Cisplatin-based Induction Chemotherapy Research Articles

Treatment Outcomes of Concurrent Nimotuzumab with Intensity Modulated Radiotherapy in Advanced Nasopharyngeal Carcinoma Patients Unfit for Concurrent Chemoradiotherapy: A Single Institute Experience

To assess the safety and efficacy of intensity-modulated radiotherapy (IMRT) combined with nimotuzumab for patients with locally advanced nasopharyngeal carcinoma (LA-NPC) medically unfit to receive concomitant chemotherapy. From 2016.6 to 2020.9, 34 newly diagnosed patients with local-regional advanced NPC medically unfit for concurrent chemoradiation had undergone definitive radiotherapy and were retrospectively evaluated. All patients were treated with IMRT combined treatment modality of nimotuzumab with or without cisplatin-based induction chemotherapy. Nimotuzumab was administered concurrently with IMRT at a weekly dose of 200 mg. Acute and late radiation-related toxicities were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 during and after IMRT. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate prognostic analyses were performed by using the Cox proportional hazard model. The median follow-up time for the entire group was 15 months (range 5 to 55 months). At the time of this analysis, a total of 2 cases developed loco-regional recurrence. In addition, 4 patients developed distant metastasis. There was a total of 5 deaths: 3 patients died from distant metastasis, 1 patient died from the progression of loco-regional disease after recurrence, and the causes of death for the additional 1 case was a nasopharyngeal ulcer and deadly bleeding. The 1-year OS rate of the whole cohort was 87.9%, and the 1-year LFFR, DFFR, and PFS rates were 100%, 91.0%, and 91.0%, respectively. During the period of concurrent nimotuzumab and IMRT, no grade 3-4 hematologic toxicities and dermatitis were observed. Grade 3-4 radiotherapy-related oral mucositis was reported in 7 patients (20.6%). No infusion reaction was observed. No acneiform eruptions were found among these patients. The most commonly observed late complication was xerostomia. The degree of dry mouth in most patients was mild-to-moderate at the time of the last follow-up. Finally, 7 patients developed either unilateral or bilateral hearing impairment. One female patient experienced a nasopharyngeal ulcer and deadly bleeding after 5 months of completion of radiotherapy. Concurrent nimotuzumab with IMRT for the treatment of LA-NPC was well tolerated, with encouraging survival data, and it could be an effective treatment alternative for patients with LA-NPC medically unfit for concomitant chemotherapy. Further clinical trials are needed to confirm these findings.

Exploratory Study of NPC-0501 Trial: Optimal Cisplatin Dose of Concurrent and Induction/Adjuvant Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma

The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking. 742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied. Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses. Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored.

Complete metabolic response with [18 F]fluorodeoxyglucose-positron emission tomography/computed tomography predicts survival following induction chemotherapy and radical cystectomy in clinically lymph node positive bladder cancer.

To determine whether repeated [18 F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) scans can predict increased cancer-specific survival (CSS) after induction chemotherapy followed by radical cystectomy (RC). Between 2007 and 2018, 86 patients with clinically lymph node (LN)-positive bladder cancer (T1-T4, N1-N3, M0-M1a) were included and underwent a repeated FDG-PET-CT during cisplatin-based induction chemotherapy. The 71 patients that had a response to chemotherapy underwent RC. Response to chemotherapy was evaluated in LNs through repeated FDG-PET-CT and stratified as partial response or complete response using three different methods: maximum standardised uptake value (SUVmax ), adapted Deauville criteria, and total lesion glycolysis (TLG). Progression-free survival (PFS) and CSS were analysed for all three methods by Cox regression analysis. After a median follow-up of 40 months, 15 of the 71 patients who underwent RC had died from bladder cancer. Using SUVmax and the adapted Deauville criteria, multivariable Cox regression analyses adjusting for age, clinical tumour stage and LN stage showed that complete response was associated with increased PFS (hazard ratio [HR] 3.42, 95% confidence interval [CI] 1.20-9.77) and CSS (HR 3.30, 95% CI 1.02-10.65). Using TLG, a complete response was also associated with increased PFS (HR 5.17, 95% CI 1.90-14.04) and CSS (HR 6.32, 95% CI 2.06-19.41). Complete metabolic response with FDG-PET-CT predicts survival after induction chemotherapy followed by RC in patients with LN-positive bladder cancer and comprises a novel tool in evaluating response to chemotherapy before surgery. This strategy has the potential to tailor treatment in individual patients by identifying significant response to chemotherapy, which motivates the administration of a full course of induction chemotherapy with a higher threshold for suspending treatment due to toxicity and side-effects.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III–IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial

Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. For the Chinese translation of the abstract see Supplementary Materials section.

