Beyond the dermis-high-risk invasive squamous cell carcinoma: a retrospective review.

OBJECTIVE: Most cutaneous squamous cell carcinomas (cSCC) are low risk and can be treated with simple excision or ablation. High-risk cSCC require invasive treatment, including radical surgery. We present our experience in treating invasive cSCC of the pelvis and extremities. METHOD: A retrospective review of the data of patients with invasive cSCC, indicated for surgery between 2014 and 2018, from a single institution was carried out. RESULTS: A total of 19 patients (nine men, 10 women) were included in the study. Mean age was 62 years; mean tumour size was 8.6cm). Of the 19 patients, five patients with paraplegia with cSCC arising from hard-to-heal ulcers died of infection or bleeding after surgery or systemic therapy. Also, nine patients with localised cSCC underwent margin-negative resection with or without radiation; one patient experienced disease relapse. Of the participants, two patients with previous transplants and multifocal aggressive cSCC underwent numerous resections but succumbed to disease, and two patients who presented with locally recurrent disease after previous positive margin resection and radiation underwent re-resection but developed recurrent disease. CONCLUSIONS: Prognosis for invasive cSCC largely depends on clinical setting. Tumours arising from ulcers in patients with paraplegia have a poor prognosis regardless of treatment. Invasive cSCC in transplant patients are often multifocal and often recur. Debulking procedures are associated with local recurrence despite radiation. Patients presenting with localised disease have a favourable prognosis with wide resection, flap coverage and adjuvant therapy.

Case report of capecitabine toxicity and use of uridine triacetate.

Fluorouracil and capecitabine are fluoropyrimidine chemotherapy agents that are commonly used for various cancers. These agents are generally well tolerated at standard doses; however, it has been reported that 31-34% of patients develop dose-limiting toxicities. Dihydropyrimidine dehydrogenase and thymidylate synthase play a major role in fluorouracil and capecitabine activity and toxicity. Uridine triacetate has shown promising results for the emergency treatment of patients who either receive an overdose of the cancer treatment fluorouracil or capecitabine or to treat patients who exhibit early-onset, severe, or life-threatening toxicity. We describe a case of a patient who developed capecitabine toxicity and was unsuccessfully treated with uridine triacetate.

BRAF-Driven Pancreatic Cancer: Prevalence, Molecular Features, and Therapeutic Opportunities.

BRAF-altered pancreatic cancer is an important molecular subgroup that activates the mitogen-activated protein kinase pathway and promotes tumorigenesis. This manuscript reviews the prevalence and molecular features of BRAF-driven pancreatic cancer and also explores the published data about targeted approaches for this subgroup. A review of the existing literature was undertaken through the PubMed database using the search terms BRAF mutation, BRAF fusion, BRAF deletion, mitogen-activated protein kinase pathway, and pancreatic cancer. Pathogenic BRAF variants are enriched in KRAS wild-type (WT) tumors and drive tumorigenesis in in vitro and experimental animal models. The majority of clinical cases are comprised of V600E mutations, N486-P490 deletions and fusions. Anecdotal evidence is building that KRAS-WT, BRAF-driven pancreatic cancers are sensitive either to BRAF inhibitors, MEK inhibitors, or combination strategies. Precision medicine has transformed the treatment landscape for several cancers. With increasing knowledge about molecular drivers in pancreatic cancer, it is critical to characterize each distinct subgroup and evaluate targeted approaches to improve clinical outcomes.

Radiation Therapy and Malignant Fistulae of Anorectal Cancers.

PURPOSE: Although fistulization is a well-studied late toxic effect of radiation therapy (RT), anorectal cancers (ARCs) can present with malignant fistulae (MF) and negatively affect quality of life. The effect of RT, often combined with concurrent chemotherapy, on MF needs systematic analysis, because practitioners are concerned that RT may exacerbate MF. We reviewed our institutional series evaluating the hypothesis that RT worsens MF. METHODS AND MATERIALS: A single-institutional retrospective analysis of patients with ARC receiving RT from 2006 to 2019 was performed. These patients were screened for MF. Any MF resected before RT and RT not directed at the site of MF were excluded. Effects were assessed by review of available follow-up documentation and imaging. RESULTS: A total of 639 patients with ARC were reviewed, and 47 had MF (7.4%). With a median follow-up of 22 months (range, 2-133 months), RT improved MF in 17 of 29 evaluable patients (59%), with 9 of 29 (31.0%) having resolution. The median time to improvement was 50 days (range, 25-117 days); the median duration of improvement was 161 days (range, 0-1941 days). Malignant fistulae persisted in 12 of 29 patients (41%), with persistent local disease in all cases; in 2 cases, MF worsened concomitant with local progression. CONCLUSIONS: In all, 7.4% of patients with ARC presented with MF. Radiation therapy led to improvement or resolution in more than half of evaluable patients. Persistence or worsening of MF was only observed in patients with refractory or progressive local disease. Based on our findings, MF is not a contraindication to RT and may be considered as an independent indication for palliative RT.

