TP53 Co-Mutation Status Association with Clinical Outcomes in Patients with EGFR-Mutant Non-Small Cell Lung Cancer.

TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1-1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1-2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0-0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0-2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice.

Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Skin flap squamous cell carcinoma developed after urethroplasty.

OBJECTIVES: To describe our experience in diagnosis and treatment of urethral carcinoma following urethroplasty with a Orandi penile skin flap. MATERIAL AND METHODS: Our patient underwent to Orandi penile skin flap urethroplasty then developed a urethral epidermoid carcinoma on the flap approximately 15 years later. We treated this case with a partial penectomy surgery and perineostomy. Surgery was followed by chemotherapy with cisplatin and 5-fluorouracil. The progression of the disease led to a salvage surgery of total penectomy and asportation of testicles and scrotum. RESULTS: Despite the success of the surgery, the disease progressed and three months after the last surgical operation the patient died. CONCLUSIONS: Urethral carcinoma on skin flap is a rare complication of the urethroplasty surgery but with severe consequences, so we recommend to undertake a long-term urological follow up in patients undergone such kind of surgery.

Surgical approach to adrenal ganglioneuroma: Case report and literature review.

OBJECTIVE: Ganglioneuroma (GN) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus. It is usually asymptomatic or with nonspecific symptoms. TC and RM scan are helpful to study GN. It is usually represented by an ovalshaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. Surgical treatment is mandatory. Literature shows how the laparoscopic approach is the most used, especially in lesions that are 6 cm or smaller. Our purpose is to describe our experience on an incidental adrenal GN of about 5 cm treated by the laparoscopic transperitoneal approach. MATERIALS AND METHODS: A 33-year-old male had ultrasound occasional finding of an about 4 cm adrenal mass. TC and RM scan identified a retroperitoneal mass (max diameter 48 mm). The lesion was removed with a transperitoneal laparoscopic approach. RESULTS: No intraoperative or postoperative complications occurred. The patient was discharged 3 days after surgery. CONCLUSIONS: Up to the present laparoscopic surgery is the best approach for GN treatment.

Automatic segmentation software in locally advanced rectal cancer: READY (REsearch program in Auto Delineation sYstem)-RECTAL 02: prospective study.

To validate autocontouring software (AS) in a clinical practice including a two steps delineation quality assurance (QA) procedure.The existing delineation agreement among experts for rectal cancer and the overlap and time criteria that have to be verified to allow the use of AS were defined.Median Dice Similarity Coefficient (MDSC), Mean slicewise Hausdorff Distances (MSHD) and Total-Time saving (TT) were analyzed.Two expert Radiation Oncologists reviewed CT-scans of 44 patients and agreed the reference-CTV: the first 14 consecutive cases were used to populate the software Atlas and 30 were used as Test.Each expert performed a manual (group A) and an automatic delineation (group B) of 15 Test patients.The delineations were compared with the reference contours.The overlap between the manual and automatic delineations with MDSC and MSHD and the TT were analyzed.Three acceptance criteria were set: MDSC ≥ 0.75, MSHD ≤1mm and TT sparing ≥ 50%.At least 2 criteria had to be met, one of which had to be TT saving, to validate the system.The MDSC was 0.75, MSHD 2.00 mm and the TT saving 55.5% between group A and group B. MDSC among experts was 0.84.Autosegmentation systems in rectal cancer partially met acceptability criteria with the present version.

Clinical validation of atlas-based auto-segmentation of pelvic volumes and normal tissue in rectal tumors using auto-segmentation computed system.

