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IntroductionThe role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer.MethodsThis retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed.ResultsAmong 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P12 months, between 6 and 12 months, and ConclusionCytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30&ndash, 82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease often presenting at an already advanced stage. Cisplatin chemoradiotherapy is the standard treatment for locally advanced disease, although its efficacy varies according to different studies. Thus, treatment selection is a challenge, especially in older patients, who frequently have several comorbidities. Moreover, the majority of patients with recurrent and/or metastatic disease are unsuitable for local treatment, either surgery or radiation therapy. The only treatment option for them is systemic therapy, but prognosis remains poor, with a median overall survival of less than 12 months. Methods: A group of Italian key opinion leaders in the field of HNSCC gathered several times in 2018 in order to retrieve a set of statements to help clinicians in their daily decision-making process for the treatment of patients with different scenarios of HNSCC. Results and Conclusion: The panel agreed on 22 statements that were identified as “good clinical points” based on the available literature or after discussion of the most relevant aspect of the underlying diseases when no international consensus was available. The panel identified a number of possible scenarios (namely 71) in which these statements may be helpful to guide decision-making for the best treatment selection.

Objectives Olaparib is approved as maintenance therapy in patients with BRCA mutated platinum sensitive (PS) recurrent ovarian cancer (OC) after response to last platinum based therapy. Few data are available regarding the use out of the registration trials and on response to further treatments after progression. Materials ad methods In this non interventional, retrospective study, patients treated with olaparib in 13 centers, according to the label, have been collected and analyzed. Primary objectives of the study are to describe effectiveness and safety of olaparib in a real world setting with a focus on post progression treatments and response. Results 234 patients were analyzed. All patients were BRCA mutated and most of them had germline mutations. Around 50% of the patients received olaparib after 3 or more lines of platinum based chemotherapy achieving a radiologic complete (CR) or partial response. 12.4% patients with stable disease were also included. Median PFS was 14.7 months (95% CI:12.6–18), with statistically longer PFS in patients with normal serum Ca125 at baseline, a CR after last platinum based therapy and that received olaparib after second platinum based therapy. Median OS was not reached. Most frequent G3-G4 toxicity was anaemia (6%) with dose discontinuation and dose reduction in 11 (4.7%) and 49 (20.9%) of cases, respectively. Among 66 patients receiving further treatment after olaparib progression and evaluable for response, ORR was 22.2, 11.1% and 9.5% in patients with Platinum Free interval (PFI) of more than 12 months, between 6 and 12 months and less than 6 months, respectively. Conclusions Olaparib is effective and safe in real world setting. Data on post-progression treatments seem to suggest cross resistance with chemotherapy and need to be confirmed in larger studies because of the potential importance in clinical practice decisions.

Purpose The aim of this Phase II, non-randomized study was to assess activity and safety of neoadjuvant chemotherapy (NACT) before chemoradiation (CT/RT) followed by radical surgery (RS) in locally advanced cervical cancer (LACC) patients. Methods and materials The primary end point was rate of pathologic complete response (pCR). FIGO Stage IB2-IVA patients were administered NACT chemotherapy (paclitaxel 80 mg/m2, carboplatin AUC 2), for 6 weeks, followed by Intensity Modulated Radiotherapy plus simultaneous boost (total dose of 50.4 Gy to CTV1, and 39.6 Gy to CTV2). Clinical response was assessed according to RECIST criteria. Responsive patients were triaged to RS. The regimen would be considered active if >20 pCRs were registered in 39 patients. Results 45 patients were enrolled into the study; 25 patients (55.5%) were FIGO stage IIB, 9 cases (20.0%) had stage III disease. At work up, pelvic lymph node involvement was documented in 38 (84.4%) patients; pCR was documented in 18 out of 40 patients (45.0%). Grade 3–4 hematological toxicity after NACT occurred in 4 patients; CT/RT associated grade 3 toxicity was found in 7 patients. Early and late postoperative complications were detected in 16, and 11 cases, respectively. Three-year PFS and OS were 66.0% and 86.0%, respectively. Conclusions NACT followed by CT/RT by IMRT and RS, is feasible and safe; failure to achieve the primary endpoint has to be recognized; however, enrollment of a higher rate of poor prognosis patients compared to historical data used to calculate sample size, could have resulted in reduced activity.

