AIM: To prospectively compare volumetric intensity-modulated arc therapy (VMAT) and conventional intensity-modulated radiation therapy (IMRT) in coverage of planning target volumes and avoidance of multiple organs at risk (OARs) in patients undergoing definitive chemoradiotherapy for advanced (stage III or IV) squamous cell cancer of the head and neck.
METHODS: Computed tomography scans of 20 patients with advanced tumors of the larynx, naso-, oro- and hypopharynx were prospectively planned using IMRT (7 field) and VMAT using two arcs. Calculated doses to planning target volume (PTV) and OAR were compared between IMRT and VMAT plans. Dose-volume histograms (DVH) were utilized to obtain calculated doses to PTV and OAR, including parotids, cochlea, spinal cord, brainstem, anterior tongue, pituitary and brachial plexus. DVH’s for all structures were compared between IMRT and VMAT plans. In addition the plans were compared for dose conformity and homogeneity. The final treatment plan was chosen by the treating radiation oncologist.
RESULTS: VMAT was chosen as the ultimate plan in 18 of 20 patients (90%) because the plans were thought to be otherwise clinically equivalent. The IMRT plan was chosen in 2 of 20 patients because the VMAT plan produced concentric irradiation of the cord which was not overcome even with an avoidance structure. For all patients, VMAT plans had a lower number of average monitor units on average (MU = 542.85) than IMRT plans (MU = 1612.58) (P < 0.001). Using the conformity index (CI), defined as the 95% isodose volume divided by the PTV, the IMRT plan was more conformal with a lower conformity index (CI = 1.61) than the VMAT plan (CI = 2.00) (P = 0.003). Dose homogeneity, as measured by average standard deviation of dose distribution over the PTV, was not different with VMAT (1.45 Gy) or IMRT (1.73 Gy) (P = 0.069). There were no differences in sparing organs at risk.
CONCLUSION: In this prospective study, VMAT plans were chosen over IMRT 90% of the time. Compared to IMRT, VMAT plans used only one third of the MUs, had shorter treatment times, and similar sparing of OAR. Overall, VMAT provided similar dose homogeneity but less conformity in PTV irradiation compared to IMRT. This difference in conformity was not clinically significant.
Volumetric intensity-modulated arc therapy; Intensity-modulated radiation therapy; Target coverage; Organs at risk
This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia.
Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS).
Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event.
ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated.
head and neck cancer; xerostomia; radiation; acupuncture; ALTENS
Prospective analysis was performed of self-reported and biochemically confirmed tobacco use in 50 head and neck cancer patients during treatment. With 93.5% compliance to complete weekly self-report and biochemical confirmatory tests, 29.4% of smokers required biochemical assessment for identification. Accuracy increased by 14.9% with weekly vs. baseline self-reported assessments. Data confirm that head and neck cancer patients misrepresent true tobacco use during treatment.
tobacco; smoking; head/neck; radiotherapy; cotinine
Tobacco use in cancer patients is associated with increased cancer treatment failure and decreased survival. Nicotine is one of over 7,000 compounds in tobacco smoke and nicotine is the principal chemical associated with addiction. The purpose of this article is to review the tumor promoting activities of nicotine. Nicotine and its metabolites can promote tumor growth through increased proliferation, angiogenesis, migration, invasion, epithelial to mesenchymal transition, and stimulation of autocrine loops associated with tumor growth. Furthermore, nicotine can decrease the biologic effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy. Common mechanisms appear to involve activation of nicotinic acetylcholine receptors and beta-adrenergic receptors leading to downstream activation of parallel signal transduction pathways that facilitate tumor progression and resistance to treatment. Data suggest that nicotine may be an important mechanism by which tobacco promotes tumor development, progression, and resistance to cancer treatment.
Cancer; lung; nicotine; smoking; tobacco
Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality. The majority of patients present with advanced (stage III-IV) disease. Such patients are treated with a variety of therapies including surgery, radiation, and chemotherapy. Despite decades of work, however, overall survival in this group has been resistant to any substantial improvement. This review briefly details the evolution to the current standard of care for advanced NSCLC, advances in systemic therapy, and novel techniques (stereotactic body radiation therapy [SBRT], and transcervical extended mediastinal lymphadenectomy [TEMLA] or video-assisted mediastinal lymphadenectomy [VAMLA]) that have been used in localized NSCLC. The utility of these techniques in advanced stage therapy and potential methods of combining these novel techniques with systemic therapy to improve survival are discussed.