PURPOSE: To evaluate in two different settings - clinical practice and education/training - the reliability, time efficiency and the ideal sequence of an atlas-based auto-segmentation system in pelvic delineation of locally advanced rectal cancer. METHODS: Fourteen consecutive patients were selected between October and December 2011. The images of four were used as an atlas and 10 used for validation. Two independent operators participated: a Delineator to contour and a Reviewer to perform an independent check (IC). The CTV, pelvic subsites and organs at risk were contoured in four different sequences. These included A: manual; B: auto-segmentation; C: auto-segmentation + manual revision; and D: manual + auto-segmentation + manual revision. Contouring was performed by the Delineator using the same planning CT. All of them underwent an IC by a Reviewer. The time required for all the contours were recorded and overlapping evaluation was assessed using a Dice coefficient. RESULTS: In the clinical practice setting there have been 13 minutes time saved between sequences A versus sequences B (from 38 to 25 minutes, p = 0.002), a mean Dice coefficient in favor of sequences A for CTV and all subsites (p = 0.0195). In the educational/training setting there have been 35.2 minutes time saved between sequences C and D 8 (from 73.1 min to 37.9 min, p = 0.002). CONCLUSION: The preliminary data suggest that the use of an atlas-based auto-contouring system may help improve efficiencies in contouring in the clinical practice setting and could have a tutorial role in the educational/training setting.

Definitive treatment of metastatic nasopharyngeal carcinoma: Report of 5 cases with review of literature.

BACKGROUND: To review the treatment outcomes of patients presenting to Memorial Sloan-Kettering Cancer Center with metastatic nasopharyngeal carcinoma. METHODS: From April 1999 to April 2008, 5 patients with histologically confirmed nasopharyngeal carcinoma initially presenting with distant metastasis underwent chemotherapy and definitive radiation therapy at our institution. Each patient received platinum-based chemotherapy concurrently with definitive radiotherapy to the primary region and subsequent consolidation radiotherapy to distant metastases. In addition, 2 patients received induction chemotherapy (cisplatin, fluorouracil), and 3 others received adjuvant chemotherapy (cisplatin or carboplatin, fluorouracil). RESULTS: Of 5 patients initially presenting to our institution with M1 disease, 2 have no evidence of disease as of their last follow-up (29 and 91 months). The remaining 3 patients had progression of disease within 12 months of the start of treatment. CONCLUSIONS: Long-term disease-free survival is possible in a select group of patients with M1 disease at presentation treated with platinum-based chemotherapy and definitive radiotherapy.

Intensity-modulated radiation therapy in oropharyngeal carcinoma: effect of tumor volume on clinical outcomes.

PURPOSE: To analyze the effect of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) on treatment outcomes in patients treated with definitive intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC). METHODS AND MATERIALS: Between September 1998 and April 2009, a total of 442 patients with squamous cell carcinoma of the oropharynx were treated with IMRT with curative intent at our center. Thirty patients treated postoperatively and 2 additional patients who started treatment more than 6 months after diagnosis were excluded. A total of 340 patients with restorable treatment plans were included in this present study. The majority of the patients underwent concurrent platinum-based chemotherapy. The pGTV and nGTV were calculated using the original clinical treatment plans. Cox proportional hazards models and log-rank tests were used to evaluate the correlation between tumor volumes and overall survival (OS), and competing risks analysis tools were used to evaluate the correlation between local failure (LF), regional failure (RF), distant metastatic failure (DMF) vs. tumor volumes with death as a competing risk. RESULTS: Median follow-up among surviving patients was 34 months (range, 5-67). The 2-year cumulative incidence of LF, RF and DF in this cohort of patients was 6.1%, 5.2%, and 12.2%, respectively. The 2-year OS rate was 88.6%. Univariate analysis determined pGTV and T-stage correlated with LF (p < 0.0001 and p = 0.004, respectively), whereas nGTV was not associated with RF. On multivariate analysis, pGTV and N-stage were independent risk factors for overall survival (p = 0.0003 and p = 0.0073, respectively) and distant control (p = 0.0008 and p = 0.002, respectively). CONCLUSIONS: In this cohort of patients with OPC treated with IMRT, pGTV was found to be associated with overall survival, local failure, and distant metastatic failure.

Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience.

PURPOSE: To update the Memorial Sloan-Kettering Cancer Center's experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC). METHODS AND MATERIALS: Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based. RESULTS: Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia ≥Grade 2 was 11% and 29%, respectively. CONCLUSIONS: Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC.

Target volume delineation in oropharyngeal cancer: impact of PET, MRI, and physical examination.