Combination Nivolumab/Ipilimumab Immunotherapy For Melanoma With Subsequent Unexpected Cardiac Arrest: A Case Report and Review of Literature.

The success of immunotherapy in the treatment of patients with advanced melanoma has paved the way for unprecedented successes in the treatment of many other malignancies. We present a case of extensively metastatic oral mucosal melanoma that responded successfully to combined immune checkpoint blockade with ipilimumab and nivolumab but developed multiple immune-related adverse events, including myocarditis, a rare event associated with immunotherapy of elderly melanoma patients. Though the acute myocarditis was managed successfully, the patient succumbed to sudden cardiac death. This case highlights the fact, that autoimmune carditis must be considered when working up the sudden onset of shortness of breath in patients on immune checkpoint blockade. After controlling the acute myocarditis with high-dose steroids, which should be tapered over 6 weeks, further cardiology care is needed, and a defibrillator might have to be implanted. Understanding the pathophysiology of immune-related adverse events could make cancer immunotherapy both more effective and safer.

Phase II trial of gemcitabine/carboplatin followed by paclitaxel in patients with performance status=2,3 or other significant co-morbidity (HIV infection or s/p organ transplantation) in advanced non-small cell lung cancer.

INTRODUCTION: The role of chemotherapy in patients with advanced non-small cell lung cancer and poor performance status or who have HIV disease or organ transplantation is unclear. While survival appears to be enhanced, serious toxicity may occur. We evaluated the efficacy of sequential, dose attenuated carboplatin/gemcitabine followed by paclitaxel in patients with PS=2,3, HIV infection or after solid organ transplantation. PATIENTS AND METHODS: Chemotherapy naive patients with PS 2,3 or who were HIV positive or post solid organ transplantation were eligible. Treatment consisted of gemcitabine: 1000 mg/m(2) d 1,8 carboplatin: AUC=5 d 1 q 21d x 2 followed by paclitaxel 80 mg/m(2) q wk x 6 followed by a 2 week break and then repeated until progression. RESULTS: 47 patients were entered. Stage IIIb/IV: 8/39, PS 2/3=26/19, HIV infection=2, solid organ transplantation=2. 12 (25%) had brain metastases. Thirty-nine patients completed two cycles of carboplatin/gemcitabine and 29 pts received at least one cycle of paclitaxel. Overall response rate was 19% (95% CI 1.2-31.7%). Median event free, overall and 1-year survivals were 3.3 months, 5.8 months and 8.4%. Toxicity was moderate with 19% experiencing grade 4 neutropenia (11% with febrile neutropenia). CONCLUSIONS: Sequential carboplatin/gemcitabine to paclitaxel is well tolerated and active in this population. The survival seen is comparable to that of other regimens utilized in PS=2 patients with superior tolerability however, the prognosis for these patients is very poor even with treatment. This is the first trial to prospectively evaluate chemotherapy for patients with HIV disease or organ transplantation and NSCLC.

Correlation of radiation dose and activity with clinical outcomes in metastatic colorectal cancer after selective internal radiation therapy using yttrium-90 resin microspheres.