Abstract B08: Overcoming cisplatin resistance in sinonasal undifferentiated carcinoma by inhibiting the TGFβ signaling pathway in vivo

Abstract Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy the prognosis remains poor. Because of the locally advanced nature of SNUC, we have used cisplatin-based induction chemotherapy before definitive surgery or radiation therapy in our institution. Unfortunately, about 30% of SNUC patients do not respond to this treatment, and the lack of response is associated with poor survival. Therefore, developing strategies to overcome resistance to induction chemotherapy is crucial. Our current gene expression analysis of SNUC specimens indicated that the TGFβ signaling pathway might be activated in nonresponders. Using the MDA8788-6 SNUC cell line established from a nonresponder, we found that TGFβ signaling is upregulated in an autocrine manner in the SNUC cell line. Since inhibition of the TGFβ pathway overcame cisplatin resistance in this cell line, we decided to examine the effects of TGFβ inhibition in vivo. Materials and Methods: The MDA8788-6 SNUC cell line were cultured under serum-free condition overnight to induce TGFβ signaling. The cells were then resuspended in the serum-free conditioned medium collected from the same cell line to maintain activation of the pathway. Two million MDA8788-6 cells in the conditioned medium were inoculated into the flank of mice subcutaneously. On the same day of the inoculation, we started treatment with i) vehicle control, ii) cisplatin only (4 mg/kg, once per week, intravenously), iii) EW-7197 only (TGFβRI specific inhibitor, 40 mg/kg, five times per week, oral gavage), and iv) cisplatin plus EW-7197. After 5 courses of treatments, the mice were sacrificed. Average tumor volume of each treatment group 31 days after the cell inoculation was compared by Tukey’s multiple comparisons test. Area under the curve (AUC) was calculated according to the tumor growth curve of each mouse from 0 to 31 days after the cell inoculation. AUC of CDDP group and CDDP plus EW-7197 group was compared by unpaired, two-tailed t test with Welch’s correction. Results: The EW-7197 treated group itself did not show antitumor growth effect compared to the control group. Comparison of AUC of the tumor volume showed significant difference between the cisplatin alone and cisplatin plus EW-7197; the combination of cisplatin and EW-7197 had better antitumor growth effect compared to cisplatin alone. Conclusions: Our finding suggests that TGFβ inhibition may offer hope to SNUC patients struggling with chemoresistance. Citation Format: Yoko Takahashi, Hideaki Takahashi, Moran Amit, Frederico O. Gleber-Netto, Diana Bell, Tong-Xin Xie, Dianna Roberts, Ahmed S. Abdelmeguid, Curtis Pickering, Jeffrey N. Myers, Ehab Y. Hanna. Overcoming cisplatin resistance in sinonasal undifferentiated carcinoma by inhibiting the TGFβ signaling pathway in vivo [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B08.

Defining risk of micrometastatic disease and tumor recurrence in patients with stage I testicular germ cell tumors.

There is controversy in the management of patients with clinical stage I non-seminomatous germ cell tumor (NSGCT). Some experts recommend surveillance for all patients regardless of risk factors while others suggest a more risk-adapted approach by using lymphovascular invasion (LVI) and the embryonal component in the primary tumor to select patients most likely to benefit from primary treatment [retroperitoneal lymph node dissection (RPLND) or chemotherapy]. With the surveillance for all strategy, only patients who relapse are treated. While this minimizes the over treatment, problem associated with the risk adapted approach, this exposes young men to the effects of full induction cisplatin-based chemotherapy when these men could have received fewer cycles of bleomycin, etoposide, and cisplatin (BEP) or a curative primary RPLND. The challenge is identifying these men who are most likely to benefit from upfront treatment more precisely. This paper explores the currently risk adapted approaches as well as promising emerging biomarkers (microRNA) that, in early data, appear to more accurately predict the presence of microscopic disease in the retroperitoneum over conventional markers.

Importance of magnesium sulfate supplementation in the prevention of hypomagnesemia and hypocalcemia during chemoradiation in head and neck cancer

In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.

