Successful Trastuzumab-Deruxtecan Rechallenge After Interstitial Lung Disease: A Case Report.

Trastuzumab deruxtecan (T-DXd) is used to treat human epidermal growth factor receptor 2-positive advanced breast cancer. Interstitial lung disease (ILD) is a severe adverse event associated with T-DXd. Current guidelines recommend permanent discontinuation of T-DXd after Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 ILD. Here, we describe a case of successful rechallenge with T-DXd after CTCAE grade 2 treatment-induced ILD. After discontinuation of T-DXd, ILD was treated with steroids until complete resolution. Given the initial beneficial antitumor response, retreatment was discussed during disease progression. In a shared decision with the patient, T-DXd was restarted at the lowest registered dose, along with low-dose steroids. ILD did not reoccur. Importantly, both clinical and radiological responses to the treatment were observed, with an improvement in the patient's quality of life. This case demonstrates that retreatment with T-DXd after a grade 2 ILD event is feasible and yields clinical benefit.

Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling.

Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.

Prediction of pathologic complete response after single-dose MR-guided partial breast irradiation in low-risk breast cancer patients: the ABLATIVE-2 trial-a study protocol.

BACKGROUND: Partial breast irradiation (PBI) is standard of care in low-risk breast cancer patients after breast-conserving surgery (BCS). Pre-operative PBI can result in tumor downstaging and more precise target definition possibly resulting in less treatment-related toxicity. This study aims to assess the pathologic complete response (pCR) rate one year after MR-guided single-dose pre-operative PBI in low-risk breast cancer patients. METHODS: The ABLATIVE-2 trial is a multicenter prospective single-arm trial using single-dose ablative PBI in low-risk breast cancer patients. Patients ≥ 50 years with non-lobular invasive breast cancer ≤ 2 cm, grade 1 or 2, estrogen receptor-positive, HER2-negative, and tumor-negative sentinel node procedure are eligible. A total of 100 patients will be enrolled. PBI treatment planning will be performed using a radiotherapy planning CT and -MRI in treatment position. The treatment delivery will take place on a conventional or MR-guided linear accelerator. The prescribed radiotherapy dose is a single dose of 20 Gy to the tumor, and 15 Gy to the 2 cm of breast tissue surrounding the tumor. Follow-up MRIs, scheduled at baseline, 2 weeks, 3, 6, 9, and 12 months after PBI, are combined with liquid biopsies to identify biomarkers for pCR prediction. BCS will be performed 12 months after radiotherapy or after 6 months, if MRI does not show a radiologic complete response. The primary endpoint is the pCR rate after PBI. Secondary endpoints are radiologic response, toxicity, quality of life, cosmetic outcome, patient distress, oncological outcomes, and the evaluation of biomarkers in liquid biopsies and tumor tissue. Patients will be followed up to 10 years after radiation therapy. DISCUSSION: This trial will investigate the pathological tumor response after pre-operative single-dose PBI after 12 months in patients with low-risk breast cancer. In comparison with previous trial outcomes, a longer interval between PBI and BCS of 12 months is expected to increase the pCR rate of 42% after 6-8 months. In addition, response monitoring using MRI and biomarkers will help to predict pCR. Accurate pCR prediction will allow omission of surgery in future patients. TRIAL REGISTRATION: The trial was registered prospectively on April 28th 2022 at clinicaltrials.gov (NCT05350722).

[Clinical efficiency research with expensive drugs: doing more with less investment]. / Doelmatigheidsonderzoek naar dure geneesmiddelen.

Novel innovative drugs have improved disease control, survival and quality of life for many patients. The costs of these drugs, however, are extremely high and threaten the long-term affordability of our health care system. Efficient use of existing drugs can decrease drug expenditure whilst improving patients' quality of life at the same time. Efficiency adjustments should not compromise treatment efficacy and therefore, clinical research on the matter is crucial. In this article, we demonstrate that efficiency research is feasible, as exemplified by the SONIA study. We make the case for a 'revolving fund' in which savings from one study are used to fund a next one. A revolving fund thus stimulates efficiency research and capitalizes research investments in the interest of both patients and society.

