Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials
Alessandra RaimondiFederico NichettiArndt StahlerHarpreet WasanEnrique ArandaGiovanni RandonAnnika KurreckAngela MeadeEduardo Díaz‐RubioMonica NigerSebastian StintzingFederica PalermoTanja TrarbachMichele PrisciandaroGreta SommerhäuserDavid J. FisherFederica MoranoFilippo PietrantonioDominik Paul Modest
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Keywords:
FOLFOX
Pooled analysis
Maintenance therapy
To dissect gene expression subgroups of FOLFOX resistance colorectal cancer(CRC) and predict FOLFOX response, gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder n = 42, non-responder n = 41) are used to develop a novel iterative supervised learning method IML. IML identified two mutually exclusive subgroups of CRC patients that rely on different DNA damage repair proteins and resist FOLFOX. IML was validated in two validation sets (HR = 2.6, p Value = 0.02; HR = 2.36, p value = 0.02). A subgroup of mesenchymal subtype patients benefit from FOLFOX. Different subgroups of FOLFOX nonresponders may need to be treated differently.
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fluorouracil＋folinate＋oxaliplatin（FOLFOX）療法が奏効し，経口摂取が可能となった腹膜播種を伴う切除不能進行胃癌の２例を経験した．症例１は66歳の男性で，食思不振，腹痛の精査で４型胃癌を指摘され，当院紹介となった．食道浸潤および腹膜播種をきたしていた．姑息手術による経口摂取改善は困難と考えられたが，全身状態は保たれており，FOLFOX療法を開始した．RECIST基準で部分奏効となり，腹水の消失および経口摂取の改善が得られた．症例２は73歳の女性で，経口摂取不良の精査で４型胃癌を指摘され，当院紹介となった．審査腹腔鏡にて多発腹膜播種を認め，FOLFOX療法を開始した．部分奏効となり，腹水の消失および経口摂取の改善が得られた．QOLの改善および予後改善という観点から，腹膜播種を伴う経口摂取不能の切除不能進行胃癌に対して，FOLFOX療法は有効な選択肢の一つと考える．
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Abstract Background FOLFOX is a combination of drugs that is widely used to treat colorectal cancer. The response rate of FOLFOX in colorectal cancer(CRC) is 30-50%. We develop a method that analyzes mechanisms of FOLFOX resistance and predicts whether a patient will benefit from FOLFOX. Methods Gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder n=42, non-responder n=41) were used to develop a supervised learning method IML and analyze subgroups of FOLFOX resistance mechanism. Datasets of 32 FOLFOX treated stage IV CRC patients and 55 FOLFOX treated stage III CRC patients were used as independent validations. Results An iterative supervised learning (IML) method identified two distinct subgroups of CRC patients who resist FOLFOX. Each subgroup relies on different types of DNA damage repair proteins and they are mutually exclusive. Protein-protein networks showed the main mechanism might be the synergistic effect of resisting apoptosis and an altered cell cycle. IML method was validated in two independent validation sets, one FOLFOX treated stage IV CRC patients(HR=2.6, p-value=0.02, 3-years survival rate of the predicted responder group 61.9%, predicted nonresponder group 18.8%) and one FOLFOX treated stage III CRC patients (estimated HR=2.36, p-value=0.02). A subgroup of mesenchymal subtype patients shows the pattern as FOLFOX responders. Conclusions IML method reflects the underlying biology of FOLFOX resistance and predicts FOLFOX response.
