Completion Of Neoadjuvant Therapy Research Articles

Pyrotinib as neoadjuvant therapy for HER2+ breast cancer: A multicenter, randomized, controlled, phase II trial.

574 Background: Pyrotinib is a new irreversible tyrosine kinase inhibitor (TKI) which significantly improved the progression-free survival (PFS) of patients with HER2+ metastatic breast cancer (MBC). In this study we aim to investigate the efficacy and safety of pyrotinib in neoadjuvant therapy. Methods: This is an open-label, multicenter, randomized controlled trial. Eligible patients (pts) aged 18–70 years with invasive carcinoma, cT2-3N0-3M0 stage, HER2-positive breast cancer were included. We randomized 34 pts into the treatment group and 33 into the controlled group from 2019-2021. Pts in the treatment group received 6 cycles of pyrotinib 400mg + trastuzumab 6mg/kg (LD 8mg/kg) + docetaxel 75mg/m2 + carboplatin (AUC = 6mg/ml·min) (TCbH+Py) treatment while the controlled group received 6 cycles of trastuzumab 6mg/kg (LD 8mg/kg) + docetaxel 75mg/m2 + carboplatin (AUC = 6mg/ml·min) (TCbH). Total pathologic complete response (tpCR) was defined as no invasive or in situ disease in the breast or axilla (ypT0/Tis, ypN0) and was assigned to be the primary outcome (NCT03756064). Results: 51 cases had completed 6 cycles of neoadjuvant therapy and successfully underwent operation (21 in the treatment group and 30 in the controlled group). In the treatment group, 6 cases have not complete neoadjuvant therapy, 6 cases quitted because of poor compliance and 1 patient has not receive operation yet. For controlled group, 3 patients have not complete neoadjuvant therapy. The tpCR rate in the treatment group is 71.4% (15/21) versus 36.7% (11/30) in the controlled group. A significant difference was determined between the two groups (p < 0.05). All pts achieved an objective response in the treatment group while in the controlled group for about 83.3% (25/30). 4 cases showed stable disease (SD) and 1 case was evaluated as progressive disease (PD) in the controlled group. The most common AE in the treatment group is diarrhoea with grade 3 occurred in 6 cases (28.6%), most of this event limited in the first treatment cycle. In the controlled group 3 pts (10%) occurred grade 3 diarrhoea. Conclusions: In this study TCbH+Py neoadjuvant therapy significantly improved the tpCR rate of HER2+ breast cancer pts for about twice higher than TCbH with a manageable safety. Clinical trial information: NCT03756064.

Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.

9502 Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen. Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response (RECIST 1.1) was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses. Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( < 10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (≥50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1 -year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016). There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment. Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Camrelizumab in combination with preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma: A single-arm, open-label, phase II study.

e16072 Background: At present, ESCC has a dismal prognosis with huge unmet clinical needs. With the potential benefit of combining PD-1 inhibitor with nCT, we conducted a phase II trial to assess the efficacy and safety of Camrelizumab plus nCT for locally advanced ESCC. Methods: 43 patients (pts) with histologically confirmed stage II/III/IVa(cT2-4aN0-3M0) ESCC were enrolled from February 2020 to February 2021.The study was divided into two stages, stage 1: we administered 1 cycle of camrelizumab for induction therapy (200 mg q2 weeks); stage2: pts received 2 cycle of camrelizumab (200 mg every 3 weeks) plus docetaxel and nedaplatin, followed by surgery within 4̃6 weeks after neoadjuvant therapy completion. Primary endpoint was major pathologic response (MPR). Secondary endpoints included pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS) and overall survival (OS). Results: At the cutoff date of Feb 5, 2021, 43 eligible pts were enrolled (63% males, median age 66), neoadjuvant treatment was completed in 33 pts and is ongoing in 3 pts. Thus far 27 out of 33 pts were resected, 6 pts are planned to undergo surgery, 3 pts were not suitable for operation after evaluation,1 pt had interval metastases preoperatively, 1 pt declined surgery, 1 pt was allergic to camrelizumab, 1 pt died due to unknown reasons. All patients underwent an R0 resection. Postoperative pathology showed that TNM stage decreased in 23 pts with 85.19% reduction rate. 17 pts (62.96%) reached major pathologic response, 8 pts (29.63%) reached pathologic complete response (no surgery related mortality). The most common AEs (all grade, grade≥3) were reduced hemoglobin (53%, 0%), hypoproteinemia (26%, 0%), neutrophil (21%, 12%), TSH reduction (21%, 0%), increased blood lactate dehydrogenase (16%, 0%), hyperthyroidism (16%, 0%), elevated alanine aminotransferase (9%, 0%), fatigue (7%, 0%), rash (5%, 2%). Date for median DFS and OS were not matured. Conclusions: Camrelizumab in combination with preoperative chemotherapy followed by surgery for locally advanced ESCC showed promising downstaging effect and MPR with good tolerance, and its efficacy and safety could be further studied in later trials. Clinical trial information: NCT03917966. Clinical trial information: NCT03917966.