e18508 Background: Immunotherapy is the standard of care in the treatment of platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Previous loco-regional treatment could have an impact on the immune system and response to Nivolumab. The aim of this study is to evaluate the efficacy and safety of Nivolumab in a real world population, identifying the impact of the clinic-pathological characteristics and previous treatment in prediction of early progression. Methods: This is a observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received Nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity, from October 2018 to October 2019. We analyzed treatment outcomes in term of early progression (within 3 months), clinical benefit, progression free survival (PFS) and overall survival (OS). To determine the influence on outcomes, the following variables were investigated: primary tumor sub-site, age, gender, ECOG, previous loco-regional treatment, previous systemic therapy, metastatic site. Results: Data from 61 pts were reviewed: 15 oral cavity, 14 oropharynx, 7 hyphofarynx, 19 larynx, 6 paranasal sinus. Median age was 66 years (29-82), 48 pts were men. Forty-nine pts (80%) had performance status (ECOG) ≥ 1 at baseline evaluation. Eleven pts (18%) had only loco-regional recurrence, while 50 pts (82%) had one or more metastatic site. 32 (52%) and 17 pts (28%) had smoking and alcohol abuse history, respectively. 44 pts (72%) received surgery followed by adjuvant radiant treatment at standard dose (28, 46%) or concomitant definitive radiotherapy (16, 26%) as upfront treatment with curative intent. With a median follow up of 4 months (range 1-11), early progression occurred in 39 pts during Nivolumab treatment (64%), while clinical benefit (stable disease and partial response) was achieved in 22 pts (36%). No G3-G4 toxicities occurred. Early progression to Nivolumab was significantly associated to previous loco-regional treatment both at univariate and multivariate analysis (p=0.003 and p= 0.04, respectively). Conclusions: Nivolumab in R/M HNSCC is effective and safe even though burdened with a high early progression rate. Loco-regional treatment, including wide neck dissection and high dose radiotherapy, may compromise the efficacy of Nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

Locally advanced cervical cancer has a poor prognosis and is difficult to treat by surgery; authors’ evaluated feasibility and safety of the simultaneous integrated boost (SIB) technique for dose escalation in patients with cervical cancer using a rotational dynamic Intensity Modulated Radiation Therapy Technique (VMAT®). Authors evaluated 10 patients affected by loco-regionally advanced, node negative, inoperable cervical cancer. All women received primary chemoradiation (CRT). Six pts received three cycles of platinum-based chemotherapy (CT) plus CRT. Three Programmed Temperature Vaporization (PTV) were delineated: PTV1 (primary, cervix and parametria with a 1cm-margin); PTV2 (body of uterus with a 1cm-margin); PTV3 (pelvic nodes). PTV1 was defined using image fusion between CT-scan and RM or PET/CT. Treatment plans, calculated using a rotational dynamic Intensity Modulated Radiation Therapy (IMRT) system on Oncentra Masterplan® (VMAT®), and consisted in a simultaneous integrated boost. Total treatment time was 45 days. Concomitant CT consisted of weekly cisplatin 40 mg/m2. Dose–volume histograms and acute gastrointestinal, genitourinary, and hematological toxicity were evaluated. Secondary endpoint was evaluation of short term disease free survival. Three months after CTRT, patients were revaluated with colposcopy and cytology and Pelvic imaging. After six and twelve months from CTRT, reevaluation included PET-CT or Chest CT scan and Abdominal and Pelvic RM. All patients concluded radiation without suspension. Cytology demonstrated complete response (CR) in 4 pts in the ERT fraction of brachytherapy (BRT) group and in 1 pts in ERT alone group. All other patients showed a partial response (PR) > 75%. After a median follow up of 20 month (range 16-22), 5 patients are free from disease (NED), 4 patients are alive with disease (AWD) and 1 patient died after three months (DOD). In 2 AWD patients, re-staging PET showed a RC of pelvic disease with evidence of disease in lomboaortic nodes. One of them received salvage radiation therapy on recurrence. After this preliminary experience, in patients with inaccessible cervical canal, authors could propose the dose escalation on PTV1, with the aim of delivering BED as near as possible to 85Gy.

