Pancreatic ductal adenocarcinoma: tumour regression grading following neoadjuvant FOLFIRINOX and radiation.

AIMS: In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX (Folinic Acid, Fluorouracil, Irinotecan, and Oxaliplatin) show superior survival. In this study, we quantitatively assess the pathological tumour response to chemoradiation in pancreatectomy specimens and reassess guidelines for tumour regression grading. METHODS AND RESULTS: We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumour regression grade (TRG) and overall survival (OS) were recorded. A quantitative analysis of residual tumour was performed on the slide with the highest tumour burden to derive a tumour-to-tumour bed ratio. On univariate analysis, only lymph node status (P = 0.043) and CAP TRG (P = 0.038) correlated with OS. Sixteen per cent of patients showed a complete pathological response. The optimal tumour-to-tumour bed ratio cut-point was 11.6%, and on a multivariate model was the only pathological parameter that correlated with OS (P = 0.016) (hazard ratio = 2.27). CONCLUSIONS: The high proportion of patients with PDAC showing complete and near-complete pathological responses supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation, while a quantitative tumour-to-tumour bed ratio is a powerful predictor of OS. The data support a two-tiered approach to TRG based on tumour-to-tumour bed ratio, and quantitative analysis merits further consideration.

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions.

PURPOSE OF REVIEW: Bladder-sparing trimodality therapy (TMT) has become an accepted alternative to cystectomy for selected muscle invasive bladder cancer (MIBC) patients unfit for cystectomy or opting for bladder preservation. This review will summarize recent advances in TMT for MIBC. RECENT FINDINGS: A growing body of literature has emerged which supports the use of TMT. However, its delivery is yet to be standardized. The role of chemotherapy and predictive biomarkers remain to be elucidated. Novel bladder-sparing approaches, drug combinations including immunotherapy and targeted therapies are under investigation in clinical trials, with the goal of ultimately enhancing survival and quality of life outcomes. Recent advances in TMT have made bladder preservation possible for MIBC patients seeking an alternative local therapy to cystectomy. With careful patient selection, TMT offers comparable survival outcomes to cystectomy, and improved quality of life as patients are able to successfully retain their bladder.

Adjuvant and Salvage Radiotherapy after Prostatectomy: ASTRO/AUA Guideline Amendment 2018-2019.

PURPOSE: The purpose of this amendment is to incorporate newly-published literature into the original ASTRO/AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guideline and to provide an updated clinical framework for clinicians. MATERIALS AND METHODS: The original systematic review yielded 294 studies published between January 1990 and December 2012. In April 2018, the guideline underwent an amendment and incorporated 155 references that were published from January 1990 through December 2017. Two new key questions were added. One on the use of genomic classifiers and the other on the treatment of oligo-metastases with radiation post-radical prostatectomy. RESULTS: A new statement on the use of hormone therapy with salvage radiotherapy after radical prostatectomy was added and long-term data was used to update an existing statement on adjuvant radiotherapy. The balance of the guideline statements were re-affirmed and references were added to the existing literature base. A discussion on the use of genomic classifiers as a risk stratification tool was added to the future research discussion. No relevant data on oligo-metastases was found. CONCLUSIONS: Hormone therapy should be offered to patients who have had radical prostatectomy and who are candidates for salvage radiotherapy. The clinician should discuss possible short- and long-term side effects with the patient as well as the potential benefits of preventing recurrence. The decision to use hormone therapy should be made by the patient and a multi-disciplinary team of providers with full consideration of the patient's history, values, preferences, quality of life, and functional status.

Systematic review of outcomes after total neoadjuvant therapy for locally advanced rectal cancer.

BACKGROUND: Advances in surgical technique and the development of combined-modality therapy have led to significantly improved local control in rectal cancer. Distant failure rates however, remain high, ranging between 20 and 30 per cent. Additional systemic chemotherapy in the preoperative period has been proposed as a means of eradicating subclinical micrometastases and improving long-term survival. The purpose of this systematic review was to evaluate the current evidence regarding induction chemotherapy in combination with standard neoadjuvant chemoradiotherapy, in terms of oncological outcomes, in patients with rectal cancer. METHODS: A systematic review of the literature was performed to evaluate oncological outcomes and survival in patients with rectal cancer who underwent induction chemotherapy and neoadjuvant chemoradiotherapy, followed by surgical resection. Four major databases (PubMed, Embase, Scopus and Cochrane) were searched. The review included all original articles published in English reporting long-term outcomes, specifically survival data, and was limited to prospective studies only. RESULTS: A total of 686 studies were identified. After applying inclusion and exclusion criteria, ten studies involving 648 patients were included. Median follow-up was 53·7 (range 26-80) months. Five-year overall and disease-free survival rates were 74·4 and 65·4 per cent respectively. Weighted mean local recurrence and distant failure rates were 3·5 (range 0-7) and 20·6 (range 5-31) per cent respectively. CONCLUSION: Total neoadjuvant therapy should be considered in patients with high-risk locally advanced rectal cancer owing to improved chemotherapy compliance and disease control. Further prospective studies are required to determine whether this approach translates into improved disease-related survival or increases the proportion of patients suitable for non-operative management.

