Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).

Evaluation of tolerance and toxicity of high-dose-rate brachytherapy boost combined with interstitial hyperthermia for prostate cancer.

Purpose The aim of this retrospective study was to evaluate the tolerance and early as well as late toxicity of high dose rate brachytherapy (HDRBT) boost combined with interstitial hyperthermia (IHT) in patients treated for prostate cancer. Material and methods Between January 2011 and June 2013 76 patients diagnosed with prostate cancer received treatment consisting of external beam radiotherapy (EBRT), followed by a HDRBT boost combined with IHT. IHT was performed before each brachytherapy fraction. Results The median follow-up time was 26.3 months (range 7-43 months). Early genitourinary (GU) grade 1 and 2 toxicities were common, but only two patients (2.6%) experienced acute urinary retention requiring temporary catheterisation (grade 2 toxicity). No grade 3 or 4 genitourinary or gastrointestinal toxicities were observed. In the group analysed, 59 of 76 patients had follow-up times longer than 18 months. The incidence of grade 2 late toxicity in the group studied did not exceed 23.7%. There were no late grade 2 or higher complications from the gastrointestinal tract. Conclusions The tolerance of HDRBT boost combined with IHT is good. The profile and the percentage of early and late complications are acceptable.

Male breast cancer: a clinicopathological study of an Egyptian population (Alexandria experience).

AIM OF THE STUDY: The purpose of this retrospective study is to evaluate the clinicopathological features and treatment results of male breast cancer presented to our tertiary referral center. MATERIAL AND METHODS: Between January 1998 and December 2005, a total of 39 men with breast cancer treated at Alexandria Main University Hospital and their medical records were reviewed. RESULTS: The median age of patients was 59 years. Only 3 (7.7%) patients had positive family history. All patients presented by breast swellings that were associated with axillary mass in about one third of them. Around 80% had hormone receptor positive (estrogen and/or progesterone receptors). Two third of patients had advanced T-stage (T3 and T4). Left sided breast cancer occurred in 51.3%. Infiltrating ductal carcinoma was the most common type of histology encountered and grade 2 was the predominant grade of tumor. Modified radical mastectomy was the most common (87.2%) type of surgery done followed by chemotherapy for 32 patients and loco-regional radiotherapy for 20 patients. Tamoxifen was administered in 31 patients. Distant relapse occurred in 7 patients (17.9%) and local recurrence occurred in 2 patients (5.1%). The 5-year disease-free survival (DFS) was 82% and the 5-year overall survival (OS) rate was 84%. Only negative axillary lymph node and positive hormone receptor status were significantly associated with favorable DFS and OS. T-stage, grade of tumor and type of chemotherapy given had no statistically significant impact on either DFS or OS. CONCLUSIONS: Male breast cancer is still under-investigated and further researches are warranted.

Role of irradiation in combined treatment of head and neck paragangliomas at the Centre of Oncology in Krakow between 1970-2005.

AIM OF THE STUDY: Aim of the study is to evaluate the results of postoperative radiotherapy of paragangliomas, prognostic factors and causes of treatment failure. MATERIAL AND METHODS: Forty-four patients (39 females and 5 males) aged 20 to 74 years were treated for paraganglioma between 1970 and 2010 at the Centre of Oncology in Kraków. Patient survival probability was estimated with the Kaplan-Meier method. Log-rank tests and Cox proportional hazard model were used in univariate and multivariate analysis, respectively. RESULTS: The most common locations of paragangliomas were the following: the ear, carotid body and internal jugular vein bulb. Forty (91%) out of them were benign and 4 - malignant. All patients underwent surgery followed by adjuvant radiotherapy. The delivered dose ranged from 50 to 72 Gy, the mean dose was 60 Gy. Five-year overall survival was 84%. Five-year relapse-free survival was 84%, either. The multivariate analysis has shown that the dose in an independent prognostic factor for the overall survival. The univariate analysis has shown significantly higher 5-year overall survival in patients who received a dose of 60 Gy or higher - 92% vs. 70% in patients who received a dose lower than 60 Gy. CONCLUSIONS: Postoperative radiotherapy with doses higher than 60 Gy in patients with paragangliomas is associated with longer overall survival.

[Predictive and prognostic value of p53, Ki-67 and EGFR in patients with advanced oral cavity and oropharyngeal cancer treated with induction chemotherapy]. / Ocena wartosci predykcyjnej i prognostycznej p53, Ki-67 i EGFR u chorych na zaawansowanego raka jamy ustnej i ustnej czesci gardla leczonych z zastosowaniem indukcyjnej chemioterapii.

