Endothelial growth factor receptor inhibitors in recurrent metastatic cancer of the head and neck

Targeted therapy has become an important new class of therapeutic agents used in squamous cell carcinoma of the head and neck (SCCHN). Among them epidermal growth factor receptor (EGFR) inhibitors have been studied the most. Today, two classes of EGFR inhibitors are routinely used in the clinic; anti‐EGFR monoclonal antibodies and small‐molecule inhibitors of the EGFR tyrosine kinase activity. These agents have been used clinically in the recurrent metastatic (R/M) settings but only cetuximab has reached a regulatory approval. Current research is focused on innovative compound design, predictive biomarker discovery, and combination strategies in order to overcome resistance. Efforts should also be focused on endpoints other than overall survival, which is the current gold standard, such as surrogate endpoints. This article summarizes the clinical evidence of the anticancer activity of EGFR inhibitors in patients with R/M SCCHN, and analyzes the current, controversial clinical issues with respect to their interpretation. © 2015 Wiley Periodicals, Inc. Head Neck 38 : E2221–E2228, 2016     

Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow-up of 9.7 years

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To evaluate the efficacy and tolerability of bicalutamide 150 mg once‐daily as immediate hormonal therapy in patients with prostate cancer or as adjuvant to radical prostatectomy or radiotherapy.

PATIENTS AND METHODS

In all, 8113 patients with localized (T1‐2, N0/Nx) or locally advanced (T3‐4, any N; or any T, N+) prostate cancer (all M0) were enrolled in three complementary, double‐blind, placebo‐controlled trials. Patients were randomized to receive standard care plus either oral bicalutamide 150 mg once‐daily or oral placebo. Primary endpoints were progression‐free survival (PFS) and overall survival (OS). Data were collated from individual trials and evaluated in a combined analysis.

RESULTS

Overall, at a median follow‐up of 9.7 years, bicalutamide significantly improved PFS (hazard ratio 0.85, 95% confidence interval 0.79–0.91; P= 0.001). Compared with placebo there was no difference in OS (hazard ratio 1.01, P= 0.77). Patients who derived benefit from bicalutamide in terms of PFS were those with locally advanced disease, with OS significantly favouring bicalutamide in patients with locally advanced disease undergoing radiotherapy (P= 0.031). Patients with localized disease showed no clinically or statistically significant improvements in PFS; there was a survival trend in favour of placebo in patients with localized disease undergoing watchful waiting (P= 0.054). The overall tolerability of bicalutamide was consistent with previous analyses, with breast pain (73.7%) and gynaecomastia (68.8%) the most frequently reported adverse events in patients randomized to bicalutamide.

CONCLUSIONS

Bicalutamide 150 mg, either as monotherapy or adjuvant to standard care, improved PFS in patients with locally advanced prostate cancer, but not in patients with localized disease. A pre‐planned subset analysis showed a benefit for OS in patients with locally advanced disease undergoing radiotherapy. Bicalutamide 150 mg might represent an alternative for patients with locally advanced prostate cancer considering androgen‐deprivation therapy.     

HN11PPRIMARY CHEMO‐RADIOTHERAPY FOR NON‐METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Purpose To review our experience of concomitant single agent cheoradiotherapy treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methodology A retrospective cohort study of 56 patients with advanced SCCHN. Patients were eligible for inclusion if they had been treated with primary concurrent chemoradiotherapy for squamous cell carcinoma of the oral cavity (p = 7%), oropharynx (p = 54%), larynx (p = 23%) or hypopharynx (p = 16%) at the Sydney Head and Neck Cancer Institute between 2000 and 2005. Patients treated previously for this disease, or with other agents (such as 5‐FU) in combination with cisplatin/carboplatin, were excluded. Treatment was 80 or 100 mg/m² of cisplatin in weeks 1, 4 and 7 of radiotherapy. Percutaneous endoscopic gastrostomy (PEG) feeding tubes were placed in 86% of patients. Results A 90% initial complete response rate was observed. The Kaplan‐Meier 3 year projected overall survival rate was 72% and 3‐year disease specific survival was 74%. Eleven percent of the patient cohort underwent salvage surgery while 14% required chemotherapy dose adjustments. Twenty percent of patients required unplanned hospital admission for the management of treatment related toxicity. Conclusion Our study affirms that our overall survival rates and treatment related toxicities, using a concomitant chemoradiotherapy protocol are comparable with other institutions. Our initial clinical response rates may reflect our selection criteria and the low percentage of patients requiring dose adjustments. Our low rate of unplanned hospital admissions may be explained by the routine use of PEG tubes to reduce treatment related complications.     

