Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Usefulness of the one-step technique in functional end-to-end anastomosis for colonic surgery: results of a prospective multicentre cohort study from the Japanese KYCC group.

BACKGROUND: Although functional end-to-end anastomosis (FEEA) using a stapler in the colorectal field has been recognised worldwide, the technique varies by surgeon, and the safety of anastomosis using different techniques is unknown. METHODS: This multicentre prospective observational cohort study was conducted by the KYCC Study Group in Yokohama, Japan, and included patients who underwent colonic resection at seven centres between April 2020 and March 2022. This study compared the incidence of surgery-related abdominal complications (SAC: anastomotic leakage [AL], anastomotic bleeding, intra-abdominal abscess, enteritis, ileus, surgical site infection, and other abdominal complications) between two different methods of FEEA (one-step [OS] method: simultaneous anastomosis and bowel resection; two-step [TS] method: anastomosis after bowel resection). Complications of Clavien-Dindo classification grade 2 or higher were assessed. RESULTS: Among 293 eligible cases, the OS and TS methods were used in 194 (66.2%) and 99 (33.8%) patients, respectively. The baseline characteristics were similar between the groups. The OS method used fewer staplers (three vs. four staplers, p < 0.00001). There were no significant differences in SAC rate between the OS (19.1%) and the TS (16.2%) groups (p = 0.44). The OS group had four cases (2.1%) of AL (two patients; grade 3, two patients; grade 2) while the TS group had one case (1.0%) of grade 2 AL (p = 0.67). Multivariate logistic regression analysis showed that male sex (odds ratio [OR] 3.95; p < 0.00001), an open surgical approach (OR 2.36; p = 0.03), and longer operative duration (OR,2.79; p = 0.002) were independent predictors of complications, whereas the OS method was not an independent predictor (OR 1.17; p = 0.66). CONCLUSIONS: The OS and the TS technique for stapled colonic anastomosis in a FEEA had a similar postoperative complication rate. TRIAL REGISTRATION NUMBER: UMIN000039902 (registration date 23 March 2020).

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.

Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Evaluation of vascular anatomy for colon cancer located in the splenic flexure using the preoperative three-dimensional computed tomography angiography with colonography.

PURPOSE: The aim of this study is to reveal the vascular branching variation in SFC (splenic flexure cancer) patients using the preoperative three-dimensional computed tomography angiography with colonography (3D-CTAC). METHODS: We retrospectively analyzed patients with SFC who underwent preoperative 3D-CTAC between January 2014 and December 2019. RESULTS: Among 1256 colorectal cancer (CRC) patients, 96 (7.6%) manifested SFC. The arterial branching from the superior mesenteric artery (SMA) was classified into five patterns, as follows: (type 1A) the left branch of middle colic artery (LMCA) diverged from middle colic artery (MCA) (N = 47, 49.0%); (2A) the LMCA diverged from the MCA and the accessory middle colic artery (AMCA) (N = 26, 27.1%); (3A) the LMCA independently diverged from the SMA (N = 16, 16.7%); (4A) the LMCA independently diverged from the SMA and AMCA (N = 3, 3.1%); (5A) only the AMCA and the LMCA was absent (N = 4, 4.1%). Venous drainage was classified into four patterns, as follows: (type 1V) the SFV flows into the inferior mesenteric vein (IMV) then back to the splenic vein (N = 50, 52.1%); (2V) the SFV flows into the IMV then back to the superior mesenteric vein (SMV) (N = 19, 19.8%); (type 3V) the SFV independently flows into the splenic vein (N = 3, 3.1%); (type 4V) the SFV is absent (N = 24, 25.0%). CONCLUSION: 3D-CTAC could reveal accurate preoperative tumor localization and vascular branching. These classifications should be helpful in performing accurate complete mesocolic excision and central vessel ligation for SFC.

Application and outcomes of a standardized lymphadenectomy in laparoscopic right hemicolectomy requiring ligation of the middle colic artery.

