Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting.

Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8−17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6−9.2), and median OS (mOS) of 20.6 months (95% CI 13.6−28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2−22.2] and 10.3 [IQR 7.4−14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5−8.6) versus 7.5 months (95% CI 6.5−10.1, p = 0.03), and 16.4 (95% CI 9.3−27.5) versus 24.2 months (95% CI 17.2−NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.

Limited Liver or Lung Colorectal Cancer Metastases. Systemic Treatment, Surgery, Ablation or SBRT.

The prognosis for oligometastatic colorectal cancer has improved in recent years, mostly because of recent advances in new techniques and approaches to the treatment of oligometastases, including new surgical procedures, better systemic treatments, percutaneous ablation, and stereotactic body radiation therapy (SBRT). There are several factors to consider when deciding on the better approach for each patient: tumor factors (metachronous or synchronous metastases, RAS mutation, BRAF mutation, disease-free interval, size and number of metastases), patient factors (age, frailty, comorbidities, patient preferences), and physicians' factors (local expertise). These advances have presented major challenges and opportunities for oncologic multidisciplinary teams to treat patients with limited liver and lung metastases from colorectal cancer with a curative intention. In this review, we describe the different treatment options in patients with limited liver and lung metastases from colorectal cancer, and the possible combination of three approaches: systemic treatment, surgery, and local ablative treatments.

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02).

BACKGROUND: RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. MATERIALS AND METHODS: We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (α = .05, ß = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. RESULTS: We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). CONCLUSION: The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. IMPLICATIONS FOR PRACTICE: This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.

Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype.

BACKGROUND: Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. METHODS: Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m2 for UGT1A1*1/*1 and 260 mg/m2 for *1/*28 patients. In the control group, the dose was 180 mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. RESULTS: The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. CONCLUSIONS: Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.

Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy.

PURPOSE: RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy. METHODS: RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS: Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease (P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD (P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations (P = .016). CONCLUSION: Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti-epidermal growth factor receptor therapy.

Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients.

INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study).

BACKGROUND: This phase II study aims to evaluate the efficacy and safety of biweekly cetuximab in combination with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) as first-line treatment of metastatic wild-type KRAS colorectal cancer. METHODS: Previously untreated patients with wild-type KRAS tumours received biweekly cetuximab (500 mg/m2 on day 1) plus FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on days 1 and 2, and fluorouracil as a 400 mg/m2 bolus followed by a 22-hour 600 mg/m2 infusion on day 1 and 2). Treatment was continued until disease progression, onset of unacceptable toxicities, metastases surgery, or discontinuation request. The primary endpoint was ORR. RESULTS: The intention-to-treat population included 99 patients with a median age of 64.1 years (range, 34-82). The ORR was 60.6% (95% CI, 50.3% to 70.3%). The median follow-up was 17.8 months; the median OS and PFS were 20.8 and 10.1 months, respectively. Metastases from colorectal cancer were surgically resected in 26 (26.3%) patients, with complete resection achieved in 18 (69.2%) patients. Median PFS and OS in patients undergoing metastatic resection were 12.6 and 29.5 months, respectively. The most common grade 3-4 toxicities were neutropenia (32.3%), acne-like rash (15.2%) and diarrhoea (11.1%). CONCLUSIONS: The efficacy of the biweekly combination of cetuximab with FOLFOX-4 in patients with wild-type KRAS tumours supports the administration of cetuximab in a dosing regimen more convenient for patients and healthcare providers. The activity of the biweekly administration is similar to what has been reported for the weekly regimen. Reported toxicity was also consistent with the known toxicity profile of weekly cetuximab. TRIAL REGISTRATION: EudraCT Number 200800690916.

