Bulky Nodal Involvement Research Articles

Prognostic Significance of Bulky Nodal Disease in Anal Cancer Management: A Multi-institutional Study.

This study aimed to assess the prognostic significance of bulky nodal involvement in patients with anal squamous cell carcinoma treated with definitive chemoradiotherapy. We retrospectively analyzed medical records of patients diagnosed with anal squamous cell carcinoma who underwent definitive chemoradiotherapy at three medical centers between 2004 and 2021. Exclusion criteria included distant metastasis at diagnosis, 2D radiotherapy, and salvage treatment for local relapse. Bulky N+ was defined as nodes with a long diameter of 2 cm or greater. A total of 104 patients were included, comprising 51 with N0, 46 with non-bulky N+, and seven with bulky N+. The median follow-up duration was 54.0 months (range, 6.4 to 162.2 months). Estimated 5-year progression-free survival (PFS), loco-regional recurrence-free survival (LRRFS), and overall survival (OS) rates for patients with bulky N+ were 42.9%, 42.9%, and 47.6%, respectively. Bulky N+ was significantly associated with inferior PFS, LRRFS, and OS compared to patients without or with non-bulky N+, even after multivariate analysis. We proposed a new staging system incorporating bulky N+ as N2 category, with estimated 5-year LRRFS, PFS, and OS rates of 81.1%, 80.6%, and 86.2% for stage I, 67.7%, 60.9%, and 93.3% for stage II, and 42.9%, 42.9%, and 47.6% for stage III disease, enhancing the predictability of prognosis. Patients with bulky nodal disease treated with standard chemoradiotherapy experienced poor survival outcomes, indicating the potential necessity for further treatment intensification.

Radiotherapy for Advanced Hodgkin Lymphoma with Initial Bulk: A Combined Analysis of Two Randomized Trials

PurposeThe role of consolidative radiotherapy (RT) in patients with advanced Hodgkin lymphoma (HL) with initial bulk is unclear. GITIL/FIL HD0607 and FIL HD0801, two randomized controlled trials with similar design and methodologies, did not identify a benefit to consolidative RT after a metabolic complete response (CR) to 6 cycles of ABVD. However, their limited sample sizes reduced statistical power to detect a small but clinically meaningful benefit to RT. Materials and MethodsIn a secondary analysis of these two phase 3 trials, reconstructed patient data were used to compare outcomes for early and complete responders randomized to no RT or RT to the site(s) of initial bulk. Estimates of progression-free survival (PFS) in the intent-to-treat (ITT) and per-protocol (PP) analyses were generated using the combined data and compared between groups using the log-rank test. ResultsA total of 412 patients were included in the ITT analysis and 373 patients were included in the PP analysis. Median age was 30-32, 42% of patients were stage IIB, and 73% of bulky sites were located in the mediastinum. For the no RT versus RT groups, 5-year ITT PFS estimates were 90.1% versus 90.1% (p=0.81). Five-year PP PFS rates were 90.9% versus 92.9% (p=0.31), respectively. There was no observed difference between no RT and RT groups in subgroups according to size of bulky disease: 5-7 cm (p=0.78), 7-10 cm (p=0.25), and >10 cm (p=0.69). ConclusionIn this combined analysis of two randomized phase 3 clinical trials, consolidative RT to initial sites of bulky nodal involvement was not associated with a PFS benefit in patients with advanced HL in metabolic CR after 2 and 6 cycles of ABVD.

Bulky nodal disease as distinctive prognosticator in anal cancer management.

