Avelumab expanded access program in metastatic Merkel cell carcinoma: Efficacy and safety findings from patients in Europe and the Middle East.

Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC.

Intraoperative radiation therapy for breast cancer-Immediate and 30-month oncological outcomes.

There is growing evidence that intraoperative radiation therapy (IORT) may be a viable option in selected patients with early breast cancer. This study reports our 4-year experience with IORT. The perioperative outcome and imaging data of all patients who underwent IORT for early breast cancer at a tertiary medical center in 2014-2018 were retrospectively retrieved. The cohort included 158 patients aged 52-84 years (mean 68) with stage I (n = 137) or II (n = 21) breast cancer. Mean applicator size was 4.13 cm; IORT added a mean of 29 minutes to the operative time. Minor wound infections (n = 18, 11.4%) requiring antibiotics and drainage were the only postoperative complication. In 25 patients (15%), postoperative mammography demonstrated a seroma (n = 22) or fat necrosis (n = 3). The risk of wound infection or a new postoperative imaging finding was unrelated to patient age, operative time, tumor size, or comorbid diabetes or obesity. After a mean of 30 months' follow-up, none of the patients who met the institutional criteria for IORT had local recurrence, regardless of age, histology, tumor grade, KI67 proliferation index, pathologic stage, Recurrence Score, or additional whole-breast irradiation or adjuvant treatment. Patients for whom a Recurrence Score was determined (n = 55, 35%) had a significantly higher tumor grade, pathologic stage, and whole-breast irradiation/adjuvant chemotherapy rate than the remaining patients. IORT may be a safe alternative to traditional external beam radiation in well-selected patients with early breast cancer, with few minor complications and good 30-month outcome.

Improved Outcome in Local Ewing Sarcoma With an Intensified Pilot Treatment Protocol SCMCIE 94.

This study evaluated the effect of an intensified pilot protocol, SCMCIE 94, on the outcome of Ewing sarcoma (EWS). The cohort included 121 patients with local or metastatic EWS treated at a tertiary pediatric medical center with the SCMCIE 94 (protocol 3, 1994 to 2011) or an earlier protocol (protocol 2, 1988 to 1994; protocol 1, 1985 to 1988). All protocols included 4 to 6 courses of chemotherapy, radiation, and surgery. Clinical data were collected retrospectively by chart review. Survival rates for protocol 3 were as follows: all patients-5-year event-free survival (EFS): 52.5%±5.6%, 10-year EFS: 49.3%±5.8%, 5-year overall survival (OS): 68.8%±5.3%, and 10-year OS: 51.1%±6.3%; patients with localized disease (any site)-5-year EFS: 63.5%±6.0% and 5-year OS: 77.2%±5.3%; patients with localized extremity disease-5-year EFS: 78.95%±8.3%, 10-year EFS: 68.6%±10.0%, 5-year OS: 90.7%±6.2%, and 10-year OS: 71.1%±11.2%. Protocol 3 was associated with an increase in 10-year EFS of 16% overall and 33% in patients with localized extremity disease compared with protocols 1+2, and a significant improvement in 5-year EFS and OS in patients with any localized disease (P=0.001). No survival benefit was found for metastatic disease. On multivariate analysis, protocol and metastatic disease were significantly independent prognostic factors. The intensified SCMCIE 94 protocol seems to increase survival in patients with localized but not metastatic EWS.

High-Dose Radiotherapy as Neoadjuvant Treatment in Non-Small-Cell Lung Cancer.

