RESUMEN
BACKGROUND: Neoadjuvant imatinib is considered for gastrointestinal stromal tumors (GISTs) when decreased tumor size provides less extensive surgery and higher R0 resection rates. This study evaluates the effectivity and safety of neoadjuvant imatinib for large or locally advanced GIST. PATIENTS AND METHODS: From the prospective database of the Dutch GIST Consortium, all patients who underwent surgery after neoadjuvant imatinib at our center between 2009 and 2022 were selected. Independent and blinded assessment of surgical strategy was performed by two surgeons, based on anonymized computed tomography (CT) scans before and after neoadjuvant imatinib. RESULTS: Of 113 patients that received neoadjuvant imatinib, 108 (95%) [mean age 61.6, standard deviation (SD) 11.5, 54% male] underwent a GIST resection. Of all GISTs, 67% was localized in the stomach and 25% in the duodenum or small intestine. In 74% of the patients with GIST, a KIT exon 11 mutation was found. Decreased tumor size was seen in 95 (88%) patients. Having a KIT exon 11 mutation [odds ratio (OR) 5.64, 95% confidence interval (CI) 1.67-19.1, p < 0.01] or not having a mutation (OR 0.19, 95% CI 0.04-0.89, p = 0.04) were positive and negative predictive values for partial response, respectively. In 55 (51%) patients, there was deescalation of surgical strategy after neoadjuvant imatinib. Surgical complications were documented in 16 (15%) patients (n = 8, grade II; n = 5, grade IIIa; n = 3, grade IIIb) and R0 resection was accomplished in 95 (89%) patients. The 5-year disease-free and overall survival were 80% and 91%, respectively. CONCLUSION: This study shows that neoadjuvant imatinib is effective and safe for patients with large or locally advanced GIST.
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Antineoplásicos , Tumores del Estroma Gastrointestinal , Humanos , Masculino , Persona de Mediana Edad , Femenino , Mesilato de Imatinib/uso terapéutico , Tumores del Estroma Gastrointestinal/patología , Terapia Neoadyuvante/métodos , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC). METHODS: Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629). RESULTS: MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)). CONCLUSIONS: MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors.
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Neoplasias Colorrectales , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN/genética , Mutación , Homólogo 1 de la Proteína MutL/genética , Sobrevivientes , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/genéticaRESUMEN
BACKGROUND: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions. METHODS: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power. DISCUSSION: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy. TRIAL REGISTRATION: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033 .
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Supervivientes de Cáncer , Neoplasias Colorrectales , Neoplasias Testiculares , Estudios de Cohortes , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/epidemiología , Estudios Transversales , Detección Precoz del Cáncer , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Platino (Metal) , Estudios Prospectivos , Sobrevivientes , Neoplasias Testiculares/tratamiento farmacológicoRESUMEN
OBJECTIVE: Chemotherapy (CT) is associated with adverse effects on cognition. Only few studies have investigated cognition in testicular cancer (TC) patients and studies on very late effects of CT on cognition are absent. Further, brain changes in relation to treatment have not been investigated in TC. The objective of the present study is to compare psychosocial functioning, cognitive performance and brain (micro)structure following surgery and CT for TC, against surgery (S)-only. METHODS: Twenty-eight CT (43.1±7.5 y) and 23 S-only (48.2±9.5y) TC survivors on average 14 yr post-treatment were examined using questionnaires, neurocognitive tests, and 3T-MRI [Diffusion Kurtosis Imaging (DKI), T1-weighted and Fluid Attenuated Inversion Recovery]. A multivariate cognitive performance score (Mahalanobis distance) was calculated to indicate the grade of cognitive performance. Kurtosis parameters, gray matter, and white matter (WM) volume were calculated from MRI data. RESULTS: Overall, the CT group showed lower cognitive performance (5.35±1.7) compared with the S-only group (4.4±0.9; P=0.03; d=0.70). Further, TC patients reported more memory problems after CT. DKI revealed a significantly higher radial kurtosis after CT in several anterior and posterior brain areas (P<0.05, corrected), but this was unrelated to cognitive performance. CONCLUSIONS: This cross-sectional study suggests that men receiving CT for TC are at risk for long-term lower cognitive performance. Although CT affected WM microstructure, this was unrelated to cognitive performance. More extensive, preferably prospective studies are warranted to confirm these results and to provide more insight into the possible mechanisms behind the observed cognitive sequelae after treatment for TC.