BACKGROUND: To determine predictive and prognostic value of p53, Ki-67 and EGFR in patients with advanced oral cavity and oropharyngeal cancer treated with induction chemotherapy. MATERIALS AND METHODS: The data form 40 patients with advanced oral cavity and oropharyngeal cancer treated between January 1988 and December 1997 were analyzed retrospectively. All patients received 1 to 3 cycles of induction chemotherapy (ICHT) consisting of cisplatin and fluoruracil. Twenty two patiemts (68%) underwent subsequent radical radiotherapy. Histologic and immunohistochemical analyzes of p53, Ki-67 and EGFR were performed in all patients. RESULTS: Response to induction chemotherapy was obtained in 18 patients (45%). None of the analyzed factors significantly influenced the chance to obtain the response to chemotherapy. The 3-year loco-regional control and overall survival rates in the group of 22 patients treated radically were 20% and 23%, respectively. CONCLUSIONS: Lack of EGFR expression is favorable prognostic factor for overall survival in patients with advanced oral cavity and oropharyngeal cancer treated with induction chemotherapy.

Prognostic value of the interval from surgery to initiation of radiation therapy in correlation with some histo-clinical parameters in patients with malignant supratentorial gliomas.

AIM OF THE STUDY: To determine the relationship between the interval from surgery to initiation of radiation therapy (ISRT) and prognostic factors, such as age, performance status, tumour location, extent of surgical resection and tumour histology in patients with malignant gliomas. MATERIALS AND METHODS: From 1995 to 2005, 308 adults patients with supratentorial malignant gliomas (198 glioblastomas, and 110 anaplastic astrocytomas) received postoperative radiotherapy with radical intent. A total tumour dose of 60 Gy in 30 fractions in 6 weeks was delivered. ISRT varied from 15 to 124 days, with median time of 37 days, and it was a cut-off value to assess the results. The end point in our study was two-year overall survival. RESULTS: The two-year overall survival rate in the whole group was 17%, with 24% for patients with ISRT value ≤ 37 days, and 14% for patients with an interval longer than 37 days (p = 0.042). Univariate analysis showed that delayed initiation of radiotherapy influenced the outcome of patients with glioblastoma older than 40 years, and with other than frontal location of tumour. Two-year overall survival rates for ISRT ≤ 37 days were 15%, 18% and 22% respectively, compared to 8%, 4% and 11% for ISRT > 37 days. In a multivariate analysis (Cox's model) the only variables that were significantly associated with worse survival were older age and ISRT prolonged for more than 37 days. CONCLUSION: The study showed longer than 37 days waiting time from surgery to initiation of radiotherapy to be a significant predictor of overall survival for adult patients with malignant supratentorial gliomas.

Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV.

AIM OF THE STUDY: The incidence of melanoma is increasing rapidly worldwide. Metastatic melanoma is still an incurable disease, although an era of new drugs is approaching. Current methods to predict outcomes in patients with advanced, metastatic melanoma are limited. A retrospective analysis of a contemporary large group of advanced melanomas was performed to determine clinical prognostic factors that accurately predict survival in patients with metastatic melanoma before the era of new targeted/immunological therapy. MATERIAL AND METHODS: The retrospective analysis of 427 patients with metastatic melanoma treated between 1995 and 2005 at two reference oncological centres. RESULTS: The median overall survival time (OS) was 7.1 months (95% CI: 6.7-7.9) and the 1-year, 2-year and 5-year survival rates were 32.3%; 12.5%; 3.9%, respectively. The median progression-free survival time (PFS) after the first line of treatment was 3.5 months (95% CI: 3.1-3.8). There were 19.1% objective responses (CR - 6.1%, PR - 13.0%) and SD - 45.5% after the first line of therapy. The most common adverse events were anaemia, neutropenia, thrombocytopenia, nausea and vomiting. IN MULTIVARIATE ANALYSES: PS (performance status) 0-1, normal serum levels of lactate dehydrogenase (LDH) and aspartate transaminase (AspAT), older age in women, palliative surgical treatment and palliative radiotherapy, type of the first line of therapy (DTIC), and metastatic melanoma of unknown primary site were independent positive predictors for survival. CONCLUSIONS: The survival rate of patients with metastatic melanoma has not changed significantly over the last years. We identified a set of independent positive predictors for OS treated with systemic therapy. DTIC still may be useful in treatment of patients in a good general condition and with normal serum levels of LDH. Because the results of treatment of metastatic melanoma are still not satisfactory, the majority of patients should be treated within prospective, randomized clinical trials.

Long-term follow-up in adult patients with low-grade glioma (WHO II) postoperatively irradiated. Analysis of prognostic factors.