BACKGROUND: Trimodality therapy (chemoradiation followed by surgery) provides a benefit in progression-free survival but not overall survival. We sought to determine if a high dose of radiation could be delivered safely and provide a clinical benefit. METHODS: Consecutive patients with stage IIIA or IIIB non-small-cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy followed by surgery were reviewed with IRB approval. RESULTS: A total of 48 patients were treated from November 2007 to May 2014. Of these, 64% had stage IIIA disease while 36% had stage IIIB; 46% had adenocarcinoma, 34% squamous, and 23% NSCLC not otherwise specified. The median dose of chemoradiotherapy was 72 Gy (60-72). Overall, 86% of patients received cisplatin (50 mg/m2) and etoposide (50 mg/m2) concurrently with radiotherapy; 72% of patients underwent lobectomy following chemoradiotherapy and 28% underwent pneumonectomy. The 30- and 90-day mortality rates were 0%. The nodal downstaging rate was 82% and there was a 64% rate of pathologic complete response. The overall survival was 29.9 months (95% CI, 19-86 months). The median time to locoregional progression was 35.1 months and the median time to distant progression was 39.3 months. Locoregional failure was 8% and distant failure was 44%. CONCLUSION: High-dose preoperative chemoradiotherapy was safe and effective. This combination should be further considered.

Vismodegib for radiation-induced multiple basal cell carcinomas (BCCs) of the scalp.

BACKGROUND: Vismodegib has been approved for treatment of locally advanced or metastatic basal cell carcinoma (BCC). Its use for postirradiation multiple BCCs has not yet been reported. OBJECTIVE: We sought to investigate the effectiveness and safety of vismodegib for the treatment of recurrent radiation-induced multiple BCCs. METHODS: Patients with recurrent multiple BCCs treated with vismodegib and a history of exposure to radiation treatment were followed up prospectively at a tertiary dermato-oncology clinic during a 19-month period. RESULTS: Eight patients met the study criteria. Mean duration of vismodegib treatment was 29 weeks (range 2-52), and of follow-up, 34 weeks (range 8-64). Drug tolerability was acceptable in 7 patients, of whom 4 showed a partial response and 3 had stable disease. In 1 patient, vismodegib was discontinued soon after its initiation because of a severe drug-induced eruption. LIMITATIONS: Small sample size and short follow-up time are limitations. CONCLUSION: Vismodegib holds promise for the treatment of the subpopulation of patients with radiation-induced multiple BCCs in whom therapeutic options have so far been limited.

Vismodegib as a neoadjuvant treatment to Mohs surgery for aggressive basal cell carcinoma.

BACKGROUND: Vismodegib, a hedgehog pathway inhibitor has been recently introduced as an oral therapy for locally advanced and metastatic basal cell carcinoma. Although treatment of patients with basal cell carcinoma with vismodegib has been associated with partial or complete clinical response, it is still unclear if it is also associated with histological cure. PATIENTS: Two patients with 3 large and aggressive basal cell carcinomas were treated with Vismodegib for 6 months. The treatment was followed by Mohs micrographic surgery. RESULTS: Two tumors disappeared clinically and one was reduced dramatically in its size following treatment with vismodegib. Mohs surgery in all three tumors revealed residual islands of BCC although margins were cleared at the end of surgery. CONCLUSIONS: Neoadjuvant therapy with vismodegib for 6 months prior to Mohs surgery was effective in reducing the size of primary and recurrent aggressive basal cell carcinoma. However, residual tumor nests were found during surgery. Further larger studies are needed to evaluate the efficacy of Vismodegib as a neoadjuvant treatment prior to Mohs surgery.

Hyperbaric oxygen therapy for hemorrhagic radiation cystitis.

BACKGROUND: Hemorrhagic radiation cystitis (HRC) is a significant clinical problem that occurs after pelvic radiation therapy and is often refractory. OBJECTIVES: To evaluate the efficacy and safety of hyperbaric oxygen therapy (HBO) for HRC. METHODS: Daily 90 minute sessions of HBO at 2 ATM 100% oxygen were given to 32 HRC patients with ASTRO grades 3-4 hematuria. RESULTS: The median age was 72.5 (48-88 years). The median time interval between radiation therapy and HBO was 4 years (1-26 years). The patients received a median of 30 HBO sessions (3-53). Hematuria resolved in 27 patients (84%) and persisted in 5. Cystectomy was required in two, and ileal-conduit and bilateral percutaneous nephrostomies were performed in one and two patients, respectively. With a median follow-up of 12 months (5-74 months), the hematuria cleared completely in 16 patients (59%) and mild hematuria requiring no further treatment recurred in 10 others. Another patient with ASTRO grade 4 hematuria needed bladder irrigation and blood transfusions. Complications included eardrum perforation in four patients and transient vertigo and mild hemoptysis in one case each. None of them required HBO discontinuation. CONCLUSIONS: HBO controlled bleeding in 84% of the patients. A durable freedom from significant hematuria was achieved in 96% of the patients. HBO seems to be an effective and safe modality in patients with HRC.

