Oncologist最新文献

Mutations in the adenomatous polyposis coli (APC) gene are frequent in colorectal cancer (CRC), whereas epidermal growth factor receptor (EGFR) mutations, particularly the L858R variant, are exceedingly rare. Their coexistence in CRC is rare and poorly described in the literature and poses diagnostic and therapeutic challenges. We describe a 69-year-old man with a history of resected CRC who presented with a lung mass and adrenal lesions, initially suspected as metastatic non-small cell lung cancer (NSCLC). Biopsy revealed poorly differentiated carcinoma with immunohistochemistry suggestive of gastrointestinal origin. Due to doubts regarding the primary site, It was decided to start systemic treatment with mFOLFIRINOX while awaiting NGS. After 7 cycles, a partial radiologic and clinical response was observed. Next-generation sequencing (NGS) became available and identified an EGFR L858R mutation, favoring NSCLC. Chemotherapy was paused and the patient was treated with gefitinib. Rapid disease progression ensued, with new brain metastases. Expanded NGS subsequently revealed concurrent APC and TP53 pathogenic variants, confirming the diagnosis of metastatic CRC harboring co-occurring with EGFR and APC mutations. The patient died 10 months after diagnosis. This case underscores the critical role of comprehensive molecular profiling via NGS in accurately diagnosing complex oncologic presentations. To our knowledge, this is the first case report of APC and EGFR L858R co-mutation in colorectal cancer. For this patient, the misclassification delayed the use of more appropriate therapies for CRC, which may have impacted clinical outcomes.

Background: APX3330 is an oral agent targeting the redox signaling activity of APE1/Ref-1 (Ref-1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref-1's redox function without affecting its DNA repair role. This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumors was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement.

Methods: Nineteen cancer patients were treated, with eight completing follow-up. Subjects received APX3330 orally twice daily in 21-day cycles, starting at 240 mg/day and escalating in 120 mg/day increments. Adverse event (AE) monitoring followed a 1 pt/cohort approach until a >G2 toxicity event, after which a 3 + 3 design was implemented. Treatment continued until disease progression, consent withdrawal, or intolerable toxicity. Antitumor activity was assessed using RECIST 1.1, and pharmacodynamic markers included serum Ref-1 levels and circulating tumor cells.

Results: Six of nineteen subjects had stable disease, and no treatment-related SAEs were observed. One subject (720 mg cohort) withdrew due to Grade 3 maculopapular rash (dose-limiting toxicity). Laboratory assessments and ECGs showed no clinically significant abnormalities.

Conclusions: APX3330 showed preliminary signals of disease control and on-target pharmacology in this first-in-human study. Based on safety and PD, the RP2D is 600 mg/day. Given the small sample size, efficacy conclusions are exploratory (ClinicalTrials.gov Identifier: NCT03375086).

Purpose: Myelotoxicity is a well-known adverse effect of alkylating chemotherapy for glioblastoma. While risk factors during first-line therapy are established, little is known about myelotoxicity recurrence in second-line treatment. This study investigates whether first-line myelotoxicity therapy predisposes patients to recurrence in the second-line setting.

Patients and methods: We conducted a retrospective cohort study of 589 patients with glioblastoma treated at the Brain Tumor Centre Amsterdam (2005-2022). Of these, 178 received second-line lomustine or rechallenge temozolomide. Myelotoxicity severity was predominantly assessed using nadir hematological values and its duration. A log-link generalized linear model evaluated associations between first-line and second-line myelotoxicity severity, adjusting for covariates. Cox proportional hazards models assessed time to myelotoxicity onset.

Results: We included 151 patients (mean age 57.1 ± 11.8 years; 66.9% male). Lomustine was given to 66.9%. Myelotoxicity occurred in 73.5% of patients, with 19.9% developing severe toxicity. First-line myelotoxicity severity was significantly associated with second-line severity (β = 1.3, p<.001). Lomustine correlated with higher myelotoxicity severity than temozolomide (β = 1.4, p=.002). Higher first-line myelotoxicity scores predicted earlier onset of any-grade (HR = 1.4, p<.001) and severe (HR = 2.1, p<.001) myelotoxicity in second-line therapy.

Conclusion: First-line myelotoxicity for glioblastoma predicts its recurrence and earlier onset in second-line therapy. Patients with toxicity in first-line have an increased risk of severe hematological toxicity upon re-exposure. Lomustine carries a higher risk for myelotoxicity than temozolomide. These findings suggest an inherent predisposition to alkylating chemotherapy-induced myelotoxicity for a subgroup of patients. Integrating prior myelotoxicity history into second-line treatment decisions may improve risk stratification and guide monitoring.

