Regression of Rectal Cancer with Radiotherapy with or without Concurrent Capecitabine — Optimising the Timing of Surgical Resection

AimsTo determine tumour regression (volume-halving time) obtained after chemo/radiotherapy, and thereby the ideal interval between the start of treatment and surgery in order to obtain a high rate of complete response.Materials and methodsIn total, 106 patients with cT3,4 rectal cancer who received preoperative radiotherapy alone or concurrently with capecitabine chemotherapy at Nottingham City Hospital, UK were studied. The rectal tumour volume visible on the computed tomography planning scan was compared with the residual pathological volume and the tumour volume-halving time calculated. The radiotherapy response was graded according to the Mandard system.ResultsFifty-three patients had radiotherapy alone, with 53 patients having concurrent chemoradiotherapy. The median tumour volume-halving time was found to be 14 days and not influenced by the addition of chemotherapy. The Mandard score, the interval from the start of treatment to surgery and the tumour volume-halving time were statistically associated with tumour regression. The median tumour volume in our series of 54 cm³ would require an interval of 20 weeks after the start of treatment to surgery to regress to <0.1 cm³ (10 volume-halving times; 140 days).ConclusionsThe initial tumour volume and median volume-halving time provide the best estimates for determining the optimum length of interval between the completion of preoperative chemo/radiotherapy and surgery in locally advanced rectal cancer.     

Study protocol of the Asian XELIRI ProjecT (AXEPT)：a multinational,randomized, non-inferiority,phase III trial of second-line chemotherapy for metastatic colorectal cancer,comparing the effcacy and safety of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab

Background:Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri?weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200mg/m2 on day 1) and capecitabine (1600mg/m2 on days 1–14), repeated every 3weeks, has shown favorable tolerability and effcacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecit?abine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second?line chemotherapy was well tolerated and had promising effcacy in Japanese patients. Methods:The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open?labelled, randomized, phase III clinical trial which was designed to demonstrate the non?inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5?lfuorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second?line chemo?therapy for patients with mCRC. Patients with 20years of age or older, histologically conifrmed mCRC, Eastern Coop?erative Oncology Group performance status 0–2, adequate organ function, and disease progression or intolerance of the ifrst?line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or with?out bevacizumab (5mg/kg on day 1), repeated every 2weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5mg/kg on day 1), repeated every 3weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non?inferiority with a power of 80% at a one?sided α of 0.025, requiring a target sample size of 600 patients. The 95% conifdence interval (CI) upper limit of the hazard ratio was pre?speciifed as less than 1.3. Conclusion:The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second?line treatment option of mCRC.     

What Is the Benefit of Bevacizumab Combined with Chemotherapy in Patients with Recurrent Ovarian,Fallopian Tube or Primary Peritoneal Malignancies?

Abstract

The aim of this retrospective analysis was to investigate the efficacy and adverse effects of the monoclonal anti vascular endothelial growth factor antibody bevacizumab (Avastin^®) combined with chemotherapeutic agents in non-protocol patients with recurrent ovarian, fallopian tube, or primary peritoneal malignancies. Using our data-bases, we identified patients treated with bevacizumab combination therapy since June2005. Responses were evaluated with Response evaluation Criteria in Solid tumorsand serum CA125 Rustin criteria. Toxicity was assessed according to the Commontoxicity Criteria (CTC) v.3.0. Data from 64 patients were included. The median patient age was 58 years, and they had undergone a median of 4.5 (range, 1-10) prior cyto-toxic chemotherapy regimens. The median length of follow-up was 8 months (range, 2-29). The most commonly used combinations were bevacizumab plus taxanes (26.6%) and plus cyclophosphamide (26.6%). A median of 4 cycles of therapy with a medianbevacizumab dose of 3,600 mg (range, 500-18,240) were administered. An overallresponse rate of 21.3% was observed in 13 patients with partial response, and an-other 42.6% of patients had stable disease. Among the patients with elevated pre-treatment serum CA125 concentration, an overall response rate of 46.3% (25/54) was observed according to modification of the Rustin criteria. Fifteen (23.4%) patients had grades 3 or 4 adverse events. Gastrointestinal perforations occurred in 2 (3.1%) patients. Seventeen (26.6%) patients had improved performance status scores. Beva-cizumab combined with chemotherapy showed promising clinical benefits, with significant response of serum CA125 concentration and moderate adverse effects.     

How to deal with giant pituitary adenomas: transsphenoidal or transcranial,simultaneous or two-staged?