The mayo clinic experience with multimodality treatment of locally advanced or recurrent colon cancer

Background Patients with incompletely resected locally advanced and recurrent colon cancers have a dismal prognosis. Since 1981, 100 colon cancer patients have been treated with combination therapy including surgical resection, chemotherapy, and external plus intraoperative radiotherapy. Methods A prospective computerized intraoperative radiation database identified patients for this retrospective review. Data collection included patient demographics, tumor and treatment variables, and morbidity, recurrence, and survival statistics. Results The mean age was 55.2 years. Follow-up was available for all patients. Fifty-nine patients have died. Median follow-up of survivors was 70.5 months. Twenty-five patients with locally advanced colon cancer had a median survival of 38.2 months and a 5-year survival of 49%. Eleven of these patients are still free of disease. Seventy-three patients treated for recurrent colon carcinoma had a median survival of 33.3 months from the time of recurrence, with a 5-year survival of 24.7%. Twenty-one are alive without evidence of recurrence. The 38 patients with recurrent disease whose disease was completely resected had a 37.4% 5-year survival. Conclusions A multimodality approach using en-bloc surgical resection with radiotherapy and chemotherapy affords some patients with locally advanced and recurrent colon cancer a chance for long-term survival. Presented at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.     

A phase 1/2 of a combination of Cetuximab and Taxane for “triple negative” breast cancer patients

50–70% of tumors of the so called “triple negative” subtype of breast cancer express EGFR. We hypothesized that addition of anti EGFR to Taxanes will result in increased effectiveness in EGFR expressing tumors. Here we set out to obtain data regarding the safety, tolerability and also the effectivity of the combination of weekly Taxane treatments with Cetuximab -an anti EGFR antibody in this subgroup of breast cancer. 18 triple negative breast cancer patients were treated with weekly Cetuximab and Taxane therapy. Addition of Cetuximab resulted in controllable Dermatologic toxicity in most patients –with grade 3 in two patients. Some impressive results were noted including one CR, one near CR and regression of chemotherapy and radiation resistance skin metastasis. Median TTF -and overall survival −6 and 12 months. Administration of Taxane Cetuximab weekly therapy for triple negative breast cancer patients is feasible. Use of anti EGFR-Taxane combinations should be assessed in larger clinical trials in this patient population perhaps in a similar manner to the lung cancer patients only in those with strong EGFR expression.     

High-dose intra-arterial cisplatin and concurrent hyperfractionated radiation therapy in patients with locally advanced primary squamous cell carcinoma of the head and neck: report of a phase II study

BACKGROUND: This phase II study evaluates the tolerability and efficacy of concurrent hyperfractionated radiation therapy (HFX-RT) and high-dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: Between December 1995 and November 1997, 20 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8-79.2 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150 mg/m(2) given at the start of RT boost treatment [start of week 6]). Seventeen patients (85%) had T4 disease, and 14 (70%) had N2/ N3 disease. RESULTS: Grade 3-5 acute toxicity was limited to one grade 4 (5%) and 14 grade 3 (70%) mucosal events. No grade 3/4 hematologic toxicity was observed. Median weight loss during therapy was 9% (range, 2%-16%). Eighteen patients had complete response (90%) at the primary site; 14 were confirmed pathologically. Among 17 patients with positive neck disease, 16 (94%) achieved complete response in the neck, including 12 of 13 patients with N2/N3 disease who underwent planned neck dissection. Active follow-up ranges from 12 to 32 months (median, 20 months) with 11 patients alive without disease, 5 dead of disease, and 4 dead of intercurrent disease. Eighteen patients (90%) remained disease free at the primary site, and the locoregional control rate is 80%. CONCLUSIONS: High-dose IA cisplatin and concurrent HFX-RT as used in this study is feasible and warrants further investigation. The high complete response rate and low grade 4 toxicity in this highly unfavorable subset of patients appears better than previously reported chemoradiation regimens for more favorable patients.     

