Blood Cytokine Analysis Suggests That SARS-CoV-2 Infection Results in a Sustained Tumour Promoting Environment in Cancer Patients.

Cytokines, chemokines, and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to a worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically, whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n = 54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n = 42). Of the 35 CCGs, 19 were common to both the solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n = 52). Of these, TNF-α, IFN-ß, TSLP, and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data demonstrate a need for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.

The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: A systematic review and meta-analysis of randomized and non-randomized trials.

BACKGROUND: Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy. OBJECTIVE: The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer. METHODS: A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors. RESULTS: The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%-31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28-26.62, P ≤.001). CONCLUSION: ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.

The predictive value of sentinel node biopsy in early breast cancer after neo-adjuvant chemotherapy: A prospective study.

OBJECTIVE: A sentinel Node (SN) has replaced axillary lymph node dissection (ALND) in patients with clinically node negative axilla (cN0). SN after Neo-adjuvant chemotherapy (NACT) is feasible but not accurate in clinically node positive (cN1-3) patients. The goal of this study is to determine the negative predictive value (NPV) of SN in cN0 breast cancer after NACT. A secondary endpoint is to determine if ALND can be avoided after NACT regardless of the pre-treatment clinical staging of the axilla, in case of a normalization of the 18F-fluoro-2-deoxy-glucose positron emission tomography scan (PET-CT scan). DESIGN: A single institution prospective study regarding the negative predictive value of the SN in breast cancer after NACT was conducted in the Multidisciplinary Breast Clinic of the Antwerp University Hospital from 29/03/2010 until 01/12/2015 (Study number: B30020108368). Inclusion criteria for study participation were: breast cancer, age above 18 years, female, tumor stages T2-T4 N0-3 or T1N1-N3. All patients were staged by a mammography, ultrasound of the axilla, MRI of the breast, PET-CT scan and bone scintigraphy. They received NACT consisting of 12 cycles of paclitaxel or 4 cycles of docetaxel followed by dose dense doxorubicin or epirubicin/cyclofosfamide or vice versa as a standard initial treatment. After 6 weeks, a PET-CT scan was performed for early tumour response evaluation. At the day of operation, a 99mTC-labelled nanocolloid was used to identify the SN. During the surgery the SN were removed separately together with a complete ALND. RESULTS: A total of 150 patients were enrolled in our study of which 129 were eligible for analysis. 53 patients had a positive SN of which 32 have a positive axillary lymph nodes (ALN), positive predictive value (PPV) was 60%; 76 patients had a negative SN of which 6 had a positive ALN (NPV 92%). The sensitivity is 84% and the specificity 76% with a false omission rate (FOR) of 8%. In total 45 patients ALN were clinical negative and no suspect lymph nodes were seen on ultrasound, MRI and PET-CT scan) and 45 patients had negative a SN, with no ALN and 2 patients had a positive SN of which 1 patients had axillary involvement (NPV 100%). The FOR of cN1: 5%, cN2: 37%, cN3 33%. A total of 22 patients out of 84 patients (26%) of which 15/49 cN1 (30%), 6/23 (26%) cN2, 1/12 (8%) have after 6 weeks of chemotherapy and normalization on PET-CT scan. A total of 17 patients had a negative SN and ALN. The FOR was in this group was 0%. CONCLUSION: A SNB should become the standard after NACT if case of a cN0. If after NACT the PET CT has normalized, no ALND should be performed if the SN is negative.

Subcutaneous trastuzumab (Herceptin) versus intravenous trastuzumab for the treatment of patients with HER2-positive breast cancer: A time, motion and cost assessment study in a lean operating day care oncology unit.

OBJECTIVE: The subcutaneous (SC) formulation of trastuzumab represents an alternative to the intravenous (IV) infusion in the treatment of patients with HER2-positive metastatic and early breast cancer. We compared the two formulations in terms of time and cost differential. STUDY DESING: We conducted a time, motion and cost assessment study in a lean operating day care oncology unit to determine and compare the time and costs of trastuzumab SC versus IV administration in patients with HER2-positive breast cancer. Outcomes were the mean costs and the mean dedicated time of the health care professional (HCP) and patient chair time. Direct observation methodology was applied to collect data and statistical analysis was performed. RESULTS: The total preparation and administration time for trastuzumab IV was 4.07 times longer than the total time required for the trastuzumab SC administration. The total patient time spent in the day care oncology unit (in minutes) was 71% shorter with using SC administration. IV administration costs € 50.4 ($54,89) more in HCP time and consumable supplies and €162.53 ($177.00) of drug wastage. SC administration was associated with a total time saving of 53.7min for the HCPs and 122.5min for the patients. The administration of trastuzumab SC was translated in a cost saving of €212.93 ($231.73) per patient episode compared to trastuzumab IV, which could lead to a total potential saving of €3,832.74 ($4,171.06) over a full course of treatment (18 cycles) CONCLUSION: SC administration of trastuzumab was associated with a substantial reduction in active HCP time, patient chair time, unit time, and overall cost. These time and cost could be used to increase capacity within existing resources in a lean operating day dare oncology unit.