Image-guided radiation therapy; non-small-cell lung cancer; targeted therapy; temla; vamla
To determine the effects of total body irradiation (TBI) dose, fractionation, and lung shielding on hematopoietic stem cell homing to the bone marrow.
Material and Methods
Bone marrow (BM) cells were extracted from tibiae and femurs of B6-GFP mice and were transplanted into B6 mice. Recipient mice had either: 1) no radiation, 2) single dose TBI at 13.6 Gray (Gy), 3) single dose TBI at 13.6 Gy with reduced lung exposure to 0.4 Gy by shielding, 4) split dose TBI at 12 Gy to twice/day over four days, or 5) split dose TBI at 12 Gy to twice/day over four days with reduced lung exposure to 0.36 Gy by shielding. The last radiation exposure preceded tail vein injection by 4–6 hours. Mice were sacrificed after 18 hours.
Homing of GFP positive, lineage negative cells was not significantly improved in any irradiated group compared to control. Homing of GFP positive, lineage negative, Kit positive cells was significantly worse in all irradiated groups.
TBI does not improve the homing of lineage negative donor BM cells to the recipient marrow. Homing of lineage negative, Kit positive donor BM cells was significantly worse following TBI, with or without lung dose reduction.
TBI; Lung Shielding; Dose Reduced; BID; Stem
Small cell cancer (SCC) of the tonsil is a rare and aggressive cancer. There are only 10 cases of tonsillar SCC reported in the English literature. We present a case of tonsillar SCC successfully treated with induction chemotherapy using carboplatin and etoposide followed by concurrent chemoradiation therapy with cisplatin as radiosensitizer. The patient remained free of recurrence after 3 years of follow-up. We also provide a succinct review of all tonsillar SCC cases reported in the English literature and their outcomes.
Tonsillar cancer; Neuroendocrine tumor; Small cell cancer; Carboplatin; Etoposide
Patient and rodent solid tumors often exhibit elevated interstitial fluid pressure (IFP). This condition is recognized as a prognostic indicator for reduced responses to therapy and decreased disease-free survival. Here we tested whether induction of a thermoregulatory-mediated rise in tissue blood flow, induced by exposure of mice to mild environmental heat stress, could influence IFP and other vascular parameters within tumors. Using several murine tumor models, we found that heating results in a sustained reduction in tumor IFP correlating with increased tumor vascular perfusion (measured by fluorescent imaging of perfused vessels, laser Doppler and magnetic resonance imaging) as well as a sustained reduction in tumor hypoxia. When radiation therapy was administered 24 hours post-heating, we also observed a significant improvement in efficacy that may be a result of the sustained reduction in tumor hypoxia. These data suggest, for the first time, that environmental manipulation of normal vasomotor function is capable of achieving therapeutically beneficial changes in IFP and microvascular function in the tumor microenvironment.
Tumor microcirculation and microenvironment; Noninvasive imaging in animal models; Modification of radiation sensitivity; Hyperthermia; Hypoxia; Interstitial fluid pressure Thermoregulation
This paper reports a novel system for magnetic resonance imaging (MRI) guided transrectal prostate interventions, such as needle biopsy, fiducial marker placement, and therapy delivery. The system utilizes a hybrid tracking method, comprised of passive fiducial tracking for initial registration and subsequent incremental motion measurement along the degrees of freedom using fiber-optical encoders and mechanical scales. Targeting accuracy of the system is evaluated in prostate phantom experiments. Achieved targeting accuracy and procedure times were found to compare favorably with existing systems using passive and active tracking methods. Moreover, the portable design of the system using only standard MRI image sequences and minimal custom scanner interfacing allows the system to be easily used on different MRI scanners.
Olfactory Neuroblastoma is a rare malignant tumor of the olfactory tract. Reports in the literature comparing treatment modalities for this tumor are limited.