Preoperative sequential chemotherapy in locally advanced squamous cell carcinoma of the head and neck

BACKGROUND: Induction chemotherapy may contribute to decreased local and distant recurrences in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) resectable for cure. METHODS: Patients with previously untreated locally advanced stage III-IV (N0-2, M0) SCCHN received a dose-dense sequential regimen combining cisplatin/5-fluorouracil followed by bleomycin/methotrexate/hydroxyurea. Induction chemotherapy was followed by locoregional surgery and/or radiation therapy. RESULTS: Among 37 patients, 23 (62%) had T4 primary tumors. Grade 3 to 4 asymptomatic hematologic toxicity occurred in less than 15% of patients. Nonhematologic toxicities were limited to grade 1 to 2 in less than 20% of patients. In the overall cohort (intent-to-treat; n = 35), 24 (68.5%) of 35 patients had objective clinical responses, including nine complete responses (25.7%). Fifty-seven percent of patients were free of disease at 2.5 years. CONCLUSIONS: Sequential induction chemotherapy is feasible and active in patients with locally advanced head and neck cancers and may further include recent compounds such as taxanes.     

Benefit of postoperative chemoradiotherapy for patients with unknown primary squamous cell carcinoma of the head and neck

BACKGROUND: Postopertative adjuvant chemoradiotherapy recently became an established modality for patients with selected high-risk locally advanced head and neck cancers. The optimal treatment of unknown primary squamous cell cancer of the head and neck (SCCHN) continues to be controversial, since major randomized studies excluded those patients. METHODS: We conducted a retrospective review of patients treated during 1995 to 2002 for unknown primary SCCHN. All patients were treated with a neck dissection followed by concurrent high-dose cisplatin (100 mg/m(2)) and bilateral neck radiotherapy. RESULTS: Thirty-seven patients were identified with nodal disease distribution of N1 (5%), N2a (22%), N2b (41%), N2c (8%), N3 (22%), and Nx (3%). Modified neck dissection was done on the majority (30/37 = 81%) of patients. With a median follow-up of 42 months among the survivors, very few patients had regional recurrence (5%) or distant failure (11%), and 89% of patients were alive. The actuarial 5-year overall survival rate could not be estimated because there were no deaths beyond 20 months after surgery. Substantial yet acceptable acute and late morbidities were demonstrated in this cohort of patients. CONCLUSIONS: Postoperative chemoradiotherapy is of potential benefit to patients with unknown primary SCCHN by improving survival and reducing failures. This treatment warrants further prospective evaluation.     

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.     

Role of targeted therapy in combination with surgery in renal cell carcinoma

Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease‐free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron‐sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population‐based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long‐term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma.     

Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer

OBJECTIVE: To evaluate, in the ongoing Early Prostate Cancer (EPC) trial programme, the efficacy and tolerability of bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer. PATIENTS AND METHODS: The EPC programme comprises three randomized, double-blind, placebo-controlled trials designed for combined analysis. Following standard care, 8113 men with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) received oral bicalutamide 150 mg once daily or oral placebo. The primary endpoints were progression-free survival (PFS) and overall survival. RESULTS: The large EPC trial programme is defining men who benefit or do not from early or adjuvant antiandrogen therapy. At a median follow-up of 7.4 years, in localized disease there is no benefit to PFS by adding bicalutamide to standard care, and there is a trend (hazard ratio, HR, 1.16; 95% confidence intervals, CI, 0.99-1.37; P = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting. However, in locally advanced disease, bicalutamide significantly improved PFS irrespective of standard care. Bicalutamide significantly improved overall survival in patients receiving radiotherapy (HR 0.65; 95% CI 0.44-0.95; P = 0.03); this was driven by a lower risk of prostate cancer-related deaths. Bicalutamide produced a trend towards improved overall survival in patients with locally advanced disease otherwise undergoing watchful waiting (HR 0.81; 95% CI 0.66-1.01; P = 0.06). No survival difference was evident in the prostatectomy subgroup. CONCLUSIONS: This ongoing programme is clarifying the role of early or adjuvant antiandrogen therapy in prostate cancer. Patients with localized disease do not appear to derive clinical benefit from added bicalutamide. However, adding bicalutamide 150 mg to standard care provides significant clinical benefits in patients with locally advanced prostate cancer, irrespective of primary therapy.     