Neoadjuvant systemic therapy in breast cancer: Challenges and uncertainties.

The management of locally advanced breast cancer (LABC) remains a major clinical issue, despite progress achieved in diagnosis and therapy. Preoperative or neoadjuvant therapy has gained interest since breast cancer has been regarded as a systemic disease. Comparing adjuvant versus neoadjuvant treatment, the neoadjuvant approach offers the advantage of downstaging the disease and testing the efficacy of therapy administered to patients. A large number of clinical trials have attempted to define the optimal neoadjuvant treatment, but little attention has been paid to the sequence of chemotherapy. Moreover, the integration of antibodies against Human Epidermal Receptor-2 (HER-2) and other biological therapies that may improve the long-term control of breast cancer patients, have a special clinical interest. In this review, we will discuss these topics attempting to answer the questions why, when and which regimen to use for patients with LABC. Especially, the introduction of the platina derivatives in neoadjuvant trials with their exceptional high pathological complete response rates are challenging to rethink the optimal treatment options in early and locally advanced breast cancer.

A clitoral verrucous carcinoma in an area of lichen planus has aggressive features.

BACKGROUND: Verrucous carcinoma of the vulva is extremely rare. It is a slow growing, low malignant variant of a squamous cell carcinoma with a cauliflower appearance. Women with lichen planus have an increased risk of developing vulval cancer. CASE PRESENTATION: A 79-year-old woman consulted for vulval itching. On clinical examination, a 3-cm large verrucous clitoral cancer in an area of lichen planus was seen. Based on her last clinical examination, the growth was estimated to be 1 cm2 per month with an invasion depth after 6 months of 5 mm. A tumor developing in an area of lichen planus appears to have more aggressive features. This is the first time that the growth of a verrucous carcinoma has been documented in an area of lichen planus. CONCLUSIONS: Clinicians and patients should be aware of the aggressive behavior of cancers developing in areas of lichen planus and adjust their surgical management together with the follow-up strategy.

Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.

BACKGROUND: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. METHODS: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. FINDINGS: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). INTERPRETATION: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.

Fine tuning of the Van Nuys prognostic index (VNPI) 2003 by integrating the genomic grade index (GGI): new tools for ductal carcinoma in situ (DCIS).

Ductal carcinoma in situ (DCIS) is considered a heterogeneous premalignant condition of the breast with a certain probability for progressing to malignancy. There is no standard of care. The updated Van Nuys Prognostic Index (VNPI) 2003 is a clinical tool in treatment decision making. This study assessed the prognostic value of the VNPI after integration of proliferative biomarkers (GGI and Ki-67). DCIS samples were divided into three VNPI subgroups (low risk [score 4-6], intermediate risk [score 7-9], high risk [score 10-12]) based on nuclear grade ± necrosis, tumor size, margin width, and age. Nuclear grade was substituted by the genomic grade index (GGI) to generate the VNPI-GGI and combined with the Ki-67 to generate the VNPI-Ki67. Disease-free survival was calculated by Kaplan-Meier survival plots with log-rank significance. Multiple regression analysis was carried out using Cox proportional hazard regression analysis. A total of 88 cases (median age 54 years) with representative tissue were identified out of 168 DCIS patients. Median follow-up was more than 5 years. Ten patients developed an ipsilateral recurrence of whom nine were invasive: six patients were classified in the VNPI subgroup 2 and three patients in the VNPI subgroup 3. One non-invasive recurrence (DCIS) was classified in the VNPI subgroup III. A statistical association was observed between a high VNPI score and a higher risk of recurrence (HR = 7.72 [95% CI 1.01-58.91], p = 0.049). Ki-67 did not improve the prognostic value of VNPI (HR = 6.5, [95% CI 0.80-53.33], p = 0.08). In contrast, the VNPI-GGI could identify more accurately high-risk DCIS patients with early relapses within 5 years (HR = 18.14 [95% CI 1.75-188], p = 0.015). GGI incorporated into the VNPI improved its prognostic value for DCIS, especially for identifying early relapses. This method should be validated and incorporated in future prospective clinical DCIS trials.

RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

PURPOSE: The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162). METHODS: The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation. RESULTS: A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5). CONCLUSIONS: Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Single-agent docetaxel, administered as a 3-weekly infusion has encouraging clinical activity against squamous cell carcinoma of the head and neck (SCCHN). Weekly administration of docetaxel is feasible and showed a favorable toxicity profile in phase I studies. We studied a weekly docetaxel regimen in heavily pretreated patients with head and neck cancer. PATIENTS AND METHODS: A total of 30 patients with proven metastatic or recurrent SCCHN were treated with docetaxel 36 mg/m weekly for 6 weeks in an 8-week schedule. Dexamethasone 20 mg or methylprednisolone 32 mg was administered 12 and 3 hours before docetaxel. No prophylactic antibiotics or growth factors were given. The primary end point was objective response rate and the secondary end points included time to progression and overall survival. RESULTS: Patients received a median of 6 administrations (range, 1-27). A partial response was documented in 2 patients (6.7%). The disease control rate defined the percentage of patients with responding or stable disease was 33.3%. The median progression-free survival was 7.4 weeks (95% confidence interval, 5.5-9.3 weeks) and the median overall survival was 17.9 weeks (95% confidence interval, 10.1-25.6 weeks). There were no episodes of grade 4 neutropenia, thrombocytopenia, or nonhematological toxicity. CONCLUSIONS: Weekly docetaxel at a dose of 36 mg/m has a mild to moderate toxicity profile in SCCHN patients. However, the response rate in predominantly pretreated patients is low and the overall survival is short.

Prognostic value of bone scintigraphy in cancer patients with osteonecrosis of the jaw.

PURPOSE OF THE REPORT: identifying imaging predictors of healing of osteonecrosis of the jaw (ONJ) in cancer patients may assist in better stratification of treatment strategies. MATERIALS AND METHODS: patients with ONJ were followed prospectively and underwent bone scintigraphy, both planar and single-photon emission computed tomography (SPECT) imaging. End points were time to healing and the number of recurrences. Studied parameters included lesion visibility, pattern of uptake, and quantification of uptake relative to the unaffected side. RESULTS: a total of 22 patients were recruited (3 men; 19 women) with a stage 1 ONJ lesion in 8, stage 2 in 9, and stage 3 ONJ in 5 patients. Median duration of follow-up was 12 months (range, 6-37). SPECT acquisitions proved superior over planar images in detecting ONJ lesions (P = 0.03). Quantification of tracer uptake in the ONJ lesion relative to the unaffected side showed increasing uptake with higher stages of ONJ: mean, 1.67 (95% confidence interval [CI], 1.17-2.18) in stage 1, 2.72 (95% CI, 2.24-3.20) in stage 2, and 4.62 (95% CI, 3.98-5.26) in stage 3. In addition, this relative ratio of uptake was found to be an independent predictor of ONJ healing (hazard ratio, 0.24; 95% CI, 0.07-0.82; P = 0.02). Neither ONJ stage nor relative ratio of uptake were predictors of the occurrence of ONJ relapses. CONCLUSIONS: bone scintigraphy in patients with ONJ is feasible and SPECT acquisitions are preferred over planar images. Relative quantification of tracer uptake provides prognostic information independent of clinical stage that may assist in identifying patients with a poor prognosis.

Scintigraphic evaluation of mandibular bone turnover in patients with solid tumors receiving zoledronic acid.

Bisphosphonates (BP) have been associated with the occurrence of osteonecrosis of the jaw (ONJ), possibly by causing an excessive bone turnover inhibition. However, little in vivo evidence exists to support this theory. The (99m)Tc-medronate scintigrams of patients with skeletal metastases and BP use (n=40) were individually matched with cancer patients without BP exposure (n=40) and controls with neither malignancy nor BP use (n=40). Patients with established ONJ or intense focal abnormalities in the studied regions were excluded. Mandibular (MBT) bone turnover was quantified relative to the femur by defining regions-of-interest with correction for background activity. The patients with BP exposure (34 female, 6 male) had a median age of 63 years (range 25-81) and received a median number of 11 zoledronic acid administrations (range 1-44). Most patients suffered from breast cancer (n=30). The mean ratio of the MBT in cancer patients with BP use over non-users was 0.88 (95% CI 0.80-0.96; p=0.003), and 0.83 (95% CI 0.73-0.94; p=0.001) when BP using oncological patients were compared with controls without malignancy or BP use. The ratio of MBT's between BP naive patients was 0.95 (95% CI 0.83-1.07; p=0.8). No dose-response effect between the number of BP administrations and MBT could be demonstrated (r=0.02; p=0.9). These findings suggest that, relative to the femur, BP exert a stronger effect on mandibular bone turnover, which strengthens the hypothesis that the inhibition of bone turnover may be important in the pathophysiology of ONJ.