The SEER database (1973-2006) was queried by diagnosis code to identify patients with Olfactory Neuroblastoma. Kaplan-Meier was used to estimate survival distributions based on treatment modality. Differences in survival distributions were determined by the log-rank test. A Cox multiple regression analysis was then performed using treatment, race, SEER historic stage, sex, age at diagnosis, year at diagnosis and SEER geographic registry.
A total of 511 Olfactory Neuroblastoma cases were reported. Five year overall survival, stratified by treatment modality was: 73% for surgery with radiotherapy, 68% for surgery only, 35% for radiotherapy only, and 26% for neither surgery nor radiotherapy. There was a significant difference in overall survival between the four treatment groups (p < 0.01). At ten years, overall survival stratified by treatment modality and stage, there was no significant improvement in survival with the addition of radiation to surgery.
Best survival results were obtained for surgery with radiotherapy.
Most men diagnosed with prostate cancer will die of other causes. Pre-treatment patient characteristics may identify patients who are likely to die of other causes. Accurate stratification of patients by risk of other cause mortality (OCM) may reduce needless treatment preventing morbidity and expense.
Materials and Methods
Using the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a cohort of men was identified with clinically localized prostate cancer who had definitive treatment with either radical prostatectomy (RP) or radiation therapy (RT), between 1995 and 2004. Pre-treatment patient characteristics were evaluated to determine if early OCM could be predicted.
Of 13,124 subjects enrolled in CaPSURE, 5,070 had clinical T1c-T3a prostatic adenocarcinoma treated with RP (77%) or RT (23%) and post-treatment follow up data. Median follow-up was 3.3 years. The cohort was divided into three groups. The prostate cancer specific mortality (PCSM) group included 55 men (1%) who died from prostate cancer. The 296 men (6%) who died from causes other than prostate cancer comprised the OCM group. A third group contained the 4719 (93%) men surviving at the end of the observation period. Factors that exclusively predicted death from non-prostate cancer causes included age at diagnosis, having a high school education or less, high clinical risk, smoking at time of diagnosis, concurrent non-prostate malignancy, and worse scores on the SF-36 physical function (PF) scale.
Several pre-treatment patient characteristics may identify patients at high risk of non-prostate cancer mortality. Future studies should consider stratifying patients by, or at least reporting, these variables.
Prostate cancer; mortality; treatment; active surveillance
Targeted prostate biopsy is challenging because no currently established imaging modality is both accurate for prostate cancer diagnosis and cost-effective for real-time procedure guidance. A system that fuses real-time transrectal ultrasound images with previously acquired endorectal coil MRI images for prostate biopsy guidance is presented here. The system uses electromagnetic tracking and intraoperative image registration to superimpose the MRI data on the ultrasound image. Prostate motion is tracked and compensated for without the need for fiducial markers. The accuracy of the system in phantom studies was shown to be 2.4 ± 1.2 mm. The fusion system has been used in more than 20 patients to guide biopsies with almost no modification of the conventional protocol. Retrospective clinical evaluation suggests that clinically acceptable spatial accuracy can be achieved.
Motion compensation; prostate biopsy; tracking; image registration
To evaluate the feasibility and utility of registration and fusion of real-time transrectal ultrasonography (TRUS) and previously acquired magnetic resonance imaging (MRI) to guide prostate biopsies.
PATIENTS AND METHODS
Two National Cancer Institute trials allowed MRI-guided (with or with no US fusion) prostate biopsies during placement of fiducial markers. Fiducial markers were used to guide patient set-up for daily external beam radiation therapy. The eligible patients had biopsy-confirmed prostate cancer that was visible on MRI. A high-field (3T) MRI was performed with an endorectal coil in place. After moving to an US suite, the patient then underwent TRUS to visualize the prostate. The US transducer was equipped with a commercial needle guide and custom modified with two embedded miniature orthogonal five-degrees of freedom sensors to enable spatial tracking and registration with MR images in six degrees of freedom. The MRI sequence of choice was registered manually to the US using custom software for real-time navigation and feedback. The interface displayed the actual and projected needle pathways superimposed upon the real-time US blended with the prior MR images, with position data updating in real time at 10 frames per second. The registered MRI information blended to the real-time US was available to the physician who performed targeted biopsies of highly suspicious areas.