Post-operative re-irradiation with hyperthermia in locoregional breast cancer recurrence: Temperature matters.

PURPOSE: To investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with postoperative re-irradiation and hyperthermia. METHODS: In this retrospective study, 112 women with resected locoregional recurrent breast cancer treated in 2010-2017 with postoperative re-irradiation 8frx4Gy (n = 34) or 23frx2Gy (n = 78), combined with 4-5 weekly hyperthermia sessions guided by invasive thermometry, were subdivided into 'low' (n = 56) and 'high' TD (n = 56) groups by the best session with highest median cumulative equivalent minutes at 43 °C (Best CEM43T50) < 7.2 min and ≥7.2 min, respectively. Actuarial LRC, OS and late toxicity incidence were analyzed. Backward multivariable Cox regression and inverse probability weighting (IPW) analysis were performed. RESULTS: TD subgroups showed no significant differences in patient/treatment characteristics. Median follow-up was 43 months (range 1-107 months). High vs. low TD was associated with LRC (p = 0.0013), but not with OS (p = 0.29) or late toxicity (p = 0.58). Three-year LRC was 74.0% vs. 92.3% in the low and high TD group, respectively (p = 0.008). After three years, 25.0% and 0.9% of the patients had late toxicity grade 3 and 4, respectively. Multivariable analysis showed that distant metastasis (HR 17.6; 95%CI 5.2-60.2), lymph node involvement (HR 2.9; 95%CI 1.2-7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8-11.6) and TD (low vs. high; HR 4.1; 95%CI 1.4-11.5) were associated with LRC. TD was associated with LRC in IPW analysis (p = 0.0018). CONCLUSIONS: High thermal dose (best CEM43T50 ≥ 7.2 min) was associated with significantly higher LRC for patients with locoregional recurrent breast cancer treated with postoperative re-irradiation and hyperthermia, without augmenting toxicity.

Predicting outcome in older patients with cancer: Comprehensive geriatric assessment and clinical judgment.

OBJECTIVES: Comprehensive Geriatric Assessment (CGA) has been incorporated into geriatric oncology to prevent unfavorable outcome from anticancer treatment. This study determined the value of CGA and medical oncologist's clinical judgment in predicting unfavorable outcome and explored whether treatment decisions can be based on CGA. PATIENTS AND METHODS: In this prospective cohort study, a multidomain CGA was performed by a geriatric nurse and geriatrician in 110 consecutive patients aged ≥70 years, newly referred to a multidisciplinary oncology clinic. CGA domains included comorbidity, polypharmacy, mood, cognition, nutrition, functionality and physical performance. Medical oncologist's clinical judgment on expected tolerance of standard treatment was noted (N = 62). Unfavorable outcome was defined as any ≥grade three chemotherapy toxicity, dose reduction, postponement of treatment, death before start of treatment and early progression before first evaluation of treatment (N = 80). RESULTS: CGA identified multidomain problems in 77 out of 110 patients (70.0%) and the medical oncologist had doubts about standard treatment tolerance in 30 out of 62 patients (48.4%). Unfavorable outcome occurred in 48 out of 80 patients (60%) who received anticancer treatment but could not be predicted by CGA, medical oncologists' clinical judgment or their combination. There was discrepancy between CGA and clinical judgment in 24 out of 62 patients (38.7%). CONCLUSION: Neither CGA, medical oncologist's clinical judgment or a combination could predict unfavorable outcome in our heterogeneous sample. CGA and clinical judgment did not align in more than one-third of patients.

Clinical management of emotions in patients with cancer: introducing the approach "emotional support and case finding".

