BACKGROUND: The combination of radiotherapy (RT) with targeted agents or immunotherapy may result in improved outcomes, but it can also increase toxicity. However, there is a paucity of high-quality toxicity data, leadin...BACKGROUND: The combination of radiotherapy (RT) with targeted agents or immunotherapy may result in improved outcomes, but it can also increase toxicity. However, there is a paucity of high-quality toxicity data, leading to an absence of evidence-based guidelines. DESIGN: To address this, European Society for Medical Oncology (ESMO) and European SocieTy for Radiotherapy and Oncology (ESTRO) initiated a series of systematic reviews followed by a Delphi consensus process to develop multidisciplinary, evidence-based consensus statements regarding the safety of combining RT with such agents. The current publication describes the combination of RT with immune checkpoint inhibitors (ICIs), vascular endothelial growth factor (receptor) [VEGF(R)] inhibitors, or multitargeted tyrosine kinase inhibitors (TKIs). By systematically covering different drug classes and irradiated areas, 76 clinical scenarios were evaluated during two Delphi rounds with 20 international experts. Safety statements were developed for each scenario, based on the systematic literature reviews. RESULTS: A total of 5921 records were screened during the systematic literature review process for ICIs, VEGF(R) inhibitors, and multitargeted TKIs, and 159 reports were selected for inclusion in the final literature reviews and the database. During the two Delphi rounds, agreement was reached regarding the safety statements for 74 clinical scenarios. CONCLUSIONS: Generally, the expected toxicity of combining RT with ICIs is low, particularly for programmed death(-ligand) 1 inhibitors. For most combinations with VEGF(R) inhibitors and multitargeted TKIs, exercising caution is recommended. The evidence-based safety statements developed during this comprehensive project provide practical guidance on combining RT with targeted cancer therapies and immunotherapy.
BACKGROUND: Nivolumab plus cabozantinib (NIVO+CABO) showed significant benefits over sunitinib (SUN) in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for previously untreated a...BACKGROUND: Nivolumab plus cabozantinib (NIVO+CABO) showed significant benefits over sunitinib (SUN) in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for previously untreated advanced renal cell carcinoma (RCC) in the phase III CheckMate 9ER trial (NCT03141177). We report final, updated efficacy and safety results with median follow-up of 5.6 years. PATIENTS AND METHODS: Patients with advanced RCC were randomized to first-line NIVO 240 mg intravenously every 2 weeks plus CABO 40 mg p.o. o.d. or SUN 50 mg p.o. o.d. (4 weeks each 6-week cycle) until disease progression or unacceptable toxicity (maximum 2 years of NIVO). The primary endpoint was PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included OS, ORR per RECIST v1.1 by BICR, and safety. RESULTS: Median (range) follow-up was 5.6 years [67.6 (60.2-80.2) months]. In intent-to-treat patients (NIVO+CABO, n = 323; SUN, n = 328), PFS favored NIVO+CABO versus SUN [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.49-0.70]. Median PFS was 16.4 versus 8.3 months, respectively; 60-month PFS rates were 13.6% versus 3.6%. OS favored NIVO+CABO versus SUN (HR 0.79, 95% CI 0.65-0.96). Median OS was 46.5 versus 35.5 months, respectively; 60-month OS rates were 40.9% versus 35.4%. ORR was greater with NIVO+CABO versus SUN (55.7% versus 27.4%; complete response 13.9% versus 4.6%). The probability of remaining in response through 60 months with NIVO+CABO versus SUN was 22.0% versus 10.0%. In all treated patients (n = 320 each arm), any-grade (grade 3-4) treatment-related adverse events occurred in 97.5% (67.8%) versus 93.1% (55.0%) with NIVO+CABO versus SUN, respectively. No new deaths due to study drug toxicity occurred since the 32.9-month median follow-up. CONCLUSIONS: Long-term efficacy benefit was observed with NIVO+CABO over SUN in this final follow-up from CheckMate 9ER and safety was consistent with previous reports. These results reaffirm NIVO+CABO as a standard of care for previously untreated advanced RCC.