Surgical resection after radiochemotherapy in patients with unresectable adenocarcinoma of the pancreas

BACKGROUND: The use of chemoradiotherapy for pancreatic cancer has been advocated for its potential ability to downstage locally advanced tumors. This article reports our experience with chemoradiotherapy for patients with unresectable, locally advanced pancreatic cancer (superior mesenteric artery or celiac axis encasement). STUDY DESIGN: Since 1998, 61 patients with radiographically unresectable, pathologically confirmed pancreatic adenocarcinoma have received standard fractionation radiation therapy (total dose, 45 Gy at 1.8 Gy, 5 d/wk) with chemotherapy, which included a continuous infusion of fluorouracil (5-FU: 650 mg/m(2)/D1-D5 and D21-D25) and cisplatin (80 mg/m(2)/bolus D2 and D22). Patients with tumor response at restaging CT scan underwent surgical exploration to determine whether the tumor was resectable. RESULTS: Thirty-eight of 61 (62%) restaged patients demonstrated a disease progression. Twenty-three patients (38%) had an objective response, with, in all cases, persistence of arterial encasement. Twenty-three patients underwent exploratory operations after chemoradiotherapy, and 13 underwent standard Whipple resection. So 13 of 23 (56%) patients who had exploratory operation, or 23 of 61 (21%) patients, underwent surgical resection. With a median followup of 27 months, median survival for the resected patients was 28 months. Median survival was 11 months in the nonresponder group (n = 38) and 20 months in the group who received a palliative procedure (n = 10). CONCLUSIONS: Locally advanced, unresectable pancreatic adenocarcinoma may be downstaged by chemoradiotherapy to allow for surgical resection. Patients whose cancer becomes resectable have a median survival at least comparable with survival after resection for initially resectable pancreatic adenocarcinoma.     

Palliative Chemotherapy and Radiotherapy for Pancreatic Cancer: Is It Worthwhile?

The role of palliative chemotherapy or radiotherapy (or both) in pancreatic cancer is discussed. In patients with disseminated pancreatic cancer chemoradiotherapy has so far not been effective in prolonging survival. Recent trials with gemcitabine has shown a modest improvement in clinical benefit and survival. Patients with locally advanced disease should be offered 5-fluorouracil and radiation therapy, as valid data have repeatedly shown better median survival compared to no therapy. The option of a second-look laparotomy to evaluate resectability after palliative chemoradiotherapy in patients with locally advanced disease should be applied liberally because currently available imaging techniques sometimes do not accurately reflect tumor size and tumor progression. New treatment strategies, such as regional perfusion, are being investigated.     

Extreme Oncoplasty: Breast Conservation for Patients Who Need Mastectomy

Extreme oncoplasty is a breast conserving operation, using oncoplastic techniques, in a patient who, in most physicians' opinions, requires a mastectomy. These are generally large, greater than 5 cm multifocal or multicentric tumors. Many will have positive lymph nodes. Most will require radiation therapy, even if treated with mastectomy. Sixty‐six consecutive patients with multifocal, multicentric, or locally advanced tumors that spanned more than 50 mm were studied (extreme cases). All patients underwent excision and oncoplastic reconstruction using a standard or split wise pattern reduction and immediate contralateral surgery for symmetry. All received postexcisional standard whole breast radiation therapy with a boost to the tumor bed. The extreme cases were compared with 245 consecutive patients with unifocal or multifocal tumors that spanned 50 mm or less (standard cases). All extreme patients were advised to have a mastectomy; all sought a breast conserving second opinion. Diagnostic evaluation included digital mammography, ultrasound, MRI, and PET‐CT (if invasive). Standard cases did extremely well. No ink on tumor was achieved 96% of the time among 245 patients. The median tumor size was 21 mm (mean 23 mm). Margins equal or greater than 1 mm were achieved in 88.6% of patients. Seventeen (6.9%) standard patients underwent re‐excision to achieve wider margins and only one patient (0.4%) was converted to mastectomy. With 24 months of median follow‐up, three patients (1.2%) experienced local recurrence. For extreme cases, no ink on tumor was achieved 83.3% of the time, which is comparable to published positive margin rates after standard lumpectomy. The median tumor size was 62 mm (mean 77 mm). Margins equal or greater than 1 mm were achieved in 54.5% of patients. Six (9.1%) extreme patients underwent re‐excision to achieve wider margins and four patients (6.1%) were converted to mastectomy. With a follow‐up of 24 months, one patient (1.5%) experienced a local recurrence. Extreme oncoplasty is a promising new concept. It allows successful breast conservation in selected patients with greater than 5 cm multifocal/multicentric tumors. It may be useful in patients with locally advanced tumors following neo‐adjuvant chemotherapy. From a quality of life point of view, it is a better option than the combination of mastectomy, reconstruction, and radiation therapy. Long‐term data on recurrence and survival are not available, using this approach. Based on historical data, it is expected the local recurrence will be somewhat higher but that there will be little or no impact on survival.     

