 22 assessable cases the objective response rate was 18% (four out of 22), with a clinical benefit rate of 41.0% (9 out of 22). Results: The median time-to-progression and overall survival were 4.08 months and 5.89 months, respectively. There was a significant difference in clinical benefit rate (odds ratio: 0.065; 95% CI: 0–0.529; p = 0.0055), as well as time-to-progression (hazard ratio: 9.18; 95% CI: 2.26–37.38; p = 0.002 adjusted for age at diagnosis and interval between initial MBC diagnosis and commencing eribulin) favoring those patients who had not been rechallenged. There was no significant difference in overall survival (hazard ratio: 1.16; 95% CI: 0.44–3.05; p = 0.770 adjusted for age at diagnosis and interval between initial diagnosis of MBC and commencing eribulin). Conclusion: Eribulin mesylate shows clinical activity; however, there appears to be differences in terms of benefit in patients based on whether patients have been rechallenged with an anthracycline and/or a taxane. These data require confirmation in larger patient groups

Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea

The PROSPECT was a randomized phase III trial that included patients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0). The trial aimed to test the hypothesis that pre-operative chemotherapy consisting of 6 cycles of FOLFOX given over a 12-week period, followed by total mesorectal excision (TME) surgery, was non-inferior to pre-operative long-course chemoradiotherapy (CRT). The primary endpoint of the study was disease-free survival (DFS), and patients were also monitored for other relevant oncological outcomes such and health-related quality of life (HRQoL) using patient-reported outcome (PRO) tools [1, 2]

Stereotactic Body Radiotherapy re-irradiation for locally recurrent rectal cancer: outcomes and toxicity

Background: Stereotactic body radiotherapy (SBRT) has emerged as a potential therapeutic option for locally recurrent rectal cancer (LRRC) but contemporaneous clinical data is limited. We aimed to evaluate the local control, toxicity and survival outcomes in a cohort of patients previously treated with neoadjuvant pelvic radiotherapy for non-metastatic LRRC, now treated with SBRT. Methods: Inoperable rectal cancer patients with ≤ 3 sites of pelvic recurrence and > 6 months since prior pelvic radiotherapy were identified from a prospective registry over 4 years. SBRT dose was 30Gy in 5 fractions, daily or alternate days, using cumulative organ at risk dose constraints. Primary outcome was local control (LC). Secondary outcomes were progression free survival (PFS), overall survival (OS), toxicity and patient reported Quality of Life scores (QoL) using EQ-VAS tool. Results: 30 patients (35 targets) were included. Median GTV size was 14.3cm3. 27/30 (90%) previously received 45-50.4Gy in 25/28 fractions, with 10% receiving an alternative prescription. All patients received the planned re-irradiation SBRT dose. The median FU was 24.5 months (IQR 17.8 – 28.8). The 1-year LC was 84.9% (95% CI 70.6 – 99) and a 2-year LC was 69% (95% CI 51.8 – 91.9). The median PFS was 12.1 months (95% 8.6 – 17.66) and median OS was 28.3 months (95% CI 17.88 – 39.5 months). No patient experienced >G2 acute toxicity and only 1 patient experienced late G3 toxicity. Patient reported QoL outcomes were improved at 3 months following SBRT (Δ EQ-VAS, +10 points, Wilcoxon signed rank, p=0.009). Conclusion: Our study demonstrates that, for small volume pelvic disease relapses from rectal cancer, re-irradiation with 30Gy in 5 fractions is well tolerated and achieves an excellent balance between high local control rates with limited toxicity

CRISPR-Cas9 Causes Chromosomal Instability and Rearrangements in Cancer Cell Lines, Detectable by Cytogenetic Methods

CRISPR-Cas9 has quickly become the method of choice for genome editing, with multiple publications describing technical advances and novel applications. It has been widely adopted as a tool for basic research and has significant translational and clinical potential. However, its usage has outpaced the establishment of essential and rigorous controls for unwanted off-target effects, manifested as small mutations, large deletions of target loci, or large-scale chromosomal rearrangements. A common application of CRISPR-Cas9 is as a tool for creating isogenic cell-line models to study the effects of precise mutations, or variants, on disease traits. Here, we describe the effect of standard CRISPR-Cas9 mutagenesis protocols on well characterized cancer cell lines. We demonstrate that commonly used methods for detecting correctly mutated clones fail to uncover large-scale rearrangements. We show that simple cytogenetic methods can be used to identify clones carrying chromosomal abnormalities and large mutations at target loci. These methods are quick and cost-efficient, and we suggest that such controls should be performed prior to publication of studies based on novel CRISPR-Cas9 mutated cancer cell lines

Immune checkpoint inhibition as a strategy in the neoadjuvant treatment of locally advanced rectal cancer