The initial rate of tumour response to vismodegib treatment, can predict a complete response outcome for periocular LA-BCC.

PURPOSE: To establish a model to predict treatment outcome of periocular locally advanced basal cell carcinoma (POLA BCC) based on initial response to treatment with vismodegib (ErivedgeTM), a sonic hedgehog inhibitor. DESIGN: Subgroup analysis of data from the STEVIE study database. METHODS: Analysis of medical history, treatment protocol, and treatment outcome of POLA BCC tumours in a STEVIE study population of 244 POLA BCC patients treated with ≥1 dose of vismodegib. RESULTS: A predictive model for complete response (CR) was established based on the initial treatment response. A cutoff value of 20% reduction in tumour size at 3 months of treatment identified the patients with a high probability (82.76%) to achieve CR. A second cutoff value of 67.7% reduction in tumour size at 6 months of treatment improved the prediction to a 95.42% probability of a CR outcome. CONCLUSIONS: A treatment model was constructed based on the prediction of a CR outcome and the initial response to vismodegib treatment at 3 and 6 months. The study result provide significant new insights can facilitate decision-making on treatment management according to tumour response in patients with POLA BCC.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Introduction: Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. Methods: A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Results: Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. Conclusions: In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

Avelumab for the treatment of locally advanced or metastatic Merkel cell carcinoma-A multicenter real-world experience in Israel.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive malignancy of the skin, affecting predominantly the fair-skinned older population exposed to high levels of ultraviolet light. Immune suppression is considered a significant risk factor. With the recent advances in the field of immunotherapy, the treatment paradigm for advanced MCC, traditionally based on chemotherapy, has largely shifted to anti-PD-L1 and PD-1 agents such as avelumab and pembrolizumab, respectively. However, real-world data remain sparse. The aim of this study was to assess real-world evidence of the effectiveness of avelumab in a diverse group of patients with MCC in Israel. METHODS: The electronic databases of five university hospitals in Israel were searched for all consecutive patients with MCC treated with at least one dose of avelumab in 2018-2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. RESULTS: The cohort included 62 patients of whom 22% were immune-suppressed. The overall response rate to avelumab was 59%. The median progression-free survival was 8.1 months, and the median overall survival, 23.5 months, with no differences between immune-competent and immune-suppressed patients. Treatment was well tolerated; any-grade toxicity developed in 34% of patients, and grade 3-4 toxicity, in 14%. CONCLUSIONS: Avelumab was found to be effective and safe for the treatment of advanced MCC in a diverse group of patients, including some with immune suppression. Further studies are warranted to evaluate the optimal sequence and duration of treatment and to assess the potential role of avelumab for earlier stages of MCC.

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma - A real-world experience from Israel.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods: The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade _3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion: This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with ¹8F-ML-10.

PURPOSE: Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of (18)F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT). MATERIALS AND METHODS: Ten patients with brain metastases treated with WBRT at 30 Gy in ten daily fractions were enrolled in this trial. Each patient underwent two (18)F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6-8 weeks following completion of the radiation therapy. Early treatment-induced changes in tumor (18)F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6-8 weeks after completion of therapy. RESULTS: In all ten patients, all brain lesions were detected by both MRI and the (18)F-ML-10 PET scan. A highly significant correlation was found between early changes on the (18)F-ML-10 scan and later changes in tumor anatomical dimensions (r = 0.9). CONCLUSION: These results support the potential of (18)F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT.

Birth month of patients with malignant neoplasms: links to longevity?

