Adverse events in the treatment of colorectal cancer : their use as predictive markers and impact on quality of life

Colorectal cancer (CRC) is a common disease in all western countries. The CRC treatment process has been revolutionised over the past years, and the prognosis of CRC has improved, but we lack information regarding the prognostic and predictive factors that would help us to optimise the therapy for an individual patient. In addition, with improved survival rates, both acute and long-term toxicities require more attention. Hypertension (HTN) is a well-recognised adverse event that is associated with all drugs involved in anti-VEGF (vascular endothelial growth factor) inhibition. The first study discussed in this thesis investigated whether HTN could act as a surrogate marker for efficacy during bevacizumab-containing therapy. According to our results, treatment-associated HTN might predict the outcome of bevacizumab-containing chemotherapy in mCRC patients and could potentially be utilized as a biomarker for continued care. The role of the H. pylori infection as a confounding gastrointestinal comorbidity in the diagnosis of CRC is not well known, and it is not established whether H. pylori infection worsens chemotherapy-induced gastrointestinal toxicity. In the second sub-study, we studied the role of different symptoms and H. pylori for CRC diagnostics. We observed that dyspeptic symptoms and the presence of H. pylori infection at the baseline delayed the initial diagnosis of CRC, but we observed no association between H. pylori infection and gastrointestinal adverse events during 5-FU-based adjuvant chemotherapy. Therefore, the eradication of H. pylori infections before providing 5-FU-based adjuvant chemotherapy cannot be routinely recommended. The association between survival and adverse events in several types of cancer has been established, but data for CRC patients are limited. In the third sub-study, we assessed whether adverse events could predict disease-free survival (DFS) or overall survival (OS) in stage II-III CRC patients. According to our results, adverse events related to treatment with adjuvant 5-FU chemotherapy in early stage CRC patients, especially non-haematological adverse events, are strongly associated with the prediction of improved DFS and OS. Adverse events could guide the clinician in bringing about dose modifications, to maximize the treatment efficacy, while ensuring a lesser level of toxicity. The use of oxaliplatin in the adjuvant setting reduces the risk of death 20% in stage III CRC patients. The major adverse event associated with oxaliplatin-based regimens is peripheral neuropathy, but the prevalence of acute and long-term neuropathy is not well established. It is not well known whether there is a difference in the neuropathy observed with two standard regimens (CAPOX and FOLFOX), and whether long-term neuropathy influences the quality of life (QOL). In the fourth sub-study, we analysed the prevalence of oxaliplatin-induced acute and long-term neuropathy during and after treatment with CAPOX and FOLFOX and studied the effect of long-term neuropathy on QOL in a real-life patient population. According to our results, long-term neuropathy is observed after therapy in a significant proportion of patients, but it does not impair global health status. Long-term neuropathy is not preventable in all patients with a reduction in the duration of therapy, but the performance status might predict the risk of long-term neuropathy.Suolistosyöpä on yleinen sairaus kaikissa länsimaissa. Sen hoito on kehittynyt viime vuosina merkittävästi, mutta edelleenkään ei tunneta riittävästi prognostisia ja prediktiivisiä tekijöitä jotka auttaisivat kohdentamaan hoitoja vain niistä todella hyötyville potilailla. Lisäksi, potilaiden ennuste on parantunut josta johtuen sekä akuuteilla, että pitkäaikaishaitoilla hoitojen jälkeen on yhä enemmän merkitystä. Verenpaineen nousu on yleinen haittavaikutus kaikilla anti-angiogeenisillä lääkkeillä. Ensimmäisessä osatyössä tutkimme, voisiko verenpaineen nousu ennustaa hoitovastetta bevasitsumabi hoidetuilla levinnyttä suolistosyöpää sairastavilla potilailla. Totesimme, että potilailla, joilla verenpaine nousi bevasitsumabihoidon aikana, oli merkitsevästi enemmän hoitovasteita ja pidempi kokonaiselinaika. Näin ollen verenpaineen nousu saattaisi osoittautua prediktiiviseksi tekijäksi bevasitsumabihoidolle. Toisessa osatyössä selvitimme suolistosyövän aiheuttaminen oireiden ja Helikobakteeri Pylorin (H. pylori) merkitystä suolistosyövän diagnostiikassa. Selvitimme myös, lisääkö H. pylori liitännäishoidon aiheuttamia mahasuolikanavan sivuvaikutuksia. Tulostemme mukaan H. pylori ei lisännyt sytostaattihoidon aikaisia sivuvaikutuksia, mutta ylävatsaoireet ja H. pylori diagnoosi aiheuttivat merkittävän viiveen itse suolistosyövän diagnosoinnissa. Tämä on tärkeä viesti kliinikolle ja korostaa huolellisen diagnostiikan merkitystä. Tulostemme perusteella H. pylorin testaamista ja häätöhoitoa ei kuitenkaan voida suositella ennen liitännäishoidon aloitusta. Osatyössä kolme tarkastelimme fluorourasiilihoidon aikaisia verenkuvamuutoksia ja mahasuolikanavan sivuvaikutuksia ja analysoimme näiden yhteyttä hoitotehoon suolistosyöpäleikkauksen jälkeen liitännäishoidetuilla potilailla. Totesimme, että erityisesti ei-hematologinen toksisuus ennusti vahvasti sekä aikaa taudin uusimaan, että kokonaiselinaikaa. Tulevaisuudessa toksisuuspohjainen annoseskalaatio on mahdollisesti avainsana liitännäishoidon tulosten parantamiseen tilanteessa, jossa uusia lääkkeitä liitännäisasetelmaan ei ole näköpiirissä. Oksaliplatiini pienentää merkittävästi kuolemanriskiä suolistosyöpäpotilailla joilla todetaan imusolmukemetastasointi, mutta oksaliplatiiniin liittyy riski vaikeallekin neuropatialle. Riittävästi ei tiedetä oksaliplatiinin aiheuttamasta pitkäaikaisesta neuropatiasta eikä siitä, miten se mahdollisesti vaikuttaa potilaiden elämänlaatuun liitännäishoidon jälkeen. Neljännessä osatyössä tutkimme oksaliplatiiniin liittyvää akuuttia- että pitkäaikasneuropatiaa ja neuropatian elämänlaatuvaikutusta. Totesimme, että pitkäaikaisneuropatia on todettavissa merkittävällä osalla potilaista vielä neljä vuotta hoidon päättymisestä, mutta se ei vaikuta potilaiden kokonaiselämänlaatuun. Potilaan suorituskykyluokka ennustaa mahdollisesti neuropatian kehittymistä, mutta liitännäishoidon kestoa lyhentämällä neuropatian kehittymistä ei ole mahdollista ehkäistä kaikilla potilailla