1 Background: This study aimed to investigate the prognostic value of bulky nodal involvement in patients with squamous cell carcinoma of anus treated with definitive chemoradiotherapy. Methods: Medical records of patients with anal squamous cell carcinoma receiving definitive chemoradiotherapy at three medical centers from 2004 to 2021 were retrospectively analyzed. Exclusion criteria were (1) distant metastasis including non-regional nodal involvement at diagnosis, (2) 2D radiotherapy, and (3) salvage treatment for local relapse. Bulky nodal disease was defined as node with long-diameter 2cm or greater. Results: A total of 104 patients were accrued, consisting of 51 patients without, 46 patients with non-bulky, and 7 patients with bulky nodal involvement. Median follow-up duration was 54.0 months (range, 6.4-162.2 months). Estimated progression-free survival (PFS), loco-regional recurrence free survival (LRRFS) and overall survival (OS) at 5 years for patients with bulky nodal disease were 42.9%, 42.9%, and 89.4%, respectively. Compared to without or with non-bulky nodal involvement, bulky nodal involvement was significantly related with poor PFS and LR RFS. New staging incorporating bulky nodal disease as N2 stage was devised: T1-2N0-1 as stage I, T3-4N0-1 as stage II, and N2 as stage III. Estimated PFS, LRRFS, and OS at 5 years were as follows: 83.5%, 85.9%, and 91.3%, 60.9%, 67.7% and 93.3%, and 42.9%, 42.9%, and 55.6% for patients with stage I, II, and III disease, respectively (p = 0.0024 for PFS, 0.0015 for LRRFS, and 0.28 for OS, respectively). Conclusions: Patients with bulky nodal disease receiving standard chemoradiotherapy had poor survival outcomes compared to the other patient groups, suggesting the need for further treatment intensification. Moreover, incorporating bulky nodal disease into the staging system improved the prognosis predictability.

A phase II study of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 followed by gastrectomy with D2 plus para-aortic nodal dissection for gastric cancer with extensive lymph node metastasis: JCOG1704.

354 Background: Prognosis of gastric cancer (GC) with extensive lymph node metastasis (ELM) is poor due to unresectability even without distant metastases. We conducted a phase II study to evaluate the safety and efficacy of preoperative chemotherapy with docetaxel (D), oxaliplatin (O), and S-1 (S) followed by extended gastrectomy. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; bulky nodal involvement around major branched arteries to the stomach (Bulky N) and/or para-aortic nodal metastases (PAN); cM0 (except para-aortic nodes); negative lavage cytology; not linitis plastica type; PS of 0 or 1; 20-75 years old. Patients received three 21-day cycles of preoperative chemotherapy of D (40 mg/m2 on day 1), O (100 mg/m2 on day 1), and S (80-120 mg /body from day 1 to day 14), and then underwent gastrectomy with D2 plus para-aortic nodal dissection. After surgery, patients received adjuvant chemotherapy with S-1 for 1 year. Primary endpoint was major pathological response rate, defined by the disappearance of more than two-thirds of the primary tumor. Expected and threshold value of major pathological response was set at 40% and 25%, respectively. Sample size was calculated to be 50 based on a one-sided alpha of 0.1, power of 0.8 and single-arm phase II study using a Southwest Oncology Group (SWOG) two-stage design. Results: Between Oct 2018 and Mar 2022, 47 patients were enrolled, of whom 46 were eligible for efficacy analysis. The median age was 67 years. The pathological type was differentiated in 33 patients and undifferentiated in 14. Twenty patients had only bulky N, 17 had only PAN, and 10 had both of bulky N and PAN. Clinical stage was III in 19 and IV in 28 patients. Except one patient refused chemotherapy, 46 patients (45 in three cycles and 1 in one cycle) completed preoperative DOS. Forty-four patients (94%) underwent gastrectomy, including 23 distal gastrectomy and 21 total gastrectomy, and 43 (91%) had an R0 resection. Major pathological response was confirmed in 26 of 46 patients (57% with 80% CI: 46-67), including pCR of 24%, which met the statistical significance (p<0.0001). According to the Becker’s criteria, grade 3 was 13, grade 2 was 12, grade 1b was 7, and grade 1a was 11. DOS-related grade 3/4 toxicities included neutropenia in 11 patients (24%), anorexia in 7 (16%), diarrhea in 4 (9%), and febrile neutropenia in 4 (9%). Surgery-related grade 3/4 toxicities were abdominal abscess in 5 (12%) and pancreatic fistula in 3 (7%). No treatment-related death was observed. Conclusions: Preoperative DOS followed by gastrectomy with D2 plus para-aortic nodal dissection is safe, feasible, and effective for GC with ELM. Clinical trial information: jRCTs031180028 .

S1801: A randomized trial of adjuvant versus neoadjuvant pembrolizumab for melanoma.