The treatment of locally advanced rectal cancer (LARC) has seen major advances over the past 3 decades, with multimodality treatment now standard of care. Combining surgical resection with radiotherapy and/or chemotherapy can reduce local recurrence from around 20% to approximately 5%. Despite improvements in local control, distant recurrence and subsequent survival rates have not changed. Immune checkpoint inhibitors have improved patient outcomes in several solid tumor types in the neoadjuvant, adjuvant, and advanced disease setting; however, in colorectal cancer, most clinical trials have been performed in the metastatic setting and the benefits confined to microsatellite instability–high tumors. In this article, we review the current preclinical and clinical evidence for using immune checkpoint inhibition in the treatment of LARC and discuss the rationale for specifically exploring the use of this therapy in the neoadjuvant setting. We summarize and discuss relevant clinical trials that are currently in setup and recruiting to test this treatment strategy and reflect on unanswered questions that still need to be addressed within future research efforts

Superior outcomes of nodal metastases compared to visceral sites in oligometastatic colorectal cancer treated with stereotactic ablative radiotherapy

Background: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. Methods: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0–2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). Results: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2–22.85). The LC at 1 year was 83.8% (CI 76.4%−91.9%) with a PFS of 55% (CI 47%−64.7%) respectively. LC at 1 year was 90% (CI 83%−99%) for nodal metastases (NM), 75% (63%−90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38–0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18–0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. Conclusion: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis

Optimising volumetric arc radiotherapy for dental rehabilitation in oropharynx cancer – a retrospective dosimetry review and feasibility planning study

Purpose: To assess the dosimetry to dentally relevant substructures within the mandible/maxilla, establish the predictors of increased mean anterior mandible dose and assess the feasibility of rationale optimisation of dose to the anterior mandible (AM) volume to aid reconstructive dental surgery planning, where the AM is a critical structure. Materials and methods: In a cohort of radically treated oropharynx cancer patients we conducted a retrospective dosimetry analysis of mandible/maxilla volumes, created using a published atlas. Comparisons of mean AM dose and clinical parameters between groups were tested using Wilcoxon rank-sum and Kruskal-Wallis tests. A multivariate linear regression model was created to assess independent predictors of increased mean AM dose. Patients with a mean AM dose over 37.5 Gy were included in feasibility planning study to test the hypothesis that it is possible to safely limit the dose whilst maintaining dose tolerances for other organs at risk. Results: 57 patients were included. Median AM mean dose was 32.2 Gy (IQR 27.7–38.7). T stage, N stage and inclusion of Level 1B were significantly associated with increased mean AM dose. Only T stage (p = .0132) and Level Ib inclusion (p = .018) remained significant in the linear regression model. 88% of plans, all of which included Level Ib, were successfully re-optimised without breaching accepted constraints. Conclusions: Oropharynx cancer patients with advanced T stage and who require Level Ib treatment receive increased mean AM dose, potentially limiting surgical dental rehabilitation options. The majority of patients can be optimised safely with appropriate AM contouring

Drug radiotherapy combinations: review of previous failures and reasons for future optimism

Combining chemotherapy with radiotherapy has resulted in significant clinical improvements in many different tumour types. However, the non-specific mechanisms by which these drugs exert their effects mean that this is often at the expense of increased side effects. Previous attempts at using targeted drugs to induce more tumour specific radiosensitisation have been generally disappointing. Although cetuximab, an EGFR monoclonal antibody, resulted in improved overall survival in HNSCC when combined with radiotherapy, it has failed to show benefit when added to chemo-radiotherapy. In addition, our inability to successfully use drug treatments to reverse tumour hypoxia is underlined by the fact that no such treatment is currently in widespread clinical use. The reasons for these failures include the lack of robust biomarkers, and the previous use of drugs with unacceptable side-effect profiles. Despite these disappointments, there is reason for optimism. Our improved understanding of key signal transduction pathways and of tumour specific DNA repair deficiencies has produced new opportunities to specifically radiosensitise tumours. Novel strategies to reduce tumour hypoxia include the use of drugs that cause vascular normalisation and drugs that reduce tumour oxygen consumption. These new strategies, combined with better compounds at our disposal, and an ability to learn from our previous mistakes, mean that there is great promise for future drug-radiotherapy combinations to result in significant clinical benefits

Radiation-induced changes in gene expression in rectal cancer specimens

PURPOSE: The standard-of-care for locally advanced rectal cancer is radiotherapy-based neoadjuvant therapy followed by surgical resection. This article reviews the evidence of molecular changes at the transcriptome level induced through radiotherapy in rectal cancer.METHODS: The PubMed search "(radiation OR radiotherapy) cancer (transcriptome OR "gene expression") rectal" was used. The studies taken forward utilised gene-expression data on both pre-treatment and post-treatment rectal adenocarcinoma biospecimens from patients treated with RT-based neoadjuvant strategies.RESULTS: Twelve publications met the review criteria. There was variation in approaches in terms of design, patient population, cohort size, timing of the post-radiotherapy sampling and method of measuring gene expression. Most of the post-treatment biospecimen retrievals were at resection. The literature indicates a broad upregulation of immune activity through radiotherapy using gene-expression data.CONCLUSION: Future studies would benefit from standardised prospective approaches to sampling to enable the inclusion of timepoints relevant to the tumour and immune response.</p