Little information has been published in the literature regarding survival outcomes of patients with Ewing’s sarcoma family tumors (ESFTs) of the spine. The purpose of this study is to explore factors that may affect the prognosis of patients with non-metastatic spinal ESFTs. A retrospective analysis of survival outcomes was performed in patients with non-metastatic spinal ESFTs. Univariate and multivariate analyses were employed to identify prognostic factors for recurrence and survival. Recurrence-free survival (RFS) and overall survival (OS) were defined as the date of surgery to the date of local relapse and death. Kaplan–Meier methods were applied to estimate RFS and OS. Log-rank test was used to analyze single factors for RFS and OS. Factors with p values ≤0.1 were subjected to multivariate analysis. A total of 63 patients with non-metastatic spinal ESFTs were included in this study. The mean follow-up period was 35.1 months (range 1–155). Postoperative recurrence was detected in 25 patients, and distant metastasis and death occurred in 22 and 36 patients respectively. The result of multivariate analysis suggested that age older than 25 years and neoadjuvant chemotherapy were favorable independent prognostic factors for RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis were favorable independent prognostic factors for OS. Age older than 25 years and neoadjuvant chemotherapy are favorable prognostic factors for both RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis are closely associated with favorable survival.     

Is dietary fat, vitamin D, or folate associated with pancreatic cancer?

Although potentially modifiable risk factors for pancreatic cancer include smoking, obesity, and diabetes, less is known about the extent to which diet affects cancer risk. Recent studies have demonstrated some consistency for dietary fat being associated with elevated pancreatic cancer risk, particularly from animal sources. However, less is known about which fatty acids pose the greatest risk. Vitamin D, due to its endogenous production following UV-B exposure, is a unique risk factor in that researchers have created several methods to assess its exposure in humans. Studies that measured vitamin D exposure differently have shown inconsistent results. Dietary studies suggest protective associations, whereas studies of circulating 25-hydroxyvitamin D status show null or positive associations with low or very high concentrations, respectively. Several, but not all epidemiologic studies provide evidence of an inverse relationship between total and/or dietary folate and risk of pancreatic cancer. Protective associations for circulating folate are more often observed among populations with inadequate status. This article reviews the current epidemiological and experimental evidence investigating the relationship of dietary fat, vitamin D, and folate with pancreatic cancer. Additionally the mechanisms by which these risk factors may contribute to cancer, the methodological challenges involved with assessing risk, and other obstacles encountered when ascertaining the magnitude and direction of these three exposures are discussed.     

Bladder preservation or complete cystectomy during pelvic exenteration of patients with locally advanced or recurrent rectal cancer,what should we do?

IntroductionIn patients with locally advanced (LARC) or locally recurrent (LRRC) rectal cancer and bladder involvement, pelvic exenteration (PE) with partial (PC) or radical (RC) cystectomy can potentially offer a cure. The study aim was to compare PC and RC in PE patients in terms of oncological outcome, post-operative complications and quality-of-life (QoL).Materials & methodsThis was a retrospective cohort analysis of a prospectively maintained surgical database. Patients who underwent PE for LARC or LRRC cancer with bladder involvement between 1998 and 2021 were included. Post-operative complications and overall survival were compared between patients with PC and RC.Results60 PC patients and 269 RC patients were included. Overall R0 resection was 84.3%. Patients with LRRC and PC had poorest oncological outcome with 69% R0 resection; patients with LARC and PC demonstrated highest R0 rate of 96.3% (P = 0.008). Overall, 1-, 3- and 5-year OS was 90.8%, 68.1% and 58.6% after PC, and 88.7%, 62.2% and 49.5% after RC. Rates of urinary sepsis or urological leaks did not differ between groups, however, RC patients experienced significantly higher rates of perineal wound- and flap-related complications (39.8% vs 25.0%, P = 0.032).ConclusionPC as part of PE can be performed safely with good oncological outcome in patients with LARC. In patients with LRRC, PC results in poor oncological outcome and a more aggressive surgical approach with RC seems justified. The main benefit of PC is a reduction in wound related complications compared to RC, although more urological re-interventions are observed in this group.     

