Imran Zoberi

Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial

BACKGROUND Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. METHODS Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II-III (> or = T2 and/or > or = N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m(2)) plus docetaxel (75 mg/m(2)) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. FINDINGS Of the 120 patients initially enrolled, one withdrew after signing consent and one patients baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0.054). The most common grade 3-4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. INTERPRETATION Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. FUNDING Novartis Pharmaceuticals and Pfizer Inc.

Posttherapy [18F] Fluorodeoxyglucose Positron Emission Tomography in Carcinoma of the Cervix: Response and Outcome

PURPOSE The aim of this study was to evaluate response to therapy using posttherapy molecular imaging with [(18)F] fluorodeoxyglucose (FDG), and to compare the response with patient outcome. PATIENTS AND METHODS This was a retrospective medical record review of 152 patients with carcinoma of the cervix. All patients underwent a pre- and posttreatment whole-body positron emission tomography (PET) imaging scan with FDG. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy whole-body FDG-PET was performed 1 to 12 months (mean, 3 months) after completion of treatment. RESULTS The posttherapy PET did not show any abnormal FDG uptake in 114 patients, and their 5-year cause-specific survival estimate was 80%. There was persistent (in the irradiated region) abnormal FDG uptake in the cervix or lymph nodes in 20 patients. Their 5-year cause-specific survival estimate was 32%. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were present in 18 patients, and none were alive at 5 years. A Cox proportional hazards model of survival outcome indicated that any abnormal posttherapy FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from cervical cancer when compared with pretreatment- and treatment-related prognostic factors (P <.0001). CONCLUSION Posttherapy abnormal FDG uptake (persistent or new) as detected by whole-body PET measures tumor response and might be predictive of tumor recurrence and death from cervical cancer. Prospective validation of these results is warranted.

PET-GUIDED IMRT FOR CERVICAL CARCINOMA WITH POSITIVE PARA-AORTIC LYMPH NODES—A DOSE-ESCALATION TREATMENT PLANNING STUDY

PURPOSE To evaluate a treatment planning method for dose escalation to the para-aortic lymph nodes (PALNs) based on positron emission tomography (PET) with intensity-modulated radiotherapy (IMRT) for cervical cancer patients with PALN involvement. One goal of this process was not to modify the traditional treatment of the pelvic region. METHODS AND MATERIALS PET images for 4 cervical cancer patents with PALN involvement were registered with their corresponding CT scans. Positive PALNs were identified on PET images, and the surrounding critical structures were delineated on CT images. The treatment machine central axis (CAX) was placed at the level of the L4-L5 vertebral body interspace. There were two distinct treatment regions: the para-aortic bed superior to the CAX and the whole pelvis region inferior to the CAX. IMRT was used for treatment planning of PALN bed irradiation. The positive PALNs identified on PET images were defined as the gross target volume, and the para-aortic bed was defined as the clinical target volume. The radiation doses were escalated from the conventional 45 Gy to 59.4 Gy for the gross target volume and 50.4 Gy for the clinical target volume in 33 fractions. The pelvis area was treated with conventional treatment methods, AP-PA beams to 50.4 Gy in 28 fractions with a brachytherapy implant boost. The placement of the CAX allowed the two treatment regions to be abutted using the treatment machines independent jaws. RESULTS Dose escalation to positive PALNs, as identified on PET images, and the PALN bed is feasible with IMRT. Treatment plans for 4 patients revealed that escalated prescription doses could be delivered to target volumes while maintaining acceptable doses to the surrounding critical structures. Strategic placement of the treatment isocenter allows the IMRT region (PALN bed) and whole pelvis fields to be treated with a relatively uniform dose distribution in the abutment region. CONCLUSION This study indicates that PET-guided IMRT could be used in a clinical trial in an attempt to escalate doses delivered to patients with cervical cancer who have positive PALNs.

Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines

Resveratrol is a polyphenol isolated from the skins of grapes that has been shown to significantly alter the cellular physiology of tumor cells, as well as block the process of initiation and progression. At least one mechanism for the intracellular actions of resveratrol involves the suppression of prostaglandin (PG) biosynthesis. The involvement of PGs and other eicosanoids in the development of human cancer is well established. PGs are synthesized from arachidonic acid via the cyclooxygenase pathway and have multiple physiological and pathological functions. In addition, evidence has arisen suggesting that PGs may be implicated in the cytotoxic and/or cytoprotective response of tumor cells to ionizing radiation (IR). As such, we hypothesized that tumor cells may exhibit changes in the cellular response to IR following exposure to resveratrol, a naturally occurring compound that inhibits cyclooxygenase-1 (COX-1) activity. Thus, clonogenic cell survival assays were performed using irradiated HeLa and SiHa cells pretreated with resveratrol prior to IR exposure, and resulted in enhanced tumor cell killing by IR in a dose-dependent manner. Further analysis of COX-1 inhibition indicated that resveratrol pretreatment: (1), inhibited cell division as assayed by growth curves; and (2), induced an early S phase cell cycle checkpoint arrest, as demonstrated by fluorescence-activated cell sorting, as well as bromodeoxyuridine pulse-chase analysis. These results suggest that resveratrol alters both cell cycle progression and the cytotoxic response to IR in two cervical tumor cell lines.

