Manon T. Huizing

Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome

BACKGROUND Overall survival (OS) and outcome of cancer patients with bisphosphonate-associated osteonecrosis of the jaw (ONJ) using conservative treatment (chlorhexidine 0.12% rinse, intermittent antibiotics, and careful sequestrectomy) are unknown. DESIGN In all, 33 ONJ patients were studied for OS and ONJ outcome. RESULTS Median duration of bisphosphonate treatment was 27 months (range 4-115) and was stopped in 25 (76%) patients. Nine (27%) cases presented with stage 1, 21 (64%) with stage 2, and 3 (9%) with stage 3 disease. During median follow-up of 23 months, 11 patients (33%) died (median survival 39 months), with no ONJ-related fatalities. Out of 30 assessable patients, 53% no longer had exposed bone, 37% had stable lesions, and 10% showed progressive necrosis. The hazard ratio for healing with doubling of bisphosphonate exposure was 0.419 [95% confidence interval (CI) 0.178-0.982; P = 0.045], stage 2 versus stage 1 disease 0.216 (95% CI 0.063-0.738; P = 0.015), and stage 3 versus stage 1 disease 0.084 (95% CI 0.008-0.913; P = 0.042). Cessation of bisphosphonate treatment did not influence outcome. CONCLUSIONS Conservative treatment of ONJ leads to mucosal closure in 53% of patients. Doubling the exposure time to bisphosphonates and higher stages of ONJ significantly reduce ONJ healing rates.

Tolerance of adjuvant letrozole outside of clinical trials

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

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

Abstract:  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.

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

PurposeThe 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).MethodsThe ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation.ResultsA 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).ConclusionsAlthough 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.

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.

The Value of the Van Nuys Prognostic Index in Ductal Carcinoma In Situ of the Breast: A Retrospective Analysis

Abstract:  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.

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)

Abstract:  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.

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

BackgroundSingle-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 MethodsA total of 30 patients with proven metastatic or recurrent SCCHN were treated with docetaxel 36 mg/m2 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. ResultsPatients 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. ConclusionsWeekly docetaxel at a dose of 36 mg/m2 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.

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 MBTs 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.

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.