INTRODUCTION: Sole utilization of computed tomography (CT) scans in gross tumor volume (GTV) delineation for head-and-neck cancers is subject to inaccuracies. This study aims to evaluate contributions of magnetic resonance imaging (MRI), positron emission tomography (PET), and physical examination (PE) to GTV delineation in oropharyngeal cancer (OPC). METHODS: Forty-one patients with OPC were studied. All underwent contrast-enhanced CT simulation scans (CECTs) that were registered with pretreatment PETs and MRIs. For each patient, three sets of primary and nodal GTV were contoured. First, reference GTVs (GTVref) were contoured by the treating radiation oncologist (RO) using CT, MRI, PET, and PE findings. Additional GTVs were created using fused CT/PET scans (GTVctpet) and CT/MRI scans (GTVctmr) by two other ROs blinded to GTVref. To compare GTVs, concordance indices (CI) were calculated by dividing the respective overlap volumes by overall volumes. To evaluate the contribution of PE, composite GTVs derived from CT, MRI, and PET (GTVctpetmr) were compared with GTVref. RESULTS: For primary tumors, GTVref was significantly larger than GTVctpet and GTVctmr (p < 0.001). Although no significant difference in size was noted between GTVctpet and GTVctmr (p = 0.39), there was poor concordance between them (CI = 0.62). In addition, although CI (ctpetmr vs. ref) was low, it was significantly higher than CI (ctpet vs. ref) and CI (ctmr vs. ref) (p < 0.001), suggesting that neither modality should be used alone. Qualitative analyses to explain the low CI (ctpetmr vs. ref) revealed underestimation of mucosal disease when GTV was contoured without knowledge of PE findings. Similar trends were observed for nodal GTVs. However, CI (ctpet vs. ref), CI (ctmr vs. ref), and CI (ctpetmr vs. ref) were high (>0.75), indicating that although the modalities were complementary, the added benefit was small in the context of CECTs. In addition, PE did not aid greatly in nodal GTV delineation. CONCLUSION: PET and MRI are complementary and combined use is ideal. However, the low CI (ctpetmr vs. ref) particularly for primary tumors underscores the limitations of defining GTVs using imaging alone. PE is invaluable and must be incorporated.

Irradiation of pacemakers and cardio-defibrillators in patients submitted to radiotherapy: a clinical experience.

AIMS AND BACKGROUND: A prospective analysis was carried out on a group of irradiated patients with pacemakers or implantable cardioverter-defibrillators to identify any relationship between the various types of devices and physical and dosimetric parameters. Cardiac toxicity of the treatment was also investigated. METHODS AND STUDY DESIGN: Forty-five irradiated patients, implanted with pacemakers or implantable cardioverter-defibrillators, were prospectively investigated from 1999 to 2007. An analysis of radiation damage to pacemakers, depending on the geometric and dosimetric characteristics of the radiation beams, was carried out. The electric and magnetic fields of linear accelerators (LINACs) were measured to evaluate any interference. The calculation of dose received by pacemakers was evaluated by dose-volume histograms. RESULTS: No dysfunction was observed in any pacemaker, nor were the substitution times negatively affected. We did not find problems with the devices due to the interaction with the electromagnetic fields. Dose-volume histograms calculated for patients treated in regions close to devices (head & neck, thorax) showed an average maximum dose equal to 2.5 Gy for the head & neck area and equal to 1.8 Gy for the thoracic area. Acute (3 cases) and late (2 cases) cardiac events were observed only in 5 patients who underwent chemoradiation treatment, but no dysfunction was observed in any pacemaker. CONCLUSIONS: Our study confirms the safety of radiotherapy for patients implanted with pacemakers or implantable cardioverter-defibrillators but suggests that chemoradiation represents a probable risk factor for cardiac toxicity. Furthermore, all cardiac events were observed in patients treated in the head and'neck or left thoracic areas. A standardized protocol is advisable in order to improve patient control during the radiotherapy treatment. It is mandatory to calculate the dose received at the pacemaker/heart, even in the case of palliative treatment.