Managing HER2-Positive Breast Cancer Amid COVID-19

Managing HER2-Positive Breast Cancer Amid COVID-19

A phase II study of neoadjuvant immunotherapy combined with chemotherapy (camrelizumab plus albumin paclitaxel and carboplatin) in resectable thoracic esophageal squamous cell cancer (NICE study): Interim results.

4060 Background: We conducted a phase II trial of preoperative chemotherapy with albumin paclitaxel and carboplatin combined with camrelizumab (NICE regimen), in patients with locally advanced esophageal squamous cell carcinoma (ESCC) with multiple lymph nodes metastasis. Initial results were analyzed to assess the efficacy and safety of this strategy. Methods: This was a prospective, multicenter, open, single arm, phase II trial. Eligible patients were histologically confirmed thoracic ESCC, staged as T1b-4a, N2-3 (≥ 3 stations), and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes) according to the 8th edition of American Joint Committee on Cancer. Patients received neoadjuvant treatment (NICE regimen) with intravenous camrelizumab (200 mg, day 1) plus albumin paclitaxel (100 mg/m2, day 1, 8, 15) and carboplatin (area under curve 5, day 1) of each 21-day cycle, for two cycles before surgery. The primary endpoint is pathological complete response (pCR) rate in the per-protocol population, which included all patients who had tumor resection and received at least one cycle of neoadjuvant treatment. Secondary endpoints include R0 resection rate, adverse events and disease-free survival. Safety was assessed in the modified intention-to-treat population. Results: Of the planned 60 patients enrolled, 55 (91.7%) patients have received the full two-cycles NICE regimen successfully, 4 patients didn’t receive the complete neoadjuvant therapy due to intolerance (3 patients) and drop out (1 patient), 1 patient died due to pneumonia on the second cycle of neoadjuvant therapy. Grade 3-5 treatment-related adverse events (TRAEs) rate was 53.3% and TRAEs resulting in discontinuation rate was 6.7%. The common grade 3-5 TRAEs included lymphopenia (50%), thrombocytopenia (10%), pneumonia (5%) and thyroid dysfunction (3.3%). At the time of writing, 47 patients underwent surgery within 27-85 days (median 36 days) after NICE treatment, in which 7 patients had delays to surgery due to TRAEs. All patients achieved radical (R0) resection. There was no in-hospital and postoperative 30-day mortality. pCR (ypT0N0) was identified in 20 (42.5%) of 47 patients and 5 (10.6%) patients had complete pathological response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). Conclusions: Preoperative NICE regimen has achieved satisfatory initial results of disease response in locally advanced thoracic ESCC. A phase III randomized controlled trial is required to demonstarate the possible survival improvement. Trial registration: ChiCTR1900026240 Clinical trial information: ChiCTR1900026240.

58P Cost-effectiveness analysis of trastuzumab emtansine versus trastuzumab for Chinese patients with residual invasive HER2-positive early breast cancer

Patients with residual invasive HER2-positive early breast cancer after completion of neoadjuvant therapy have a high risk of recurrence or death despite of receiving standard treatment of Trastuzumab. Trastuzumab emtansine (T-DM1), which act as a breakthrough therapy, has been proved to reduce 50% incidence of recurrence or death compared with Trastuzumab alone. This study was aimed to estimate cost-effectiveness of T-DM1 vs. trastuzumab as the adjuvant treatment in China. A validated 6-state Markov model with monthly cycle was constructed to estimate the lifetime incremental cost-effectiveness ratio (ICER). Main clinical input was the time spent in invasive disease-free survival state, estimated by parametric extrapolations to survival data observed in the clinical trial Katherine. Utilities were calculated from EQ-5D of patients in Katherine and the published literatures. The costs obtained both from real world data and local published resources including drugs, administration, adverse events management, follow-up and therapeutic costs. Furthermore, indirect costs were included when analyzed from the society perspective. Costs and outcomes were both discounted at 5%. Sensitivity analysis were conducted to verify the robustness of the results. T-DM1 provided 1.49 more QALYs with additional costs than trastuzumab. From healthcare system perspective, the ICER was CNY 112,004/QALY. Further 39% lower indirect costs in T-DM1 group resulting an ICER of CNY 98,757/QALY from the society perspective. Both ICERs were between 1∼2 times GDP per capita, far below the local threshold of 3 times GDP per capita in 2019 (CNY 212,676). Acquisition cost of T-DM1 is partially offset by the prevention of disease recurrences over the time. Cost for managing recurrences in T-DM1 group was 44% lower than that in trastuzumab group. Probabilistic sensitivity analysis showed that T-DM1 was more cost-effective in more than 95% simulations at local threshold regardless of the perspective. Compared to trastuzumab, T-DM1 is more cost-effective as the adjuvant treatment for patients with residual invasive HER2-positive early breast cancer in China.

