Japan Clinical Oncology Group Study Research Articles

Consideration of factors of low accrual and methods for setting appropriate accrual periods: Japan Clinical Oncology Group study

BackgroundPoor patient accrual can delay reporting of clinical trials and, consequently, the development of new treatments. For reducing the risk of additional resource requirements, a method for setting planned accrual periods with minimal deviation from the actual accrual periods is desirable. Risk factors for poor patient accrual and the appropriate method of estimating the required accrual period for timely completion of clinical trials were evaluated using the data of trials conducted by the Japan Clinical Oncology Group.MethodsThe study included 199 trials that started patient accrual between January 1, 1990, and June 30, 2021. The explanatory variables included factors that could be evaluated prior to trial commencement. We also evaluated whether the estimation methods for accrual pace could lead to completion within the planned accrual period.ResultsApproximately 23.6% of trials were completed within the planned accrual period. The risk factors for trial extension included planned accrual periods > 3 years (reference group: ≤ 3 years, odds ratio [OR] 0.37, 95% confidence interval [CI]: 0.15–0.92, P = 0.033) and stratified trial design (reference group: nonrandomized phase II trials, nonrandomized phase III trial [OR: 3.28, 95% CI: 0.99–10.9, P = 0.051], randomized phase II trial [OR: 3.91, 95% CI: 0.75–20.30, P = 0.105], and randomized phase III trial [OR: 9.29, 95% CI: 3.39–25.40, P < 0.001]). The method of estimating the accrual pace based on past clinical trials facilitated timely completion of the trial (OR: 3.51; 95% CI: 1.73–7.10, P < 0.001), unlike the estimation method based on survey evaluation of the accrual pace for participating institutions (OR: 1.12, 95% CI: 0.56–2.26, P = 0.751). Furthermore, the discrepancy between planned and actual accrual periods was minimal when using the methods of considering the accrual pace of past clinical trials.ConclusionsConsidering the accrual pace of past clinical trials is useful for estimating the required accrual period if data from past trials are available. When conducting a survey, it is necessary to be cautious of overestimating the cases at each facility.

Final results of a randomized phase II/III study comparing perioperative adriamycin plus ifosfamide and gemcitabine plus docetaxel for high-grade soft tissue sarcomas: Japan Clinical Oncology Group study JCOG1306.

11503 Background: We have previously reported long-term follow-up results of the favorable efficacy of perioperative chemotherapy with adriamycin plus ifosfamide (AI) for high-grade soft tissue sarcomas (STS) (JCOG0304). We have also reported the results of the second interim analysis of a phase II/III trial to confirm the non-inferiority of perioperative gemcitabine plus docetaxel (GD) to AI for high-grade STS (JCOG1306) in 2020 ASCO Annual Meeting. This study was terminated at the preplanned second interim analysis based on the point estimate of hazard ratio (HR) being above the pre-specified allowable HR of 1.61. The estimated 2-year overall survival (OS) was 94.3% (95% confidence interval (CI) 83.4–98.1%) in AI and 91.6% (80.9–96.4%) in GD (HR 2.55, 95% CI 0.80–8.14) in the analysis. We herein report the final results of JCOG1306 at 5-year follow-up. Methods: Patients with operable, FNCLCC grade 2/3 STS primary tumor (T2bN0M0 or anyTN1M0, AJCC 7th edition) or first local recurrent tumor in the extremities or trunk were randomized to AI or GD. Chemotherapy consisted of adriamycin 60 mg/m2 plus ifosfamide 10 g/m2 for AI or gemcitabine 1,800 mg/m2 plus docetaxel 70 mg/m2 for GD. The treatments were repeated for 3 courses preoperatively and 2 courses postoperatively in a 3-week interval. The primary endpoint in phase III part was OS. Planned sample size was 140 with a one-sided alpha of 0.1, power of 0.7 and a non-inferiority margin of 8% at 3-year OS (HR of 1.61), assuming 3-year OS of AI to be 85% and that of GD as 87%. Results: A total of 143 patients were enrolled between February 2014 and September 2018, and 5-year follow-up has finished in September 2023. Seventy and 73 patients were assigned to AI and GD, respectively, and included in the efficacy analysis. At the final analysis with a median follow-up of 6.0 years, the estimated 5-year OS was 90.0% (95% CI 80.1–95.1%) in AI and 76.1% (64.5–84.4%) in GD (HR 2.67, 95% CI 1.23–5.80). The estimated 5-year progression-free survival was 65.2% (95% CI: 52.7–75.2%) in AI and 57.4% (45.2–67.8%) in GD (HR: 1.33, 95% CI 0.81–2.18). At the 5-year follow-up analysis, there were no treatment-related deaths in both arms. Conclusions: The results of the second interim analysis were confirmed in the final analysis after five-year follow-up, i.e., non-inferiority of GD to AI in terms of OS could not be confirmed. In the perioperative chemotherapy for high-grade STS in the extremities and trunk, AI remains the standard regimen. Clinical trial information: jRCTs031180003 .