AIM: To report the long-term follow-up of a cohort of adult patients with LGG post-operatively irradiated in one institution, and to identify prognostic factors for progression free survival. BACKGROUND: There is little consensus about the optimal treatment for low-grade glioma (LGG), and the clinical management of LGG is one of the most controversial areas in neurooncology. Radiation therapy is one option for treatment of patients with LGG, whereas other options include postoperative observation. MATERIALS AND METHODS: Between 1975 and 2005, 180 patients with LGG (WHO II) received postoperative irradiation after non radical (subtotal or partial) excision. Patients had to be 18 years of age or older, and have histologic proof of supratentorial fibrillary (FA), protoplasmic (PA) or gemistocytic astrocytoma (GA). Radiotherapy was given within 3-10 weeks after surgery. Treatment fields were localized and included the preoperative tumor volume, with a 1-2 cm margin, treated to a total dose of 50-60 Gy in 25-30 fractions over 5-6 weeks. RESULTS: Actuarial ten-year progression free survival (APFS) in the whole group was 19%. The worse prognosis was observed in patients with GA. Ten-year APFS rates for GA, PA and FA were 10%, 18% and 22%, respectively. CONCLUSION: The findings from our long-term cohort of 180 patients with LGG confirmed by uni- and multivariate analysis demonstrated that only astrocytoma histology significantly determined the prognosis. The best survival was observed in patients with the fibrillary variant, and the worst for the gemistocytic one.

Application of IMRT in adjuvant treatment of soft tissue sarcomas of the thigh-Preliminary results.

BACKGROUND: Fracture of the femur is the most frequent late complication in patients with soft tissue sarcomas (STS) who receive external beam radiotherapy after limb-sparing surgery. AIM: To reduce the risk of bone fracture following radiotherapy of STS of the thigh, we minimized the dose to the femur and to surrounding normal tissues by applying intensity modulated radiation therapy (IMRT). We report preliminary results of post-surgery IMRT of the thigh in patients with STS in this extremity. MATERIALS AND METHODS: 10 adult patients undergoing post-operative radiotherapy of STS of the thigh were treated using IMRT. Clinical IMRT plans with simultaneous integrated boost (SIB) and 3-phase three-dimensional conformal radiotherapy (3D-CRT) were designed to adequately treat the planning target volume and to spare the femur to the largest extent possible. Dose distributions and dose-volume histograms were compared. RESULTS: For either technique, a comparable target coverage was achieved; however, target volume was better covered and critical structures were better spared in IMRT plans. Mean and maximum doses to OAR structures were also significantly reduced in the IMRT plans. On average, the mean dose to the femur in 3D-CRT plans was about two times higher than that in IMRT plans. CONCLUSION: Compared with 3D-CRT, the application of IMRT improves the dose distribution within the concave target volumes and reduces dose to the OAR structures without compromising target coverage.

Thymoma: Results of treatment and role of radiotherapy.

PURPOSE: The aim of this study is to assess results of treatment, factors influencing prognosis with regard to causes of failure and treatment tolerance in patients with thymoma. MATERIAL AND METHODS: Between 1966 and 2006, 63 patients with thymoma had been treated at the Centre of Oncology in Krakow. Patients were treated by means of different treatment modalities: surgery followed by radiotherapy (52%), radiotherapy alone (13%), chemoradiotherapy alone (15%), surgery followed by chemoradiotherapy (5%), surgery alone (5%) and others. RESULTS: The 10-year locoregional recurrence-free survival (LRRFS) was 79%, disease free survival (DFS) was 57% and overall survival (OS) was 57%. Masaoka stage was the only independent prognostic factor for LRRFS. Masaoka stage and method of radiotherapy delivery (higher photon energies), were independent prognostic factors for OS. For DFS, the independent prognostic factors were age, type of treatment (favoured surgery followed by radiotherapy or chemoradiotherapy), Masaoka stage and year of start of treatment. Most common reactions were lung fibrosis in 36% of patients (mainly asymptomatic in most patients), pneumonitis (9%) and oesophagitis (4%). CONCLUSIONS: Surgery combined with radiotherapy and chemoradiotherapy and modern radiotherapy techniques are correlated with improvement of survival in patients with early stage thymoma.

Prognostic and predictive significance of p53, EGFr, Ki-67 in larynx preservation treatment.