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目的：FOLFOX 是第三期大腸直腸癌術後標準輔助性化學治療。但是許多病人無法完成完整療程。本研究欲探討完成完整FOLFOX 療程的比率及其無法完成的原因。方法：由台北榮總大腸直腸外科資料庫收集2009 年一月至2015 年十二月第三期大腸直腸癌術後接受FOLFOX 治療之病人之基本資料、接受Oxaliplatin 之劑量及無法完成之原因做分析。結果：研究期間內內共866 個第三期大腸直腸癌病人接受手術。其中110 人沒有接受後續輔助性化學藥物治療，199 人接受其他療法，5 人於其他他醫院治療。最後收集572人分析。290 人 (50.6%) 完成完整療程，其Oxaliplatin 累計計劑量之中位數為984 mg/m^2(644~1210 mg/m^2)。無法完成完整療程的病人中，78 人 (27.7%) 是因為主治醫師預防性停藥，72 人 (25.5%) 因週邊神經病變，30 人 (10.6%) 因疾病進展更換療法，18 人 (6.4%)因對Oxaliplatin 過敏，19 人 (6.7%) 因為白血球過低過肝腎功能惡化，17 人 (6.0%) 因嚴重噁心嘔吐，12 人 (4.3%) 因為整體身體狀況變差，36 人 (12.8%) 自行要求停藥。因週邊神經病變而中斷治療的患者，其Oxaliplatin 的累積劑量中位數為746 mg/m^2，而因對Oxaliplatin 過敏中斷治療的患者，其累積劑量中位數為680.4 mg/m^2。結論：半數病人能完成完整療程，週邊神經病變及及醫師預防性停藥是無法完成完整療程之主因。研發預防或減緩週邊神經經病變副作用之化學治療方法應能增加完整療程達成率。
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Colon cancer is a leading global cancer-related cause of morbidity and mortality. The oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) regimen is a standard chemotherapeutic approach used to treat colon cancer. However, chemoresistant tumor cells typically lead to the emergence of recurrent FOLFOX-resistant tumors after initial treatment. As such, it is vital that novel approaches to identifying and eliminating such chemoresistant tumors be developed in an effort to improve patient chemotherapy outcomes.In total, 100 samples of serum were obtained between April 2014 and April 2019 from patients who had been pathologically diagnosed with colon cancer from the Xiamen Haicang Hospital, and after these patients received FOLFOX chemotherapy treatment, serum samples were collected again. The expression of has_circ_0055625 in these serum samples was assessed via qPCR. Additionally, 5-FU IC50 values were detected via CCK-8 assay.We found has_circ_0055625 to be significantly upregulated in colon cancer patient serum. After FOLFOX treatment, chemotherapy-resistance was associated with the upregulation of has_circ_0055625.In summary, these data may provide a foundation for future studies of chemotherapeutic resistance in patients undergoing FOLFOX treatment, potentially guiding treatment adjustment strategies. However, further work will be necessary to expand upon these findings.
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A 73-year-old man had undergone right hemicolectomy for advanced colon cancer in May 2006, and he concurrently had multiple liver metastases. After the operation, the patient was given chemotherapy with FOLFIRI. A partial response was achieved for twelve months, and then the liver tumors enlarged. Second-line chemotherapy with FOLFOX was delivered. After several months the liver tumors further enlarged and a new pulmonary lesion appeared with an increased serum CEA level. Therefore, chemotherapy with S-1 (120 mg/day) was started, with 2 weeks' administration followed by a one-week drug-free period. Several months later, the liver tumors and tumor makers decreased. S-1 is expected to be an effective agent for the treatment of advanced colon cancer with liver metastases after FOLFIRI and FOLFOX.