Lepage C, Phelip JM, Cany L
… +28 more, Barbier E, Manfredi S, Deguiral P, Laly M, Baconnier M, Jary M, Latrive JP, Terrebonne E, Lièvre A, Jafari M, Ben Abdelghani M, Ain JF, Breysacher G, Boillot-Benedetto I, Pelaquier A, Prost P, Ezenfis J, Rinaldi Y, Le Foll C, Berthelet O, Darut-Jouve A, Dahan L, Piche T, Lagasse JP, Bibeau F, Laurent-Puig P, Bouché O, PRODIGE 13 investigators/collaborators
BACKGROUND: Intensive follow-up of patients after curative surgery for colorectal cancer is recommended by various scientific societies. However, these recommendations are based mainly on expert opinions, while the resul...BACKGROUND: Intensive follow-up of patients after curative surgery for colorectal cancer is recommended by various scientific societies. However, these recommendations are based mainly on expert opinions, while the results of the few clinical trials are controversial. Moreover, no survival benefit has been demonstrated to date. PATIENTS AND METHODS: PRODIGE-13 is a cooperative prospective multicentre controlled phase III trial evaluating by factorial plan the impact of (i) intensive radiological monitoring [alternating abdominal ultrasound (US)/computed tomography (CT) scan/3 months] versus standard monitoring (US/3 months and thoracic radiography/6 months) and (ii) carcinoembryonic antigen (CEA) assessment versus no assessment, in the follow-up of resected stage II or III colorectal cancer with no evidence of residual disease on baseline postsurgical investigation in France and Belgium. The primary endpoint was 5-year overall survival (OS). RESULTS: Altogether, 2009 patients were randomly assigned. Among them, 16% had rectal cancer, and 44% left colon cancer; 75.9% were <75 years old. With a median follow-up of 7.8 years, cancer recurred in 22.3% of patients (local 10.5%, metastatic 72.9%, both 16.6%). The 5-year OS rates were 82.1% [95% confidence interval (CI) 78.5% to 85.2%] in group A (intensive imaging + CEA) versus 84.1% (95% CI 80.5% to 87.0%) in group B (intensive imaging alone), versus 83.6% (95% CI 80.1% to 86.6%) in group C (standard imaging + CEA) versus 79.5% (95% CI 75.7% to 82.8%) in group D (standard imaging alone) [P (log-rank) = 0.170]. Median OS was not reached in the four groups. Five-year relapse-free survival (RFS) was 73.8% in the CT-scan surveillance group versus 69.3% in the no-CT-scan group [hazard ratio (HR) 0.89, 95% CI 0.76-1.03, P = 0.108]. Five-year RFS was 71.3% in the CEA surveillance group versus 71.8% in the no-CEA group (HR 1.00, 95% CI 0.86-1.16, P = 0.959). CONCLUSIONS: Among patients with stage II or III colorectal cancer, after curative surgery, the implementation of CEA and/or CT-scan surveillance did not provide any benefit in 5-year OS for the overall population of the study.
BACKGROUND: The benefit of anthracyclines for patients with high 21-gene recurrence score (RS) is unclear, despite the widespread use of RS to guide adjuvant chemotherapy treatment for hormone receptor (HR)-positive /hum...BACKGROUND: The benefit of anthracyclines for patients with high 21-gene recurrence score (RS) is unclear, despite the widespread use of RS to guide adjuvant chemotherapy treatment for hormone receptor (HR)-positive /human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This study aimed to assess whether patients with RS ≥ 31 would have improved outcomes with the addition of anthracyclines to taxane-based chemotherapy. PATIENTS AND METHODS: We included patients from TAILORx with RS ≥ 11 who received treatment with either taxanes with cyclophosphamide (TC) or taxane with anthracyclines/cyclophosphamide (T-AC). Distant recurrence-free interval (DRFI), distant recurrence-free survival (DRFS), and overall survival (OS) were compared, controlling for age, tumor size and grade, receptor status, and RS. Spline regression was used to estimate adjusted hazard ratio (aHR) for receipt of T-AC (versus TC) for these endpoints as a function of RS. RESULTS: A total of 2549 patients who received either T-AC or TC were included in the primary analysis. In patients with RS ≥ 31, receipt of T-AC was associated with improved DRFI (5-year rate of 96.1% with T-AC versus 91.0% with TC, aHR 0.31, P = 0.006), DRFS (95.4% versus 89.8%, aHR 0.49, P = 0.032), and a trend toward improved OS (adjusted 5-year rate 97.3% versus 93.6%, aHR 0.67, P = 0.31). Spline regression demonstrated increasing anthracycline benefit with increasing RS. CONCLUSION: Patients with early-stage, HR-positive/HER2-negative breast cancer with the highest genomic risk disease (RS ≥ 31) may benefit from the addition of an anthracycline to taxane-based adjuvant chemotherapy. Genomic RS testing may predict anthracycline benefit more accurately than clinicopathological factors such as nodal status.