BACKGROUND: In 2001, the Proceedings of National Academy of Sciences (USA) published a study on the relationship between month of birth and longevity. Subsequent studies revealed differences in month of birth among patients with acute myocardial infarction, a major killer in industrialized countries. The aim of the present study was to analyze month of birth in patients with malignant neoplasms, another major fatal disease. METHODS: The study sample consisted of 44,487 patients (22,584 male) diagnosed with a malignant neoplasm at Rabin Medical Center in 1994-2011. The number of patients born in each month of the year was calculated for the whole group and by gender. Student's t-test was used to compare mean (standard deviation) monthly, quarterly and trimester values. RESULTS: There was a strong trend (p=0.06) for a higher mean number of births in the first trimester of the year than in the second and third trimesters. The difference was significant for male patients (p=0.03) but not female patients (p=0.13-0.15). CONCLUSIONS: Patients born in the first trimester of the year are more affected by malignancies, particularly males. The overall monthly birth distribution of oncology patients is in line with the paradigm linking birth month with longevity.

Merkel cell carcinoma in lymph nodes with and without primary origin.

The prognosis of MCC with lymph node involvement was better in patients with an unknown than a known primary. Treatment with a uniform aggressive combined chemoradiation regimen, with or without lymphadenectomy, led to better survival rates than previously reported.

Automatic localization of the prostatic urethra for image guided radiation therapy.

Treatment of prostate cancer with radiation therapy (RT) requires image guided RT (IGRT) to focus the radiation on the target volumes while minimizing doses to organs at risk. Here we describe a urinary catheter that allows imaging of the prostatic urethra and uses it for automatic localization of the prostate for IGRT. The catheter has a contrast lumen that can be empty or full with contrast. Computerized tomography is performed twice, with contrast lumen empty and full, allowing urethral autosegmentation using digital subtraction. Under ultrasound, continuous urethral visualization is possible by pumping aerated gel in- and out of the contrast lumen.

Maintaining consistent bladder filling during external beam radiotherapy for prostate cancer.

Radiation therapy for patients with prostate cancer is preferably provided with a full urinary bladder. Full bladder can potentially move the small intestine out of the radiation treatment regions, and results in decreased small bowel radiation dose and gastrointestinal toxicity. Maintaining consistent bladder filling during computerized tomography simulation scan used for treatment planning and at daily radiation treatments is challenging. Here we present an in-development urinary catheter with a floating balloon that drains the bladder only when urine reaches to a prespecified level, and review current methods used in clinic to ensure consistent bladder filling. These includes bladder filling protocols, ultrasound scanning and biofeedback techniques.

Is local excision after complete pathological response to neoadjuvant chemoradiation for rectal cancer an acceptable treatment option?

PURPOSE: The role of local excision in patients with good histological response to neoadjuvant chemoradiation for locally advanced rectal cancer is unclear, mainly because of possible regional nodal involvement. This study aims to evaluate the correlation between pathological T and N stages following neoadjuvant chemoradiation for locally advanced rectal cancer and the outcome of patients with mural pathological complete response undergoing local excision. METHODS: This investigation was conducted as a retrospective analysis. Between January 1997 and December 2007, 320 patients with T3 to 4Nx, TxN+ or distal (≤ 6 cm from the anus) T2N0 rectal cancer underwent neoadjuvant concurrent chemoradiation followed by surgery. Radiotherapy was standard and chemotherapy consisted of common fluoropyrimidine-based regimens. RESULTS: After chemoradiation, 93% patients had radical surgery, 6% had local excision, and 3% did not have surgery. In the 291 patients undergoing radical surgery, the pathological T stage correlated with the N stage (P = .036). We compared the outcome of patients with mural complete pathological response (n = 37) who underwent radical surgery (group I) and those (n = 14) who had local excision only (group II). With a median follow-up of 48 months, 4 patients in group I had a recurrence and none in group II had a recurrence; one patient died in group I and none died in group II. Disease-free survival, pelvic recurrence-free survival, and overall survival rates were similar in both groups. CONCLUSION: In this retrospective study, nodal metastases were rare in patients with mural complete pathological response following neoadjuvant chemoradiation (3%), and local excision did not compromise their outcome. Therefore, local excision may be an acceptable option in these patients.