Outcomes of young patients diagnosed with locally advanced rectal cancer.

The incidence of rectal cancer is higher in the older population. In developed nations, there has been a rise in incidence in young onset colorectal cancer (CRC). We examined the outcomes of locally advanced rectal cancer (LARC) in younger patients (yRC) compared with older patients, using a retrospective audit. All cases of LARC referred to two tertiary referral cancer centres in Western Sydney were examined. Patient demographics, presenting symptoms, treatment, relapse free survival (RFS), overall survival (OS) and progression free survival (PFS) were obtained. Under 50 years old was used as the cut-off age for defining yRC. All 145 consecutive patients were treated for LARC, including 28 in the yRC and 117 in the older patient group. Median follow-up was 54 months. yRC were more likely to complete neoadjuvant therapy (100% vs. 86%; P=0.032) and to undergo more extensive surgical procedures (24% vs. 2%, P<0.0001). yRC were more likely to have microsatellite high (MSI) tumours (30% vs. 4.7%; P=0.003). yRC demonstrated significantly poorer RFS compared with the standard group (HR 2.79; median RFS 4.67 vs. 16.02 months; P=0.023). In the relapsed setting, yRC had poorer PFS compared with the standard group (median PFS 2.66 vs. 9.70, P=0.006, HR 3.04). A difference in OS was also seen between the two groups, with yRC demonstrating poorer OS (median OS 40.46 vs. 58.26 months, HR 3.48, P=0.036). Patients under 50 years with LARC are more likely to have MSI tumours with a more aggressive disease course and poorer RFS, PFS and OS. Initiatives to improve early detection of these patients may improve outcomes. Further research is necessary to understand this disease and optimise its treatment.

Abstract PS5-03: Celtil score and long-term survival outcome in early stage HER2-positive (HER2+) breast cancer treated with anti-HER2-based chemotherapy: A correlative analysis of neoALTTO trial