Docetaxel, ifosfamide and cisplatin in solid tumour treatment: a phase I study.

Docetaxel, ifosfamide and cisplatin have proven activity in a broad range of solid tumours and interfere with different phases of the cell cycle. We performed a phase I study with the aim to determine the maximum tolerated dose (MTD) of docetaxel, ifosfamide and cisplatin in patients with solid tumours and to define the safety, dose-limiting toxicity (DLT) and the recommended dose and administration schedule of docetaxel, ifosfamide and cisplatin for further phase II testing. Docetaxel was given by 1-h infusion on day 1, followed by ifosfamide 1000 mg/m(2)/day as a continuous infusion for 5 days. Mesna was added at the same doses to the same infusion bag and was continued for 12 h after the end of ifosfamide. Cisplatin was administered as a 24-h infusion concomitantly with ifosfamide, but in separate infusion bags, either on day 5 (schedule A) or on day 1 (schedule B). Escalation steps were planned only for docetaxel (60, 75, 85 mg/m(2)) and cisplatin (50, 75, 100 mg/m(2)). No intrapatient dose escalation was permitted. Prophylactic ciprofloxacin was used after a protocol amendment was implemented. No prophylactic haematopoietic growth factors were used. Cycles of docetaxel, ifosfamide and cisplatin were given at 3-week intervals. Toxicity was scored according to National Cancer Institute Canada-Common Toxicity Criteria 2. The MTD was defined as the dose at which a DLT was observed in fewer than two of six patients during the first treatment cycle. In total, 85 patients received 309 cycles. Only three escalation steps could be explored and DLTs were observed at each dose level. In total, 32 patients and 49 cycles showed DLTs. Febrile neutropenia occurred in 20 patients (24%). Only two DLTs were nonhaematological (one cerebral infarction and one encephalopathy grade 4). Neutropenia grade 4 lasted for greater than 7 days and/or thrombocytopenia grade 4 was dose limiting in 10 patients. Febrile neutropenia occurred in five of 41 patients (12%) who received prophylactic ciprofloxacin and in 15 of 44 patients (34%) who did not. MTD was reached at level 3 (docetaxel, 75 mg/m(2) and cisplatin, 75 mg/m(2)). With a lower dose of docetaxel (60 mg/m(2)) both schedules A and B were feasible, although, overall, schedule A seemed to be better tolerated. On the basis of this phase I study, the recommended docetaxel, ifosfamide and cisplatin regimen is docetaxel (60 mg/m(2)) on day 1, ifosfamide (1000 mg/m(2)/day) on days 1-5 and cisplatin (75 mg/m(2)) given on day 5. It is associated with substantial haematological toxicity, but this is feasible provided prophylactic antibiotics are used.

A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Concomitant chemotherapy and radiotherapy (chemoradiation; CRT) is the standard treatment for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). CRT improves local control and overall survival (OS) when compared to radiotherapy (RT) alone. Induction chemotherapy (IC) reduces the risk of distant metastases (DM) and improves OS by 5% with the use of cisplatin/infusional 5 fluorouracil (PF) in meta-analysis. Adding a taxane to PF in the IC regimen confers a better outcome. Sequential treatment (ST) of IC followed by CRT is therefore under active investigation in multiple phase III trials. METHODS: We compared the outcome of two cohorts of patients (pts) with LA-SCCHN treated at our institution with CRT (n = 27) or ST (n = 31), respectively. CRT consisted of GEM 100 mg/m2 weekly + conventional RT (70 Gy); ST consisted of the same CRT preceded by platinum-based IC. RESULTS: Response to IC: complete 8 (26%), partial 20 (65%), stable 1, progressive 1, not evaluable 1. Median follow up of the surviving pts: for CRT 73 months, for ST 51 months. Median time to distant metastasis (TDM) was for CRT 23.6 months, for ST not reached. Median OS was for CRT 20.2 months, for ST 40.2 months. Cox regression analysis, taking into account age, T and N stage and tumor site, showed a hazard ratio with ST of 1.190 for time to locoregional failure (p = 0.712), 0.162 for TDM (p = 0.002), and 0.441 for overall survival (OS) (p = 0.026). CONCLUSION: TDM and OS were found significantly longer in the ST cohort without a reduced locoregional control. Notwithstanding the limitations of a non-randomized single-center comparison, the results are in line with very preliminary data of randomized comparisons suggesting an improved outcome with ST.