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143 Background: BOLD-100 is a first-in-class metallotherapeutic with a unique multimodal mechanism of action currently in phase 2 clinical development for the treatment of advanced gastrointestinal cancers. Standard treatment options for patients (pts) with metastatic colorectal cancer (mCRC) include FOLFOX or CAPOX in first or second line therapy. This study explored the benefit of BOLD-100 + FOLFOX in previously treated mCRC patients. Methods: This prospective, phase 2 study evaluates BOLD-100 + FOLFOX in pts with mCRC. All pts received prior standard treatment, including FOLFOX or CAPOX. Pts received 625 mg/m2 of BOLD-100 + FOLFOX on day 1 of each 14-day cycle and treated until progressive disease or unacceptable toxicity. The primary objective is to evaluate PFS, OS, and ORR in treated patients. Disease Control Rate (DCR) was also determined. Results: As of 31Aug2023, 36 pts with advanced mCRC were treated. Median age was 62 years (range 40-78), 56% were women, all pts were ECOG 0 (25%) or 1 (75%). Enrolled pts had a median of 4 prior systemic therapies, including FOLFOX/CAPOX. All but one patient had stage IV disease. On study, pts received a median of 6 cycles of BOLD-100 + FOLFOX [range 1-17]. Five pts remain on treatment with 19 in follow-up. Median PFS was 3.9 [2.7, 5.7] months, median OS 9.6 [6.0, 17] months, ORR 7% [1,20] and DCR 76% [58, 88] in the 29 evaluable pts. Two pts achieved a partial response, and 2 pts had target tumor lesion decreases between 20-29%. Study treatment was well tolerated. Of the 36 treated pts, 33 had 1 or more treatment-emergent adverse events (AEs), most common neutropenia (n=17, 47%), nausea (n=15, 42%), vomiting (n=8, 22%), fatigue (n=7, 19%), infusion related reaction (n=7, 19%), and pruritus (n=6, 17%). Most related AEs were grade (G) 1-2. 15 pts (42%) had G3/4 neutropenia. Despite previous oxaliplatin treatment, fewer than 6% of pts reported peripheral neuropathy or peripheral sensory neuropathy and all were G1/2. Conclusions: BOLD-100 + FOLFOX is an active and well-tolerated treatment in this heavily pre-treated Stage IV mCRC study population. There were no new safety signals. The mPFS, mOS, ORR and DCR data demonstrate significant clinical benefit and improvement over the currently available therapies, with minimal treatment emergent neuropathy or significant toxicities. This promising treatment combination should be further studied. Clinical trial information: NCT04421820 .
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Objective To investigate the effects of preoperative FolFox neoadjuvant chemotherapy on the expression of Smad4 in colorectal carcinoma.Methods Fifteen cases of advanced colorectal carcinoma were treated by preoperative FolFox neoadjuvant chemotherapy(the FolFox neoadjuvant chemotherapy group),18 cases by 5-FU chemotherapy(the 5-FU chemotherapy group) and 21 cases by operation(the control group).The expression of Smad4 was detected by immunohistochemical SP method.Results Among the three groups,the expression level of Smad4 gradually increased(P 0.05).The positive expressions of Smad4 in the three groups were 19.0 %(4/21) in the control group,61.1%(11/18) in the 5-FU chemotherapy group and 93.3%(14/15) in the FolFox neoadjuvant chemotherapy group respectively.The difference was significant(P 0.05).Conclusion Preoperative FolFox neoadjuvant chemotherapy could induce high level of Smad4 expression,which could be an effective chemotherapy.
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9530 Background: Although 12 cycles of Adj FOLFOX are recommended for stage III and high risk stage II colon cancer, toxicity may preclude completion of treatment. We used the NCCN Colorectal Cancer Outcomes Database to identify how frequently Adj FOLFOX is discontinued prematurely for toxicity in a non-clinical trial population. Methods: Newly diagnosed stage II-III colon cancer pts treated with Adj FOLFOX at 7 NCI-designated comprehensive cancer centers between 9/05–12/07 were identified. We assessed completion of the prescribed adjuvant chemotherapy (AC) course, including Adj FOLFOX and 5FU-based adjuvant treatment alone subsequent to discontinuation of oxaliplatin (oxal). Dose limiting toxicity (DLT) of Adj FOLFOX was defined as premature discontinuation of Adj FOLFOX due to toxicity. We evaluated potential predictors of Adj FOLFOX DLT, including older age and history of diabetes in a multivariable logistic model controlling for stage and center. We measured the duration of Adj FOLFOX use in weeks, from first to last dose. Results: 293 pts began Adj FOLFOX. Pts who experienced DLT (40%) had a shorter duration of Adj FOLFOX and were less likely to complete AC, even after oxal was discontinued. The only significant predictor of experiencing a DLT was a history of diabetes. Conclusions: Our analysis of patients treated outside of a clinical trial demonstrated a notably high rate of discontinuation of Adj FOLFOX due to DLT, particularly in pts with diabetes. The results underscore the need for systematic assessment of toxicity especially among diabetics. [Table: see text] [Table: see text]
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