PURPOSE: Yttrium-90 (Y)-resin microspheres are prescribed using activity. We evaluated overall survival (OS) and radiographic tumor response after selective internal radiation therapy (SIRT) with resin microspheres in patients with liver metastases from colorectal cancer. PATIENTS AND METHODS: We retrospectively reviewed 60 metastatic colorectal cancer patients treated at our institution with SIRT using Y-resin microspheres. Each patient underwent pre-SIRT MRI or computed tomography imaging of the liver with intravenous contrast. Patients underwent post-treatment imaging at 2-3-month intervals with response assessed according to unidimensional Response Evaluation Criteria in Solid Tumors (RECIST) criteria as well as published three-dimensional volumetric criteria. We then related the prescribed activity established by the body surface area method and the corresponding prescribed dose to radiographic treatment response and OS. RESULTS: The median follow-up after the first SIRT treatment was 8.9 months. The mean prescribed activity and the prescribed dose were 26.6 mCi and 52.8 Gy, respectively. OS was not significantly associated with either prescribed activity or prescribed dose. Prescribed dose was also not related to response. However, a significant relationship was found between a higher prescribed activity and an improved radiographic response by RECIST (P=0.04) at the second follow-up. CONCLUSION: The prescribed activity of Y-resin microspheres may be correlated with radiographic response by RECIST criteria at 4-6 months post-treatment. For a more accurate prediction of response, a valid dose calculation model based on post-Y PET dosimetry is likely needed given the heterogeneous dose delivery seen in SIRT.

Phase II trial of the novel retinoid, bexarotene, and gemcitabine plus carboplatin in advanced non-small-cell lung cancer.

PURPOSE: Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, a plateau in efficacy with currently available agents has been reached. Previous studies of the retinoid, bexarotene, a retinoid X receptor-specific ligand, have indicated that it may improve outcome in advanced NSCLC. PATIENTS AND METHODS: Patients with previously untreated stage IIIB or stage IV disease, a performance status of 0 to 2, and adequate organ status were entered. Treatment consisted of up to six cycles of carboplatin (area under the curve = 5.0 on day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) administered every 21 days. Bexarotene 400 mg/m2 orally was to be administered continuously beginning on day 1 and until progression of disease. All patients received atorvastatin 10 mg orally beginning before bexarotene. The objective was to demonstrate a 1-year survival rate of more than 50%. RESULTS: Forty-eight patients were entered; all were assessable for survival, and 47 were assessable for toxicity and response. The therapeutic regimen was well tolerated except for hypertriglyceridemia. The median time to progression was 6.7 months, and overall median survival was 12.7 months. There was a 25% response rate and a 1-year survival rate of 53%. These results were compared with the outcome of 33 patients treated at our institution with two-drug, platinum-based chemotherapy on controlled trials with similar entry criteria in the previous 5 years. CONCLUSION: Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.

High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival.

OBJECTIVE: We sought to study the clinical characteristics and outcomes of patients treated with a surgery-inclusive multimodality approach for Pancoast tumors. METHODS: Clinical records of patients with Pancoast lung cancer who were enrolled for multimodality treatment between 1993 and 2003 at our institution were reviewed retrospectively. RESULTS: Thirty-six patients completed neodjuvant chemoradiation followed by en bloc surgical resection, whereas one patient received high-dose radiation alone followed by surgical intervention. There were 22 men and 15 women. Thirty-four lobectomies and 3 pneumonectomies were performed. Pretreatment non-small cell lung cancer stages were IIB, IIIA, IIIB, and IV (presenting with solitary brain metastasis) in 18, 8, 6, and 5 cases, respectively. R0 resection was achieved in 36 (97.3%) patients. Operative mortality was 2.7% (n = 1). High-dose radiotherapy was successfully tolerated in all but 1 patient. Mean total radiation dose was 56.9 Gy. Pathologic complete response was found in 40.5% (n = 15) of patients. Recurrences were found in 50% (n = 18) of patients. Brain metastasis was the most common recurrence (n = 9), followed by other distant recurrences (n = 4) and local recurrences (n = 5). Median survival time for the group is 2.6 years, and median survival time (pathologic complete response) is 7.8 years. It is noteworthy that median survival time of patients with positive pretreatment lymph nodes (12 patients) was not reached. CONCLUSIONS: Surgical resection of Pancoast tumors after neoadjuvant high-dose radiation and chemotherapy can be safely performed. High-dose radiation in trimodality treatment is well tolerated and might be beneficial. Similar to other studies, late central nervous system relapse is problematic and indicates a need for assessing the role of prophylactic cranial irradiation in this disease.