The current approach to the management of emotions in patients with cancer is "distress screening and referral for the provision of psychosocial care." Although this approach may have certain beneficial effects, screening and referral programs have shown a limited effect on patient psychological well-being. We argue that this limited effect is due to a mismatch between patient needs and the provision of care, and that a fundamental reconceptualization of the clinical management of emotions in patients with cancer is needed. We describe the rationale and characteristics of "emotional support and case finding" as the approach to the management of emotions in patients with cancer. The two main principles of the approach are: (1) Emotional support: (a) The treating team, consisting of doctors, nurses, and allied health staff, is responsive to the emotional needs of patients with cancer and provides emotional support. (b) The treating team provides information on external sources of emotional support. (2) Case finding: The treating team identifies patients in need of mental health care by means of case finding, and provides a referral to mental health care as indicated. We present a novel perspective on how to organize the clinical management of emotions in patients with cancer. This is intended to contribute to a fruitful discussion and to inform an innovative research agenda on how to manage emotions in patients with cancer.

High ctDNA molecule numbers relate with poor outcome in advanced ER+, HER2- postmenopausal breast cancer patients treated with everolimus and exemestane.

We determined whether progression-free survival (PFS) in metastatic breast cancer (MBC) patients receiving everolimus plus exemestane (EVE/EXE) varies depending on circulating tumour DNA (ctDNA) characteristics. Baseline plasma cell-free DNA (cfDNA) from 164 postmenopausal women with ER-positive, HER2-negative MBC refractory to a nonsteroidal aromatase inhibitor and treated with standard EVE/EXE (Everolimus Biomarker Study, Eudract 2013-004120-11) was characterised for 10 relevant breast cancer genes by next-generation sequencing with molecular barcoding. ctDNA molecule numbers, number of mutations and specific variants were related with PFS and overall survival (OS). Missense hotspot mutations in cfDNA were detected in 125 patients. The median of 54 ctDNA molecules per mL plasma distinguished patients with high and low/no ctDNA load. Patients with low/no ctDNA load (N = 102) showed longer median PFS of 5.7 months (P = 0.006) and OS of 124.8 months (P = 0.008) than patients with high ctDNA load (N = 62; 4.4 months and 107.7 months, respectively) in multivariate analyses. Patients with < 3 specific mutations (N = 135) had longer median PFS of 5.4 months compared to those with ≥ 3 mutations (3.4 months; P < 0.001). In conclusion, MBC patients with low/no ctDNA load or < 3 hotspot mutations experience longer PFS while treated with EVE/EXE.

Screening and Stepped Care Targeting Psychological Distress in Patients With Metastatic Colorectal Cancer: The TES Cluster Randomized Trial.

BACKGROUND: This study evaluated the effectiveness of a screening and stepped care program (the TES program) in reducing psychological distress compared with care as usual (CAU) in patients with metastatic colorectal cancer starting with first-line systemic palliative treatment. PATIENTS AND METHODS: In this cluster randomized trial, 16 hospitals were assigned to the TES program or CAU. Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale and the Distress Thermometer/Problem List (at baseline and 10 and 18 weeks). Stepped care was offered to patients with distress or expressed needs, and it consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental healthcare. The primary outcome was change in psychological distress over time, and secondary outcomes were quality of life, satisfaction with care, and recognition and referral of distressed patients by clinicians. Linear mixed models and effect sizes were used to evaluate differences. RESULTS: A total of 349 patients were randomized; 184 received the TES program and 165 received CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress, 26.1% of which entered the stepped care program (14.7% used only watchful waiting and 11.4% used at least one of the other treatment steps). The observed low use of the TES program led us to pursue a futility analysis, which showed a small conditional power and therefore resulted in halted recruitment for this study. No difference was seen in change in psychological distress over time between the 2 groups (effect size, -0.16; 95% CI, -0.35 to 0.03; P>.05). The TES group reported higher satisfaction with the received treatment and better cognitive quality of life (all P<.05). CONCLUSIONS: As a result of the low use of stepped care, a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer did not improve psychological distress. Our results suggest that enhanced evaluation of psychosocial concerns may improve aspects of patient well-being.

Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands.

OBJECTIVE: To investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population. DESIGN: Retrospective, nationwide cohort study. SETTING: Specialised tertiary gender clinic in Amsterdam, the Netherlands. PARTICIPANTS: 2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment. MAIN OUTCOME MEASURES: Incidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people. RESULTS: The total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5). CONCLUSIONS: This study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.