Results of a randomized phase II trial of 2nd-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib: Japan Clinical Oncology Group study JCOG1802 (2ND-STEP).

11551 Background: Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD) are the candidates of second-line chemotherapy for advanced soft tissue sarcomas (STS), although there is no clear evidence showing which is better among those agents. This clinical trial aims to determine the most promising regimen among trabectedin, eribulin, and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: This study, JCOG1802, is a multicenter randomized phase II selection design trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 years old or older, ECOG performance status of 0–2, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy of doxorubicin-based regimen for STS, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival (OS), disease-control rate (DCR), response rate (RR), and adverse events. The planned total sample size was set at 120 patients to select the most promising regimen with a probability of at least 80%, assuming a median PFS of 3 months in the worst regimen and 4 months in the best regimen. The regimen demonstrating the most favorable point estimate of hazard ratio for PFS is chosen for the subsequent phase III trial. Results: From December 2019 to March 2023, 120 patients with advanced STS were enrolled (31 with leiomyosarcomas, 26 with liposarcomas, 18 with translocation-related sarcomas, and 45 with others) and randomized. Median PFS for trabectedin was 2.9 months (95% CI 1.3-5.3), for eribulin was 2.2 months (1.5-3.8), and for pazopanib was 3.7 months (2.6-5.2), respectively. The hazard ratios for eribulin and pazopanib compared to trabectedin were 1.22 (0.77-1.94) and 0.99 (0.63-1.56), respectively. Median OS for trabectedin was 14.8 months (10.8-29.1), for eribulin was 13.3 months (7.6-20.1), and for pazopanib was 15.7 months (9.8-not estimable). DCR for trabectedin was 50.0% (32.4-67.6), for eribulin was 34.3% (19.1-52.2), and for pazopanib was 64.9% (47.5-79.8). Conclusions: Pazopanib showed the best PFS and OS as the second-line treatment for patients with advanced STS among trabectedin, eribulin, and pazopanib. A phase III trial comparing GD with pazopanib is planned as the next step. Clinical trial information: jRCTs031190152 .

A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study)

BackgroundMinimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP).MethodsThis is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP.DiscussionIf our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy.Trial registrationThis trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705].

Protocol digest of a randomized controlled Phase III study comparing surgery alone versus adjuvant nivolumab versus adjuvant S-1 for locally advanced oesophageal squamous cell carcinoma with no pathological complete response after neoadjuvant chemotherapy followed by curative esophagectomy: Japan Clinical Oncology Group study JCOG2206 (SUNRISE Trial)

Abstract Although the efficacy of postoperative therapy with nivolumab after preoperative chemoradiotherapy for locally advanced oesophageal cancer has been proven in Western countries, the survival benefits of postoperative therapy after preoperative chemotherapy with docetaxel, cisplatin and 5-FU or cisplatin plus 5-FU as the Japanese standard therapy remain controversial. This randomized Phase III trial was designed to confirm the superiority of postoperative therapy with nivolumab over observation alone and S-1 over observation alone in patients with locally advanced oesophageal squamous cell carcinoma with no pathological complete response after preoperative chemotherapy followed by curative esophagectomy. A total of 450 patients will be enrolled from 56 hospitals in Japan over 5.5 years. The primary endpoint is relapse-free survival, and the secondary endpoints are disease-free survival, overall survival, adverse events and incremental cost-effectiveness ratio. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230219 (https://jrct.niph.go.jp/latest-detail/jRCTs031230219).