Prognostic significance of oncogenic markers in ductal carcinoma in situ of the breast: a clinicopathologic study.

Ductal carcinoma in situ (DCIS) is a heterogeneous malignant condition of the breast with an excellent prognosis. Until recently mastectomy was the standard treatment. As the results of the National Surgical Adjuvant Breast and Bowel Project-17 trial and the introduction of the Van Nuys Prognostic Index (VNPI) less radical therapies are used. Objectives are to identify clinicopathologic and biologic factors that may predict outcome. Cases of DCIS diagnosed in two Belgian University Centers were included. Paraffin-embedded material and Hematoxylin and Eosin stained slides of DCIS cases were reviewed and tumor size, margin width, nuclear grade, and comedo necrosis were assessed. Molecular markers (estrogen receptor, progesterone receptor, HER1-4, Ki67, and c-myc) were assayed immunohistochemically. Applied treatment strategies were correlated with the prospective use of the VNPI score. Kaplan-Meier survival plots were generated with log-rank significance and multiple regression analysis was carried out using Cox proportional hazards regression analysis; 159 patients were included with a median age of 54 years (range 29-78); 141 had DCIS and 18 DCIS with microinvasion. The median time of follow-up was 54 months (range 5-253). Twenty-three patients developed a recurrence (14.5%). The median time to recurrence was 46 months (range 5-253). Before the introduction of the VNPI, 37.5% of the DCIS patients showed a recurrence while thereafter 6.7% recurred (p < 0.005). Two recurrences occurred in the VNPI group I (7.1%); seven in the VNPI group II (8.5%) (median time to recurrence 66.3 months) and 14 in the VNPI group III (28.5%) (median time to recurrence 40.2 months) (disease-free survival [DFS]: p < 0.05). A Cox proportional hazards regression analysis indicated that tumor size, margin width, pathologic class, and age were independent predictors of recurrence, but none of the studied molecular markers showed this. Overexpression of HER4 in the presence of HER3 was found to be associated with a better DFS (p < 0.05). This study confirms the value of the VNPI score and questions the benefit of an aggressive approach in the low-risk DCIS lesions. Independent predictors for recurrence included size, margin width, pathologic class, and age, but none of the molecular markers were part of it. Overexpression of HER4 in the presence of HER3 was associated with a better DFS.

Bisphosphonates in oncology: rising stars or fallen heroes.

The introduction of bisphosphonates in oncology has dramatically changed the management of patients with metastatic bone disease. In this manuscript, we thoroughly scrutinize the available body of clinical trials supporting the use of bisphosphonates in this setting and review new and ongoing research. Additionally, we summarize the data showing the benefits of bisphosphonate use in the prevention of treatment-induced bone loss and the intriguing emerging evidence on the antitumor potential of some of these agents when used in the adjuvant setting. Finally, we address the need for a careful consideration of potential benefits of bisphosphonate therapy and the risk for osteonecrosis of the jaw, a recently recognized late-toxicity of their use.

Docetaxel, ifosfamide and cisplatin (DIP) in squamous cell carcinoma of the head and neck.