TPS9585 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time, we are not able to predict which patients will derive benefit from AT and experience cure. While curative intent is the goal of treatment for primary melanoma, patients with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with response and survival. Treating with anti-PD1 while tumor remains visible in the body may generate a stronger immune response against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies of NAT with anti-PD-1 therapy have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients with Stage IIIB to oligometastatic, resectable Stage IV are randomized 1:1 to AT or NAT. Patients getting AT undergo surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery, or death due to any cause. Secondary endpoints include RECIST and iRECIST response rates, as well as a number of surgical outcomes. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT after 3 doses of PEM. Surgical pathology grossing instructions to ensure readout for pathologic response are provided in the form of training slides. Enrollment is at 40% of a planned 500 patients. Clinical trial information: NCT03698019.

S1801: A randomized phase II trial of adjuvant versus neoadjuvant pembrolizumab (PEM) for melanoma.

TPS10090 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time we are not able to predict which patients will derive benefit from AT and experience cure. While curative surgery is the goal of early treatment of primary melanoma, some cases with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with survival. Treating with anti-PD1 while tumor transiently remains in the body may generate a stronger immune response from tumor-infiltrating lymphocytes against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies using NAT with have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with PEM (NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients are randomized 1:1 to the AT or the NAT. Patients getting AT receive surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin AT within 84 days of surgery, relapse after surgery, or death due to any cause. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT with 3 doses of PEM. Enrollment is at 94 of a planned 500 patients. Clinical trial information: NCT03698019.

Multicenter phase II study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PII).

399 Background: Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach, therefore, we have conducted a phase II study to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (G-SOX) followed by gastrectomy with D2/3 lymph node dissection for LAGC, and the primary endpoint of curative resection rate was met [Miki A, ESMO 2019]. We show longer follow-up data from this study. Methods: Patients with adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3; bulky nodal involvement around major branched arteries to the stomach were enrolled. Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results: Between August 2015 and March 2017, forty-one patients were in enrolled. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Grade 3 or higher toxicities during neoadjuvant chemotherapy of G-SOX were neutropenia (7%), fatigue (7%), diarrhea (5%) and thrombocytopenia (2%). No treatment related deaths were observed. Surgical complications including postoperative complications were observed in 13 patients (35%). Pathological response rate after neoadjuvant G-SOX was 40%. With a median follow-up period of 33.8 months, 3year-relapse free survival and 3year-ovearll survival was 54.3% and 73.1%, respectively. Conclusions: An update analysis confirmed that neoadjuvant chemotherapy of G-SOX is a feasible and might be one of the promising strategies for patients with LAGC. Clinical trial information: UMIN000018661.

Bilan d’extension et classification TNM actualisée du cancer bronchique non à petites cellules

Initial staging of lung cancer is of major importance for an optimal management and for prognosis evaluation. CT is the first imaging modality for identifying evident metastatic stages or bulky nodal involvement. For other cases, PET CT plays a major role for nodal staging, with the need to obtain a histological confirmation if it changes the therapeutic strategy. This is the same for single metastasis, if technically possible. The 8th edition of the TNM classification is now to be used in clinical routine. Most changes concern the T status, where the prognostic role of tumor size is increased. Every centimeter up to 5cm is now taken into account, and tumors of more than 5 or 7cm are now respectively classified as T3 and T4. There are no major changes regarding the N status. A distinction is made between single (M1b) versus multiple (M1c) extrathoracic metastasis in view of their different prognosis.

Phase I study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PI)

BackgroundThe prognosis of locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. One promising approach is neoadjuvant chemotherapy. Combination chemotherapy with S-1 and oxaliplatin (SOX) is recognised as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of SOX for locally advanced gastric cancer has not been reported. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with SOX for locally advanced gastric cancer.MethodsPatients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as S-1 (80 mg/m2/day, twice daily) for 14 days, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph node dissection followed by adjuvant S-1 (80 mg/m2/day, twice daily) for 1 year. Escalation of oxaliplatin dose was planned (starting at level 0, oxaliplatin 100 mg/m2; level 1, 130 mg/m2).ResultsSix patients were enrolled. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with S-1 80 mg/m2/day twice daily could be administered with acceptable toxicity. Peripheral neuropathy was observed in all patients but with no functional disorders. No treatment-related death was observed and the incidence of operative morbidity was tolerable. Resection with curative intent was undertaken in all patients with R0 resection performed in five (83%) and R1 in one. Two of the six patients had a pathological complete response (33%).ConclusionNeoadjuvant chemotherapy with an SOX regimen was feasible in patients with locally advanced gastric cancer. The recommended phase II dose was determined to be oxaliplatin 130 mg/m2 in combination with S-1 80 mg/m2/day, twice daily.