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Antineoplásicos/efectos adversos , Trastornos del Conocimiento , Sobrevivientes , Neoplasias Testiculares/tratamiento farmacológico , Sustancia Blanca/patología , Adulto , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sustancia Blanca/efectos de los fármacosRESUMEN
AIM: Higher imatinib exposure is correlated with longer time to progression, while the variability in exposure is high. This provides a strong rationale for therapeutic drug monitoring, which has therefore been implemented in routine clinical practice in our institute. The aim of this study is to evaluate whether pharmacokinetically (PK)-guided dose increases are feasible in daily clinical practice and result in an improved exposure (Cmin≥1100 ng/mL) and longer progression-free survival (PFS). METHODS: This retrospective study included all patients with a gastrointestinal stromal tumour (GIST) in the Netherlands Cancer Institute who started imatinib treatment at a dose of 400 mg and of whom PK plasma samples were available. Of these patients, minimum plasma concentrations (Cmin) of imatinib, frequency and successfulness of PK-guided dose increases and PFS in the palliative treatment setting were analysed. RESULTS: In total, 169 consecutive patients were included, of whom 1402 PK samples were collected. In 126 patients (75%), Cmin was below the efficacy threshold of 1100 ng/mL. In 78 of these patients (62%), a PK-guided dose increase was performed, which was successful in 49 patients (63%). PFS was similar in patients with and without imatinib dose increase. However, due to the small number of patients with progressive disease, no definite conclusions on the effect on PFS could yet be drawn. CONCLUSION: This is the largest cohort evaluating PK-guided dose increases of imatinib in patients with GIST in routine clinical practice and demonstrating its feasibility. PK-guided dose increases should be applied to optimise exposure in the significant subset of patients with a low Cmin.
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Monitoreo de Drogas , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/uso terapéutico , Anciano , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Neoplasias Gastrointestinales/epidemiología , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/epidemiología , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
OBJECTIVES: To evaluate response, time to progression and survival of patients with limited disease (LD) small cell carcinoma of the bladder (SCCB) treated with sequential chemoradiation in analogy to LD small cell lung cancer (SCLC). METHODS: Of 42 patients with SCCB treated at our institution between 1993 and 2007, 17 with LD SCCB treated with chemoradiation were identified and retrospectively analysed. LD was defined as any pT, cN0-1, cM0. SCCB was defined according to WHO criteria. All patients had platinum-based chemotherapy after transurethral resection (TUR) prior to local radiotherapy with 56-70 Gy. RESULTS: Sixteen patients were male, 1 female. Median age was 62 years. Median overall survival is 32.5 months. All had a clinical local response (15 CR, 2 PR). Systemic progression occurred in 8 (47%) with a median time to progression of 6 months (range 1-16 months), 8 died with a median survival of 17.5 months. Currently, 7 are free of disease (FOD) including 2 at 80 and 87 months. Four (23.5%) had a local recurrence as late as 43 and 50 months; 3 required a salvage cystectomy. CONCLUSIONS: Clinical results of sequential chemoradiation for LD SCCB are comparable to contemporary series of LD SCCB treated with cystectomy and upfront or adjuvant chemotherapy. Long-term survival of more than 5 years after chemoradiation can be achieved. The risk of local recurrence is lower than reported, but late recurrences occur. These data suggest that bladder sparing with systemic chemotherapy and local control by radiotherapy should be further investigated in this aggressive disease.