The rationale for weekly administration of paclitaxel, which acts on microtubules to arrest mitosis, is that more frequent delivery of moderate doses may achieve greater efficacy than standard doses every 3 weeks, through more sustained exposure of dividing tumor cells to its cytotoxic effects. This dose–dense approach to treatment may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. More frequent exposure to paclitaxel may also enhance its apoptotic and antiangiogenic effects. Paclitaxel activity is considered to be independent of p53 status, in contrast to anticancer drugs that produce lesions on DNA, which achieve a better response if p53 is functional. Weekly therapy also has advantages in terms of improving paclitaxel therapeutic index. Clinical studies show that weekly paclitaxel is effective and that toxicity is acceptable. The response rates of single-agent paclitaxel varied from 21 to 86% in breast cancer, from 20% to 65% in ovarian cancer and from 30% to 56% in non-small cell lung cancer.

TPS5612 Background: Endometrial cancer (EC) patients with advanced or recurrent disease and endometrioid histology have a short progression-free survival (PFS). These malignancies are hormone dependent and endocrine therapy with aromatase inhibitors is well established. Palbociclib is an oral and selective inhibitor of cyclin-dependent kinases CDK4 and CDK6. Studies in breast cancer have demonstrated superiority of letrozole treatment in combination with palbociclib vs. letrozole monotherapy in oestrogen receptor positive (ER+) HER2- advanced disease. The combination is generally well tolerated with an acceptable toxicity profile. This multicenter, prospective, double-blind, placebo-controlled, randomized, phase II trial is evaluating the efficacy of letrozole when combined with palbociclib against letrozole-placebo combination therapy in women with ER+ advanced or recurrent EC. Methods: The primary objective of this trial is to demonstrate superiority of palbociclib against placebo in combination with letrozole, as defined by investigator-assessed progression-free survival (PFS). Key eligibility criteria include: histologically confirmed ER+ EC of endometrioid type; stage 4 or recurrent disease; prior surgery, adjuvant chemotherapy, radiation therapy, hormonal therapy (e.g. megestrol acetate) is permitted; measurable/evaluable disease according to RECIST 1.1. 78 patients will be randomized 1:1 to receive palbociclib 125mg daily or placebo on days 1-21 and letrozole 2.5mg daily on days 1-28 in a 28 days cycle until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include PFS in sub-populations, overall response rate, disease control rate, PFS2, time to first subsequent therapy, time to second subsequent therapy, overall survival, safety & tolerability, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24) and PFS in patients with or without retinoblastoma protein-expressing tumors. The following cooperative groups are participating: NSGO (DK, FIN, NOR), MITO (ITA), GEICO (SPA) & NOGGO (GER). Clinical trial information: NCT02730429.

e11517 Background: MBC remains an incurable disease with median survival of 2-3 years despite new drugs. The gain of benefit from third-line chemotherapy (CT3) in MBC is unknown. The validation of PPS as surrogate endpoint and its correlation to OS is under debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 114 pts treated for MBC, 67 with at least 3 lines CT, to show the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Moreover, we evaluated PPS for each line and its relation to OS. Results: Median age at M+ diagnosis was 58 years (29-87), median site of disease 2 (1-6), 66.7% visceral, HER-2+ pts 31.1%, median number of anti-Her-2 treatment 2 (1-6); 56.1% received a maintenance treatment (37% M1, 13% M2), median number of treatment 3 (1-8). Median OS for all pts was 47.1 (95%CI: 36.5-57.6). No difference in OS for pts with maintenance treatment vs not, respectively 49.1 vs 45.6 P=0.17. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive vs negative p=0.03) number of lines ( >3 vs ≤ 3) p< 0.0001 and number of metastatic sites (>2 vs ≤2) p=0.01. We evaluated relation between PFS and OS and PPS and OS until 6th line of therapy with a linear regression model. Conclusions: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until 6th line of treatment. PPS as surrogate endpoint of OS is a valid hypothesis to be evaluated in prospective trials of MBC [Table: see text]