BACKGROUND: Complete mesocolic excision with central vessel ligation may be important for accurate staging and improving the prognosis of right-sided colon cancer. Although the procedure is often performed laparoscopically, approaching the middle colic artery (MCA) is technically demanding, especially when complete ligation of arteries at their roots is desired. We standardized our laparoscopic approach by establishing the dissection boundary along the superior mesenteric artery to achieve D3 lymphadenectomy in the region of the MCA. The aim of the present study was to evaluate, on the basis of perioperative and short-term oncologic outcomes, the feasibility and safety of our technique METHODS: We conducted a retrospective study on consecutive patients with cancer located at the ascending colon and transverse colon who had laparoscopic right hemicolectomy requiring ligation of the MCA. RESULTS: There were 41 patients (22 males, median age 71 years [range 49-86] years). The median operation time was 285 min, and blood loss volume was 40 mL. Conversion to open surgery was required in 1 case. Complications that were Clavien-Dindo grade III or above occurred in 3 patients (7.3%). There was no anastomotic leakage. The median number of lymph nodes harvested was 46. CONCLUSIONS: Our technique was shown to be a safe, feasible, and useful strategy for performance of right hemicolectomy requiring ligation of the MCA in cases of colon cancer. The technique facilitates maximal lymph node dissection. Having obtained favorable outcomes, we look forward to investigation into long-term outcomes.

Colorectal cancer treated by resection and extended lymphadenectomy: patterns of spread in left- and right-sided tumours.

BACKGROUND: Whether tumour side affects the anatomical extent and distribution of lymph node metastasis in colon cancer is unknown. The impact of tumour side on the anatomical pattern of lymphatic spread in colon cancer was assessed. METHODS: Patients with stage III colon cancer from a Japanese multi-institutional database who underwent extensive (D3) lymphadenectomy, which is similar in concept to complete mesocolic excision with central venous ligation, were divided into groups with right- and left-sided tumours. Based on location, mesenteric lymph nodes were categorized as paracolic (L1), intermediate (L2) or central (L3). The Kaplan-Meier method was used to evaluate disease-free survival (DFS) and overall survival (OS), and multivariable Cox models were used to evaluate the association between anatomical lymph node level, metastatic pattern and outcome. RESULTS: A total of 4034 patients with stage III colon cancer (right 1618, left 2416) were included. Unadjusted OS was worse in patients with right colon cancer (hazard ratio 1·23, 95 per cent c.i. 1·08 to 1·40; P = 0·002), but DFS was similar. Right-sided tumours more frequently invaded L3 nodes than left-sided lesions (8·5 versus 3·7 per cent; P < 0·001). The proportion of patients with a skipped pattern of lymphatic spread was higher in right than in left colon cancer (13·7 versus 9·0 per cent; P < 0·001). In multivariable analysis, invasion of L3 nodes was associated with worse OS in left but not in right colon cancer. The presence of skipped metastasis was associated with worse DFS in left, but not right, colon cancer. CONCLUSION: There are significant differences in the pattern of lymph node invasion between right- and left-sided stage III colon cancer, and in their prognostic significance, suggesting that tumour side may dictate the operative approach.

ANTECEDENTES: Se desconoce si la lateralidad del tumor influye en la extensión anatómica y en la distribución de las metástasis en los ganglios linfáticos (lymph node metastasis, LN) en el cáncer de colon. Se evaluó el impacto de la lateralidad del tumor en el patrón anatómico de diseminación linfática en el cáncer de colon. MÉTODOS: Los pacientes con cáncer de colon en estadio III recogidos en una base de datos japonesa multicéntrica, que se sometieron a una linfadenectomía ampliada (D3), conceptualmente similar a la escisión completa del mesocolon con ligadura venosa central, se dividieron en cáncer de colon del lado derecho y cáncer de colon del lado izquierdo. Según la ubicación, las LN mesentéricas se clasificaron como paracólicas (L1), intermedias (L2) o centrales (L3). Se utilizó el método de Kaplan-Meier para evaluar la supervivencia libre de enfermedad (disease-free survival, DFS) y la supervivencia global (overall-survival, OS), y se utilizaron modelos de Cox multivariados para evaluar la asociación entre el nivel L y el patrón metastásico con el resultado. RESULTADOS: Se incluyeron 4.034 pacientes con cáncer de colon en estadio III (cáncer de colon derecho: n = 1.618, cáncer de colon izquierdo: n = 2.416). La OS no ajustada fue peor en el cáncer de colon derecho (cociente de riesgos instantáneos, hazard ratio, HR 1,23, i.c. del 95%: 1,08-1,4; P = 0,002), pero la DFS fue similar. La afectación de los ganglios L3 fue más frecuente en pacientes con cáncer de colon derecho que izquierdo (8,5% versus 3,7%, P < 0,001). En el cáncer de colon derecho, la proporción de pacientes con patrón de diseminación linfática discontinuo, con salto entre niveles, fue mayor en comparación con el cáncer de colon izquierdo (13,7% versus 9%; P < 0,001). En el análisis multivariante, la invasión de los ganglios L3 se asoció con una peor OS en el cáncer de colon izquierdo, pero no en el cáncer de colon derecho. La presencia de metástasis discontinuas se asoció con una peor DFS en el cáncer de colon izquierdo, pero no en el cáncer de colon derecho. CONCLUSIÓN: Existen diferencias significativas en el patrón de invasión de los LN entre el cáncer de colon derecho e izquierdo en estadio III, así como en su importancia pronóstica, lo que sugiere que la lateralidad del tumor puede determinar el abordaje quirúrgico.