Ryu SY, Deng W, Albuquerque K
… +17 more, Koh WJ, Mayadev J, Heugel A, Kim BJ, Kim DY, Cho CH, Kim JW, No JH, Mannel RS, Miller K, Fabian D, Chase DM, Gil KM, Small W, Rodgers W, Leath CA, Monk BJ
BACKGROUND: To determine whether adjuvant chemoradiation (CRT) with weekly cisplatin improves recurrence-free survival (RFS) compared with radiation (RT) in pathologically proven intermediate risk early-stage cervical ca...BACKGROUND: To determine whether adjuvant chemoradiation (CRT) with weekly cisplatin improves recurrence-free survival (RFS) compared with radiation (RT) in pathologically proven intermediate risk early-stage cervical cancer following radical hysterectomy and lymphadenectomy. METHODS: Post-surgical patients with stage I-IIA cervical cancer with pathologically noted intermediate risk factors including combinations of capillary lymphatic space involvement, stromal invasion, and tumor size were randomly assigned in a 1 : 1 ratio to receive either adjuvant CRT or RT (NCT01101451). Patients received conformal RT, or intensity modulated radiation therapy. In the CRT arm, 6 weekly cycles of cisplatin 40 mg/m were administered during RT. RFS was the primary endpoint in randomized and eligible patients. Secondary endpoints included overall survival (OS), quality of life (QoL), and adverse events (AEs). RESULTS: Of the 340 randomized patients, 316 were eligible and most had Federation of Gynecology and Obstetrics (2009) stage IB and squamous cell carcinoma histology. Out of 316 patients, 292 (92.4%) received 28 fractions of RT with a median dose of 50.4 Gy and a median treatment duration of 39 days. Three-year RFS was 88.5% in the CRT arm and 85.4% in the RT arm. Both RFS [hazard ratio (HR) 0.698, 95% confidence interval (CI) 0.408-1.192, P = 0.09], as well as OS [HR 0.586, 95% CI 0.286-1.199, P = 0.07] favored CRT compared with RT alone. Grade 3 or 4 AEs occurred in 43% and 15% in the CRT and RT arms, respectively (P < 0.01). A transient decline in QoL occurred in the CRT arm compared with RT after starting treatments and recovered to pre-treatment level by 36 weeks. CONCLUSION: Although RFS and OS favored CRT, the addition of cisplatin during RT did not statistically improve RFS or OS in cervical cancer patients with intermediate pathological risk factors following radical hysterectomy and lymphadenectomy. CRT increased grade 3 and 4 AEs with a transient decline in QoL.
Gounder MM, Martin-Romano P, Italiano A
… +20 more, Siu LL, Cassier PA, Falchook GS, Lossos IS, Rasco DW, Hilton JF, McKean MA, Opdam FL, Strauss J, De Jonge M, Vermaat JSP, Crossman T, Zajac M, Tarkar A, Gonzalez Carreras F, Kremer BE, Barbash O, Segal S, Parasrampuria R, Postel-Vinay S
BACKGROUND: Protein arginine methyltransferase 5 inhibition often leads to a decrease in cell growth and survival in cancer cell lines. GSK3326595 is a first-generation protein arginine methyltransferase 5 inhibitor. PAT...BACKGROUND: Protein arginine methyltransferase 5 inhibition often leads to a decrease in cell growth and survival in cancer cell lines. GSK3326595 is a first-generation protein arginine methyltransferase 5 inhibitor. PATIENTS AND METHODS: METEOR-1 was a first-in-human, open-label, multicenter, three-part phase I study (NCT02783300) in patients with solid tumors and non-Hodgkin lymphoma (NHL). The objectives of part 1 were to determine the recommended phase II dose (RP2D), assess safety, evaluate preliminary clinical activity, and study the pharmacokinetics of oral GSK3326595 monotherapy. Part 2 enrolled patients at the RP2D to further evaluate clinical activity and safety. Part 3 explored the RP2D of GSK3326595 with pembrolizumab. RESULTS: A total of 288 patients were treated. In part 1, 69 patients received once daily (od) or twice a day (b.i.d.) GSK3326595 in doses ranging from 12.5 to 600 mg/day. In part 2, 218 patients received either 400 mg or 300 mg od, with the RP2D amended from 400 mg to 300 mg od due to toxicities. In part 3, 10 patients received GSK3326595 at 100 mg/day with pembrolizumab 200 mg intravenously every 3 weeks. Pharmacokinetics revealed that GSK3326595 was rapidly absorbed (T: 2-3 hours), with a mean terminal half-life of 4-6 hours. Dose-dependent increases in plasma exposure (C and AUC) were observed with both od and b.i.d. dosing. The most common adverse events at the RP2D included fatigue (57%), nausea (48%), and anemia (48%). Four partial responses (PRs) were observed in part 1 at doses of 200 mg (n = 2), 300 mg (n = 1), and 400 mg (n = 1). Two complete responses and one PR were seen in NHL [i.e. follicular (n = 2) lymphoma, diffuse large B-cell lymphoma (n = 1)], one PR in adenoid cystic carcinoma, and one PR in HR-positive breast cancer in part 2. No responses were observed in part 3. CONCLUSIONS: GSK3326595 monotherapy demonstrated modest antitumor activity. Further research in adenoid cystic carcinoma and NHL is warranted.