Phase 2 study of cryptophycin 52 (LY355703) in patients previously treated with platinum based chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Cryptophycin 52 is a novel antitubulin drug with in vitro and in vivo activity in non-small cell lung cancer. Based upon promising Phase 1 data, a multicenter trial was performed to evaluate the drug in previously treated non-small cell lung cancer (NSCLC). METHODS: Patients with Stage IIIb (pleural effusion) or Stage IV NSCLC and performance status 0-1 with adequate organ function who had received at least one and no more than two prior chemotherapy regimens (one of which must have contained a platinum agent) were eligible. Cryptophycin 52 was administered at a dose of 1.5 mg/m(2) day 1 and 8 every 3 weeks. Patients were reassessed every two cycles. RESULTS: Twenty-six patients were enrolled of whom 25 are evaluable for toxicity and response. There were no responders, toxicity was predominantly neurologic in the form of peripheral neuropathy and constipation. After the first 12 patients were enrolled, the dose was lowered to 1.125 mg/m(2) day 1 and 8. Toxicity was substantially reduced with this maneuver. Median survival was 4.1 months. The median number of cycles was two, however ten patients received four or more courses of therapy. CONCLUSION: Cryptophycin 52 failed to produce measurable responses utilizing this schedule. In 40% of patients there was evidence of disease stabilization. Toxicity at 1.5 mg/m(2) was unacceptable. Since activity and toxicity may be dose and schedule dependent, other schedules of cryptophycin 52 should be considered.

Stereotactic Ablative Radiotherapy (SABR): Impact on the Immune System and Potential for Future Therapeutic Modulation.

Stereotactic ablative radiotherapy (SABR) has been demonstrated to provide excellent local control in several malignancies. Recent reports have suggested that this ablative dose may impact disease outside of the radiated area. Furthermore, these studies have implicated immune modulation as the primary mechanism of disease response outside the irradiated area. More specifically, T-cell stimulation and tumor necrosis factor-α modulation following high dose irradiation have been suggested as the responsible components of this phenomenon. In addition, the "abscopal effect" may play a role in disease response outside of the radiated area. We review the current literature regarding the effects of ablative radiation therapy, the potential for immune modulation from it, and the mechanisms of the distant effects it elicits.

18F-FDG PET/CT in a recurrent diffuse malignant peritoneal mesothelioma.

Peritoneal mesothelioma is a rare and aggressive tumor. Early diagnosis of the disease is difficult, delaying effective treatment. We report a case of recurrent, biphasic, diffuse, malignant peritoneal mesothelioma. Initial abdominal computed tomography showed abnormal but nonspecific findings suggestive of an ovarian malignancy, with a negative endoscopy and laboratory studies. An abdominal exploratory laparotomy found widespread malignancy within the peritoneum with a pathological diagnosis of peritoneal mesothelioma. A PET/CT imaging showed diffusely increased metabolic activity throughout the peritoneum, with no evidence of thoracic or pleural involvement. This case demonstrates the PET/CT findings seen with malignant recurrent peritoneal mesothelioma.

Outcomes after trimodality therapy for esophageal cancer: the impact of histology on failure patterns.

OBJECTIVES: This retrospective analysis of patients undergoing neoadjuvant chemoradiation followed by surgical resection was performed to determine if histology or pathologic response affected local-regional control (LRC), survival outcomes or patterns of failure. METHODS: We performed a review of 164 patients who underwent neoadjuvant chemoradiation followed by surgical resection from 1992 to 2006 for esophageal cancer. Information on patient characteristics, pathologic response, failure patterns, and survival was collected. Survival was estimated by the Kaplan-Meier method, and Cox multivariable Regression model was used to analyze trends. RESULTS: The median follow-up was 18 months and 27 months in surviving patients. The 3-year overall survival (OS) and LRC was 46% and 79%. The overall response for the entire cohort included a pathologic complete response (pCR) rate of 41.4%, 21.3% with microscopic residual disease (mRD) and 36.3% with gross residual disease (gRD). The 3-year OS of patients who achieved a pCR versus mRD versus gRD was 58%, 53%, and 29%. OS was significantly improved in patients with a pCR and mRD compared with gRD (P = 0.001). On multivariate analysis both pCR and mRD correlated with an improved OS. Squamous cell cancers (SCC) had a higher rate of pCR than adenocarcinomas (AC), 54% versus 34.8% (P = 0.01). The 3 year LRC for patients with SCC and AC was 100% and 71% (P = 0.03). Among SCC with recurrence, there were no local failures and all failed distantly (P = 0.001). CONCLUSIONS: Patients with microscopic residual disease following trimodality therapy had similar outcomes to patients achieving a pCR. Patients with SCC were more likely to achieve a pCR, and had a higher propensity to fail distantly when compared with patients with AC. This data should be considered in the design of future clinical trials.