A randomized controlled trial comparing primary tumor resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (PRIM-BC): Japan Clinical Oncology Group study JCOG1017.

523 Background: The possibility of primary tumor resection (PTR) improving the survival of de-novo Stage IV breast cancer (dn-StIV BC) patients has been evaluated by several prospective studies but remains controversial. We designed this phase 3 trial (JCOG1017) comparing with/without primary dissection after initial systemic therapy based on clinical subtype in dn-StIV BC patients. Methods: Dn-StIV BC patients were enrolled in the first registration. All patients received systemic therapies according to clinical subtypes. The patients not showing refractory disease were randomized to systemic therapy alone (arm A) or PTR plus systemic therapy (Arm B). The same systemic therapy was continued after randomization as additional therapy, for as long as possible. The primary endpoint was overall survival (OS). Secondary endpoints included the proportion of patients without progression at metastatic sites after initial systemic therapies for 3 months, local relapse-free survival (LRFS), primary tumor resection-free survival, and incidence of local ulcer/local bleeding and adverse events. The median overall survival time (MST) after initial systemic therapy for patients with dn-StIV BC was 20 months, on average, and a clinically relevant prolongation of the MST of Arm B was considered to be 6.0 months or longer (hazard ratio: 0.77). The required number of events was 359, to obtain a statistical power of 80% with a one-sided significance level of 0.05. Thus, the planned sample size was 410 patients for the second registration, assuming an accrual period of 7 years and a follow-up time of 4 years. Results: 570 patients were enrolled between 11/5/2011 and 31/5/2018 in the first registration. Of these, 407 eligible patients were randomized to either Arm A (N = 205) or Arm B (N = 202). The patient characteristics were well balanced between the two arms. The MST of randomized patients was 70 months, with 221 deaths. The difference in OS was not statistically significant (HR 0.857, 90% CI 0.686-1.072, one-sided p = 0.1283). MST was 69 months in Arm A and 75 in Arm B. The proportions of patients without progression at metastatic sites in Arms A and B were 81.5% and 67.3%, respectively (p = 0.0014). LRFS in Arm B was significantly longer than that in Arm A (median LRFS 20 vs 63 months: HR 0.415, 95% CI 0.327-0.527, p &lt; 0.0001). In Arm B, patients with incomplete resection had poorer outcomes than those in whom resection was complete (94 vs. 61 months, HR 1.971 (1.161-3.347) p = 0.0120). In the subgroup analysis, PTR improved survival in patients with ER-positive tumors, pre-menopausal status or single-organ metastasis. Conclusions: PTR is not recommended for all dn-StIV BC patients but can control local disease and is acceptable in a select population of patients because of the clear improvement in local control. Clinical trial information: UMIN000005586 .

A confirmatory trial of modified radical hysterectomy for patients with FIGO stage IB1 cervical cancer with tumor diameter preoperatively estimated at 2 cm or less: Japan Clinical Oncology Group study, JCOG1101.