Phase I study of neoadjuvant chemotherapy with xeloda and oxaliplatin (G-XELOX) for locally advanced gastric cancer.

149 Background: Prognosis for locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is a promising approach, and combination chemotherapy with Xeloda and oxaliplatin (G-XELOX) is recognized as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of G-XELOX for locally advanced gastric cancer has not been reported. The aim of this study was to evaluate the incidence of dose limiting toxicities (DLTs) during the neoadjuvant chemotherapy and to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with oxaliplatin with a fixed Xeloda dose for locally advanced gastric cancer. Methods: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as Xeloda (2000 mg/m2/day, b.i.d.) for 14 days, repeatedly every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant S-1 (80 mg/m2/day, b.i.d.) for one year. A decrease of oxaliplatin dose was planned (starting at level 1, 130 mg/m2). Results: Six patients (5 male, 1 female) with a median age of 72 (range 68-79) were enrolled. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with Xeloda 2000 mg/m2/day, b.i.d. could be administered with acceptable toxicity. No treatment-related death was observed. Most frequent drug-related AEs during the neoadjuvant chemotherapy period were G1 anemia, G1/2 thrombocytopenia and G1 peripheral neuropathy. One patient refused surgical resection, therefore five received resection with curative intent. Of the five patients, all achieved a pathological downstaging after neoadjuvant G-XELOX therapy. The incidence of operative morbidity was tolerable. Conclusions: Neoadjuvant chemotherapy with G-XELOX regimen was feasible by patients with locally advanced gastric cancer. Clinical trial information: UMIN000015950.

Patients with Multifocal Macroscopic Papillary Thyroid Carcinoma Have a Low Risk of Recurrence at Early Follow-Up after Total Thyroidectomy and Radioactive Iodine Treatment

Background: Multifocal thyroid cancer involvement is a common presentation in papillary thyroid cancer. The risk of recurrence of intrathyroidal multifocal papillary microcarcinoma (<1 cm) is documented to be low. However, the risk of recurrence of multifocal macroscopic thyroid cancer is not known. Prior studies have suggested that both the number of foci and the presence of nodal involvement at diagnosis are important predictors of recurrence in multifocal papillary thyroid carcinoma (PTC). Objectives: In this retrospective review of 99 patients presenting with multifocal macroscopic PTC (with 2 tumor foci >1 cm) without gross extrathyroidal extension, we examined the clinical outcomes of patients in the first 2 years after the initial therapy and at the end of the follow-up period (median: 5 years). Results: Half of the patients presenting with multifocal macroscopic PTC had nodal involvement at diagnosis. Only 4 patients had a recurrence on long-term follow-up, all with classic or tall-cell variant PTC with bulky nodal involvement at diagnosis. The number of tumor foci did not influence the risk of recurrence in this cohort. The median time to recurrence in these 4 patients was 11 years, with all patients having a recurrence after 9 years of follow-up. None of patients developed distant metastasis or died from thyroid cancer. Conclusions: Patients presenting with multifocal macroscopic papillary thyroid cancer without bulky nodal involvement or gross extrathyroidal extension have a low risk of thyroid cancer recurrence.

Multicenter phase II study of neoadjuvant chemotherapy consisted with S-1 and oxaliplatin followed by gastrectomy for locally advanced gastric cancer.

TPS180 Background: Prognosis for locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. In our phase I study, neoadjuvant chemotherapy of S-1 and oxaliplatin (SOX) had manageable toxicities and good pathological complete response rate (33%) in patients with locally advanced gastric cancer. Based on the results of this phase I study, we initiate a multi-institutional, single-arm, open label, phase II study (Neo G-SOX PII study). The aim of this study is to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (SOX) followed by gastrectomy with D2/3 lymph node dissection; clinical T4; clinically resectable gastric cancer of type 4 or large type 3 (over 8 cm); bulky nodal involvement around major branched arteries to the stomach Methods: Eligibility criteria include histologically proven adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3 (over 8 cm); bulky nodal involvement around major branched arteries to the stomach; resectable peritoneal dissemination (pathological CY1 or P1, except for clinical CY1 or P1). Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint is curative resection rate. Key secondary endpoints include pathological response, R0/1 resection rate, dose-intensity, overall survival, relapse free survival and safety. We set the threshold curative resection rate at 65% and the expected curative resection rate at 80%. Given a one-sided α of 0.1 and statistical power of 80%, 40 patients was required. Clinical trial information: UMIN000018661 Clinical trial information: UMIN000018661.