Prolonged interval between neoadjuvant chemoradiotherapy and esophagectomy does not benefit the outcome in esophageal cancer: a systematic review and meta-analysis.

Whether a prolonged interval between neoadjuvant chemoradiotherapy (nCRT) and esophagectomy could benefits conditions such as rectal cancer, still remains unknown. We therefore performed the current study to evaluate the influence of the interval between nCRT and esophagectomy on the clinical outcomes in patients with esophageal cancer. PubMed and Embase were searched to identify eligible cohort studies. The primary outcome was five-year overall survival (OS), and secondary outcomes included the incidence of anastomotic complications, perioperative mortality, pathologic complete response (pCR) rate, positive circumferential resection margin (CRM) rate, and R0 resection rate. A random-effects model was used for all meta-analyses irrespective of heterogeneity. Ten cohort studies with 2383 patients were included. Overall, the pooled estimate revealed that the prolonged interval has no impact on five-year OS (odds ratio (OR) 0.87, 95% CI 0.66 to 1.14, P = 0.30), with low heterogeneity (PH = 0.78, I2 = 0%). However, it was associated with an increased risk of anastomotic complication (OR 1.71, 95% CI 1.15 to 2.54, P = 0.008), with no effect on perioperative mortality (OR 1.20, 95% CI 0.79 to 1.83, P = 0.40). Additionally, the prolonged interval failed to increase the pCR rate (OR 1.02, 95% CI 0.78 to 1.33, P = 0.89). Even worse, it was correlated with a decreased R0 resection rate (OR 0.60, 95% CI 0.41 to 0.88, P = 0.009) and increased positive CRM rate (OR 2.20, 95% CI 1.44 to 3.36, P < 0.001). This study suggests that the prolonged interval between nCRT and esophagectomy fails to result in better outcomes, and in fact, could worsen clinical outcomes, with increasing anastomotic complications, and undermine resection completeness. However, this conclusion should be treated with caution because of the limitations of retrospective cohort study and substantial clinical heterogeneity. (The study was registered at PRESPERO as CRD42016048210).

What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients.

We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS.

Treatment of Locally Recurrent Rectal Carcinoma in Previously (Chemo)Irradiated Patients: A Review.

BACKGROUND: Local recurrence after rectal cancer treatment occurs in ≈5% to 10% of patients. Neoadjuvant (chemo)radiotherapy for primary rectal cancer renders treatment of recurrent disease more difficult. OBJECTIVE: The purpose of this study was to review contemporary multimodality therapies, including their outcome, for locally recurrent rectal carcinoma after (chemo)radiotherapy and complete surgical resection of primary rectal cancer. DATA SOURCES: A comprehensive literature search of PubMed and EMBASE was performed. STUDY SELECTION: All English language articles presenting original patient data regarding treatment and the respective outcome of previously irradiated locally recurrent rectal cancer were included. INTERVENTIONS: All of the treatment modalities for locally recurrent rectal cancer were reviewed. MAIN OUTCOME MEASURES: Primary outcome parameters were local control, metastasis-free survival, and overall survival. Secondary outcome parameters were perioperative morbidity and mortality, and prognostic factors for treatment outcome. RESULTS: Of 854 studies, 9 studies and 474 patients with locally recurrent rectal carcinoma were included. Various treatment regimens were used, most with curative intent. Reirradiation was composed of (neo-)adjuvant external beam radiotherapy (with or without concurrent chemotherapy), additional intraoperative radiotherapy, or intraoperative radiotherapy only. Surgical technique highly varied, depending on the extent of the lesion. Radiation toxicity, perioperative morbidity, and mortality were generally acceptable. Outcome was better after curative intent treatment, any surgical resection, and R0 resections in particular. Moreover, reirradiation is associated with increased complete resection rates, which in turn positively affected local control and overall survival. LIMITATIONS: Most studies were retrospectively designed, with highly variable therapies, patient populations, and duration of follow-up. CONCLUSIONS: A complete resection is the most important prognostic factor and should be the goal of treatment in locally recurrent rectal carcinoma. Reirradiation seems safe and of additional value in reaching a complete resection. Considering the available evidence, at present reirradiation should be given on a case-specific basis, with all of the patients entering an international prospective database.

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features.

BACKGROUND: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). RESULTS: Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02). CONCLUSIONS: The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies. TRIAL REGISTRY: Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.