Abstract Background: Biomarkers to help escalate or de-escalate systemic therapies are urgently needed in early-stage HER2+ breast cancer patients. The combination of high stromal tumor infiltrating lymphocytes (TILs) and low tumor cellularity at 2 weeks of anti-HER2 therapy (CelTIL score) has been associated with high rates of pathologic complete response (pCR) after completion of neoadjuvant therapy. However, the value of CelTIL as a prognostic biomarker is unknown. Here, we present an independent validation of CelTIL in the NeoALTTO phase III trial. Methods: NeoALTTO randomized 455 patients (pts) with HER2+ early breast cancer to receive lapatinib (arm A), trastuzumab (Arm B) or lapatinib and trastuzumab (Arm C) for 6 weeks, followed by the assigned anti-HER2 treatment combined with paclitaxel weekly for 12 weeks. After surgery, patients received 3 cycles of fluorouracil, epirubicin and cyclophosphamide, and then continued the assigned anti-HER2 treatment for 34 weeks. CelTIL was centrally evaluated in tumor biopsies performed at week 2 in arms B and C using the pre-established formula (CelTIL score = -0.8 × tumor cellularity [%] + 1.3 ×TILs [%]). The primary objective was to evaluate the association of CelTIL (as a continuous variable and using the pre-established 33.59% cut-off as defined by Nuciforo P, et al; Ann Oncol. 2018) with event-free survival (EFS). Secondary objectives were to evaluate the association of CelTIL with overall survival (OS) and pCR. Univariable and multivariable analyses were performed adjusting for hormone-receptor status, pre-treatment tumor size and nodal status, planned type of surgery, pCR status, and treatment arm. Results: The CelTIL score was evaluable in 196 samples (108 samples in arm B and 88 samples in arm C), of which 45.4% (89/196) had low CelTIL score and 54.6% (107/196) had a high CelTIL score. As a continuous score, higher CelTIL levels were independently associated with improved EFS (hazard ratio [HR]=0.84 per 10% increment; 95% CI 0.73-0.97; P=0.006), but not OS (HR=0.85; 95% CI 0.71-1.03; P=0.094). Using the pre-established cutoff, the 5-year EFS estimate was 76% (95% CI 68-85%) and 60% (95% CI 50-72%) in pts with high- and low-CelTIL, respectively (adjusted HR=0.53; 95% CI 0.30-0.94; p=0.030). Moreover, the 5-year OS rate was 86% (95% CI 80-94%) and 73% (95 CI 64-84%) in high- and low-CelTIL respectively (adjusted HR=0.43; 95% CI 0.20-0.92; p=0.029). CelTIL as a continuous score was also independently associated with higher rates of pCR (odds ratio [OR]=1.18; 95% CI 1.02-1.36; p=0.024). The pCR rate in the high-CelTIL group was 37% (40/107) versus 18% (16/89) in the low-CelTIL group (adjusted OR=2.60; 95% CI 1.31-5.14; p=0.006). Conclusions: CelTIL score measured at week 2 of anti-HER2 therapy is significantly associated with long-term survival outcomes in early-stage HER2+ breast cancer, independently of pCR status and other prognostic variables. Further validation of this biomarker could help select early-on pts candidates for escalation or de-escalation of systemic therapy. Citation Format: Nuria Chic, Stephen Luen, Paolo Nuciforo, Roberto Salgado, Debora Fumagalli, Florentine Hilbers, Yingbo Wang, Evandro de Azambuja, Itsvan Lang, Serena Di Cosimo, Cristina Saura, Jens Huober, Aleix Prat, Sherene Loi. Celtil score and long-term survival outcome in early stage HER2-positive (HER2+) breast cancer treated with anti-HER2-based chemotherapy: A correlative analysis of neoALTTO trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-03.

Intention to treat outcomes among patients with pancreatic cancer treated using International Study Group on Pancreatic Surgery recommended pathways for resectable and borderline resectable disease.

The International Study Group on Pancreatic Surgery recommends upfront surgery for resectable pancreatic cancer or borderline resectable-venous (BR-V) disease and neoadjuvant therapy (NAT) among those with arterial involvement (BR-A or locally advanced, LA). Though neoadjuvant therapy (NAT) is a promising strategy, outcomes are rarely reported on intention-to-treat (ITT) basis. This study presents ITT outcomes where pathways to surgery were in line with International Study Group on Pancreatic Surgery guidelines. Patients recommended for potentially curative treatment with PDAC between 2012 and 2017 (n= 345) were classified as resectable, BR-A/BR-V or LA, according to NCCN criteria. The primary outcome was overall survival. Secondary outcomes were resection rates, positive margins and toxicity among patients receiving NAT. At surgery, the resection rates were 78% (172/221), 65% (35/54) and 54% (21/39) for those with resectable, BR-V and BR-A/LA disease, respectively (P< 0.0001). The median survival of those resected in the BR-A/LA cohort was 31 months. However, on an ITT basis, there was no significant difference in survival between resectable, BR-V and BR-A/LA disease (median: 19 versus 15 versus 19 months; P= 0.585). On review, some 31 (44%) patients of the BR-A/LA cohort either did not receive or did not complete NAT. To realize benefits of NAT, more patients need to complete NAT and to undergo resection. Upfront resection for BR-V disease is associated with equivalent outcomes to upfront surgery for resectable disease or NAT for BR-A/LA disease. Strategies to increase the proportion of patients who complete NAT and undergo resection are needed.

Camrelizumab in combination with preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma: A single-arm, open-label, phase II study.