Conte PF, Dieci MV, Bisagni G
… +19 more, Schmid P, Zambelli A, Piacentini F, De Laurentiis M, Favaretto AG, Tamberi S, Bianchi GV, Zamagni C, Cinieri S, Corsi DC, Del Mastro L, Ferro A, Gennari A, Mion M, Musolino A, Nicolé L, Del Bianco P, De Salvo GL, Guarneri V
BACKGROUND: The A-BRAVE trial evaluated the efficacy of avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody, as adjuvant treatment of patients with early triple-negative breast cancer (TNBC) at high risk. PATIEN...BACKGROUND: The A-BRAVE trial evaluated the efficacy of avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody, as adjuvant treatment of patients with early triple-negative breast cancer (TNBC) at high risk. PATIENTS AND METHODS: A-BRAVE is a phase III study that randomly assigned patients with high-risk early TNBC to 1 year of avelumab versus observation, after completion of standard surgery and (neo)adjuvant chemotherapy. High-risk was defined as either: (i) ≥pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (stratum A); or (ii) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (stratum B). Coprimary endpoints were disease-free survival (DFS) in the intention-to-treat (ITT) and stratum B populations. Secondary endpoints were overall survival (OS) and DFS in PD-L1-positive patients. PD-L1 was evaluated in treatment-naïve tumor samples by immunohistochemistry (73-10 RUO assay, Agilent Technologies) and digital pathology. RESULTS: From June 2016 to October 2020, 466 patients were randomly assigned: 383 entered stratum B (82%) and 83 entered stratum A (18%). At a median follow-up of 52.1 months, avelumab did not significantly improve DFS in the ITT population [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.61-1.09, P = 0.172; 3-year DFS estimates were 68.3% for avelumab versus 63.2%], or in stratum B (HR 0.80, 95% CI 0.58-1.10, P = 0.170; 3-year DFS estimates were 66.9% for avelumab versus 60.7%). In a descriptive analysis, avelumab reduced the hazard of OS events: HR 0.66, 95% CI 0.45-0.97. The 3-year OS estimates for avelumab and control arm were 84.8% (95% CI 79.5% to 88.8%) and 76.3% (95% CI 70.1% to 81.3%), respectively. PD-L1 status was prognostic but not predictive for avelumab benefit in terms of DFS (test for interaction P = 0.155). CONCLUSIONS: For patients with TNBC at high risk of relapse who complete standard treatment with surgery and (neo)adjuvant chemotherapy, 1 year of adjuvant avelumab versus observation did not improve DFS. However, a descriptive analysis suggests a potential favorable impact on OS.
BACKGROUND: Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-programmed cell death protein or ligand 1 [PD-(L)1] therapy in LEAP-004. Here, we report results from LEAP-0...BACKGROUND: Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-programmed cell death protein or ligand 1 [PD-(L)1] therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma. PARTICIPANTS AND METHODS: Participants with unresectable stage III or IV melanoma, previously untreated with PD-(L)1 inhibitors were randomly assigned 1 : 1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and overall survival (OS). PFS was formally tested at the first interim analysis; OS at the final analysis. An external data monitoring committee regularly reviewed safety and efficacy. Three interim analyses and a final analysis were planned. RESULTS: Overall, 674 participants were assigned to lenvatinib plus pembrolizumab (n = 334) or placebo plus pembrolizumab (n = 340). Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab [hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.59-0.88, P = 0.0008]. This benefit was not maintained at final analysis (HR 0.83, 95% CI 0.69-1.00). Median OS at final analysis was 25.8 months for lenvatinib plus pembrolizumab versus 39.5 months for placebo plus pembrolizumab (HR 1.20, 95% CI 0.97-1.48, P = 0.9521). Grade 3-5 treatment-related adverse events occurred in 58.7% of participants receiving lenvatinib plus pembrolizumab versus 29.0% receiving placebo plus pembrolizumab. CONCLUSIONS: Lenvatinib plus pembrolizumab did not provide additional benefit versus placebo plus pembrolizumab in participants with unresectable advanced melanoma. Thus, the trial was terminated early, and the third interim analysis became the final analysis. Immunotherapy remains the standard of care for advanced melanoma.