Long-term follow-up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212).

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.

ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.

Search for Boosted Dark Matter Interacting with Electrons in Super-Kamiokande.

A search for boosted dark matter using 161.9 kt yr of Super-Kamiokande IV data is presented. We search for an excess of elastically scattered electrons above the atmospheric neutrino background, with a visible energy between 100 MeV and 1 TeV, pointing back to the Galactic center or the Sun. No such excess is observed. Limits on boosted dark matter event rates in multiple angular cones around the Galactic center and Sun are calculated. Limits are also calculated for a baseline model of boosted dark matter produced from cold dark matter annihilation or decay. This is the first experimental search for boosted dark matter from the Galactic center or the Sun interacting in a terrestrial detector.

Search for Nucleon and Dinucleon Decays with an Invisible Particle and a Charged Lepton in the Final State at the Super-Kamiokande Experiment.

Search results for nucleon decays p→e^{+}X, p→µ^{+}X, n→νγ (where X is an invisible, massless particle) as well as dinucleon decays np→e^{+}ν, np→µ^{+}ν, and np→τ^{+}ν in the Super-Kamiokande experiment are presented. Using single-ring data from an exposure of 273.4 kton·yr, a search for these decays yields a result consistent with no signal. Accordingly, lower limits on the partial lifetimes of τ_{p→e^{+}X}>7.9×10^{32} yr, τ_{p→µ^{+}X}>4.1×10^{32} yr, τ_{n→νγ}>5.5×10^{32} yr, τ_{np→e^{+}ν}>2.6×10^{32} yr, τ_{np→µ^{+}ν}>2.2×10^{32} yr, and τ_{np→τ^{+}ν}>2.9×10^{31} yr at a 90% confidence level are obtained. Some of these searches are novel.

Search for neutrinos from annihilation of captured low-mass dark matter particles in the sun by super-kamiokande.

Super-Kamiokande (SK) can search for weakly interacting massive particles (WIMPs) by detecting neutrinos produced from WIMP annihilations occurring inside the Sun. In this analysis, we include neutrino events with interaction vertices in the detector in addition to upward-going muons produced in the surrounding rock. Compared to the previous result, which used the upward-going muons only, the signal acceptances for light (few-GeV/c^{2}-200-GeV/c^{2}) WIMPs are significantly increased. We fit 3903 days of SK data to search for the contribution of neutrinos from WIMP annihilation in the Sun. We found no significant excess over expected atmospheric-neutrino background and the result is interpreted in terms of upper limits on WIMP-nucleon elastic scattering cross sections under different assumptions about the annihilation channel. We set the current best limits on the spin-dependent WIMP-proton cross section for WIMP masses below 200 GeV/c^{2} (at 10 GeV/c^{2}, 1.49×10^{-39} cm^{2} for χχ→bb[over ¯] and 1.31×10^{-40} cm^{2} for χχ→τ^{+}τ^{-} annihilation channels), also ruling out some fraction of WIMP candidates with spin-independent coupling in the few-GeV/c^{2} mass range.