5532 Background: The standard surgery for Stage IB1 uterine cervical cancer is radical hysterectomy (RH, Piver class III hysterectomy). However, RH is highly invasive, and there is a need to establish less invasive techniques. We conducted a single-arm confirmatory trial (JCOG1101) to evaluate the efficacy and safety of modified radical hysterectomy (MRH) in patients with tumor diameter ≤ 2 cm Stage IB1 cervical cancer (jRCT: jRCTs031180167). Methods: From January 2013 to August 2017, 240 patients were enrolled from 40 institutions in Japan. Eligibility criteria included: (1) FIGO 2008 Stage IB1 cervical cancer; (2) histologically proven squamous cell carcinoma, adenocarcinoma (mucinous or endometrioid) or adenosquamous carcinoma; (3) tumor diameter ≤ 2 cm (measured by MRI or conization specimen); and (4) neither distant LN metastasis nor distant metastasis in CT. In case that the cancer could be microinvasive, conization was required to exclude Stage IA cases. The protocol surgery involved cutting the anterior layer of the vesicouterine ligament of the uterus and dissecting regional lymph nodes. Only laparotomy was permitted: laparoscopy and robotic surgery were not allowed. Postoperative irradiation was administered in cases where pelvic LN or parametrial invasion was positive, depth in the cervical wall invasion was ≥ 2/3, or surgical margin was &lt; 1 cm by pathological findings. The primary endpoint was 5-year overall survival (OS). We set the expected 5-year OS of MRH at 95.8% (5-year OS of RH in JCOG0806A, retrospective observational study) and the threshold 5-year OS at 90.8%. Results: Among 225 eligible patients, 193 (85.8%) were pT1b1 (UICC 7th), and 184 (81.8%) had pathological maximal tumor diameter ≤ 2 cm. Parametrial involvement, lymph node metastasis, ≥ 2/3 stromal invasion and &lt; 1 cm surgical margin were observed in 3 (1.3%), 16 (7.1%), 30 (13.3%) and 11 (4.9%) patients, respectively. Thirty-nine patients (17.3%) underwent adjuvant (chemo)radiation. Median follow-up was 77.7 months. Five patients (2.2%) died, and 5-year OS was 98.2% (90% CI: 96.0-99.2, &gt; 90.8%). Thirteen patients (5.8%) relapsed (8 local recurrence and 5 distant recurrence), and 5-year relapse-free survival was 94.7% (95% CI: 90.8-96.9%). Self-urination was observed in all patients, and residual urine disappearance up to 56 days after urethral catheter removal was observed in 213 patients (94.7%). Median time to disappearance of residual urine after urethral catheter removal was 1 day. There was no treatment-related death. Grade 3/4 non-hematological adverse events were observed in 17 patients (7.6%), including 8 infection and 4 hemorrhage. Conclusions: In this study, MRH was as effective as RH and less invasive. MRH can be considered a standard surgery for tumor diameter ≤ 2 cm Stage IB1 uterine cervical cancer. Clinical trial information: UMIN000009726 , jRCTs031180167 .

Plan quality association between dummy run and individual case review in a prospective multi-institutional clinical trial of postoperative cervical cancer patients treated with intensity-modulated radiotherapy: Japan clinical Oncology Group study (JCOG1402)

Background and purposeThe Japan Clinical Oncology Group (JCOG) 1402 conducted a multicenter clinical trial of postoperative intensity-modulated radiotherapy (IMRT) for high-risk uterine cervical cancer patients. We assess effectiveness of the quality assurance (QA) program in central review through dummy runs (DRs) performed before patient enrollment and post-treatment individual case review (ICR), and clarify the pitfalls in treatment planning. Material and methodsThe ICRs were conducted using the same QA program as the DR for 214 plans. The deviations were compared with those demonstrated in the DRs, and the pitfalls were clarified. Fifteen face-to-face meetings were held with physicians at participating institutions to provide feedback. ResultsTwo-hundred and eighty-eight deviations and nine violations were detected in the 214 plans. The patterns of the deviations observed in the ICRs were similar to that in the DR. Frequent deviations were observed in clinical target volume (CTV) delineations, 50% in the DRs and 37% in the ICRs, respectively. In the ICRs, approximately 1.4 deviations/violations were observed per plan, which was lower than DR. Nine violations included inaccurate CTV delineation and improper PTV (planning target volume) margin, which had risks in loco-regional failures by inadequate dose coverage. ConclusionsOur developed QA program commonly used in DR and ICR clarified the pitfalls in treatment plans. Although the frequent deviations in CTV delineations were observed in the ICR, the deviations decreased compared to that in the DR. More specified face-to-face meetings with participating institutions will be necessary to maintain the quality of IMRT in the clinical protocol.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib

BackgroundSoft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS.MethodsThe JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial.DiscussionThis is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCTs031190152) on December 5, 2019.

Frequency of lymph node metastasis according to tumor location in clinical T1 early gastric cancer: supplementary analysis of the Japan Clinical Oncology Group study (JCOG0912).