BACKGROUND: The optimal management of advanced laryngeal and hypopharyngeal cancers (L&HC) must involve consideration of both survival and functional effect of the given treatment approach. Despite over two decades of investigations of several treatment options, including surgery, radiotherapy, chemotherapy or some combinations thereof, little consensus exists as to which treatment offers the best survival, together with functional speech and swallowing. AIM: To determine predictive and prognostic value of p53, EGFr, Ki-67 in patients with advanced laryngeal and hypopharyngeal cancer, treated with larynx preservation intent. MATERIALS AND METHODS: Thirty-three patients received 2-3 cycles of induction chemotherapy (ICHT) consisting of cisplatin and fluoruracil and underwent subsequent radical radiotherapy. Immunohistochemical analyzes of p53, EGFr and Ki-67 were performed. RESULTS: Response to ICHT was obtained in 24 patients (75%). Better response to ICHT was correlated only with EGFr expression (p = 0.04, RR = 1.91). The 5-year loco-regional control (LRC) and disease-specific survival (DSS) rates were 48% and 57%, respectively. The 5-year larynx preservation rate was 68% in responders to ICHT compared to 21% in non-responders (p = 0.02). It was also higher in patients without EGFr expression (but not significantly, p = 0.43). CONCLUSION: Lack of EGFr expression is a favorable predictive factor for response to ICHT. Neither p53 nor Ki-67 have predictive and prognostic value in larynx preservation treatment.

Tracheal cancer: Role of radiation therapy.

PURPOSE: To assess the results of tracheal cancer patients treatment and factors influencing prognosis. BACKGROUND: Primary malignant neoplasms of the trachea are rare. The treatment of choice for tracheal carcinomas is resection. Radiation therapy is recommended as a part of radical treatment or for palliation of symptoms. MATERIALS AND METHODS: Between 1962 and 2006, 50 patients diagnosed with tracheal cancer were treated at the Centre of Oncology in Krakow. The analysis focused on locoregional recurrence-free survival (LRRFS), disease free survival (DFS) and overall survival (OS). Survival rates, univariate and multivariate analyses of prognostic factors were performed using the Kaplan-Meier method, the log rank test and Cox's proportional hazard method, respectively. For over 40 years, patients were treated using different modalities: surgery followed by radiotherapy (6%), radiotherapy (78%), chemoradiotherapy (8%), and symptomatic treatment (8%). RESULTS: The 5-year LRRFS was 18%, DFS was 15% and OS was 17%. gender (favoured females) was the only prognostic factor for LRRFS. For OS, the independent prognostic factors were performance status (favoured Karnofsky higher than 80), stage and year of start of the treatment (later than 1988 vs. earlier - 5-year OS 20% vs. 12%). 5-year OS in the following (strongly differentiated over the time) treatment modalities were: surgery followed by radiotherapy (66%), radiotherapy (16%), chemoradiotherapy (0%), and symptomatic treatment (0%). Of 44 patients treated with radiotherapy symptomatic partial response was observed in 32 patients and follow-up imaging studies revealed complete response in 5 patients, partial response in 25, stable disease in 4 or progressive disease in 4. CONCLUSIONS: Radical treatment in patients in early stage and good performance status seems to be correlated with the improvement of survival. However, despite the fact that results of treatment are poor, radiotherapy offers symptomatic improvement.

Salvage brachytherapy in combination with interstitial hyperthermia for locally recurrent prostate carcinoma following external beam radiation therapy: a prospective phase II study.

Optimal treatment for patients with only local prostate cancer recurrence after external beam radiation therapy (EBRT) failure remains unclear. Possible curative treatments are radical prostatectomy, cryosurgery, and brachytherapy. Several single institution series proved that high-dose-rate brachytherapy (HDRBT) and pulsed-dose-rate brachytherapy (PDRBT) are reasonable options for this group of patients with acceptable levels of genitourinary and gastrointestinal toxicity. A standard dose prescription and scheme have not been established yet, and the literature presents a wide range of fractionation protocols. Furthermore, hyperthermia has shown the potential to enhance the efficacy of re-irradiation. Consequently, a prospective trial is urgently needed to attain clear structured prospective data regarding the efficacy of salvage brachytherapy with adjuvant hyperthermia for locally recurrent prostate cancer. The purpose of this report is to introduce a new prospective phase II trial that would meet this need. The primary aim of this prospective phase II study combining Iridium-192 brachytherapy with interstitial hyperthermia (IHT) is to analyze toxicity of the combined treatment; a secondary aim is to define the efficacy (bNED, DFS, OS) of salvage brachytherapy. The dose prescribed to PTV will be 30 Gy in 3 fractions for HDRBT, and 60 Gy in 2 fractions for PDRBT. During IHT, the prostate will be heated to the range of 40-47°C for 60 minutes prior to brachytherapy dose delivery. The protocol plans for treatment of 77 patients.