Background: Financial toxicity (FT) refers to the negative effects of the economic burden of medical care on patients that potentially lead to poor well-being and quality of life. Individuals with breast cancer are especially prone to high out-of-pocket costs (OOPCs). We aimed to evaluate the FT rate of individuals with breast cancer and determine particularly vulnerable patients.

Methods: A comprehensive search of PubMed/Medline, Embase, Global Index Medicus, Web of Science (WOS), and EBSCO was performed from inception to July 28, 2025. Studies on FT in participants with breast cancer were included. Pooled estimates of FT rates with 95% confidence intervals (CIs) were calculated using the random-effects model. The primary outcome was FT. The secondary outcomes included the rates of participants in high-income countries (HICs), middle-income, and low-income countries (LMICs) who incurred FT based on income, OOPCs, or patient-reported impact of expenditures during diagnosis and treatment of breast cancer.

Results: 66 studies involving 29426 participants with breast cancer were enrolled in our study. Most studies were from HICs (46 studies), and the others were from LMICs (20 studies). The definition of FT was significant difference among these studies. The pooled FT rate was 39.3% (95% CI, 32.4%-46.6%) in HICs and 72.3% (95% CI, 56.8%-83.8%) in LMICs.

Conclusions: FT is a substantial burden among patients with breast cancer worldwide. While the burden of FT is still disproportionately higher in LMICs, nearly 40% of patients in HICs also experienced FT. However, the gap between the two settings may be narrowing.

Background: Adjuvant 5-FU monotherapy was previously the standard treatment for stage II/III rectal cancer. This study compared adjuvant FOLFIRI, FOLFOX and 5-FU/LV.

Methods: Eligible patients had T3-T4 N0 or Tany N1-3 rectal adenocarcinoma ≤12 cm from the anal verge and received pre- or postoperative 5-FU chemoradiotherapy (CRT). Patients were randomized to adjuvant FOLFIRI (8 cycles), FOLFOX (8 cycles), or 5-FU/LV weekly (6/8 weeks; 3 cycles). The trial planned to enroll 3,150 patients but was closed early following activation of an alternative adjuvant rectal cancer study including bevacizumab (E5204). The primary endpoint was overall survival (OS); secondary endpoints included disease-free survival (DFS), sphincter preservation, tolerability, and quality of life (QOL).

Results: The trial enrolled 225 patients (179 randomized) before early closure. Grade 3/4 toxicity occurred in 59%, with neutropenia, leukopenia, and diarrhea being the most common. At a median follow-up of 9.7 years, no significant OS or DFS differences were observed. The rate of sphincter preservation was numerically higher with FOLFIRI and FOLFOX vs. 5-FU/LV, but the difference was not statistically significant.

Conclusion: FOLFOX and FOLFIRI can be safely administered after CRT in rectal cancer patients safely with expected toxicities. Due to early trial closure and small sample size, the survival analysis was underpowered to detect a significant difference between regimens.

Clinicaltrials.gov identifier: NCT00068692.

Ampullary carcinoma (AC) is a rare malignancy often classified within biliary tract cancers (BTC), but lacks dedicated treatment guidelines. This post-hoc analysis evaluated outcomes of patients with advanced AC enrolled in the ABC-01, ABC-02, and ABC-03 clinical trials to provide reference data for future studies. Patients with advanced AC formed the "Descriptive cohort," while those treated with cisplatin-gemcitabine (CisGem) comprised the "CisGem-treated cohort." Among 534 trial participants, 28 (5.24%) had AC, and 17 received CisGem. The median age was 63.93 years, and 75.00% were male. Most patients had metastatic disease at baseline (89.29%). Median follow-up for the CisGem-treated cohort was 10.23 months (95% CI 5.98-14.43). The objective response rate was 23.52%, and disease control was achieved in 58.82% of patients. Estimated median progression-free survival (PFS) and overall survival (OS) were 7.98 months (95% CI 6.86-8.44) and 11.76 months (95% CI 5.94-14.88), respectively, comparable to outcomes in other BTCs. No reliable prognostic or predictive factors for PFS, OS, or ORR were identified, likely reflecting small sample size. This analysis underscores the rarity of advanced AC and the challenges in recruiting adequate numbers for dedicated trials. While CisGem remains an appropriate standard-of-care regimen, modest survival outcomes highlight the need for improved therapies. Molecular profiling has revealed potentially actionable alterations, including HER2 amplification and KRAS mutations, supporting precision oncology approaches. This study provides the most comprehensive reference dataset to date for advanced AC treated with CisGem and emphasizes the importance of international collaboration and molecularly guided research to improve outcomes in this rare malignancy.

Background: Bevacizumab and temsirolimus target angiogenic and mTOR pathways in cancer progression.