The frequency of lymph node metastases per lymph node site in early gastric cancer has not been well clarified from the data based on prospective studies. This exploratory analysis aimed to determine the frequency and location of lymph node metastases in clinical T1 gastric cancer using the data from JCOG0912 to investigate the validity of the extent of standard lymph node dissection defined in Japanese guidelines. This analysis included 815 patients with clinical T1 gastric cancer. The proportion of pathological metastasis was identified for each lymph node site per tumor location (middle third and lower third) and four equal parts of the gastric circumference. The secondary aim was identification of the risk factor for lymph node metastasis. Eighty-nine patients (10.9%) had pathologically positive lymph node metastases. Although the overall frequency of metastases was low (0.3-5.4%), metastases were widely located in each lymph node sites when primary lesion was in the middle third of the stomach. No. 4sb and 9 showed no metastasis when primary lesion was in the lower third of the stomach. Lymph node dissection of metastatic nodes resulted in a 5-year survival in more than 50% of patients. A tumor greater than 3cm and a T1b tumor were associated with lymph node metastasis. This supplementary analysis demonstrated that nodal metastasis from early gastric cancer is widely and disorderly not depending on the location. Thus, systematic lymph node dissection is necessary to cure the early gastric cancer.

Long-term outcomes after laparoscopy-assisted total or proximal gastrectomy with nodal dissection for clinical stage I gastric cancer: Japan Clinical Oncology Group study (JCOG1401).

305 Background: JCOG0912 supports the non-inferiority of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG) for clinical stage I gastric cancer relapse-free survival (RFS), suggesting that LADG should be considered a standard treatment option when performed by experienced surgeons. No prospective study evaluating laparoscopy-assisted total gastrectomy (LATG) and laparoscopy-assisted proximal gastrectomy (LAPG) has been completed in terms of both safety and long-term survival. Considering that the results of the phase III trial to evaluate the long-term outcome of LADG (JCOG0912) could guarantee that of LATG/LAPG, we conducted a single-arm confirmatory trial (JCOG1401) to evaluate the safety of LATG/LAPG for clinical stage I proximal gastric cancer and JCOG1401 confirmed the safety of LATG/LAPG. Long-term outcomes as the secondary endpoints of this study are reported here after 5-year follow-up period. Methods: Laparoscopic operators were limited to credentialed surgeons. The extent of nodal dissection was selected based on the Gastric Cancer Treatment Guidelines in Japan. The primary endpoint was the proportion of grade 2 (CTCAE ver. 4.0) or greater esophageal anastomotic leak. The sample size was determined to be 245 considering a threshold of 8% and expected value of 3% with a one-sided alpha error of 2.5% and statistical power of 90%. The secondary endpoints were overall survival (OS) and RFS. Results: Between April 2015 and February 2017, 245 patients were enrolled. Among them, 1 patient was excluded from safety analysis due to ineligible. LATG/LAPG was performed in 195/49. 170/47/17/8/2 patients had pStage IA/IB/II/IIIA/IIIB disease and 190/31/15/8 patients had pT1/T2/T3/T4 disease, respectively. Grade 2 or greater esophageal anastomotic leak was 2.5% (6/244) (95% CI 0.9-5.3), as previously reported. 5-year OS was 91.2% (95% CI 86.9-94.2). 5-year RFS was 90.0% (95% CI 85.5-93.2). Among 22 deaths, 14 patients died without recurrence and 8 patients died with recurrence. Twelve recurrences were observed in 5/2/4/1 patients for pT1/T2/T3/T4. The sites of recurrence were peritoneal metastasis in 2 cases, hematogenous metastasis in 9 cases (liver: 6, bone: 2, lung: 1), and other in 1 case. Conclusions: The long-term outcomes of LATG/LAPG for Stage I gastric cancer patients were excellent and seem comparable to those of open procedures. Similar to JCOG0912, JCOG1401 guarantee the long-term survival of LATG/LAPG. Clinical trial information: UMIN000017155 .

Single-arm confirmatory trial of total neoadjuvant therapy and watch-and-wait strategy for patients with low rectal cancer: Japan Clinical Oncology Group study (JCOG2010, TOWARd study).