Long-Term Use of Nimotuzumab in Combination With Intensity-Modulated Radiotherapy and Chemotherapy in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma: Experience of a Single Institution

In this retrospective review of a single institution’s experience, the efficacy and safety of the long-term use of nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC) were studied. Between August 2008 and March 2014, 39 newly diagnosed patients with stages III–IV NPC were treated with IMRT, chemotherapy, and nimotuzumab. Twenty patients were diagnosed with stage III (51.3%), 14 with stage IVA (35.9%), and 5 with stage IVB (12.8%) disease. All patients received at least one cycle of cisplatin-based induction chemotherapy followed by IMRT and more than nine cycles of nimotuzumab at 200 mg/week. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Accumulated survival was calculated according to the Kaplan–Meier method. The log-rank test was used to compare survival differences. With a median follow-up of 46 months (range, 22–86 months), the estimated 3-year local recurrence-free, regional recurrence-free, distant metastasis-free, progression failure-free, and overall survival rates were 92.1%, 89.7%, 82.5%, 77.6%, and 86.8%, respectively. Univariate analysis showed that clinical stage and the cycle of induction chemotherapy were related with prognosis. The median cycle for the addition of nimotuzumab was 12 weeks. Grade 3 radiation-induced mucositis was observed in 15.8% of the treated patients. No skin rash or infusion reaction was observed, which is distinctly different from what was reported in patients treated with nimotuzumab. The major toxicities observed were grades I–II mucositis and leukocytopenia. Long-term use of nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities in patients.

Childhood Nasopharyngeal Carcinoma: State-of-the-Art, and Questions for the Future.

In children, nasopharyngeal carcinoma (NPC) is a very rare tumor, mostly Epstein-Barr Virus related and quite always diagnosed at a locally advanced stage. With current protocols associating induction cisplatin-based chemotherapy and concomitant chemoradiotherapy, prognosis is excellent with overall survival higher than 85%. However, long-term toxicities are frequent. Improvement in radiation therapy modalities like intensity-modulated radiation therapy and new strategies with radiation dose adaptation to chemotherapy response have been introduced to reduce acute and long-term toxicities. Actually, 2 main questions remain: is it possible to pursue a therapeutic deescalation in children with low-risk NPC or very good response to induction chemotherapy in order to reduce the risk of late effects? Could an immunologic maintenance treatment improve prognosis of children with high-risk NPC? International collaborative groups and prospective trials including biological studies are necessary to answer these questions to improve childhood NPC treatment and knowledge.

Abstract 42: Identification of gene expression patterns distinguishing responders and non-responders to induction chemotherapy in sinonasal undifferentiated carcinoma

Abstract Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy the prognosis remains poor, and the median survival time is less than 18 months. Because of its locally advanced nature, cisplatin-based induction chemotherapy has been used in our institution to downstage unresectable tumors before definitive surgery or radiation therapy. Interestingly, our previous study showed that response to induction chemotherapy is a prognostic indicator and may be used to select patients for definitive local treatment. In this study, we performed gene expression analysis on SNUC specimens to identify molecular markers to predict/distinguish between responders and non-responders to induction chemotherapy. Materials and Methods: Twenty-seven formalin-fixed paraffin-embedded samples from 24 patients treated at MD Anderson Cancer Center between 1999 to 2016 were used in this study. Among them, 12 specimens were treatment-naïve. Gene expression analysis was performed on an HTG EdgeSeq Oncology Biomarker Panel. Unsupervised clustering analysis and Mann-Whitney test were performed using JMP software and IBM SPSS Statistics 23, previously. Pathway analysis was performed using Ingenuity Pathway Analysis. Results: First, we attempted to identify a set of genes which could predict response to induction chemotherapy. Unfortunately, unsupervised clustering analysis on treatment-naïve specimen was incapable of distinguishing between responders and non-responders. However, using discriminant analysis we succeeded in finding genes classifying patients into responders and non-responders. Then we studied the tumor specimens harvested after induction chemotherapy; differentially expressed genes between the two groups (Mann-Whitney test; p<0.05) were analyzed for pathway analysis. Multiple upstream regulators related to cell survival and proliferation including Transforming growth factor beta 1 were predicted to be activated in the non-responders' specimens. Conclusions: Our study revealed the possibility that cell survival and proliferation pathways are upregulated in non-responders to induction chemotherapy in SNUC. This finding suggests that non-responders to induction chemotherapy might be treated by inhibiting those pathways. Our comprehensive gene expression study is a significant step towards developing new therapeutic approaches in SNUC. Citation Format: Yoko Takahashi, Diana Bell, Frederico O. Gleber-Netto, Tong-Xin Xie, Dianna Roberts, Curtis Pickering, Jeffrey N. Myers, Ehab Y. Hanna. Identification of gene expression patterns distinguishing responders and non-responders to induction chemotherapy in sinonasal undifferentiated carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 42.