Resultados tras resección hepática laparoscópica: una opción adecuada en patología maligna / Results after laparoscopic liver resection: An appropriate option in malignant disease

Introducción El abordaje laparoscópico no ha tenido una gran difusión en la cirugía hepática, aunque ha demostrado ser seguro y factible en pacientes seleccionados incluso en enfermedad maligna. Se presenta la experiencia y resultados en el tratamiento de la enfermedad hepática maligna por laparoscopia. Material y método Entre febrero de 2002 y mayo de 2011 se realizaron 71 resecciones hepáticas laparoscópicas, 43 por enfermedad maligna (solo se incluyó a pacientes con más de un año de seguimiento). La edad media fue de 63 años y el 58% fueron varones. El 49% de las lesiones estaban situadas en los segmentos ii - iii . Se realizaron 30 segmentectomías, 7 resecciones limitadas y 6 hepatectomías mayores. Resultados El tiempo operatorio fue de 163 min. Hubo 3 conversiones. Cinco casos (11%) fueron transfundidos. La ingesta se inició a las 32 h y la estancia hospitalaria fue de 6,7 días. No hubo reintervenciones y sí un caso de mortalidad. Nueve pacientes (21%) presentaron complicaciones. El número medio de lesiones resecadas fue 1,2, con un tamaño de 3,5 cm. Todas las resecciones fueron R0. La supervivencia fue del 69 y del 43,5% a los 36 y 60 meses en metástasis hepáticas de cáncer colorrectal (MHCCR), y del 89 y 68% a los 36 y 60 meses en hepatocarcinoma (HCC).Conclusiones La resección hepática por laparoscopia en enfermedad maligna es factible y segura. Debe cumplir los mismos preceptos oncológicos que la cirugía abierta. En pacientes seleccionados ofrece resultados oncológicos a largo plazo similares a los obtenidos en cirugía abierta (AU)

Introduction Treatment of oesophageal cancer with curative intent requires a multidisciplinary approach. Neoadjuvant therapy, the radicality of resection and extension of lymphadenectomy have been associated with increased operative morbidity and mortality. The aim of this study was to assess the results of surgical treatment of oesophageal cancer since the presence of an interdisciplinary esophagogastric tumour board. Methods Patients with cancer of the oesophagus and oesophagogastric junction who underwent oesophagectomy between January 2005 and March 2012 were included in this retrospective study. Data concerning type of resection, postoperative complications, mortality and survival were analysed. Results Of the 392 patients with a diagnosis of oesophageal cancer over the study period, 100 underwent oesophagectomy. Seventy-four patients received neoadjuvant treatment. Eighty-two patients underwent transthoracic resection while a transhiatal was used in 10 patients. Colon interposition was required in 8 cases. An R0 resection was achieved in 98 patients. Anastomotic leaks developed in 15 patients, 9 were intrathoracic and 6 were cervical. Postoperative morbidity occurred in 42% of patients, and intra-hospital and 90-day mortality was 2%. Median length of hospital stay was 16 days. The respective actuarial survival at 1 and 5 years were 82% and 56%.ConclusionsSurgical treatment with curative intention for oesophageal cancer is only possible in a quarter of patients diagnosed. The high morbidity rate was mainly due to intrathoracic complications (AU)

[Results after laparoscopic liver resection: an appropriate option in malignant disease]. / Resultados tras resección hepática laparoscópica: una opción adecuada en patología maligna.

INTRODUCTION: The laparoscopic approach is not yet widely used in liver surgery, but has proven to be safe and feasible in selected patients even in malignant disease. The experience and results of a hepato-pancreato-biliary (HPB) surgery unit in the treatment of malignant liver disease by laparoscopic approach is presented. MATERIAL AND METHODS: Between February 2002 and May 2011, 71 laparoscopic liver resections were performed, 43 for malignant disease (only patients with more than one year of follow-up were included). Mean age was 63 years old and 58% of the patients were male. Forty-nine per cent of the lesions were located in segments ii-iii. Thirty segmentectomies were performed, 7 limited resections and 6 major hepatectomies. RESULTS: The median operative time was 163 min. There were 3 conversions. Five cases (11%) required blood transfusion. The oral intake began at 32 h and the median hospital stay was 6.7 days. There were no reoperations and there was one case of mortality. Nine patients (21%) had postoperative complications. The mean number of resected lesions was 1.2, with an average size of 3.5 cm. All resections were R0. The median survival after resection of colorectal liver metastases (CLM) was 69% and 43.5% at 36 and 60 months, respectively, and 89% and 68% at 36 and 60 months, respectively, in hepatocellular carcinoma (HCC). CONCLUSION: The laparoscopic liver resection in malignant disease is feasible and safe in selected patients. The same oncological rules as for open surgery should be followed. In selected patients it offers similar long-term oncological results as open surgery.