Diagnosis and Treatment Experience of 14 Cases of Breast Cancer Associated with Pregnancy or Lactation

Objective： To explore the diagnosis and treatment experience of breast cancer associated with pregnancy or lactation. Methods： From January 1990 to December 2005, 14 cases with breast cancer associated with pregnancy or lactation were analyzed retrospectively （TNM stage Ⅱ, 2 cases; stage Ⅲ, 11 cases; stage Ⅳ, 1 case）. Diagnosis was established by fine needle aspiration biopsy primarily or routine pathological method if necessary. Abortion was used for discontinuation of pregnancy in 1 case with early pregnancy and 1 case with meddle pregnancy. 2 patients with late pregnancy received cesarean section, 10patients of breast cancer associated with lactation received multidisciplinary and-tumor treatment after discontinuation of lactation. Results： Diagnosis was confirmed by fine noodle aspiration biopsy in 9 cases and by secondary routine pathological method in the other 5 cases, 12 cases were followed up, 1 case of stage Ⅳ died of metastasis 5 months after diagnosis. 3-, 5-year survival rates in 10 cases of stage Ⅲ were 66% and 30% respectively. One case remained alive without recurrence for 8 years up to now. Conclusion： A thorough breast examination is necessary at the first antenatal visit physicians should aggressively pursue work-up in women with a palpable breast tass. In the patients during the second and third trimness, the various modalities available for treatment inholding abortion and their risks and beneath modalities available for treatment including abortion and their risks and benefits must be discussed openly with patients and their families.     

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug–drug interaction potential

Purpose

Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug–drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib’s teratogenic potential warranted a DDI study with oral contraceptives (OCs).

Methods

This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 μg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2–7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).

Results

The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 μM (range 7.93–62.4 μM). Rosiglitazone AUC_0–inf and C _max were similar with concomitant vismodegib [≤8 % change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC_0–inf and C _max (≤5 % change in GMRs; N = 27); norethindrone C _max and AUC_0–inf GMRs were higher (12 and 23 %, respectively) with concomitant vismodegib.

Conclusions

This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.     

Malignancy or inflammation? A case report of a young man with fever of unknown origin

A case of a young man with fever of unknown origin is presented. This diagnosis can be frustrating for both patients and physicians because the diagnostic workup often involves numerous noninvasive and invasive procedures that sometimes fail to explain the fever. In the presented case some of the imaging diagnostic findings suggested malignant hematological disorder. However, histopathological and microbiological investigation proved vertebral osteomyelitis caused by Staphylococcus haemolyticus. Diagnosis was established by positron emission tomography, magnetic resonance imaging, and culture and histopathological analysis of a spinal biopsy. 3 months of antibiotic therapy was curative. Biopsy and microbiological investigation may be necessary in patients with fever, back pain and evidence of a spinal lesion on imaging, even if neoplastic disease is suspected.     

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer

AimThe phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.Patients and methodsA 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.ResultsAll 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a ‘14 days on, 7 days off’ schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.ConclusionCombining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.     

The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination?

Peptide vaccines incorporate one or more short or long amino acid sequences as tumor antigens, combined with a vaccine adjuvant. Thus, they fall broadly into the category of defined antigen vaccines, along with vaccines using protein, protein subunits, DNA, or RNA. They remain one of the most immunogenic approaches, based on measures of T-cell response in the blood or in draining lymph nodes. However, existing peptide vaccines have had limited success at inducing clinical tumor regressions, despite reliable induction of T-cell responses. Several new developments offer promise for improving peptide vaccines, including use of long peptides, optimization of adjuvants including toll-like receptor agonists, and combination with systemic therapies that may reduce tumor-associated immune dysfunction, such as blockade of PD-1/PD-L1 interactions. To apply these new approaches optimally, it will be critical to study their effects in the context of defined antigens, for which peptide vaccines are optimal.     

Treatment of patients with advanced soft tissue sarcoma: disappointment or challenge?

PURPOSE OF REVIEW: We give an overview on the emerging compounds for patients with soft tissue sarcoma. Included are recent developments in targeted therapy, focusing on the following: antiangiogenic and immunomodulatory drugs (e.g. anti-cytotoxic T lymphocyte associated antigen-4 monoclonal antibody), Bcl-2 antisense therapy, raf kinase and mammalian target of rapamycin inhibition, heat shock protein modulators, minor groove binders and other agents being developed. RECENT FINDINGS: Soft tissue sarcomas are a heterogeneous group of tumours that arise predominantly from the embryonic mesoderm. They account for fewer than 1% of all adult malignancies. The prognosis of patients with advanced metastatic soft tissue sarcoma remains poor, with disease-free survival at 5 years below 10%. Complete resection remains the only potentially curative treatment option. Only few chemotherapeutic agents have been identified to be active, with reported response rates for doxorubicin and ifosfamide of around 20%. New strategies are urgently needed to improve outcomes. SUMMARY: Understanding of the molecular biology and pathogenesis of soft tissue sarcomas has been enhanced, and in the near future this should translate into molecular tumour characterization and development of new therapeutic strategies.