SC01.02 PET-CT for Response Assessment During Induction Therapy of N2 NSCLC

Approximately 30% of patients with non-small cell lung cancer (NSCLC) are found to have locally advanced stage III tumors at initial diagnosis. For these patients the curative therapeutic options include definitive high-dose radiotherapy with concurrent chemotherapy or, alternatively, induction treatment followed by surgery. Preoperative chemotherapy or combined radiochemotherapy protocols followed by resection result in cure rates of 25-35 percent at 3 years for locally advanced NSCLC. However, surgical resection in patients with stage IIIa N2 remains an issue of controversy depending on the extent of lymph node involvement. Neoadjuvant chemo- or radiochemotherapy is being used to reduce disease burden in the mediastinum before surgery since patients who are downstaged via neoadjuvant therapy and then undergo resection experience a significantly longer 5-year survival of 40% to 50% than those who are found to have residual N2 disease at the time of surgery. Thus, identification of patients who are N2 negative after completion of their neoadjuvant therapy is a critical component for patient selection for thoracotomy. However, clinical restaging in these patients often is challenging. Endoscopic ultrasound guided biopsies (EUS/EBUS-FNA) have increasingly become available and are currently preferred procedures for staging and restaging before surgery due to their high diagnostic accuracy.1 Serial PET-CT imaging captures anatomical changes and additionally offers semiquantitative information about morphometric and metabolic tissue changes during induction treatment. Issues of PET-CT performance and quality assurance concerning standardization have been clarified during recent years and the validity of repeated measurements has been approved.2 Successful induction treatment regimens have been frequently found to reduce 18F-FDG uptake and thus PET-CT allows to assess the therapeutic response. Reduction in FDG-uptake of mediastinal lymph nodes after induction therapy has been shown to correlate well with histopathologic response,3 while postinduction PET avidity taken alone was not consistently found to be associated with pathological N2 involvement.4 In the direct comparison of EUS-FNA with PET-CT for restaging after induction chemoradiotherapy, concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases was observed in 63% patients treated within a prospective study but the diagnostic accuracy of PET-CT was limited.5 Nevertheless, serial FDG-uptake measurements seem to provide prognostic information during induction therapy. Data collected in prospective trials suggest that a decrease in SUVmax between 45% to 60% optimally separates between responders and non-responders.6-9 In a recent large retrospective analysis, a decrease in SUVmax greater than 60% in the involved mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary tumor site.10 An analysis of a randomized trial in potentially resectable stage III NSCLC of induction treatment (including a hyperfractionated accelerated radiotherapy phase) and definitive radiochemotherapy compared with induction treatment followed by surgery confirmed that as early as after two cycles of cisplatin-based induction chemotherapy percentage of SUVmax remaining represents a significant prognostic parameter.9 PET-response was of higher importance than all other clinical factors. Cut-off levels between 0.45 and 0.55 were predictive for freedom from extracerebral progression in all randomized patients. No important differences in the predictive value were observed comparing resection versus definitive radiochemotherapy. PET-response was closely related to extracerebral distant metastases but not to local recurrences, independent of treatment. One might conclude that less PET-responsive tumors are successfully controlled by intensified hyperfractionated accelerated radiochemotherapy or neoadjuvant radiochemotherapy and resection at loco-regional sites so that the highest risk of relapse remains at extracerebral distant sites. Therefore, a selection or intensification of the local therapy according to SUV-decrease is not warranted by these data. Functional imaging has not yet been fully established for treatment guidance but prospective evaluation is underway. In the group of poor-responding patients, treatment intensification by independent systemic options such as targeted therapy or immunomodulating therapy may become emerging new treatment options within clinical trials. 1. De Leyn EJCTS 2014, 2. Young, EJC 1999, 3. Pöttgen CCR 2006, 4. Ripley JTCS 2016, 5. Stigt, Lung Cancer 2009, 6. Hoekstra, JCO 2005, 7. Eschmann, Lung Cancer 2007, 8. Dooms, JCO 2008, 9. Pöttgen, JCO 2016, 10. Barnett ATS 2016. PET-CT; N2; induction, restaging

A role of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer plus hydronephrosis with or without pelvic nodal involvement.