Helical Tomotherapy Planning for Left-Sided Breast Cancer Patients With Positive Lymph Nodes: Comparison to Conventional Multiport Breast Technique

PURPOSE To evaluate the feasibility of using helical tomotherapy for locally advanced left-sided breast cancer. METHODS AND MATERIALS Treatment plans were generated for 10 left-sided breast cancer patients with positive lymph nodes comparing a multiport breast (three-dimensional) technique with the tomotherapy treatment planning system. The planning target volumes, including the chest wall/breast, supraclavicular, axillary, and internal mammary lymph nodes, were contoured. The treatment plans were generated on the tomotherapy treatment planning system to deliver 50.4 Gy to the planning target volume. To spare the contralateral tissues, directional blocking was applied to the right breast and right lung. The optimization goals were to protect the lungs, heart, and right breast. RESULTS The tomotherapy plans increased the minimal dose to the planning target volume (minimal dose received by 99% of target volume = 46.2 +/- 1.3 Gy vs. 27.9 +/- 17.1 Gy) while improving the dose homogeneity (dose difference between the minimal dose received by 5% and 95% of the planning target volume = 7.5 +/- 1.8 Gy vs. 37.5 +/- 26.9 Gy). The mean percentage of the left lung volume receiving >or=20 Gy in the tomotherapy plans decreased from 32.6% +/- 4.1% to 17.6% +/- 3.5%, while restricting the right-lung mean dose to <5 Gy. However, the mean percentage of volume receiving >or=5 Gy for the total lung increased from 25.2% +/- 4.2% for the three-dimensional technique to 46.9% +/- 8.4% for the tomotherapy plan. The mean volume receiving >or=35 Gy for the heart decreased from 5.6% +/- 4.8% to 2.2% +/- 1.5% in the tomotherapy plans. However, the mean heart dose for tomotherapy delivery increased from 7.5 +/- 3.4 Gy to 12.2 +/- 1.8 Gy. CONCLUSION The tomotherapy plans provided better dose conformity and homogeneity than did the three-dimensional plans for treatment of left-sided breast tumors with regional lymph node involvement, while allowing greater sparing of the heart and left lung from doses associated with increased complications.

Physiologic FDG-PET three-dimensional brachytherapy treatment planning for cervical cancer ☆

PURPOSE To compare conventional two-dimensional (2D) orthogonal radiography-based brachytherapy treatment planning for cervical cancer with a three-dimensional (3D) treatment planning technique based on 18F-fluoro-deoxyglucose-positron emission tomography (FDG-PET). METHODS AND MATERIALS Eleven cervical cancer patients were included in this prospective study that evaluated one tandem and ovoid brachytherapy procedure for each patient. The patient underwent FDG-PET of the pelvis to visualize the tumor followed by a second FDG-PET scan with the FDG isotope placed inside the tandem and ovoid applicators to visualize the treatment source positions for 3D treatment planning. The tumor volumes were delineated using a binary threshold technique in which the threshold FDG-PET image intensity was 40% of the peak tumor intensity. RESULTS FDG-PET provides a reliable estimate of the cervical cancer volume and 3D spatial relationship of the tumor to the tandem and ovoid applicators. The maximal bladder and rectal doses determined from the 3D FDG-PET dose-volume histograms were found to be higher than those obtained using 2D treatment planning. The minimal dose to the tumor volume defined by FDG-PET ranged from 50 to 475 cGy for treatment plans designed to deliver 650 cGy to Point A and exhibited an inverse correlation with tumor volume. CONCLUSION Physiologic FDG-PET brachytherapy treatment planning is feasible and accurate relative to conventional 2D treatment planning. The use of FDG-PET offers a unique method for tumor visualization and identifies the limitations of conventional brachytherapy treatment planning for coverage of large tumors and estimation of the dose to normal structures. This technique has the potential for improving isodose tumor coverage for patients with cervical cancer while sparing critical structures.

A treatment planning study comparing HDR and AGIMRT for cervical cancer

The customization of brachytherapy dose distributions for gynecologic malignancies is limited by the spatial positioning of the applicators. We tested the hypothesis that applicator-guided intensity modulated radiation therapy (AGIMRT) has the potential to deliver highly conformal dose distributions to cervical tumors, representing improvement over distributions obtained with intracavitary brachytherapy. A commercial three-dimensional (3-D) treatment planning system was used to create plans for ten cervical cancer patients treated at our institution. Dose distributions of conventionally designed high dose rate (HDR) plans were compared against those of AGIMRT. Tumor delineation was based on a previously published binary threshold technique, using image intensity on positron emission tomography (PET) scans. AGIMRT treatment schedules were designed using two fraction sizes: 6.5 Gy, to directly reproduce the HDR fractionation, and 1.8 Gy, to simulate traditional external beam fractionation. The average minimum tumor dose was significantly greater for the AGIMRT dose distributions than for the HDR distributions (64.2 Gy vs 33.6 Gy; p = 0.005). The mean percent tumor volume at the prescription dose was higher for the AGIMRT plans (90.0% vs 58.2%; p = 0.005). Using AGIMRT, the mean percent volume at the tolerance limit was decreased for the bladder (6.1% vs 16.6%; p = 0.047) but increased for the rectum (4.1% vs 2.2%; p = 0.646). Our study suggests that there may be conceptual and dosimetric advantages to replacing HDR with AGIMRT for patients with large-volume cervical tumors. This investigation is being expanded using sequential PET images to model tumor regression and compare brachytherapy and AGIMRT throughout the course of therapy.