222 Background:At present, esophageal cell carcinoma (ESCC) has a dismal prognosis with huge unmet clinical needs. With the potential benefit of combining PD-1 inhibitor with neoadjuvant chemotherapy (nCT), we conducted a phase II trial to assess the efficacy and safety of Camrelizumab (anti-PD-1 antibody) plus nCT for locally advanced ESCC. Methods:26 patients (pts) with histologically confirmed stage Ⅱ/Ⅲ/Ⅳa (cT2-4aN0-3M0) ESCC were enrolled from February 2020 to September 2020.The study was divided into two stages, stage1: we administered 1 cycle of Camrelizumab for induction therapy (200 mg q2 weeks); stage2: pts received 2 cycles of Camrelizumab (200 mg every 3 weeks) plus docetaxel and nedaplatin, followed by surgery within 4~6 weeks after neoadjuvant therapy completion. Primary endpoint was major pathologic response (MPR). Secondary endpoints included pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS) and overall survival (OS). In total 40 pts will be enrolled. Results:At the cutoff date of Sep 22, 2020, 26 eligible pts were enrolled (65% males, median age 63), neoadjuvant treatment was completed in 17 pts and is ongoing in 7 pts. Thus far 12 out of 17 pts were resected, 5 pts are planned to undergo surgery, 1 pt had interval metastases preoperatively, 1 pt declined surgery. All patients underwent an R0 resection. Postoperative pathology showed that T stage decreased in 10 pts with 83% reduction rate. 5 pts (42%) reached major pathologic response, 3 pts (25%) reached pathologic complete response, the others maintained stable disease (33%). No grade 3 immunotherapy related AEs were observed, no surgery related mortality. The most common AEs (all grade, grade≥3) were anemia (31%, 3%), leukopenia (7%, 0%), neutrophil (3%,0%), hypoalbuminemia (21%, 0%), hematochezia (14%, 0%), fatigue (10%, 0%) and thyroid dysfunction (24%, 0% ). Date for median PFS and OS were not matured. Conclusions:Camrelizumab in combination with preoperative chemotherapy followed by surgery for locally advanced ESCC showed promising downstaging effect and MPR with good tolerance, and its efficacy and safety could be further studied in later trials. Clinical trial information: NCT03917966.

Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC).

335 Background: Only 10-15% of newly diagnosed HCC patients are candidates for a potentially curative resection, and most patients who receive resection eventually recur. Historical systemic therapies including sorafenib, as well as locoregional therapies, have not demonstrated benefit in the perioperative setting. Novel combinations of targeted therapies and immunotherapies demonstrate higher response rates than sorafenib in HCC. Here, we report the feasibility and efficacy of neoadjuvant combination therapy with cabozantinib plus nivolumab, followed by surgical resection, in patients with borderline resectable or locally advanced HCC. Methods: We conducted an open-label, single-arm, phase I study in patients with HCC with borderline resectable or locally advanced HCC (including multinodular disease, portal vein involvement, or other high-risk features). Patients received 8 weeks of therapy with cabozantinib 40 mg oral daily plus nivolumab 240 mg IV every two weeks, followed by restaging and possible surgical resection. The primary endpoint was feasibility, defined by the percentage of patients experiencing a treatment-related adverse event that precluded continuing on to surgery within 60 days of the planned date for surgical evaluation. Results: We enrolled 15 patients of whom 14 patients completed neoadjuvant therapy and underwent surgical evaluation. Adverse events were consistent with prior experience with these agents, and the trial met its primary endpoint, with no patients experiencing a treatment-related adverse event that precluded timely surgical assessment. Of patients completing neoadjuvant therapy, 1 patient declined surgery, 1 tumor could not be resected, and 12 patients underwent successful R0 surgical resection. 5/12 (41.7%) resected patients had a major or complete pathologic response. At a median follow up of one year, 4/5 pathologic responders are without recurrence. We performed an in-depth profiling of the surgical resection biospecimens and identified an enrichment of IFNγ+ effector memory CD4+ and granzyme B+ effector CD8+ T cells as well as tertiary lymphoid aggregates in the pathologic responders. We further analyzed the spatial relationships of cell types in responders and non-responders, which identified distinct spatial arrangement of B cells in responders, and proximity of arginase-1 expressing myeloid cells to T cells in nonresponders. Conclusions: This study is, to our knowledge, the first use of a targeted therapy in combination with an immune checkpoint inhibitor in the neoadjuvant setting in HCC, and the first use of modern systemic therapies to expand surgical resection criteria. Neoadjuvant cabozantinib and nivolumab is feasible, and may result in pathologic responses and long-term disease-free survival in a group of patients who may be outside traditional resection criteria. Clinical trial information: NCT03299946.