BACKGROUND: Adjuvant immunotherapy is currently the standard of care for patients with resected renal cell carcinoma (RCC) at increased risk of recurrence, but there are no biomarkers available to guide treatment. Kidney...BACKGROUND: Adjuvant immunotherapy is currently the standard of care for patients with resected renal cell carcinoma (RCC) at increased risk of recurrence, but there are no biomarkers available to guide treatment. Kidney injury molecule-1 (KIM-1) has previously been described as a potential circulating biomarker in RCC. PATIENTS AND METHODS: Biomarkers and outcomes among patients who participated in a randomized phase III trial of adjuvant atezolizumab versus placebo in resected RCC (IMmotion010) were evaluated. This trial did not meet its primary endpoint of disease-free survival (DFS) in the intention-to-treat population. An affinity-based proximity extension proteomics assay was used to compare levels of circulating proteins among baseline (post-nephrectomy) serum samples and samples taken at the time of recurrence. RESULTS: Serum KIM-1 was the most significantly enriched protein at recurrence versus baseline. Patients with serum KIM-1 at baseline had worse DFS [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.35-2.09], but also had improved DFS when treated with adjuvant atezolizumab versus placebo (HR 0.72, 95% CI 0.52-0.99). An increase in KIM-1 during follow-up was associated with worse DFS compared with patients with no increase in KIM-1. Within the KIM-1 subgroup, longer DFS following atezolizumab treatment was associated with increased baseline expression of T-effector and Th1 signatures, while shorter DFS was associated with increased baseline expression of matrix remodeling genes and protumor cytokines. CONCLUSION: These analyses suggest that elevated post-nephrectomy plasma KIM-1 level and kinetics are prognostic, supporting the hypothesis that KIM-1 is a biomarker for minimal residual disease in RCC. As KIM-1 patients are also enriched for benefit from adjuvant immunotherapy, biomarker-driven adjuvant therapy should be evaluated as a potential new paradigm in RCC.
BACKGROUND: The CHAARTED trial investigated the long-term survival of patients with metastatic hormone-sensitive prostate cancer (HSPC) treated with androgen deprivation therapy (ADT) with or without docetaxel (Taxotere)...BACKGROUND: The CHAARTED trial investigated the long-term survival of patients with metastatic hormone-sensitive prostate cancer (HSPC) treated with androgen deprivation therapy (ADT) with or without docetaxel (Taxotere). This analysis focuses on 10-year overall survival (OS) stratified by disease volume and on-therapy prostate-specific antigen (PSA) levels at 6 months. PATIENTS AND METHODS: OS was calculated using the Kaplan-Meier method from randomization to death or last known alive date. Patients were grouped based on baseline disease characteristics [high-volume (HV) or low-volume (LV)] and PSA levels at 6 months (<0.2 ng/ml versus ≥0.2 ng/ml). Multivariable Cox regression analysis was used to evaluate correlation of PSA nadir with OS adjusted for treatment arm, disease volume, Gleason score, and prior local therapy. RESULTS: Of 790 patients, 225 were without recorded death after a median follow-up of 10 years. The 10-year OS was 25.9% (ADT + docetaxel) versus 22.5% [ADT; hazard ratio (HR) 0.78, P = 0.004]. HV patients treated with docetaxel had significantly higher OS (20.9% versus 11.4%, P < 0.0001). PSA <0.2 ng/ml at 6 months was associated with improved median OS in both ADT + docetaxel (100.3 versus 45.4 months, P < 0.0001) and ADT (116.8 versus 31.8 months, P < 0.0001) arms. PSA nadir <0.2 ng/l at 6 months was an independent predictor of improved OS (HR 0.41, P < 0.0001) adjusting for disease volume, prior local therapy, Gleason score and treatment arm. CONCLUSIONS: Long-term follow-up confirms that ADT + docetaxel significantly improves OS in metastatic HSPC patients with HV disease. PSA nadir <0.2 ng/ml at 6 months is a strong prognostic marker for OS, supporting its use in response-adapted de-escalation strategies.