Radiation therapy in the management of locally advanced prostate cancer

Locally advanced prostate cancer generally refers to those patients with clinical stages T3-4 disease. Patients with locally advanced cancer frequently are included in clinical trials that examine treatment for patients at high risk for relapse based on presenting prostate-specific antigen, high Gleason score, or advanced clinical stage. There is a growing body of evidence that suggests that men with localized prostate cancer benefit from high-dose radiation therapy delivered with three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, or proton beam therapy. Most importantly, neoadjuvant and adjuvant androgen-deprivation therapy have significantly improved outcomes in men with locally advanced or high-risk prostate cancer. Although questions remain regarding the optimal timing and duration of adjuvant hormonal therapy, a combination of long-term androgen deprivation started before radiation therapy and continued for 2 years represents a North American standard of care for this patient population.     

Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer?

Recent studies suggest that neoadjuvant chemoradiation can downstage locally advanced pancreatic tumors. There is limited evaluable data to support this approach. We review our experience with preoperative chemoradiation for surgically staged, locally advanced pancreatic cancer to determine whether patients are downstaged with multimodal therapy allowing for curative resection. A prospectively collected database from Memorial Sloan-Kettering Cancer Center was reviewed. Patients admitted between January 1993 and March 1999 with locally advanced pancreatic adenocarcinoma were identified (N = 163). Chemoradiation was administered to 87 (53.3%) of 163, and regimens varied from standard 5-fluorouracil/gemcitabine-based therapies to experimental protocols. Only three patients (3/87; 3.4%) had a sufficient clinical response on restaging to warrant reexploration. Of these, two thirds were unresectable on subsequent laparoscopy because of extensive vascular involvement or metastatic disease. Only one patient underwent a potentially curative resection, with a survival of 18 months despite negative margins and no nodal involvement. The overall median survival for all patients with locally advanced disease treated with chemoradiation was 11 months (6.5 months without multimodal therapy; P = 0.004). Although hemora-diation is associated with improved overall survival in locally advanced disease, it rarely leads to surgical “downstaging” allowing for potentially curative pancreatic resections. Novel multimodality approaches are required. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, California, May 21–24, 2000 (poster presentation).     

Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who received second-line immune checkpoint inhibitors

BackgroundThe therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited.Patients and MethodsThe objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy.Results2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79–1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84–1.19]) while receiving second-line ICI.ConclusionsSurvival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.     

Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66–84; placebo, 77 mo, IQR 69–85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80–1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m² compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC.Patient summaryIn the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC.This trial is registered at Clinicaltrials.gov as NCT01235962.     

Intraoperative radiation therapy for biliary tract carcinoma: results of a 5-year experience

The results of a 5-year experience with use of intraoperative radiation therapy (IORT) in the management of locally advanced bile duct carcinoma are presented. Fifteen patients received IORT doses between 5 and 20 Gy for localized disease, which was either primary and resected with microscopic residual (2 patients), primary and unresected (10 patients), or recurrent (3 patients). Thirteen patients also received postoperative radiation therapy. The median survival of the 12 patients with primary disease was 14 months, with disease controlled in the porta hepatis in 5 of 10 evaluable patients. The three patients with recurrent disease survived 2, 9, and 11 months. There were two operative deaths, for an operative mortality of 13%. Acute and chronic complications are reviewed. Cholangitis is the most frequent in both categories. This aggressive approach in the therapy for advanced disease has an acceptable level of morbidity and may warrant the use of IORT as part of the management of biliary tract cancer.     

Nonfunctioning islet cell carcinoma of the pancreas: case report

Islet cell carcinomas have an incidence of 5 per million per year; 50 per cent of these are nonfunctioning islet cell tumors. The presenting symptoms mimic pancreatic ductal adenocarcinoma. The CT finding of a pancreatic head mass that spares the main duct may distinguish between the two. The treatment of choice is resection. Most nonfunctioning islet cell tumors are not discovered until metastases are present. However, favorable survival rates have been reported in locally advanced tumors that have undergone resection. Liver metastases carry an unfavorable prognosis. Five-year survival over 60 per cent has been reported. Node-negative patients have a median survival of more than 10 years, and node-positive patients who have undergone resection have a median survival of 75 months. Streptozotocin and 5-fluorouracil are used postoperatively in patients with advanced disease. Considering the favorable survival with resection aggressive surgical treatment is mandated in cases of nonfunctioning islet cell tumors.