Dosimetric consequences of uncorrected setup errors in helical Tomotherapy treatments of breast-cancer patients

BACKGROUND AND PURPOSE The Tomotherapy Hi-Art II system allows acquisition of pre-treatment MVCT images to correct patient position. This work evaluates the dosimetric impact of uncorrected setup errors in breast-cancer radiation therapy. MATERIALS AND METHODS Breast-cancer patient-positioning errors were simulated by shifting the patient computed-tomography (CT) dataset relative to the planned photon fluence and re-computing the dose distributions. To properly evaluate the superficial region, film measurements were compared against the Tomotherapy treatment planning system (TPS) calculations. A simulation of the integrated dose distribution was performed to evaluate the setup error impact over the course of treatment. RESULTS Significant dose differences were observed for 11-mm shifts in the anterolateral and 3-mm shifts in the posteromedial directions. The results of film measurements in the superficial region showed that the TPS overestimated the dose by 14% at a 1-mm depth, improving to 3% at depths >or=5mm. Significant dose reductions in PTV were observed in the dose distributions simulated over the course of treatment. CONCLUSIONS Tomotherapys rotational delivery provides sufficient photon fluence extending beyond the skin surface to allow an up to 7-mm uncorrected setup error in the anterolateral direction. However, the steep dose falloff that conforms to the lung surface leads to compromised dose distributions with uncorrected posteromedial shifts. Therefore, daily image guidance and consequent patient repositioning is warranted for breast-cancer patients.

Comparison of accelerated partial breast irradiation via multicatheter interstitial brachytherapy versus whole breast radiation

BackgroundBrachytherapy as adjuvant treatment for early-stage breast cancer has become widely available and offers patients an expedited treatment schedule. Given this, many women are electing to undergo brachytherapy in lieu of standard fractionation radiotherapy. We compare outcomes between patients treated with accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy versus patients who were also eligible for and offered APBI but who chose whole breast radiation (WBI).MethodsPatients treated from December 2002 through May 2007 were reviewed. Selection criteria included patients with pTis-T2N0 disease, ≤ 3 cm unifocal tumors, and negative margins who underwent breast conservation surgery. Local control (LC), cause-specific (CSS) and overall survival (OS) were analyzed.Results202 patients were identified in the APBI cohort and 94 patients in the WBI cohort. Median follow-up for both groups exceeded 60 months. LC was 97.0% for the APBI cohort and 96.2% for the WBI cohort at 5 years (ns). Classification by 2010 ASTRO APBI consensus statement categories did not predict worse outcomes.ConclusionAPBI via multicatheter interstitial brachytherapy provides similar local failure rates compared to WBI at 5 years for properly selected patients. Excellent results were seen despite the high fraction of younger patients (< 60 years old) and patients with DCIS.

Analysis of fat necrosis after adjuvant high-dose-rate interstitial brachytherapy for early stage breast cancer

PURPOSE To report the incidence and potential predictors of fat necrosis in women with early stage breast cancer treated with adjuvant high-dose-rate (HDR) multicatheter interstitial brachytherapy. METHODS AND MATERIALS Between 2003 and 2010, 238 treated breasts in 236 women were treated with accelerated partial breast irradiation using HDR interstitial brachytherapy. Selection criteria included patients with Tis-T2 tumors measuring ≤3cm, without nodal involvement, who underwent breast-conserving surgery. Ninety-nine percent of treatments were to a total dose of 34Gy. The presence and severity of fat necrosis were prospectively recorded during followup. Cosmesis was qualitatively scored in all patients. Cosmesis was quantitatively measured via the percentage breast retraction assessment in 151 cases. RESULTS Median followup was 56 months. The crude rate of fat necrosis was 17.6%. The rate of symptomatic fat necrosis was 10.1%. In univariate analysis, acute breast infection and anthracycline-based chemotherapy, number of catheters, volume encompassed by the prescription isodose, volume encompassed by the 150% isodose (V150), volume encompassed by the 200% isodose, and integrated reference air kerma were significantly associated with fat necrosis. There was significant collinearity between the brachytherapy-related factors; of these, V150 was most predictive. In multivariate analysis, only V150 was significantly associated with fat necrosis. At 3 years, patients with fat necrosis were more likely to have a fair or poor cosmetic outcome and a larger percentage breast retraction assessment. CONCLUSIONS Mammary fat necrosis is a common adverse event after breast-conserving surgery and HDR interstitial brachytherapy. Fat necrosis is associated with worse qualitative and quantitative cosmetic outcomes. Minimizing exposure volumes, such as V150, may decrease the incidence of fat necrosis and improve cosmesis.