Methods: This phase I study enrolled 48 heavily pretreated patients with advanced solid tumors, including an ovarian cancer expansion cohort. Patients received bevacizumab biweekly plus temsirolimus weekly in a 3 + 3 design to assess safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Exploratory analyses included tumor genomic profiling and dynamic contrast-enhanced MRI (DCE-MRI).

Results: Patients had a median age of 59 and median four prior therapies. Common tumor types were ovarian (27%) and head and neck (15%). Treatment-related adverse events occurred in 93.8%, with 31.2% ≥grade 3. Five patients experienced DLTs, including grade 3 enteritis, fatigue, bowel obstruction/abdominal ileus/pulmonary embolism, bowel perforation and grade 3/4 elevated liver enzymes. MTD was bevacizumab 10 mg/kg biweekly plus temsirolimus 20 mg weekly. Overall, objective response rate (ORR) was 7.3% and 19.5% achieved stable disease ≥6 months (clinical benefit rate [CBR] 26.8%). In ovarian cohort, ORR was 16.7% and CBR 33.3%. Patients with tumor regression on DCE-MRI had lower ΔKtrans values.

Conclusion: Combination therapy showed acceptable safety and modest activity. Molecular and imaging findings were exploratory and limited. These preliminary observations could inform future biomarker studies. (ClinicalTrials.gov Identifier: NCT01552434).

Background: Polypharmacy is associated with increased risks of adverse outcomes in people with cancer and medicine use evolves over the course of the disease trajectory. We estimated the prevalence of polypharmacy in people with colorectal cancer (CRC), stratified by extent of disease spread at diagnosis, during each year from one year prior to five years following diagnosis and determined factors associated with polypharmacy at diagnosis and two and five years post-diagnosis.

Patients and methods: Our retrospective cohort study used linked administrative health records from New South Wales (NSW), Australia to examine medicine use in all NSW residents ≥18 years diagnosed with CRC between 2013-2017. We defined polypharmacy as concomitant exposure to ≥ 5 medicines, excluding antineoplastics, during at least one 90-day quarter in each year from diagnosis. We used logistic regression to examine associations between polypharmacy and relevant factors.

Results: Of 19,056 people diagnosed with CRC, 6,797 (35%), 8,482 (45%), and 3,777 (20%) were diagnosed with localised, regional, and metastatic disease, respectively. Within these groups, 74%-79% experienced polypharmacy at any time during the study period; with nearly 50% experiencing polypharmacy two through five years from diagnosis. Age (≥70 years), female sex, comorbidities, colon cancer diagnosis, and socioeconomic disadvantage were associated with increased likelihood of polypharmacy at all landmarks.

Conclusion: Polypharmacy is highly prevalent among Australians with CRC. For those treated with curative intent, higher polypharmacy rates are concerning, indicating excess morbidity and impaired quality of life among survivors cured of cancer but who may continue to experience poorer health than the general population.

Background: Despite the proven efficacy of TRK inhibitors in advanced NTRK fusion-positive sarcomas, chemotherapy remains the default first-line therapy in many developing countries. This real-world study directly compares outcomes of TRK inhibitors with chemotherapy.

Methods: We retrospectively analyzed fifty children with advanced NTRK fusion-positive sarcomas treated at three centers (2018-2024). Endpoints included treatment failure rate, objective response rate (ORR), mutilating surgery, time to treatment failure and event-free survival (EFS). Subgroup analyses were conducted for infantile fibrosarcoma (IFS) and NTRK-rearranged spindle cell tumors.

Results: The efficacy of TRK inhibitors (n = 37) was markedly superior compared to chemotherapy (n = 13). Treatment failure was almost eliminated (2.7% vs 61.5%, p < 0.001), and ORR was significantly higher (91.9% vs 53.8%, p = 0.006). Subgroup analysis revealed that TRK inhibitors prevented mutilating surgery in IFS (0.0% vs 42.9%, p < 0.001) and improved the ORR in NTRK-rearranged spindle-cell tumors (95.0% vs 0.0%, p < 0.001) in which chemotherapy was ineffective. TRK inhibition also induced faster tumor shrinkage, smaller preoperative burden, and 40% pathological complete responses. Finally, TRK inhibitor also prolonged the time-to-treatment failure and EFS.

Conclusion: Upfront TRK inhibition provided faster, deeper responses, avoided mutilating surgeries, and enabled curative resections. These findings support TRK inhibitors as the preferred first-line option for children with NTRK fusion-positive sarcomas.

Implications for practice: In children with NTRK fusion-positive sarcomas, upfront TRK inhibition yielded faster, deeper responses and eliminated mutilating surgery in our cohort. These data support TRK inhibitors as preferred neoadjuvant options, particularly to facilitate non-morbid resections and to avoid functional disability.