Five patients underwent limited focal biopsy and fiducial marker placement with real-time TRUS-MRI fusion. The Gleason scores at the time of enrolment on study were 8, 7, 9, 9, and 6. Of the 11 targeted biopsies, eight showed prostate cancer. Positive biopsies were found in all patients. The entire TRUS procedure, with fusion, took ≈10 min.
The fusion of real-time TRUS and prior MR images of the prostate is feasible and enables MRI-guided interventions (like prostate biopsy) outside of the MRI suite. The technique allows for navigation within dynamic contrast-enhanced maps, or T2-weighted or MR spectroscopy images. This technique is a rapid way to facilitate MRI-guided prostate therapies such as external beam radiation therapy, brachytherapy, cryoablation, high-intensity focused ultrasound ablation, or direct injection of agents, without the cost, throughput, or equipment compatibility issues that might arise with MRI-guided interventions inside the MRI suite.
magnetic resonance; ultrasound; prostate cancer; imaging; transrectal
Multi-modality fusion imaging for targeted prostate biopsy is difficult because of prostate motion during the biopsy procedure. A closed-loop control mechanism is proposed to improve the efficacy and safety of the biopsy procedure, which uses real-time ultrasound and spatial tracking as feedback to adjust the registration between a preoperative 3D image (e.g. MRI) and real-time ultrasound images. The spatial tracking data is used to initialize the image-based registration between intraoperative ultrasound images and a preoperative ultrasound volume. The preoperative ultrasound volume is obtained using a 2D sweep and manually registered to the MRI dataset before the biopsy procedure. The accuracy of the system is 2.3±0.9 mm in phantom studies. The results of twelve patient studies show that prostate motion can be effectively compensated using closed-loop control.
motion compensation; prostate biopsy; image registration
To assess the feasibility and early toxicity of selective, IMRT-based dose escalation (simultaneous integrated boost) to biopsy proven dominant intra-prostatic lesions visible on MRI.
Patients with localized prostate cancer and an abnormality within the prostate on endorectal coil MRI were eligible. All patients underwent a MRI-guided transrectal biopsy at the location of the MRI abnormality. Gold fiducial markers were also placed. Several days later patients underwent another MRI scan for fusion with the treatment planning CT scan. This fused MRI scan was used to delineate the region of the biopsy proven intra-prostatic lesion. A 3 mm expansion was performed on the intra-prostatic lesions, defined as a separate volume within the prostate. The lesion + 3 mm and the remainder of the prostate + 7 mm received 94.5/75.6 Gray (Gy) respectively in 42 fractions. Daily seed position was verified to be within 3 mm.
Three patients were treated. Follow-up was 18, 6, and 3 months respectively. Two patients had a single intra-prostatic lesion. One patient had 2 intra-prostatic lesions. All four intra-prostatic lesions, with margin, were successfully targeted and treated to 94.5 Gy. Two patients experienced acute RTOG grade 2 genitourinary (GU) toxicity. One had grade 1 gastrointestinal (GI) toxicity. All symptoms completely resolved by 3 months. One patient had no acute toxicity.
These early results demonstrate the feasibility of using IMRT for simultaneous integrated boost to biopsy proven dominant intra-prostatic lesions visible on MRI. The treatment was well tolerated.
As a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy.
Patients and methods
Nine patients (4 women, 5 men) undergoing radiation therapy were enrolled in this prospective study. The patients had up to four weekly CT scans performed during their course of radiation therapy. Pancreas, duodenum and non-duodenal small bowel were then contoured for each CT scan. On the initial scan, a four-field plan was generated to fully cover the pancreas. This plan was registered to each subsequent CT scan. Dose-volume histogram (DVH) analyses were performed for the duodenum, non-duodenal small bowel, large bowel, and pancreas.
With significant individual variation, the volume of duodenum receiving at least 80% of the prescribed dose was consistently greater than the remaining small bowel. In the patient with the largest inter-fraction variation, the fractional volume of non-duodenal small bowel irradiated to at least the 80% isodose line ranged from 1% to 20%. In the patient with the largest inter-fraction variation, the fractional volume of duodenum irradiated to at least the 80% isodose line ranged from 30% to 100%.