Elevated postoperative CA19-9 in patients with pancreatic cancer following the completion of neoadjuvant therapy and surgery - implications for adjuvant therapy and surveillance

Elevated postoperative CA19-9 in patients with pancreatic cancer following the completion of neoadjuvant therapy and surgery - implications for adjuvant therapy and surveillance

Biliary complications during neoadjuvant therapy for pancreatic cancer

Introduction: Neoadjuvant therapy prior to resection of pancreatic head cancer increases time to surgery and thus the possibility of biliary complications. We determined the frequency and impact of biliary complications during neoadjuvant therapy prior to resection. Methods: We completed a retrospective study of patients treated with neoadjuvant therapy for pancreatic head adenocarcinoma from May 2014 through March 2019. Results: Of the 59 patients identified, the average age was 67 and 50.8% were male. Neoadjuvant therapy regimens included gemcitabine and abraxane + chemo-radiation (28 patients, 47.5%), FOLFIRINOX + chemo-radiation (15 patients, 25.4%) and remaining 16 patients received alternative therapeutic combinations based on tolerance. Six (10.1%) patients died prior to completion of neoadjuvant therapy. After completion of all neoadjuvant therapy, 34 (57.6%) patients went on to resection while 19 (32.2%) showed disease progression precluding surgical extirpation. Biliary complications during neoadjuvant therapy affected 16 patients (27%). Biliary interventions included percutaneous cholecystostomy drain (3 patients, 5.1%), ERCP with stent placement or exchange (6 patients, 10.1%), percutaneous transhepatic drain (4 patients, 6.8%) and hospital admission for cholangitis with medical treatment only (2 patients, 3.3%). Eight of the 16 patients with biliary complications went on to surgical resection (50%) compared to 26 of the 43 (60.4%) patients who did not have biliary complications. (χ2=0.18, p = 0.67). Conclusion: Biliary complications during neoadjuvant therapy for pancreatic head cancer are relatively common, but do not significantly affect proceeding to surgical resection.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreatic cancer

BackgroundThe role of neoadjuvant stereotactic body radiation therapy (SBRT) in patients with borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) remains controversial. MethodsWe retrospectively evaluated BRPC and LAPC patients treated at our institution who underwent 2–3 months of chemotherapy followed by SBRT to a dose of 30–33 Gy. Overall survival (OS) and recurrence-free survival (RFS) were estimated and compared by Kaplan–Meier and log-rank methods. ResultsWe identified 103 (85 BRPC and 18 LAPC) patients treated per our neoadjuvant paradigm between 2011 and 2018, with resectability based on NCCN definitions. Median follow up was 25 months. Of patients completing neoadjuvant therapy, 73 (71%) underwent definitive resection. Seventy-one (97%) patients with definitively resected tumors had R0 resection and 5 (7%) had a complete pathologic response CR to neoadjuvant therapy. The median overall survival (OS) of the cohort was 24 months. Those with a complete or marked pathologic response had significantly better OS than those with a moderate response (41 vs 24 months, p < 0.02) and patients unable to undergo definitive surgery (17 months, p < 0.0003). Six resected patients experienced grade ≥3 surgical complications. ConclusionsNeoadjuvant chemotherapy and SBRT are associated with promising pathologic response rates and R0 resection rates, with acceptable perioperative morbidity.

Timing to imaging and surgery after neoadjuvant therapy for breast cancer

Neoadjuvant therapy (NAT) is increasingly used in breast cancer (BC), yet, the recommended time interval between NAT completion, preoperative imaging assessment, and breast surgery is not clearly defined. This single-center retrospective study investigated tumor growth between NAT completion and surgery. The analysis included 106 BC patients who received NAT (69% chemotherapy alone, 31% chemotherapy plus anti-HER2 therapy), had post-NAT breast MRI, and definitive surgery between 2012 and 2019. The median time interval between end-of-treatment and surgery was 6 weeks; 90% had surgery within 8 weeks of NAT completion, and 10% had surgery 8–12 weeks after NAT completion. No significant correlation was found between any of the time intervals (i.e., NAT completion-to-surgery, NAT completion-to-MRI, post-NAT MRI to surgery) and the tumor size as captured in the pathology report. The only parameter that was significantly correlated with pathological tumor size was tumor size as measured on the post NAT MRI (P < .0001). The difference in tumor size between post NAT MRI and surgical pathology did not correlate with the time interval between end-of-treatment and surgery. The ratio between residual tumor size on post-NAT MRI and the time interval from the end-of-treatment to surgery, significantly correlated with the tumor size on surgical pathology (P < .0001) suggesting that NAT has a beneficial effect weeks after end-of-treatment. In conclusion, our results suggest that for patients undergoing neoadjuvant chemotherapy, surgery within 4–8 weeks of completing NAT is reasonable, and is unlikely to result in a clinically significant change in residual tumor size.

Total Neoadjuvant Therapy for Operable Pancreatic Cancer.