Axillary lymph node metastases in adenoid cystic carcinoma of the breast. A rare finding.

Adenoid cystic carcinoma (ACC) of the breast is a rare malignant salivary-type neoplasm that has a good prognosis and represents less than 1% of all breast cancers. It is a triple negative carcinoma that presents as a painful mass. The mean age at the time of diagnosis is 50-60 years old. The solid variant of this type of tumour with basaloid features and presence of nodal metastases is very rare and considered to have a more aggressive clinical course. We present a case with presence of axillary lymph node metastases that was successfully treated with no evidence of recurrence one year after the diagnosis and review the literature.

Neoadjuvant treatment of borderline resectable and non-resectable pancreatic cancer.

Neoadjuvant therapy is increasingly becoming a valid treatment option for patients with locally advanced pancreatic cancer (LAPC). In borderline resectable disease, neoadjuvant therapy is employed to improve the probability of margin-clear resections. In non-metastatic, non-resectable pancreatic cancer, treatment primarily aims to induce disease control, but may achieve conversion to surgical resectability in some patients. Several treatment modalities including chemotherapy, chemoradiotherapy (CRT) or the sequential use of both have been investigated in numerous, mostly small and non-randomized studies. Nevertheless, there is a consistent finding that neoadjuvant therapy can induce resectability in up to 30%-40% of LAPC patients. Once resection has been achieved, overall survival appears to be comparable to that observed for primarily resectable patients. Thus, patient selection evolves as an important aspect of neoadjuvant therapy; retrospective analyses identified induction chemotherapy as an appropriate tool to define LAPC patients who may benefit most from subsequent treatment with CRT. The clinical importance of induction chemotherapy may further increase once highly active protocols such as the FOLFIRINOX or the gemcitabine plus nab-paclitaxel regimen are introduced into novel multimodality treatment concepts.

Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy. Outcome in patients with locally advanced head and neck cancer.

BACKGROUND: Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. MATERIALS AND METHODS: The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity-modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT-related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. RESULTS: The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. CONCLUSION: Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired.

Chemoradiation of rectal cancer.

The treatment of locally advanced rectal cancer is a challenge. Surgery, chemotherapy and radiotherapy comprise the multimodal therapy that is administered in most cases. Therefore, a multidisciplinary approach is required. Because this cancer has a high rate of local recurrence, efforts have been made to improve clinical outcomes while minimizing toxicity and maintaining quality of life. Thus, total mesorectal excision technique was developed as the standard surgery, and chemotherapy and radiotherapy have been established as neoadjuvant treatment. Both approaches reduce locoregional relapse. Two neoadjuvant treatments have emerged as standards of care: short-course radiotherapy and long-course chemoradiotherapy with fluoropyrimidines; however, long-course chemoradiotherapy might be more appropriate for low-lying neoplasias, bulky tumours or tumours with near-circumferential margins. If neoadjuvant treatment is not administered and locally advanced stage is demonstrated in surgical specimens, adjuvant chemoradiotherapy is recommended. The addition of chemotherapy to the treatment regimen confers a significant benefit. Adjuvant chemotherapy is widely accepted despite scarce evidence of its benefit. The optimal time for surgery after neoadjuvant therapy, the treatment of low-risk T3N0 neoplasms, the convenience of avoiding radiotherapy in some cases and tailoring treatment to pathological response have been recurrent subjects of debate that warrant more extensive research. Adding new drugs, changing the treatment sequence and selecting the treatment based on prognostic or predictive factors other than stage remain experimental.

Intensity-modulated arc therapy with cisplatin as neo-adjuvant treatment for primary irresectable cervical cancer. Toxicity, tumour response and outcome.

PURPOSE: The goal of this work was to evaluate the feasibility and outcome of intensity-modulated arc therapy ± cisplatin (IMAT ± C) followed by hysterectomy for locally advanced cervical cancer. PATIENTS AND METHODS: A total of 30 patients were included in the study. The primary tumour and PET-positive lymph node(s) received a simultaneous integrated boost. Four weeks after IMAT ± C treatment, response was evaluated. Resection consisted of hysterectomy with or without lymphadenectomy. Tumour response, acute and late radiation toxicity, postoperative morbidity and outcome were evaluated. RESULTS: All hysterectomy specimens were macroscopically tumour-free with negative resection margins; pathological complete response was 40%. In 2 patients, one resected lymph node was positive. There was no excess in postoperative morbidity. Apart from two grade 3 hematologic toxicities, no grade 3 or 4 acute radiation toxicity was observed. No grade 3, 1 grade 4 (4%) intestinal, and 4 grade 3 (14%) urinary late toxicities were observed. The 2-year local and regional control rates were 96% and 100%, respectively. The 2-year distant control rate was 92%. Actuarial 2-year progression free survival rate was 89%. Actuarial 1- and 2-year overall survival rates were 96% and 91%, while 3-year overall survival was 84%. CONCLUSION: Surgery after IMAT ± C is feasible with low postoperative morbidity and radiation toxicity. Local, regional, distant control and survival rates are promising.