TPS269 Background: Radical surgery is the standard treatment for advanced lower rectal cancer, but postoperative complications and sequelae are major problems. Recently, some patients treated with preoperative chemoradiotherapy (CRT) have been reported to achieve a clinical complete response (cCR) and be cured with a subsequent watch-and-wait strategy (W&amp;W) without surgery. Moreover, the introduction of total neoadjuvant therapy (TNT) consisting of CRT and systemic chemotherapy has increased proportion of cCR. However, most previous studies on W&amp;W have reported cases in which cCR was achieved incidentally as a result of preoperative CRT or TNT for advanced lower rectal cancer. It is unclear whether combining TNT that is highly effective in early stage rectal cancer and subsequent W&amp;W without surgery is an effective intention-to-cure treatment for advanced lower rectal cancer when cCR is obtained after TNT. The purpose of this single-arm confirmatory trial is to evaluate the efficacy and safety of TNT and intended W&amp;W for cT2-T3 advanced lower rectal cancer with a tumor diameter of 5 cm or less. Methods: Key eligibility criteria include low rectal adenocarcinoma with tumor diameter 5 cm or less, cT2 or cT3 tumor depth, no lymph node metastasis, no distant metastasis, no history of pelvic irradiation or rectal surgery, age 18-75 years, and sufficient organ function. Eligible patients are receiving TNT. CRT consists of the standard dose of capecitabine (1650 mg/m2/day) and radiotherapy (45 Gy/25 fractions to whole pelvis plus boost of 5.4 Gy/3 fractions to primary tumor). Consolidation chemotherapy consists of 4 courses of CAPOX (oxaliplatin 130 mg/m2 on day1 and capecitabine 2000 mg/m2/day on day1-14). After completing TNT, patients will be re-staged according to Memorial Sloan Kettering Cancer Center Criteria. Patients with cCR at the primary site will move to W&amp;W, patients with a near complete response will move to either W&amp;W or undergo local resection, and patients with an incomplete response will undergo total mesorectal excision. All patients will be followed every 3 months for 2 years after re-staging, and every 6 months for 3 years after that. The primary endpoint in phase II is the proportion of cCR at re-staging by central review and in phase III is 5-year overall survival (OS). In the phase II part, 40 patients were required with a one-sided alpha of 5%, power of 80%, a threshold value of 20%, and an expected value of 40%. Based on the results of previous studies, we set the threshold 5-year OS at 87% in the phase III part. The sample size was calculated as 105 including the phase II part with a one-sided alpha of 5%, power of 80%, and the expected 5-year OS of 95%. The first patient was enrolled in September 2022. Clinical trial information: jRCTs031220288 .

Protocol digest of a phase III trial to evaluate the efficacy of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative S-1 in locally advanced gastric cancer: Japan Clinical Oncology Group study JCOG1509 (NAGISA Trial)

Abstract In Japan, postoperative chemotherapy is a standard care for stage II/III gastric cancer after curative resection with D2 lymph node dissection, and the clinical outcomes of patients with stage III gastric cancer are unsatisfactory. A combination of oral S-1 and oxaliplatin, that is the standard chemotherapy regimen for unresectable advanced/recurrent gastric cancer associated with a high response rate, was considered the most promising preoperative chemotherapy regimen. This randomized phase III trial was started in September 2016 to confirm the superiority of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative chemotherapy compared with D2 gastrectomy with postoperative chemotherapy for patients with clinical T3–4N1–3 M0 locally advanced gastric cancer in terms of overall survival. A total of 470 patients will be enrolled from 63 hospitals in Japan for 8.5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031180350 [https://jrct.niph.go.jp/latest-detail/jRCTs031180350].

416P A randomized controlled trial to compare laparoscopic surgery with open surgery for symptomatic, non-curable stage IV colorectal cancer (CRC): First efficacy results from Japan clinical oncology group study JCOG1107