A phase II study of systemic chemotherapy with docetaxel, cisplatin, and S-1 (DCS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection for gastric cancer with extensive lymph node metastasis (ELM): Japan Clinical Oncology Group Study JCOG1002.

116 Background: Gastric cancer with ELM is commonly regarded as unresectable with poor prognosis. We previously reported the safety and efficacy of cisplatin and S-1 (CS) followed by D2 gastrectomy with PAN dissection for this target (JCOG0405, Br J Surg 2014). Methods: Eligibility criteria included histologically proven gastric adenocarcinoma; bulky nodal involvement around major branched arteries to the stomach (Bulky N) and/or PAN metastases; cM0 (except PANs); negative lavage cytology; neither Borrmann type 4 nor large (8cm or more) type 3; PS 0 or 1. Patients received two or three cycles of induction chemotherapy of docetaxel (40mg/m2 day1), cisplatin (60mg/m2 day1), and S-1 (80mg/m2from day 1 to 14) every 4 weeks, and then underwent D2 gastrectomy with PAN dissection. After R0 resection, postoperative chemotherapy with S-1 was given for one year. The primary endpoint is response rate (RR) of NAC by central peer review. The planned sample size was 50 patients, provided 80% power under the hypothesis of primary endpoint as the expected RR of 80% and threshold RR of 65% with a one-sided alpha of 10%. Results: Between 07/2011 and 05/2013, 53 patients were enrolled and 1 patient was ineligible: 30 had Bulky N, 14 had PAN metastases, and 9 had both. 51of 52 patients (98.1%) completed a planned NAC. The clinical RR was 57.7% (30/52) (80%CI [47.9%-67.1%], one-sided p=0.89). The R0 resection rate was 84.6% (45/52). During DCS chemotherapy, grade 3/4 neutropenia occurred in 39.6% and grade 3/4 non-haematological adverse events in 20.8%. The incidence of grade 3/4 adverse events related to surgery was 30.6%. There was no treatment-related death. The pathological finding revealed minor response (residual tumor &lt;1/3) was achieved in 50.0% (26/52) and major response (residual tumor &lt;2/3) in 34.6% (18/52). The long-term survival is still under follow-up. Conclusions: Preoperative DCS revealed feasible but could not show sufficient efficacy. Preoperative CS is still being considered a standard treatment for this population. Clinical trial information: UMIN000006069.

Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Introduction:For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988).Patients and Methods:Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis.Results:Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively.According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts.Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts’ decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4).Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission.With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases.The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups.Conclusion:Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. [Display omitted] Disclosuresde Guibert:Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

A phase II study of preoperative chemotherapy with S-1 (S) and cisplatin (P) followed by D3 gastrectomy for gastric cancer (GC) with extensive lymph node metastasis (ELM): Survival results of JCOG0405.

70 Background: GC with ELM, especially in case of M1(LYM), is regarded unresectable in many countries, while challenge is ongoing in Japan to treat them by intensive chemotherapy followed by super extended surgery. In our previous phase II study (JCOG0001) for the same population, iritotecan plus P (IP) chemotherapy followed by surgery showed remarkable survival of 27.0% at 3 years but its toxicity led to rather high treatment related death (TRD). Development of safer and more effective treatment is urged. Methods: Eligibility criteria included histologically proven gastric adenocarcinoma; bulky nodal involvement around major branched arteries to the stomach and/or para-aortic nodal metastases; cM0 (except para-aortic nodes); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Patients (pts) received two or three 28- day cycles of induction chemotherapy of S (80 mg/m2 from day 1 to 21) and P (60 mg/m2 on day 8), and then underwent D3 gastrectomy. Primary endpoint was R0 resection and key secondary endpoint was 3-year survival. Other secondary endpoints included response rate and adverse events. Results: Between 02/2005 and 06/2007, 53 pts were enrolled and 2 pts were ineligible. Only surrogate endpoints of efficacy and feasibility were reported in ASCO-GI 2008, which included clinical response of 64.7%, R0 of 82.4%, pathological response of 51.0%, and no TRD with low toxicities. The 3-year overall survival, which we first clarified in this report, was 58.8% (95% CI, 44.1-70.9%). Conclusions: Preoperative SP followed by D3 gastrectomy demonstrated excellent 3-year survival with low mortality compared with preoperative IP, which was far better result than expected against this unresectable population. This multimodal treatment is highly promising for GC with ELM. [Table: see text]

An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer (GC) with extensive lymph node metastasis (ELM).