Postoperative serum CA19-9, YKL-40, CRP and IL-6 in combination with CEA as prognostic markers for recurrence and survival in colorectal cancer

Background In colorectal cancer (CRC) patients, guidelines only recommend measurement of preoperative carcinoembryonic antigen (CEA), although postoperative CEA may be more informative. However, the sensitivity of both preoperative and postoperative CEA in identifying relapse is limited. We studied whether CA19-9, YKL-40, C-reactive protein (CRP) and interleukin (IL)-6 add prognostic information combined with postoperative CEA. Material and methods This post-hoc analysis included 147 radically resected stage II (n = 38), III (n = 91) and IV (n = 18) CRC patients treated with adjuvant 5-fluorouracil (5-FU)-based therapy in the phase III LIPSYT study (ISRCTN98405441). We collected postoperative blood samples a median of 48 days after surgery. We analysed relapses, sensitivity, positive predictive value (PPV) and disease-free (DFS) and overall survival (OS) by bootstrap, Kaplan-Meier and adjusted Cox-models in the elevated vs. normal biomarker groups. Results Elevated postoperative CEA associated with impaired DFS (HR 7.23; CI(95%)3.85-13.58), impaired OS (HR 7.16; CI(95%)3.76-13.63), and more relapses (HR 7.9; CI(95%)3.4-18.2); but sensitivity for CEA in finding relapses was only 31% (CI(95%)21-48%). Normal CEA combined with an elevated YKL-40 or elevated CRP showed more relapses (HR for YKL-40 2.13 [CI(95%)1.10-4.13], HR for CRP 3.14 [CI(95%)1.21-8.16]), impaired DFS (HR 2.18 [CI(95%)1.12-4.24] or 3.23 [CI(95%)1.34-7.82]), and impaired OS (2.33 [CI(95%)1.24-4.40] or 2.68 [CI(95%)1.12-6.44]). Elevated CEA combined with a concomitantly elevated CA19-9, YKL-40, CRP or IL-6 showed a respective PPV of 100, 90, 100, and 100%. Conclusion In radically operated stage II to IV CRC patients who received adjuvant 5-FU-based chemotherapy, a postoperatively elevated CEA alone or in combination with CA19-9, YKL-40, CRP, or IL-6, or a normal CEA combined with an elevated YKL-40 or with an elevated CRP, may indicate patients at high risk of relapse.Peer reviewe