Prognostic significance of CD44 variant 2 upregulation in colorectal cancer.

BACKGROUND: CD133 and CD44 are putative cancer stem cell (CSC) markers in colorectal cancer (CRC). However, their clinical significance is currently unclear. Here, we evaluated primary CRC cell isolates to determine the significance of several CSC markers, including CD133 and CD44, as predictors of tumourigenesis and prognosis. METHODS: CD133- and CD44-positive cells from fresh clinical samples of 77 CRCs were selected by flow cytometric sorting and evaluated for tumourigenicity following subcutaneous transplantation into NOD/SCID mice. Cancer stem cell marker expression was examined in both xenografts and a complementary DNA library compiled from 167 CRC patient samples. RESULTS: CD44(+), CD133(+) and CD133(+)CD44(+) sub-populations were significantly more tumourigenic than the total cell population. The clinical samples expressed several transcript variants of CD44. Variant 2 was specifically overexpressed in both primary tumours and xenografts in comparison with the normal mucosa. A prognostic assay using qRT-PCR showed that the CD44v2(high) group (n=84, 5-year survival rate (5-OS): 0.74) had a significantly worse prognosis (P=0.041) than the CD44v2(low) group (n=83, 5-OS: 0.88). CONCLUSIONS: CD44 is an important CSC marker in CRC patients. Furthermore, CRC patients with high expression of CD44v2 have a poorer prognosis than patients with other CD44 variants.

Search for trilepton nucleon decay via p→e+νν and p→µ+νν in the Super-Kamiokande experiment.

The trilepton nucleon decay modes p→e+νν and p→µ+νν violate |Δ(B-L)| by two units. Using data from a 273.4 kt yr exposure of Super-Kamiokande a search for these decays yields a fit consistent with no signal. Accordingly, lower limits on the partial lifetimes of τp→e+νν>1.7×10(32) years and τp→µ+νν>2.2×10(32) years at a 90% confidence level are obtained. These limits can constrain Grand Unified Theories which allow for such processes.

Search for nucleon decay via n→ν[over ¯]π0 and p→ν[over ¯]π+ in Super-Kamiokande.

We present the results of searches for nucleon decay via n→ν[over ¯]π0 and p→ν[over ¯]π+ using data from a combined 172.8 kt·yr exposure of Super-Kamiokande-I,-II, and-III. We set lower limits on the partial lifetime for each of these modes: τn→ν[over ¯]π0>1.1×10(33) years and τp→ν[over ¯]π+>3.9×10(32) years at a 90% confidence level.

First indication of terrestrial matter effects on solar neutrino oscillation.

We report an indication that the elastic scattering rate of solar B8 neutrinos with electrons in the Super-Kamiokande detector is larger when the neutrinos pass through Earth during nighttime. We determine the day-night asymmetry, defined as the difference of the average day rate and average night rate divided by the average of those two rates, to be [-3.2 ± 1.1(stat) ± 0.5(syst)]%, which deviates from zero by 2.7 σ. Since the elastic scattering process is mostly sensitive to electron-flavored solar neutrinos, a nonzero day-night asymmetry implies that the flavor oscillations of solar neutrinos are affected by the presence of matter within the neutrinos' flight path. Super-Kamiokande's day-night asymmetry is consistent with neutrino oscillations for 4 × 10(-5) eV(2) ≤ Δm 2(21) ≤ 7 × 10(-5) eV(2) and large mixing values of θ12, at the 68% C.L.

Search for dinucleon decay into kaons in Super-Kamiokande.

A search for the dinucleon decay pp → K+ K+ has been performed using 91.6 kton·yr data from Super-Kamiokande-I. This decay provides a sensitive probe of the R-parity-violating parameter λ112''. A boosted decision tree analysis found no signal candidates in the data. The expected background was 0.28±0.19 atmospheric neutrino induced events and the estimated signal detection efficiency was 12.6%±3.2%. A lower limit of 1.7×10(32) years has been placed on the partial lifetime of the decay O16 → C14K+ K+ at 90% C.L. A corresponding upper limit of 7.8×10(-9) has been placed on the parameter λ112''.

Evidence for the appearance of atmospheric tau neutrinos in super-Kamiokande.

Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 ± 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.