Overall survival (OS) for operable pancreatic cancer (PC) is optimized when 4-6months of nonsurgical therapy is combined with pancreatectomy. Because surgery renders the delivery of postoperative therapy uncertain, total neoadjuvant therapy (TNT) is gaining popularity. We performed a retrospective cohort study of patients with operable PC and compared TNT with shorter course neoadjuvant therapy (SNT). Primary outcomes of interest included completion of neoadjuvant therapy (NT) and resection of the primary tumor, receipt of 5months of nonsurgical therapy, and median OS. We reviewed 541 consecutive patients from 2009 to 2019 including 226 (42%) with resectable PC and 315 (58%) with borderline resectable (BLR) PC. The median age was 66years (IQR [59, 72]), and 260 (48%) patients were female. TNT was administered to 89 (16%) patients and SNT was administered to 452 (84%). Both groups were equally likely to complete intended NT and surgery (p = 0.90). Patients who received TNT and surgical resection were more likely to have a complete pathologic response (8% vs 4%, p < 0.01) and were more likely to receive at least 5months of nonsurgical therapy (67% vs 45%, p < 0.01). The median OS was 26months [IQR (15, 57)]; not reached among patients treated with TNT, and 25months [IQR (15, 56)] among patients treated with SNT (p = 0.19). TNT ensures the delivery of intended systemic therapy prior to a complicated operation without decreasing the chance of successful surgery; a window of operability was not lost. Patients who can tolerate SNT will likely benefit from TNT.

Abstract A51: Personalized monitoring of treatment response using Targeted Digital Sequencing of circulating tumor DNA

Abstract Background: Accurate circulating biomarkers for detecting residual disease can help guide therapy decisions, particularly in early-stage cancer patients. However, currently available methods lack the sensitivity required to confidently assess the presence of residual disease in patients with low tumor burden. To address this need, we have developed TARDIS (Targeted Digital Sequencing), a personalized, multiplexed amplicon sequencing method capable of tracking as many as 100 or more mutations simultaneously. Methods: We obtained tumor biopsies and longitudinal plasma samples from patients with early-stage breast cancer, glioblastoma, and pancreatic cancer. Each tumor biopsy was analyzed whole-exome sequencing. Founder mutations were selected, accounting for copy number alterations (analyzed using sequenza) and a consensus allele fraction approach that combined pyclone and custom in-house methods. Patient-specific TARDIS primers were designed to detect these mutations in plasma cfDNA. Error suppression in TARDIS was achieved using a combination of unique molecular identifiers and fragment sizes to group sequencing reads into read families. Results: In 33 patients with early-stage breast cancer treated with neoadjuvant therapy, we targeted between 3 and 116 (mean 30) mutations per patient and analyzed between 1 and 4 longitudinal plasma samples using TARDIS. Prior to treatment, we detected ctDNA in 100% patients with Stage I-III breast cancer (n=32, 95% CI= 89%-100%). We detected tumor-specific mutations in 100% of baseline breast cancer plasma samples. After completion of neoadjuvant therapy and before surgery, ctDNA levels were significantly lower in patients with pathologic complete response (pathCR, no evidence of disease at surgery) compared to patients with residual disease (median tumor fractions 0.003% and 0.017%, respectively, p=0.0058, AUC=0.83). Conclusions: TARDIS enables highly sensitive detection of ctDNA in patients with nonmetastatic cancers. Analysis of longitudinal plasma samples using TARDIS holds promise for personalizing the extent of treatment in patients with curable disease. Multiple clinical validation studies across cancer types are ongoing to define quantitative thresholds for changes in ctDNA levels that could improve clinical decision making. Citation Format: Bradon R. McDonald, Tania Contente-Cuomo, Stephen-John Sammut, Michelle D. Stephens, Ahuva Odenheimer-Bergman, Brenda Ernst, Nieves Perdigones, Suet-Feung Chin, Maria Farooq, Rosa Mejia, Patricia A. Cronin, Karen S. Anderson, Heidi E. Kosiorek, Donald W. Northfelt, Ann E. McCullough, Bhavika K. Patel, Jeffrey N. Weitzel, Thomas P. Slavin, Carlos Caldas, Barbara A. Pockaj, Muhammed Murtaza. Personalized monitoring of treatment response using Targeted Digital Sequencing of circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A51.