Lead Time and Prognostic Role of Serum CEA, CA19-9, IL-6, CRP, and YKL-40 after Adjuvant Chemotherapy in Colorectal Cancer

Simple Summary Colorectal cancer is the third most common cancer worldwide. Recurrence risk after curative intent surgery combined with adjuvant chemotherapy is substantial. Unlike many other cancers, curative metastasectomy is possible upon recurrence, which raises the question of personalized surveillance strategies according to individual risk factors. We studied whether elevated biomarkers, such as gold standard CEA and experimental CA19-9, IL-6, CRP, and YKL-40 after adjuvant therapy, are associated with disease-free and/or overall survival, and whether the diagnostic time from the elevated biomarker to the diagnosis of metastases can be prolonged by combining these biomarkers. We show that elevated post-adjuvant CEA, IL-6, and CRP are associated with impaired survival and that elevated IL-6 finds recurrences in patients with normal CEA. Lead time is shorter with CEA than with experimental biomarkers. Our findings thus may impact the follow-up strategies after curative intent treatment aiming at finding operable relapses. These biomarkers are readily available and feasible in clinical practice. In colorectal cancer (CRC), 20-50% of patients relapse after curative-intent surgery with or without adjuvant therapy. We investigated the lead times and prognostic value of post-adjuvant (8 months from randomisation to adjuvant treatment) serum CEA, CA19-9, IL-6, CRP, and YKL-40. We included 147 radically resected stage II-IV CRC treated with 24 weeks of adjuvant 5-fluorouracil-based chemotherapy in the phase III LIPSYT-study (ISRCTN98405441). All 147 were included in lead time analysis, but 12 relapsing during adjuvant therapy were excluded from post-adjuvant analysis. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired disease-free survival (DFS) with hazard ratio (HR) 5.21 (95% confidence interval 2.32-11.69); 3.72 (1.99-6.95); 2.58 (1.18-5.61), respectively, and elevated IL-6 and CRP with impaired overall survival (OS) HR 3.06 (1.64-5.73); 3.41 (1.55-7.49), respectively. Elevated post-adjuvant IL-6 in CEA-normal patients identified a subgroup with impaired DFS. HR 3.12 (1.38-7.04) and OS, HR 3.20 (1.39-7.37). The lead times between the elevated biomarker and radiological relapse were 7.8 months for CEA and 10.0-53.1 months for CA19-9, IL-6, CRP, and YKL-40, and the lead time for the five combined was 27.3 months. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired DFS. The lead time was shortest for CEA.Peer reviewe

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89–0.91 with the 15D, 0.85–0.87 with the EQ-5D, 68–80 with the EQ-5D-VAS, and 68–79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors’ well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89–0.91 with the 15D, 0.85–0.87 with the EQ-5D, 68–80 with the EQ-5D-VAS, and 68–79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors’ well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

BackgroundKRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting. MethodsPatients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors. ResultsThe KRAS-G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference KRAS-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors. ConclusionsIn these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.Peer reviewe

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied. Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status. Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups. Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Peer reviewe

Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): A nationwide prospective intervention study

Background: Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice.Methods: A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival.Findings: In 2012-2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Sixhundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80.4 months in R0/1-resected (HR 0.15; CI95% 0.12-0.19), 39.1 months in R2-resected/LAT (0.39; 0.29-0.53) patients, and 20.8 months in patients treated with "systemic therapy alone" (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively.Interpretation: Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later. </p