BACKGROUND: We evaluated the distribution and risk of disease progression (PD) in first-line therapy of unresected metastatic colorectal cancer (mCRC) patients receiving chemotherapy + biologics. The aim of the analysis...BACKGROUND: We evaluated the distribution and risk of disease progression (PD) in first-line therapy of unresected metastatic colorectal cancer (mCRC) patients receiving chemotherapy + biologics. The aim of the analysis is to provide guidance for the timing of disease reassessments during first-line therapy. PATIENTS AND METHODS: Individual data of 2939 unresected patients from TRIBE, MOMA, TRIBE2, VALENTINO, ATEZOTRIBE, TRIPLETE, FIRE-3, XELAVIRI, PANAMA, FIRE-4 and FIRE-4.5 were analyzed. The frequency and risk of PD events were calculated for individual timepoints during therapy. RAS/BRAF profiling, tumor sidedness, type of therapy and early tumor shrinkage (ETS) were used to identify subgroups for risk assessment. A Cox regression model to predict first-line progression-free survival (PFS) was built. RESULTS: In the overall population, the maximum frequency of PD events was observed at 7.6 months, with an absolute PD risk of 19%. Then, the PD risk flattened, achieving a maximum of 23% at 14 months in RAS/BRAF-wild-type patients (n = 1786), 25% at 10 months in RAS-mutant patients (n = 973) and 35% at 8 months in BRAF-mutant patients (n = 180). Eastern Cooperative Oncology Group performance status >0, right-sidedness, initially unresected primary tumor, higher number of organs involved by metastases and BRAF mutation were independently associated with a higher risk of PD in first line. The impact of baseline characteristics on PFS was mitigated after incorporation of ETS in the model. CONCLUSIONS: The distribution of PD events does not follow a Gaussian pattern, with the highest density observed between the third and fourth reassessment of a bimonthly surveillance schedule. In clearly unresectable patients, restaging should focus on the interval between 6 and 10 months and not on the initiation of systemic therapy. Our model might be helpful to schedule radiological reassessments according to baseline characteristics, early response and the expected duration of each treatment efficacy.
BACKGROUND: Early-onset colorectal cancer (EOCRC, diagnosis before age 50) is increasing globally. Survival comparisons with late-onset colorectal cancer (CRC) are inconsistent, however, and long-term excess mortality re...BACKGROUND: Early-onset colorectal cancer (EOCRC, diagnosis before age 50) is increasing globally. Survival comparisons with late-onset colorectal cancer (CRC) are inconsistent, however, and long-term excess mortality remains poorly understood. This Swedish population-based study aimed to evaluate trends in incidence, survival, and long-term excess mortality in early- versus late-onset CRC. MATERIALS AND METHODS: We identified all incident colorectal adenocarcinomas recorded in the Swedish National Cancer Register from 1993 to 2019. Incidence trends were quantified using annual percentage changes and relative survival differences were assessed using excess mortality rate ratios, both from Poisson regression models with 95% confidence intervals (CIs). RESULTS: A total of 47 864 right-sided colon, 40 664 left-sided colon, and 47 082 rectal cancer cases were included. EOCRC patients were more frequently diagnosed with metastatic disease, compared with late-onset CRC. EOCRC incidence increased across all subsites, with annual percentage changes ranging from 2.04 (95% CI 1.51-2.56) for rectal to 2.64 (95% CI 2.02-2.37) for right-sided colon cancer, while an increase among late-onset cases was observed only for right-sided colon cancer. Crude 5-year relative survival was similar across age groups, but after full adjustment (including metastatic stage), EOCRC was associated with better survival, with excess mortality rate ratios ranging from 0.76 (95% CI 0.68-0.84) for rectal cancer to 0.83 (95% CI 0.74-0.92) for right-sided colon cancer. Notably, excess mortality remained elevated 5-10 years after diagnosis in both age groups. CONCLUSIONS: EOCRC incidence is increasing in Sweden, aligning with global trends. Although younger patients were more often diagnosed at an advanced stage of disease, they had similar crude survival and better stage-adjusted survival, compared with older patients. The persistent long-term excess mortality in both groups, even during periods when CRC patients are typically considered statistically cured, highlights the need for extended follow-up and tailored survivorship care.