Mitigation of obesity-promoted diseases by Nigella sativa and thymoquinone.

Obesity is closely associated with increased incidence of cardiovascular diseases, cancer, insulin resistance, and immune dysfunction, and thus obesity-mitigation strategies should take into account these secondary pathologies in addition to promoting weight loss. Recent studies indicate that black cumin (Nigella sativa) has cardio-protective, anti-cancer, anti-diabetic, antioxidant, and immune-modulatory properties. While black cumin and/or its major bioactive constituent, thymoquinone have demonstrated bioactivity in a variety of disease models, the mechanisms of action are largely unknown. Given the growing interest in and the use of functional foods and nutraceuticals, as well as the increase in obesity and chronic diseases worldwide, further research into the therapeutic/preventive effects of black cumin may be beneficial.

Physical activity programmes for patients undergoing neo-adjuvant chemoradiotherapy for rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Patients diagnosed with localized rectal cancer should undergo Neoadjuvant Radio-Chemotherapy (NACRT) followed, a few weeks later, by surgical resection. NACRT is known to cause significant decline in the physical and psychological health of patients. This literature review aims to summarize the effects of a prehabilitation programme during and/or after NACRT but before surgery. METHODS: Articles included in this review have been selected by two independent researchers on Pubmed, Google Scholar, and Cochrane databases with the following terms: "Rectal Cancer AND Physical Activity" and "Exercise AND Rectal Cancer." RESULTS: We obtained 560 articles. We selected 12 of these, representing 7 series but only one randomized study, constituting 153 patients in total. Most studies included have considerable variation in their prehabilitation programmes, in terms of supervision, training content, frequency, intensity, duration, and temporality, in regard to NACRT and surgery. Implementing a prehabilitation programme during NACRT seems feasible and safe, with adherence ranging from 58% to 100%. VO2max (maximal oxygen consumption during incremental exercise) was improved in three of the studies during the prehabilitation programme. No significant difference in the step count, 6-minute-walk test, or quality of life was seen. CONCLUSIONS: Prehabilitation programmes during NACRT for localized rectal cancer patients are safe and feasible; however, due to considerable variation in the prehabilitation programmes and their small size, impact on fitness, quality of life, and surgical outcome are unknown. Larger randomized studies are needed.

Predicting treatment response from longitudinal images using multi-task deep learning.

Radiographic imaging is routinely used to evaluate treatment response in solid tumors. Current imaging response metrics do not reliably predict the underlying biological response. Here, we present a multi-task deep learning approach that allows simultaneous tumor segmentation and response prediction. We design two Siamese subnetworks that are joined at multiple layers, which enables integration of multi-scale feature representations and in-depth comparison of pre-treatment and post-treatment images. The network is trained using 2568 magnetic resonance imaging scans of 321 rectal cancer patients for predicting pathologic complete response after neoadjuvant chemoradiotherapy. In multi-institution validation, the imaging-based model achieves AUC of 0.95 (95% confidence interval: 0.91-0.98) and 0.92 (0.87-0.96) in two independent cohorts of 160 and 141 patients, respectively. When combined with blood-based tumor markers, the integrated model further improves prediction accuracy with AUC 0.97 (0.93-0.99). Our approach to capturing dynamic information in longitudinal images may be broadly used for screening, treatment response evaluation, disease monitoring, and surveillance.

Adamantinoma-like Variant of Ewing Sarcoma in the Metatarsal Bone After Chemotherapy: Report of a Case Successfully Treated with Pedicled Osteocutaneous Fibular Transfer.

Adamantinoma-like Ewing sarcoma is a rare variant of Ewing sarcoma with histologic and immunohistochemical evidence of squamous differentiation. This variant most commonly occurs in the head and neck region with a few cases reported in the long bones of the limbs. It may be associated with poorer clinical outcome and could pose a diagnostic challenge, particularly if it occurs in older patients or as a metastatic lesion. We present a case of Ewing sarcoma in the metatarsal of an 11-year-old boy that manifested adamantinoma-like morphology after neoadjuvant chemotherapy. Chemotherapy has been reported to induce neuronal maturation and rhabdoid morphology in cases of Ewing sarcoma, but no reports of treatment-induced squamous differentiation with P40/P63 expression have been demonstrated. This is also the first documented case treated with a pedicled osteocutaneous fibular transfer in a metatarsal malignancy, which is usually treated by either ray or below-knee amputation.