Pneumonectomy for lung cancer after preoperative concurrent chemotherapy and high-dose radiation.

BACKGROUND: We studied the clinical characteristics and outcomes of patients undergoing pneumonectomy after preoperative concurrent chemoradiation for non-small cell lung cancer. METHODS: Clinical records of patients with non-small cell lung cancer who underwent pneumonectomy at our institution between 1995 and 2005 after preoperative concurrent chemoradiation were reviewed retrospectively. RESULTS: Twenty-nine patients underwent pneumonectomy after preoperative concurrent chemoradiation. Of the 21 men and 8 women who were treated, 1 had stage IIB (T3N0M0) and the remainder had stage IIIA or IIIB non-small cell lung cancer. Mean patient age at surgery was 53.4 years. There were 15 right pneumonectomies, of which 2 were for pancoast tumors. All patients received concurrent preoperative chemoradiation. Mean total radiation dose was 61.1 Gy. All patients went on to have complete (R0) resection by pneumonectomy. Pathologic complete response was found in 16 patients (55.2%). All patients were discharged alive from the hospital after pneumonectomy. Median hospital length of stay was 5 days (mean 8.6). Ninety-day mortality after surgery was 3.4% (n = 1). Recurrences have been found in 11 patients (38%), including brain metastases (n = 6), bone metastases (n = 4), liver metastases (n = 2), and cervical lymph node metastases (n = 2). One patient had a contralateral new primary lung cancer develop 70 months after undergoing pneumonectomy. Estimated 5-year disease-free survival is 48%. Median survival time has not been reached. CONCLUSIONS: Pneumonectomy can be performed safely after preoperative concurrent chemoradiation, even with high-dose radiation. The frequency of disease recurrence in the brain underscores the need to evaluate the role of prophylactic cranial radiation in non-small cell lung cancer.

Phase I/II trial of hyperfractionated radiation and chemotherapy followed by surgery in stage III lung cancer.

BACKGROUND: We have previously demonstrated that high-dose chemoradiotherapy followed by resection for patients selected on the basis of mediastinal sterilization was feasible and resulted in excellent outcomes. This study was designed to determine the ability to intensify our prior approach utilizing hyperfractionated radiation and more aggressive consolidative chemotherapy. METHODS: Patients with documented stage IIIA/B nonsmall-cell lung cancer, performance status 0 to 2, and adequate organ function were eligible. A phase I portion utilized escalating doses of carboplatin and vinorelbine, commencing with areas under the curve of 1 and 5 mg/m(2), respectively, and concurrent 69.6 Gy hyperfractionated radiotherapy. A phase II portion utilized the identical radiotherapy with carboplatin/vinorelbine at the maximum tolerated dose established in phase I. Patients for whom mediastinal nodal clearance was demonstrated underwent resection. All patients were to receive consolidation chemotherapy consisting of carboplatin/vinorelbine for three cycles, followed by docetaxel for three cycles. Prophylactic cranial irradiation was offered to patients after completion of therapy. RESULTS: Forty-seven patients participated in the study (33 IIIA, 14 IIIB; 15 men, 32 women; median age, 56 years). The maximum tolerated dose for concurrent carboplatin/vinorelbine and hyperfractionated radiotherapy was established at areas under the curve of 1 and 10 mg/m(2), respectively. Twenty-eight patients completed trimodality treatment including surgery. Median survival time for the entire study cohort (n = 47) is 29.6 months, and it is 55.8 months for patients with mediastinal clearance who underwent resection (n = 28). CONCLUSIONS: Surgical resection of locally advanced stage IIIA and IIIB nonsmall-cell lung cancer after induction hyperfractionated radiation and concurrent chemotherapy is safe and well tolerated. Whether this approach is superior to less aggressive therapy is uncertain and will require comparative studies.