Predictors of recurrence and implications for overall survival in borderline resectable pancreatic cancer patients treated with total neoadjuvant therapy: A retrospective cohort study.

e16781 Background: Borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) is a subset of pancreatic cancer with unique prognostic implications. A multimodality, neoadjuvant therapy (NAT) approach has known benefits such as downstaging tumors, reducing the risk of a positive margin, and treating micrometastatic disease. Patient selection and therapy sequencing are controversial owing to the high risk of recurrence. Therefore, we aimed to identify factors predicting recurrence and overall survival (OS) in BR PDAC patients undergoing NAT. Methods: We identified BR PDAC patients treated with NAT followed by surgery at Moffitt Cancer Center between 2008-2015. We evaluated clinical, demographic, and perioperative factors to identify predictors of recurrence and OS. Statistical analyses were performed with univariate and multivariable Cox regression models. Results: 117 patients with BR PDAC who received NAT were evaluated; 53 (45%) were female and 64 (55%) were male. Of those, 91 (78%) received gemcitabine/xeloda/taxotere and the remainder received other gemcitabine or 5FU regimens. 107 (91%) patients received neoadjuvant radiation, mainly 5-day dose painted SBRT. Post- NAT CA 19-9 normalized in 39 (33%) and 11 (9%) additional patients normalized after surgery. Pathologic treatment effect was appreciated in 85 (73%) patients and pathologic complete response (pCR) was seen in 18 (15%). 95 (81%) patients initiated adjuvant therapy. In multivariable analysis, the strongest predictor of recurrence was higher log(10) post-operative CA 19-9 (HR 2.29; 95% CI, 1.40-3.75). Time from initiation of NAT to surgery ≥ 5 months also predicted recurrence (HR 2.08; 95% CI, 1.16-3.72). In OS analysis, 71 patients had recurrence after multimodality treatment; 61 (86%) died and 10 (14%) were alive. In multivariable analysis, the strongest predictors of prolonged OS from recurrence were female gender (HR 0.47; 95% CI, 0.26-0.84) and presence of a treatment effect (HR 0.37; 95% CI, 0.15-0.93). Conclusions: We observed treatment effects and pCR comparable to other institutions, supporting a multimodality approach to BR PDAC. Higher post-operative CA 19-9 and time to surgery ≥ 5 months from initiation of NAT were associated with an increased risk of recurrence. These data suggest that timely receipt of surgery after completion of NAT may impact recurrence and OS in BR PDAC.

Myosteatosis to predict postoperative morbidity in pancreatic ductal adenocarcinoma patients receiving neoadjuvant chemotherapy.

e16754 Background: Myosteatosis (adipose deposits in muscle) can be detected on cross-sectional imaging through variations in Skeletal Muscle Density (SMD). Patients with myosteatosis tend to have lower overall survival, increased chemotherapy toxicity, and shorter progression-free intervals across cancer types. We investigated whether changes in myosteatosis during neoadjuvant chemotherapy can predict postoperative morbidity risk in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: This is a retrospective cohort study from 2014-2019 of patients with biopsy-proven PDAC who completed neoadjuvant chemotherapy and R0/1 resection (R1: margin &lt; 1mm or microscopically positive). We obtained preoperative patient (age at diagnosis, baseline body mass index (BMI), sex, race, comorbidities) and treatment data (neoadjuvant chemotherapy regimen and duration, time from completion of systemic therapy to surgery, type of operation). Primary outcomes were postoperative complications and 90-day readmission. Average SMD was measured using imaging analysis software at the L3 level on axial abdominal CT scans at the time of diagnosis and at completion of neoadjuvant therapy (SliceOmatic TomoVision QC, Can). We defined SMDΔ as the decrease in SMD during neoadjuvant chemotherapy. Descriptive statistics and Student’s t-test were performed with STATA. Results: We identified 44 patients who received neoadjuvant chemotherapy, achieved a R0/1 resection, and had available CT scans for body composition evaluation. The postoperative complication rate was 43% (n = 19) and 90-day readmission rate was 30% (n = 13). Lower SMD at diagnosis was associated with increased postoperative delirium (p &lt; 0.01) and 90-day readmission (p = 0.02). Greater SMDΔ was associated with increased ICU utilization (p &lt; 0.01) and tube feeding upon discharge (p = 0.03). There was no significant association between preoperative BMI or albumin and our primary outcomes. Conclusions: Preoperative SMD and SMDΔ, rather than albumin or BMI, can predict postoperative morbidity in PDAC patients who received neoadjuvant chemotherapy. This study provides the framework for future studies to develop and validate a tool to predict postoperative morbidity risk in these patients.

Importance of Normalization of CA19-9 Levels Following Neoadjuvant Therapy in Patients With Localized Pancreatic Cancer.

Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear. Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response. CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (≥35 U/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19-9 (Q1-4); 2) proportional changes in CA19-9 (ΔCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35 U/dL) of preop CA19-9; and 4) normalization of postop CA19-9. Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80 U/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of ΔCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9. Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival.