Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.

BACKGROUND: Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS: The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION: Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION: Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). METHODS: This study is prospective single-arm, multicenter phase II trial adopting Simon's two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3-4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. RESULTS: 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33-73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. CONCLUSION: In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1 .

Trends of partial and radical nephrectomy in managing small renal masses.

OBJECTIVE: Use of partial nephrectomy (PN) for renal tumors appears to have relatively lower incidence rates in Jordan. We sought to characterize its trend at King Hussein Cancer Center for the last 10 years. MATERIAL AND METHODS: A retrospective review of our renal cell cancer data was performed. We identified 169 patients who had undergone surgery for renal tumors measuring ≤7 cm between 2005 and 2015. We characterized tumor size, pathology, type of surgery and clinical outcomes. Factors associated with the use of PN were evaluated using univariable and multivariable logistic regression models. RESULTS: Of the 169 patients, 34 (20%) and 135 (80%) had undergone partial and radical nephrectomy (RN) respectively for tumors ≤7 cm in diameter. Total number of 48 patients with tumors of ≤4 cm in diameter had undergone either PN (n=19; 40%) or RN (n=29; 60%). The frequency of PN procedures steadily increased over the years from 6% in 2005-2008, to 32% in 2013-2015, contrary to RN which was less frequently applied 94% in 2005-2008, and 68% in 2013-2015. In multivariable analysis, delayed surgery (p=0.01) and smaller tumor size (p=0.0005) were significant independent predictors of PN. During follow-up period, incidence of metastasis was lower in PN versus RN (13% and 32%, respectively, p=0.043). Local recurrence rates were not significantly different between PN (6.9%) and RN (7.2%) (p=0.99). The mean tumor sizes for patients who had undergone PN and RN were 4.1 and 5.5 cm respectively, (p<0.0001). The mean follow-up period for PN was 20 months, and for RN 33 months, (p=0.0225). CONCLUSION: Partial nephrectomy for small renal tumors is relatively less frequently applied in Jordan, however an increase in its use has been observed over the years. Our data showed lower rates of distant metastasis and similar rates of local recurrence in favor of PN.

Clinicopathologic Features of Translocation Renal Cell Carcinoma.

BACKGROUND: Translocation renal cell carcinomas (TFE3 RCC) are associated with variable genetic rearrangements of the TFE3 gene on chromosome Xp11.2. Translocation tumors represent 1% to 5% of all cases of RCC, with the greatest frequency among children and young adults. We sought to characterize the clinicopathologic features of translocation RCC at a Middle Eastern institution. MATERIALS AND METHODS: The clinical and pathologic data from a single institution were retrospectively reviewed. A total of 14 patients with translocation RCC had been diagnosed from 2005 to 2014. The outcome measures included patient characteristics, clinical manifestations, pathologic features, treatment outcomes, cancer-specific survival, and progression-free survival. RESULTS: The mean age at diagnosis was 35 years. Of the 14 patients, 5 were female. Translocation RCC was an incidental diagnosis for all but 2 of the 14 patients. The mean tumor size was 9 cm; 1 patient had bilateral tumors, and 3 presented with positive lymph nodes. Three patients underwent partial nephrectomy. Three patients had developed metastasis at 4 months, 5 months, and 3 years after diagnosis. One patent had died 4 months after surgery and one had died 21 months after surgery (both of metastases). The disease-free survival rate was 71% at a mean follow-up of 31 months. CONCLUSION: Translocation RCC is a rare and potentially aggressive subtype of kidney cancer. An overall survival of > 3 years has been noted, unless metastasis is present at diagnosis.

Clinico-pathological outcomes of post- primary and salvage chemotherapy retroperitoneal lymph node dissection for mixed germ cell tumors, King Hussein Cancer Center experience.

OBJECTIVE: We sought to characterize clinical and pathologic outcomes of advanced mixed germ cell tumors after retroperitoneal lymph node dissection for post-chemotherapy residual masses. MATERIAL AND METHODS: Between January 2006 and November 2015, 56 patients underwent retroperitoneal lymph node dissection (RPLND) for residual masses of greater than 1 cm after receiving either primary chemotherapy or salvage chemotherapy. Retrospective review of the patients' characteristics, clinical, pathological, and treatment outcomes were performed after institutional review board (IRB) and ethics committee approval. RESULTS: The mean age at diagnosis was 30 years. Ninety percent of the patients received 3-4 cycles of BEP (bleomycin/etoposide/cisplatin) as primary chemotherapy, and 29% of them salvage chemotherapy prior to lymph node dissection. The mean size of the residual masses after chemotherapy was 6 cm. The histological findings were necrosis in 30%, viable tumor in 34% and teratoma in 36% of the retroperitoneal masses. The mean time to relapse after RPLND was 11 months, out of 9 relapses, 6 were in the retroperitoneum, 1 in the lung and 1 in the kidney and 1 in the contralateral testicle. CONCLUSION: Our results indicated higher incidence of viable germ cell tumor in the retroperitoneal residual masses after primary and salvage chemotherapy when compared with previously reported global incidence rates.