Predictors for use of psychosocial services in patients with metastatic colorectal cancer receiving first line systemic treatment.

BACKGROUND: Patients with advanced disease experience high levels of psychological distress, yet there is low uptake of psychosocial services offered to patients who screened positive for distress. In this study we aimed to identify predictors for use of psychosocial services in patients with metastatic colorectal cancer (mCRC) receiving first line chemotherapy enrolled in a prospective cluster randomized trial (CRT). METHODS: Patients completed measures on psychological distress, physical distress, and quality of life at baseline. Demographics, clinical characteristics at baseline and clinical events during treatment (e.g. severe adverse events, clinical benefit) were extracted from patient records. Patients reported psychosocial service utilization in- and outside the hospital after 10, 24 and 48 weeks of treatment. Multivariable logistic regression models were used to identify predictors for the use of psychosocial services. RESULTS: Out of 349 patients, seventy patients (20.0%) used psychosocial support services during the follow-up period. Use of psychosocial services was associated with younger age, a higher educational level, presence of more pain (at baseline), and the expressed need to talk to a professional (at baseline). In addition, patients without progressive disease within the first ten weeks of treatment were more likely to use psychosocial services . CONCLUSIONS: One in five patients with mCRC receiving first line palliative treatment used psychosocial services during this prospective longitudinal CRT. Sociodemographic factors (age, education), clinical factors (pain and no progressive disease) and the expressed need to talk to a professional predicted use of psychosocial services. Identification of these predictors may contribute to the understanding of factors that determine the need for psychosocial services. TRIAL REGISTRATION: Netherlands Trial Register NTR4034 .

Impact of Patient- and Clinician-Reported Cumulative Toxicity on Quality of Life in Patients With Metastatic Castration-Naïve Prostate Cancer.

Background: Current toxicity evaluation is primarily focused on high-grade adverse events (AEs) reported by clinicians. However, the cumulative effect of multiple lower-grade AEs may also impact patients' quality of life (QoL). Further, patient-reported toxicity may be more representative of patients' treatment experiences. This study aimed to determine whether cumulative toxicity comprising all-grade AEs is more associated with QoL than cumulative toxicity comprising high-grade AEs only, and whether patient-reported cumulative toxicity is more associated with QoL than clinician-reported cumulative toxicity. Methods: Patients with metastatic castration-naïve prostate cancer participating in the phase III GETUG-AFU 15 trial completed questionnaires on AEs (at 3 and 6 months) and QoL (at baseline and 3 and 6 months). Clinicians reported AEs during clinical visits. Cumulative toxicity scores were calculated for clinicians and patients in 3 ways: total number of high-grade AEs, total number of all-grade AEs, and total number of all AEs multiplied by their grade (severity score). Relationships between cumulative toxicity scores and QoL were studied using longitudinal regression analyses; unstandardized (B) and standardized regression coefficients (ß) are reported. Results: Of 385 patients, 184 with complete QoL and toxicity data were included. Clinician-reported all-grade AEs (B, -2.2; 95% CI, -3.3 to -1.1; P<.01) and severity score (B, -1.4; 95% CI, -2.2 to -0.7; P<.01) were associated with deteriorated physical QoL, whereas the total number of high-grade AEs was not. All patient-reported scores were significantly (P<.01 for all) associated with deteriorated physical and global QoL. Standardized regression coefficients indicated that patient-reported toxicity scores were more associated with QoL outcomes than clinician-reported scores, with the strongest association found for the all-grade AEs and severity cumulative toxicity scores. Conclusions: Patient- and clinician-based cumulative toxicity scores comprising all-grade AEs better reflect impact on patient QoL than toxicity scores comprising high-grade AEs only. To assess the effect of toxicity on QoL, patient-reported cumulative toxicity scores are preferred.

Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials.