The volume of small bowel irradiated during four-field pancreatic radiation therapy changes substantially between fractions. This suggests dose escalation may be possible. However, dose limits to the duodenum should be stricter than for other segments of small bowel.
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
The risk of severe cardiovascular toxicity, specifically thromboembolic events (TE), in patients with cervical cancer receiving concurrent irradiation and cisplatin chemotherapy is reported to be less than 1% in several large prospective trials. However, the anecdotal risk appears to be far higher.
Results and discussion
A review of several prospective trials demonstrates no treatment related grade 4 cardiovascular toxicities and only two grade 5 toxicities in 1424 (0.1%) collective patients. A recent publication and our own unpublished experience finds 6 of 128 (4.7%) patients developed grade 4 to 5 cardiovascular (thrombosis/embolism) toxicity. The differenc in incidence of severe or life threatening cardiovascular toxicity of 0.1 versus 4.7% is highly statistically significant (p < 0.00001.)
This dramatic difference in incidence of cardiovascular toxicity raises the possibility that cardiovascular toxicities were inadequately reported on the listed prospective trials. For those patients enrolled in prospective trials, we suggest that thromboses should be diligently documented and reported. Only after the true incidence of thromboses is established can we implement appropriate levels of early screening and intervention that may prevent life threatening complications.
This paper reports the development, evaluation, and first clinical trials of the access to the prostate tissue (APT) II system—a scanner independent system for magnetic resonance imaging (MRI)-guided transrectal prostate interventions. The system utilizes novel manipulator mechanics employing a steerable needle channel and a novel six degree-of-freedom hybrid tracking method, comprising passive fiducial tracking for initial registration and subsequent incremental motion measurements. Targeting accuracy of the system in prostate phantom experiments and two clinical human-subject procedures is shown to compare favorably with existing systems using passive and active tracking methods. The portable design of the APT II system, using only standard MRI image sequences and minimal custom scanner interfacing, allows the system to be easily used on different MRI scanners.
Image-guided intervention; MRI; prostate cancer; robot manipulators
Epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsies from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).
Methods and Materials
A pilot phase I dose-escalation study. Eligibility included stage III-IVB HNSCC, age ≥18 years, no prior RT or chemotherapy, adequate organ function and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation and apoptosis in biopsies.
Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m2 I.V. weekly × 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (1), and interstitial pneumonitis (1). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only one demonstrated a reduction in phosphorylated-EGFR, decreased downstream signaling and reduced cellular proliferation after initiating GEF.
GEF inhibition of EGFR was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared to our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.
Epidermal growth factor receptor; head and neck cancer; gefitinib; paclitaxel; radiation
To test whether intrarectal Amifostine limits symptoms of radiation proctitis as measured by the RTOG GI toxicity score and the expanded prostate cancer index composite (EPIC) score.
Methods and Materials
Patients with localized prostate cancer recieved Amifostine as a rectal suspension 30–45 min before daily 3D-conformal radiation treatments (3D-CRT). The first 18 patients received 1gm of Amifostine and the next 12 patients received 2gm. Toxicity was assessed at baseline, during treatment, and at follow-up visits using RTOG grading and the EPIC Quality of Life (QoL) 50 item questionnaire. The “Bowel Function” subset of the bowel domain (EPIC-BF), which targets symptom severity, and “Bowel Bother” subset of the bowel domain (EPIC-BB), which assesses quality of life, were evaluated and compared to the RTOG GI toxicity score.
Median follow-up was 30 months (range 18–36). Overall, the EPIC-BF and EPIC-BB scores both track closely with the RTOG GI toxicity score. Seven weeks after the start of radiation therapy, the incidence of RTOG Grade 2 toxicity was 33% in the 1gm group (6/18) compared with 0% (0/12) in the 2gm group and trended towards statistical significance (p=0.06). A significant difference between Amifostine groups was observed using the EPIC-BF score at 7 weeks (p=0.04). A difference in EPIC-BB score between dose groups was evident at 7 weeks (p=0.07) and was significant at 12 months (p=0.04).
Higher doses of Amifostine produce significant improvements in acute and late bowel QoL (up to one year following therapy) as measured by the EPIC score.
Amifostine; Prostate; Radiation-induced Proctitis; EPIC; Quality of Life