To retrospectively evaluate the failure patterns of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. Patients with muscle-invasive bladder cancer underwent maximal transurethral resection of bladder tumor and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Radiotherapy was given with 45Gy to the pelvis, 50.4Gy to the bladder, and 64.8Gy to the tumor bed. Three protocols of trimodality treatment were used: Protocol A, three cycles of cisplatin and fluorouracil (CF), followed by CCRT with 6 weekly cisplatin; Protocol B, three cycles of weekly paclitaxel plus CF, followed by CCRT with 6 weekly paclitaxel and cisplatin; Protocol C, three cycles of gemcitabine and cisplatin, followed by CCRT with 6 weekly cisplatin. Interval cystoscopy confirmed complete response (CR) after induction chemotherapy and 40-50Gy of radiotherapy. Patients without CR were referred for salvage cystectomy. A total of 60 patients were enrolled, including 11 patients with unfavorable factors defined as hydronephrosis and/or pelvic nodal involvement. After a median follow-up of 86.7 months, the 5-year overall, progression-free, and bladder preservation-specific survival rates were 76.3%, 62.9%, and 71.5%, respectively. Three patients underwent salvage cystectomy for invasive bladder recurrence. Of 45 surviving patients, 42 patients (93.3%) retained functioning bladders. Patients with unfavorable factors had significantly lower metastasis-free survival (p=0.002), but not bladder preservation-specific survival (p=0.25). With trimodality treatment involving visually complete transurethral resection of bladder tumor, cisplatin-based induction chemotherapy, and CCRT, patients with unfavorable factors maintained satisfactory bladder preservation but not systemic control.

Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy.

The purpose of this study was to evaluate the expression of excision repair cross-complementation group 1 (ERCC1) in locoregionally advanced nasopharyngeal carcinoma (NPC) treated with cisplatin-based induction chemotherapy. Eighty-five patients with locoregionally advanced NPC treated with cisplatin-based induction chemotherapy were included in this study. The expression level of ERCC1 protein in cancer tissues was detected by immunohistochemistry, and the expression level was divided into the high- and low-expression groups according to their expression level. The objective response rate (ORR) and the long-term disease control rate of two groups were compared between the two groups. The expression level of ERCC1 in NPC tissues was detected by immunohistochemistry. Forty-one cases had the high ERCC1 expression, and 44 cases had the low ERCC1 expression. The cases for complete response, partial response, stable disease, and progression disease were 1, 19, 21 in the ERCC1 high expression group and 3, 29, 12 for the ERCC1 low-expression group which indicated that the ORR in ERCC1 low group were significant higher than that of ERCC1 high expression group (P < 0.05). The 5-year overall survival, 5-year disease-free survival (DFS), and 5-year local recurrence-DFS were not statistical different between two group (P < 0.05); but the 5-year distant-DFS for ERCC1 low group were significant higher than ERCC1 high group (P < 0.05). Cisplatin-induced short-term ORR was decreased in nasopharyngeal carcinoma patients with high ERCC1 expression, which increased the risk of metastasis.

Intratumor Textural Heterogeneity on Pretreatment (18)F-FDG PET Images Predicts Response and Survival After Chemoradiotherapy for Hypopharyngeal Cancer.

Increasing evidence suggests that intratumor heterogeneity of solid tumors characterized by textural features on 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) images is associated with response to chemoradiotherapy (CRT) and survival. The current study aimed to determine whether a similar relationship exists in hypopharyngeal squamous cell carcinoma (HPSCC). This study investigated 27 patients with HPSCC who underwent cisplatin-based induction chemotherapy followed by definitive CRT underwent pretreatment (18)F-FDG PET/CT. Standardized uptake value (SUV), metabolic tumor volume (MTV), and textural features (coarseness, busyness, complexity, and contrast) of primary tumors were measured. Patients were classified as nonresponders or responders according to the response evaluation criteria in solid tumors. The capacity of each parameter to classify response was assessed using the Mann-Whitney U test. Cox-proportional hazard models were used to identify variables associated with disease-free survival (DFS) and overall survival (OS). Of 70 patients, 58 (83%) had complete or partial response after CRT. Responders showed lower maximum SUV (P=0.037), lower MTV (P=0.039), lower coarseness (P<0.001), and busyness (P=0.015) compared with nonresponders. Multivariate analysis showed that high coarseness (P=0.001, hazard ratio [HR] 5.65; 95% confidence interval [CI] 2.12-15.07) and busyness (P=0.045; HR 2.56; 95% CI 1.02-6.42) were independently associated with poor DFS, and that high coarseness (P=0.013; HR 2.48; 95% CI 1.21-5.09) was independently associated with poor OS. Abnormal coarseness in baseline (18)F-FDG PET scans may be useful for predicting response and survival after CRT in HPSCC patients.