PURPOSE: Delayed chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of moderately emetogenic chemotherapy not containing anthracyclines and cyclophosphamide (non-AC MEC). In this review, we summarize current literature to update recommendations for delayed CINV prophylaxis after non-AC MEC. METHODS: We conducted a systematic search in PubMed and conference proceedings from ASCO, ESMO, and MASCC. Included randomized controlled trials (RCTs) aimed to prospectively evaluate the efficacy of two or more antiemetic strategies in the prevention of delayed CINV after the administration of non-AC MEC. At least one of the following endpoints was used: complete response, complete control, no nausea, no vomiting, and/or no use of rescue medication. RESULTS: Our search provided 247 publications. Nine met the predefined criteria. Included RCTs reported outcomes on palonosetron, aprepitant, casopitant, netupitant/palonosetron (NEPA), olanzapine, and megestrol acetate. CONCLUSIONS: Superiority of palonosetron over first-generation 5-HT3 receptor antagonists for the prevention of acute and delayed CINV after non-AC MEC has not been proven. The addition of an NK1 receptor antagonist to first-generation 5-HT3 receptor antagonists does not significantly improve the incidence of delayed CINV after non-AC MEC. The efficacy of a single-day regimen of dexamethasone with palonosetron is non-inferior to multiday dexamethasone. NEPA, olanzapine, and megestrol acetate show highly effective complete response (CR) rates.

Screening and treatment of psychological distress in patients with metastatic colorectal cancer: study protocol of the TES trial.

BACKGROUND/INTRODUCTION: Psychological distress occurs frequently in patients with cancer. Psychological distress includes mild and severe forms of both anxious and depressive mood states. Literature indicates that effective management of psychological distress seems to require targeted selection of patients (T), followed by enhanced care (E), and the application of evidence based interventions. Besides, it is hypothesized that delivering care according to the stepped care (S) approach results in an affordable program. The aim of the current study is to evaluate the (cost)-effectiveness of the TES program compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC). METHODS: This study is designed as a cluster randomized trial with 2 treatment arms: TES program for screening and treatment of psychological distress versus usual care. Sixteen hospitals participate in this study, recruiting patients with mCRC. Outcomes are evaluated at the beginning of chemotherapy and after 3, 10, 24, and 48 weeks. Primary outcome is the difference in treatment effect over time in psychological distress, assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes include quality of life, patient evaluation of care, recognition and management of psychological distress, and societal costs. DISCUSSION: We created optimal conditions for an effective screening and treatment program for psychological distress in patients with mCRC. This involves targeted selection of patients, followed by enhanced and stepped care. Our approach will be thoroughly evaluated in this study. We expect that our results will contribute to the continuing debate on the (cost-) effectiveness of screening for and treatment of psychological distress in patients with cancer. TRIAL REGISTRATION: This trial is registered in the Netherlands Trial Register NTR4034.

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study.

BACKGROUND: Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. METHODS: Fourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS. RESULTS: The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole. CONCLUSION: Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study.

PURPOSE: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. EXPERIMENTAL DESIGN: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. RESULTS: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. CONCLUSION: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies.

The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial.

PURPOSE: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma. METHODS: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; α = 0.05; ß = 0.10). RESULTS: Thirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm. CONCLUSION: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients.

PURPOSE: To better understand the mechanisms underlying (in)sensitivity of tumors to anticancer drugs, assessing intra-tumor drug pharmacokinetics (PKs) could be important. We explored the feasibility of microdialysis in tumor tissue for multiple days in a clinical setting, using carboplatin as model drug. METHODS: Plasma and microdialysate samples from tumor and adipose normal tissues were collected up to 47 h after dosing in eight carboplatin-treated patients with an accessible (sub)cutaneous tumor. RESULTS: Pharmacokinetics were evaluable in tumor tissue in 6/8 patients and in adipose normal tissue in 3/8 patients. Concentration-time curves of unbound platinum in both the tissues followed the pattern of the curves in plasma, with exposure ratios of tissue versus plasma ranging from 0.64 to 1.46. CONCLUSIONS: Microdialysis can be successfully employed in ambulant patients for multiple days, which enables one to study tissue PK of anticancer drugs in normal and malignant tissues in more detail.

213Bi-[DOTA0, Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model.

PURPOSE: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated. EXPERIMENTAL DESIGN: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model. RESULTS: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02). CONCLUSIONS: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.