The benefits of laparoscopic surgery (LAP) compared with open surgery (OP) have been suggested; however, the long-term survival of LAP for symptomatic, non-curable colorectal cancer (CRC) is still unclear. We conducted a trial to confirm the non-inferiority of LAP to OP in terms of progression-free survival (PFS). Only accredited surgeons from 42 Japanese institutions participated. Eligibility criteria included (1) pathologically proven adenocarcinoma or adenosquamous carcinoma; (2) primary tumor located at the cecum, ascending, transverse, descending, sigmoid and rectosigmoid colon; (3) primary tumor with bowel stenosis and/or bleeding. (4) having at least one to three incurable factors. Patients received mFOLFOX6+BEV or CapeOX+BEV after surgery. The planned sample size was 194 patients with a power of 70%, a one-sided alpha of 5% and the non-inferiority margin of the hazard ratio (HR) as 1.38. A total of 195 patients were randomized (OP 95, LAP 100) between Jan 2013 and Jan 2021. Surgery was performed 92 in OP and 98 in LAP. Postoperative chemotherapy was given in 82 in OP and 86 in LAP. Median PFS was 9.7 months (95% CI: 8.7-11.3) in OP, and 10.4 months (9.1-12.4) in LAP. The non-inferiority of LAP was confirmed (HR: 1.02 [91.4% CI: 0.79-1.32 (< 1.38)], p for non-inferiority = 0.021). Median OS was 23.9 months (95% CI: 18.6-29.4) in OP, and 25.4 months (19.4-29.0) in LAP (HR: 0.99, 95% CI [0.72-1.36]). Proportion of mortality in hospital was 1.1% in OP, 0% in LAP. Postoperative complications (G2-G4) included ileus (OP 12.0%, LAP 5.1%), wound infection (OP 2.2%, LAP 2.0%), and anastomotic leakage (OP 0%, LAP 2.0%). LAP is acceptable as a standard treatment for symptomatic, non-curable stage IV CRC.

A randomized phase II trial of preoperative chemotherapy of S-1/CDDP with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

285 Background: The efficacy of trastuzumab has been established for HER2-positive advanced gastric cancer patients with metastatic disease. However, it remains unclear if the addition of trastuzumab to preoperative chemotherapy is effective for treatment of HER2-positive locally advanced gastric cancer. Methods: Eligible patients with HER2-positive gastric cancer with extensive lymph node metastasis were randomized to preoperative S-1/cisplatin (SP) (group A) or SP plus trastuzumab (group B). In both groups, patients received S-1, 80–120 mg/body, on days 1–14 and cisplatin, 60 mg/m2, on day 1, q21, 3-4 courses. Additionally, in group B, patients received infusions of trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1). After gastrectomy, adjuvant chemotherapy with S-1 was performed for 1 year in both groups. The primary endpoint was overall survival, and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year overall survival (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results: The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either group A (22 patients) or group B (24 patients). Patient characteristics were well balanced between the groups. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in group A and in 23 patients (95.8%) in group B, and R0 resection was achieved in 20 patients (90.9%) in group A and 22 patients (91.7%) in group B. The incidences of grade 3 or 4 hematological/non-hematological adverse events during preoperative chemotherapy were 27.3/18.2% in group A and 4.2/8.3% in group B. Objective response rate (CR/PR) tended to be higher in group B (66.7% [16/24]) than in group A (36.4% [8/22], p = 0.08). Pathological response rate (&gt; grade 1b in Japanese classification, 22.7% [5/22] vs. 50.0% [12/24], p = 0.07) and the proportion of patients achieving downstage to ypStage 0/I/II (22.7% [5/22] vs. 50.0% [12/24], p = 0.07) were also higher in group B than in group A. Conclusions: Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to show better radiological and pathological response rates. Better survival outcomes are expected by adding trastuzumab to preoperative chemotherapy with SP for locally advanced gastric cancer with extensive nodal metastasis. Clinical trial information: UMIN000016920.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas

BackgroundPreoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis.MethodsUsing data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board.ResultsA total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893–18.188, p = 0.070).ConclusionThe standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO.Trial registrationUMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Long-term survival of patients with T1bN0M0 esophageal cancer after thoracoscopic esophagectomy using data from JCOG0502: a prospective multicenter trial.