BACKGROUND: Docetaxel, ifosfamide and cisplatin have all shown activity in squamous cell carcinoma of the head and neck (SCCHN). The optimal combination of the three drugs is, however, unknown. Considering the favorable results of taxane-containing triplets as induction chemotherapy in locally advanced (LA) SCCHN, DIP (docetaxel, ifosfamide, cisplatin) was studied in this setting as part of a phase I dose- and sequence-exploring study. PATIENTS AND METHODS: D (60 or 75 mg/m(2)) was given by 60-min infusion on day 1, I (1000 mg/m(2)/day), with mesna until 12 hours after I, by 24-h infusion days 1-5, and P (50 or 75 mg/m(2)) by 24-h infusion on days 1 or 5. The cycles were repeated every 21 days. Toxicities according to the National Cancer Institute Common Toxicity Criteria version 2 (NCI-CTC2) were evaluated weekly and response was evaluated every 2 cycles according to the World Health Organization (WHO) criteria. Thereafter, radiotherapy (RT, cumulative dose 70 Gy) or chemoradiation (CRT), both with conventional fractionation, were planned. RESULTS: Twenty-two patients (18 male, 4 female; age 41-66 years, performance status 0-1, 2 T4N0, 3 T3N2, 11 T4N2, 3 T unknown N3, 1 T1N3 and 2 T4N3) received a median of 4 DIP cycles (range 1-5). Grade 4 neutropenia occurred in 18 patients, grade 3 and 4 thrombocytopenia in 5 and 1 patients, respectively, and grade 3 anemia in 5 patients. Gastrointestinal and mucosal toxicities were generally mild/moderate. Vascular complications (probably not DIP-related) precluded local treatment in two patients. Moreover, one patient died on day 13 of the first DIP (neutropenic sepsis and myocardial infarction). The remaining patients received RT (n=2) or CRT (n=17; 16 of these with gemcitabine). The response to 2 x DIP was 95% (1 complete response, 19 partial responses, 1 stable disease); the complete response rate increased to 42% after 4 x DIP. No dose or sequence effect was evident. The minimum follow-up of the surviving patients was 51 months, with median relapse-free survival of 13.8 months and median overall survival of 18.8 months. Only four patients relapsed at distant sites. CONCLUSION: DIP is highly active in previously untreated LA SCCHN, however, toxicity of DIP in this population is substantial.

Osteonecrosis of the jaw related to the use of bisphosphonates.

PURPOSE OF REVIEW: Osteonecrosis of the jaw associated with the use of potent nitrogen containing bisphosphonates is a new and challenging clinical entity with a high impact on quality of life. This review attempts to consolidate the rapidly expanding literature into practical guidelines and provides expert consensus for areas of uncertainty. RECENT FINDINGS: Diagnostic criteria and a staging system for osteonecrosis of the jaw have been proposed, and histomorphologic analysis has confirmed osteonecrosis of the jaw as a proper disease, distinctively different from osteoradionecrosis. Various guidelines for the management of osteonecrosis of the jaw have been suggested and further retrospective research has provided new insights into its epidemiology. SUMMARY: Osteonecrosis of the jaw is a distinct entity of uncertain origin that is increasingly being observed in patients treated with potent aminobisphosphonates, although the etiology is probably multifactorial. Recent data confirm the predisposition of multiple myeloma patients to develop osteonecrosis of the jaw. Although various treatment strategies have been reported, conservative management remains the mainstay of therapy.

The value of the Van Nuys Prognostic Index in ductal carcinoma in situ of the breast: a retrospective analysis.

The Van Nuys Prognostic Index 1996 (VNPI), based upon tumor size, pathological grade and tumor margins, is a guideline for the treatment of ductal carcinoma in situ (DCIS). It was thought to strongly decrease overtreatment. In 2003, age was added to the index as a fourth prognostic factor. We examined changes in treatment modality after applying the VNPI retrospectively and investigated if the addition of age to the Index causes a shift in treatment. The influence of each prognostic factor on disease-free survival (DFS) was calculated. We performed a retrospective file study of DCIS patients treated between 1985 and 2003 at the University Hospital, Antwerp. Patients were assigned a Van Nuys Score 1996 and 2003. The influence of tumor size, pathological grade, tumor margins and age on DFS was calculated with the Kaplan-Meier method and the log-rank test. We identified 104 DCIS cases with a median follow-up of 36 months. Twelve patients showed recurrence (11.5%), of whom seven were invasive (58%). Seventeen of the 29 women diagnosed before 1997 were undertreated according to the VNPI 1996 and six of them showed recurrence. The remaining three recurrences were correctly treated. Seventy-five patients diagnosed after 1997 were all treated according to the VNPI 1996 and only three had a recurrence. The introduction of age caused no significant shift in treatment modalities. Significant differences in DFS were seen between large (>41 mm) and small (<15 mm) tumors (p = 0.0074), old (>60 years) and young (<40 years) patients (p = 0.024) and Van Nuys Subgroup 2 and 3 (p = 0.04). Tumor margins and pathological grade showed no significant difference in DFS. The VNPI can be a useful tool in the treatment of DCIS. However, this Index is not evidence-based, using a relatively small retrospective series of patients. The validity of the modified VNPI must be prospectively confirmed with large numbers of DCIS patients.