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Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/radioterapia , Adulto , Anciano , Carcinoma de Células Pequeñas/mortalidad , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare and lethal disease. Previously, we and others have reported a bladder sparing strategy with platinum-etoposide-based chemotherapy followed by radiotherapy of the bladder. Little is known on frequency and treatment of intravesical recurrence following this approach. The objective of this study is to describe the incidence of intravesical recurrences and their management. MATERIALS AND METHODS: Retrospective study including all patients with SCCB treated at a single institution from 1993 until 2016. All patients with limited disease (LD) SCCB who had a bladder sparing approach with sequential chemotherapy and radiotherapy were identified. Intravesical and overall recurrence rate, overall and disease specific survival, salvage treatment options and their results were retrieved. RESULTS: Of the 110 patients with SCCB (82% male) with a mean age of 65 years and a median follow up of 48 months, 89 patients (81%) had LD-SCCB. Of these, 65 were treated with chemotherapy and radiotherapy, with a median overall recurrence free survival of 22 months (CI: 14-30). Of 65 patients, 23 (35%) progressed to distant metastasis without intravesical recurrence after a median of 9 months (CI: 8-11), whereas 14 patients (22%) developed isolated intravesical recurrence at a median of 24 months (CI: 14-34). Local recurrence contained SCCB, urothelial carcinoma, and carcinoma in situ and was treated with various local salvage treatments including TURB, cystectomy, neoadjuvant chemotherapy, and BCG. Following salvage treatment a complete response was seen in 64%. Median overall survival for intravesical vs. systemic recurrence was different, with 28 (CI: 9-47) and 8 (CI: 5-11) months, respectively (P<0.001). CONCLUSION: SCCB is a serious potentially lethal disease. Even in patients with LD-SCCB a high percentage rapidly develops systemic disease. This suggests that systemic therapy is more important than the type of local treatment to control the disease but small sample sizes limit the ability to distinguish between different treatment options in this study. A bladder sparing approach can be a reasonable alternative to major surgery. However, in those surviving long enough isolated intravesical recurrence occurs even after many years. Our results indicate that long term follow up is required because salvage therapy can be successful in the majority of patients.
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Carcinoma de Células Pequeñas/mortalidad , Terapia Neoadyuvante/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Tratamientos Conservadores del Órgano/mortalidad , Terapia Recuperativa , Neoplasias de la Vejiga Urinaria/mortalidad , Administración Intravesical , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
Twenty-two patients with metastatic renal cell carcinoma and removal of the primary tumor were treated with subcutaneous pegylated interferon alfa-2b (PEG-Intron) to evaluate toxicity and efficacy. Start dose was 3.0 microg/kg/week, escalated to 6.0 microg/kg/week. After 2 months, therapy was extended in case of response or stable disease (SD) until progressive disease (PD) or relapse for a maximum of 2 years. National Cancer Institute common toxicity criteria (NCI-CTC) were monitored every 2-4 weeks. After 2 months, nine patients did not continue (8 PD, 1 SD with grade 4 CTC) and 13 extended treatment [three partial response (PR), 10 SD], of these, 11 progressed. One patient with PR developed a durable complete response later. Overall response rate was 13.6% (3/22). Median overall survival is 13 months (range 3-35 months). Dosage was escalated to 6 microg/kg/week in three patients. NCI-CTC grade 2 and 3 required dose attenuation in 12 patients during escalation, and reduction in 10 during the trial. Three patients discontinued because of grade 4 CTC (two fatigue, one hyperglycemia). Fatigue was the major dose-limiting toxicity. These results suggest an efficacy and toxicity of PEG-Intron comparable to standard interferon alfa-2b in patients with mRCC and removal of the primary tumor.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Portadores de Fármacos , Femenino , Humanos , Interferón alfa-2 , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Polietilenglicoles , Proteínas Recombinantes , Tasa de SupervivenciaRESUMEN
OBJECTIVES: To evaluate the feasibility and efficacy of a therapeutic algorithm for the management of small cell carcinoma of the bladder derived from the treatment of small cell lung cancer. METHODS: During a 10-year period, 25 patients (23 men and 2 women; median age 64 years, with 8 [32%] older than 75 years) with small cell carcinoma of the bladder were defined as having limited disease (LD) or extensive disease (ED) in analogy to the classification of small cell lung cancer. Patients with LD were eligible for chemotherapy and sequential radiotherapy. Patients unfit for chemotherapy were offered complete transurethral resection and radiotherapy or cystectomy for large symptomatic tumors. Patients with ED were offered palliative chemotherapy. RESULTS: Of the 25 patients, 17 (68%) had LD and 8 (32%) ED. Without regard to stage, the median survival of those receiving chemotherapy was 15 months versus 4 months for those who did not. The median survival for those with LD was 12 months versus 5 months for those with ED. Nine patients (52.9%) with LD could not undergo chemoradiotherapy because of comorbidity and reduced performance (n = 7), progression (n = 1), or drug-related death (n = 1). Five of those patients underwent TUR and radiotherapy and two cystectomy. CONCLUSIONS: The prognosis of small cell carcinoma of the bladder is poor. This treatment algorithm offers bladder sparing for most patients, with few long-term remissions in patients with small, confined tumors. None of the patients died of locoregional tumor progression, supporting that cystectomy is not the treatment of choice for those with LD. With a significant proportion of elderly patients with comorbidities, chemoradiotherapy was not feasible in more than one half of the patients with LD.