Do seminoma germ cell elements affect perioperative outcomes following post-chemotherapy retroperitoneal lymph node dissection for metastatic testis cancer?

378 Background: Post-chemotherapy retroperitoneal lymph node dissections (PC-RPLND) performed at high-volume centers are safe and comparable in risk to primary RPLNDs. The desmoplastic reaction encountered during PC-RPLND in patients with seminoma components increases the complexity of surgical dissection. We examined whether the presence of seminoma at diagnosis was associated with more adverse events in the perioperative setting. Methods: A single institution review board approved retrospective review identified 108 patients undergoing PC−RPLND from 1992 to 2012. All patients had received at least first-line cisplatin-based induction chemotherapy. Of these, 11 patients undergoing redo PC-RPLNDs were excluded from analysis. Patients were divided into two groups; those with any seminoma element in their orchiectomy or retroperitoneal specimens and those without seminoma elements. We performed independent t-tests and Chi-squared analysis of the data. Results: Of 97 patients undergoing PC-RPLND, 33 had seminoma components in their diagnostic specimens. Using the Clavien classification system to stratify post-operative complications, the percentage of seminomatous elements (less than 50% compared to more than 50%) within the primary tumor did not correlate with a higher incidence of complications; even when examining only major complications (p=0.673). There was a trend towards higher nephrectomy rate for tumors with seminoma elements compared to those without (27% vs. 8.5%, p = .058). The nephrectomy rate did show a dependence on the pathologic size of the residual mass regardless of histology (31% for more than 10 cm, 6.8% for 5 to 10 cm, 0% for 0 to 5 cm p = 0.021). There was also a trend towards blood loss greater than one liter for patients with seminoma elements compared to those without (63% vs. 43%, p = 0.078), while the transfusion rate was similar between the two groups (p=0.785). Post−operative length of stay was independent of a patient’s histology (p=0.94). Conclusions: PC-RPLND remains a safe and necessary therapeutic procedure. The presence of seminoma germ cell elements in our patient cohort did not result in a more complicated perioperative course surrounding PC-RPLND.

Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus

The aim of this study was to retrospectively analyze the long-term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. Patients received high-dose external beam radiotherapy and concurrent cisplatin-based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin-based induction chemotherapy before definitive chemoradiation. Fifty-five patients (46 men, 9 women, median age 58 years, range 35-72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50-70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long-term survivors were observed with a follow-up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty-four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long-term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long-term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer.

A clinical-based risk score for decision making for surgery after induction chemotherapy in malignant pleural mesothelioma patients.

7587 Background: Scoring tools predicting the potential benefit from surgery after induction chemotherapy in mesothelioma patients may influence decision making. Our score is based on 4 clinical variables available before surgery. Methods: 128 patients were uniformly treated with cisplatin based induction chemotherapy followed by extrapleural pneumonectomy between 1999 and 2011. Based on clinical experience and survival influencing factors resulting from uni-and multivariate analysis, we designed a risk score. All 4 variables building up the score were available for 59 patients: pre chemotherapy volumetry above 500 ml, non-epithelioid histotype in the diagnostic biopsy, pre chemotherapy CRP value above 30 mg/l and progressive disease after chemotherapy according to modified RECIST criteria. The 5 resulting groups were analyzed for overall survival (OAS) and progression free survival (PFS) using Kaplan-Meier and Cox regression model. Results: The score strongly stratified patients into high and low risk groups for shorter OAS (Table) (p&lt;0.0005). As to PFS, patients with Score 0 also had significantly longer median PFS (16 months; 95% CI: 12; 20) in comparison to patients with score 3 or higher (6 months; 95% CI: -; -) (p&lt;0.0005). In Cox regression analysis the risk factor for shorter OAS and PFS increased correspondingly to our score. Conclusions: Our new score based on 4 clinical variables available before surgery identifies patients’ subgroups who may benefit from surgery after induction chemotherapy, which will be further assessed prospectively. [Table: see text]

Salvage chemotherapy for metastatic germ cell tumours: The known unknowns.