90 Background: GC with ELM (bulky N2 metastasis and / or para-aortic lymph node metastases [PAN]) is commonly regarded unresectable, while in JCOG combined modality treatment has been tested since 2000 (JCOG0001 and JCOG0405). Both trials met their primary endpoints (i.e., 3 year-survival of 27.3% in JCOG0001 and R0 resection of 82.4% in JCOG0405). The survival and the toxicity profile were quite different between the trials despite the similar eligibility with an outstanding 3-year survival of 58.8% in JCOG0405. This study is conducted to explore if survival is still better in JCOG0405 after adjusting baseline factors and if there is a subset of patients (pts) who benefit more from either treatment. Methods: Eligibility criteria for both included histologically proven gastric adenocarcinoma; bulky nodal involvement around major branched arteries to the stomach and/or PAN; cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Pts received two or three cycles of induction chemotherapy of IP: irinotecan (70 mg/m2 on day 1 and day 15) and cisplatin (80 mg/m2 on day 1) in JCOG0001, or SP: S1 (80 mg/m2 from day 1 to 21) and cisplatin (60 mg/m2 on day 8) in JCOG0405, followed by D3 gastrectomy. Multivariate analysis for overall survival adjusting baseline factors and treatment (IP/SP) was performed with a Cox regression model. Interaction tests were also carried out between baseline factors and treatment. Results: After adjusting baseline factors, SP was superior than IP for overall survival (HR=0.335: 0.184 – 0.612). There was only interaction effect between treatment and the status of lymph node metastases (bulkyN+/PAN- vs bulkyN-/PAN+ vs bulkyN+/PAN+; p=0.1306). Conclusions: SP was shown to be the favorable treatment for GC with ELM by multivariate analysis, while poor prognosis in pts having both bulky N+ and PAN+ may necessitate further treatment improvement. No significant financial relationships to disclose.

Characteristic clinicopathologic features of adult B-cell lymphoblastic lymphoma with special emphasis on differential diagnosis with an atypical form probably of blastic lymphocytic lymphoma of intermediate differentiation origin

Lymphoblastic lymphoma is typically of thymic T-cell phenotype. Lymphoblastic lymphoma of B-cell origin (B-lymphoblastic lymphoma) has been relatively poorly described. Whether B-lymphoblastic lymphoma should be managed like its T-cell counterpart remains to be clarified. From 1983 to 1991, 10 adult patients were diagnosed as having B-lymphoblastic lymphoma at National Taiwan University Hospital by using the histomorphologic criteria of international working formulation. B-cell phenotype was determined by the immunohistochemistry method. Clinicopathologic features of these 10 patients were reviewed. Seven patients were grouped as typical type and were characterized by an aggressive clinical course with lymph node (7 of 7), bone marrow (6 of 7), liver (3 of 7), spleen (3 of 7), and central nervous system (2 of 7) involvement. The median survival time was 8 months. In contrast, three patients had an atypical clinical picture. They were older patients (64-73 years) and were characterized by a relatively less aggressive course with predominantly bulky nodal involvement. Two of these three patients are alive (31 and 49 months, respectively) and well at this report, with one of them being repeatedly experiencing disease remission with the use of simple salvage chemotherapeutic regimens. Further studies revealed that tumor tissues of these three atypical cases had strong expression of CD5 (Leu-1) marker. B-lymphoblastic lymphoma diagnosed by histomorphologic criteria should be further distinguished from a relatively favorable subtype, which probably represents a variant of blastic lymphocytic lymphoma of intermediate differentiation as described by Lardelli et al. Clinical features of typical B-lymphoblastic lymphoma, except for the lack of mediastinal involvement, is similar to its T-cell counterpart.