Thoracoscopic esophagectomy (TE) is considered the standard surgery for esophageal cancer because of its superiority over open esophagectomy (OE) in terms of short-term outcomes. However, few prospective multicenter studies have evaluated its long-term survival after TE. This study aimed to investigate whether the prognosis for patients with T1bN0M0 esophageal cancer after TE is not inferior to OE using data from the Japan Clinical Oncology Group Study (JCOG0502), a prospective multicenter trial comparing esophagectomy with chemoradiotherapy. Data of patients in JCOG0502 after esophagectomy were used to compare the overall survival (OS) and relapse-free survival (RFS) after OE versus TE. OE or TE was selected at the surgeon's discretion. A hazard ratio and 95% confidence interval (CI) were calculated via Cox proportional-hazards model. Of the 210 patients who underwent esophagectomy, 109 underwent OE, whereas 101 underwent TE. The 5-year OS was 88.9% after OE and 85.0% after TE. The hazard ratio of TE for OS was 1.53 (95% CI, 0.84-2.78; p = 0.16) and 1.10 (95% CI, 0.52-2.35; p = 0.80) in the univariable and multivariable analyses, respectively. The 5-year RFS was 85.3% after OE and 79.1% after TE. The hazard ratio of TE for RFS was 1.39 (95% CI, 0.81-2.38; p = 0.23) and 0.88 (95% CI, 0.44-1.74; p = 0.70) in the univariable and multivariable analyses, respectively. The prognosis for patients with T1bN0M0 esophageal cancer after TE was not inferior to OE.

A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)

BackgroundThe current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved.MethodsThis multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71–75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020.DiscussionIf the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.Trial registrationRegistry number: jRCTs031200099.Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.

Identification of patient subgroups with unfavorable long-term outcomes associated with laparoscopic surgery in a randomized controlled trial comparing open and laparoscopic surgery for colon cancer (Japan Clinical Oncology Group Study JCOG0404).

BackgroundPreviously, we conducted a randomized controlled trial (JCOG0404) for stage II/III colon cancer patients and reported that the long‐term survival after open surgery (OP) and laparoscopic surgery (LAP) were almost identical; however, JCOG0404 suggested that survival of patients after LAP with tumors located in the rectosigmoid colon, cT4 or cN2 tumors, and high body mass index (BMI) might be unfavorable.AimTo identify the patient subgroups associated with poor long‐term survival in the LAP arm compared with the OP arm.MethodsPatients aged 20–75, clinical T3 or deeper lesion without involvement of other organs, clinical N0‐2 and M0 were included. The patients with pathological stage IV and R2 resection were excluded from the current analysis. In each subgroup, the hazard ratio for LAP (vs. OP) in overall survival (OS) from surgery was estimated using a multivariable Cox regression model adjusted for the clinical and pathological factors.ResultsIn total, 1025 patients (OP, 511 and LAP, 514) were included in the current analysis. Adjusted hazards ratios for OS of patients with high BMI (>25 kg/m2), pT4, and pN2 in LAP were 3.37 (95% confidence interval [CI], 1.24–9.19), 1.33 (0.73–2.41), and 1.74 (0.76–3.97), respectively. In contrast, that of rectosigmoid colon tumors was 0.98 (0.46–2.09).ConclusionsAlthough LAP is an acceptable optional treatment for stage II/III colon cancer, the present subgroup analysis suggests that high BMI (>25 kg/m2), pT4, and pN2 except for RS were factors associated with unfavorable long‐term outcomes of LAP in patients with colon cancer who underwent curative resection. (JCOG 0404: NCT00147134/UMIN‐CTR: C000000105.)

Prospective evaluation of watchful waiting for early-stage lung cancer with ground-glass opacity: a single-arm confirmatory multicenter study: Japan Clinical Oncology Group study JCOG1906 (EVERGREEN study).

Among early-stage lung cancers that show ground-glass nodules on chest computed tomography, the lung cancer surgical study group of the Japan Clinical Oncology Group previously reported that nodules of ≤2 cm with a consolidation/tumor ratio of ≤0.25 were considered radiologically non-invasive cancers with a low risk of metastasis. However, there is no consensus based on high-quality evidence about the optimal timing of surgical intervention for radiologically non-invasive cancers. In June 2020, we launched a multi-institutional, single-arm confirmatory trial to evaluate the efficacy and safety of watchful waiting for patients with radiologically non-invasive lung cancer. It is planned that a total of 720 patients will be enrolled from 49 institutes over a 5-year period. The primary endpoint is 10-year overall survival (OS). The secondary endpoints are 5-year OS, operation-free survival, proportion of extensive lung resection, proportion of unresectable progression, lung cancer-specific survival and adverse events.