Salvage chemotherapy for metastatic germ cell tumours: The known unknowns.

Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma

Intestinal-type adenocarcinoma (ITAC) of the ethmoid sinus is a rare, occupational-related tumor. Optimal treatment consists of surgery and radiotherapy, while chemotherapy is still investigational. The molecular profile of ITAC is characterized by the occurrence of TP53 mutations associated with genotoxic agents such as wood dust. We investigated the role of p53 functionality in relation to the primary treatment. We retrospectively reviewed 100 medical charts of consecutive patients with a first diagnosis of ITAC treated at our Institute; 74 patients were evaluable for TP53 analysis. Thirty (41%) were treated from 1991 to 2006 with craniofacial resection followed by radiotherapy (Group A), compared with 44 patients (59%) treated from 1996 to 2006 with cisplatin-based induction chemotherapy (PFL) followed by standard treatment (Group B). Five-year OS in Group A was 42%, while in Group B it was 70% (p = 0.041); 5-year DFS in Group A was 40%, while in Group B it was 66%, (p = 0.009) (p = 0.061 and 0.003 at Cox multivariable OS and DFS analyses). Analyzing each group according to p53 functional status, only for Group B patients (who received preoperative chemotherapy) both OS and DFS were in favor of functional p53 (p = 0.023 and p = 0.010, respectively). No impact of p53 functional status as a biomarker was observed in Group A. Functional p53 may predict PFL-chemotherapy efficacy, offering a possible increase in survival when induction chemotherapy is given to a selected population. On the other hand, upcoming innovative approaches should be explored in the presence of non-functional p53.

Teratoma identified after postchemotherapy retroperitoneal lymphadenectomy

The histologic finding of teratoma occures in aproximately 40% of all postchemotherapy retroperitoneal lymphadenectomy (PC-RPLA) for disseminated nonseminomatous testicular tumors (NSTT). We evaluated patients undergoing PCRPLA for teratoma to determine risk factors for recurrence and clinical outcome. Among a survey of 193 patients submitted to PC-RPLA due to metastatic NSTT from 1980-2005, we identified 82 patients (42%) who were found to have only teratoma in the retroperitoneum. Sixty-seven patients (82%) received only induction cisplatin-based chemotherapy, and 15 (18%) required 2nd line chemotherapy. PC-RPLA histology revealed mature teratoma (MT) in 86%, immature teratoma (IMT) in 12% and teratoma with malignant transformation (TMT) in 2%. Sixteen patients (19%) relapsed within median free interval of 22 months. Among 13 patients submitted to redo- RPLA, discordant histology occurred in 6 patients (46%) (2 TMT, 4 viable germ cell tumors [GCT]), all with worst histology in comparison to primary RPLA. One relapsing patient with only elevated serum tumor markers (STMs) achieved complete response with chemotherapy alone. Two patients relapsed at 21 and 74 months with widespread metastasis and died despite salvage chemotherapy. Seven of 13 patients (54%) who were rendered free of disease (FOD) with redo-RPLA, relapsed again. All but one died despite salvage treatment (2 of chemotherapy related toxicity) within mean survival time (MST) of 86.7+/-26.1 (95% confidence interval [CI], 98.79- 149.21). At mean follow-up (MFU) of 135+/-62.6 months (95% CI, 98.79-149.21), alive and free of disease (AFD) are 90% patients. The probability of being reccurence-free at 5- and 10- year was 87% and 81%, respectively. The 5- and 10- year probability of disease speciphic survival (DSS) were 98% and 89%, respectively. On multivariate analysis residual mass size (p<0.005) and worse IGCCCG risk group (p=0.01) predicted disease recurrence. Patients with residual teratoma after PC-RPLA continue to exibit a 19% risk of recurrence even 10 years after RPLA, with 46% recurrence being with worse histology. These data support that these patients should undergo long-term surveillance of their retroperitoneum in the setting of a large residual mass or elevated IGCCCG classification risk.