Jonathan J. Beitler

Endobronchial brachytherapy and external-beam radiotherapy in patients with endobronchial obstruction and extrabronchial extension

PURPOSEnTo evaluate the efficacy of high-dose rate endobronchial brachytherapy (HDR-EB) with concomitant short-course external-beam radiotherapy (EBRT) in patients with both endobronchial and extrabronchial tumor.nnnMETHODS AND MATERIALSnPatients with endobronchial disease and extrabronchial lesions greater than 2.5cm were treated with three 5Gy HDR-EB and 37.5Gy EBRT delivered over 3.5 weeks. Flexible fiberoptic bronchoscopy was performed with the patient under conscious sedation, and tumor location, length of lesion, percentage of lumen occlusion, and presence of bleeding were recorded. Fluoroscopic visualization of the guide wire in the catheter tip assisted in demarcating the proximal and distal extent of the intraluminal tumor. 5Gy was prescribed to a distance of 1cm from the catheter and a computerized treatment planning system was used to optimize the dose distribution to the gross target volume with 1.5-2cm margins at the distal and proximal ends. Bronchoscopic and symptomatic response rates were assessed at the third HDR-EB and patients were seen in follow-up every 2 months.nnnRESULTSnOne hundred seventeen endobronchial treatments were delivered to 33 patients with primary carcinoma, and 8 patients with metastatic carcinoma. The median age was 69 (range = 36-94); 95% reported dyspnea; 71% cough and 22% hemoptysis. Seventy-two percent of patients reported resolution of their symptoms and 54% achieved a bronchoscopic response (at least 50% decrease in intraluminal obstruction). In a multivariate logistic model including stage, age, primary tumor type, and Karnofsky performance status (KPS) as predictors, only KPS was statistically associated with bronchoscopic response (OR = 1.1; 95%CI = 1.01-1.13) and palliation of symptoms (OR = 1.3; 95%CI = 1.05-1.59). The overall median survival was 5.2 months and was associated with bronchoscopic response (11 months in responders vs 4 in nonresponders) and symptom resolution (8 months in responders vs 1.5 in nonresponders). In a multivariate Cox survival model with stage, age, primary tumor type, and KPS as predictors, only KPS was significantly associated with survival (RR = 0.92;95%CI = 0.88-0.95).nnnCONCLUSIONSnHDR-EB with concomitant EBRT is an effective treatment regimen for patients with both endobronchial and extrabronchial tumor. Patients with higher performance status are more likely to have resolution of disease and have longer median survival.

Radiofrequency ablation of head and neck tumors: Dramatic results from application of a new technology

Radiofrequency ablation (RFA) is a new treatment modality used over the past decade predominantly in the treatment of unresectable liver tumors. We find no prior reported series on the use of RFA for malignant tumors of the head and neck.

Parotid Gland Tumors: A Comparison of Postoperative Radiotherapy Techniques Using Three Dimensional (3D) Dose Distributions and Dose-Volume Histograms (DVHs)

PURPOSEnTo compare different treatment techniques for unilateral treatment of parotid gland tumors.nnnMETHODS AND MATERIALSnThe CT-scans of a representative parotid patient were used. The field size was 9 x 11 cm, the separation was 15.5 cm, and the prescription depth was 4.5 cm. Using 3D dose distributions, tissue inhomogeneity corrections, scatter integration (for photons) and pencil beam (for electrons) algorithms and dose-volume histogram (DVH), nine treatment techniques were compared. [1] unilateral 6 MV photons [2] unilateral 12 MeV electrons [3] unilateral 16 MeV electrons [4] an ipsilateral wedge pair technique using 6 MV photons [5] a 3-field AP (wedged), PA (wedged) and lateral portal technique using 6 MV photons [6] a mixed beam technique using 6 MV photons and 12 MeV electrons (1:4 weighting) [7] a mixed beam technique using 6 MV photons and 16 MeV electrons (1:4 weighting) [8] a mixed beam technique using 18 MV photons and 20 MeV electrons (2:3 weighting) [9] a mixed beam technique using 18 MV photons and 20 MeV electrons (1:1 weighting).nnnRESULTSnUsing dose-volume histograms to evaluate the dose to the contralateral parotid gland, the percentage of contralateral parotid volume receiving > or = 30% of the prescribed dose was 100% for techniques [1], [8] and [9], and < 5% for techniques [2] through [7]. Evaluating the hottest 5 cc of the ipsilateral mandible and temporal lobes, the hot spots were: 152% and 150% for technique [2], 132% and 130% for technique [6]. Comparing the exit doses, techniques [1], [8] and [9] contributed to > or = 50% of the prescribed dose to the contralateral mandible and the temporal lobes. Only techniques [2] and [6] kept the highest point doses to both the brain stem and the spinal cord below 50% of the prescribed dose.nnnCONCLUSIONnThe single photon lateral field [1] and the mixed electron-photon beams [8] and [9] are not recommended treatment techniques for unilateral parotid irradiation because of high doses delivered to the contralateral parotid gland and high exit doses which are associated with Xerostomia. The en face electron beam technique [2] and the mixed electron-photon beam technique [6] are unacceptable due to the excessive dose heterogeneity to the contiguous normal structures. In spite of optimal dose fall-off achieved using the en face technique [3], most patients cannot tolerate the resulting high skin doses. We conclude that the ipsilateral wedge pair [4], the 3-field [5], and the mixed electron-photon beam [7] techniques are optimal techniques in providing relatively homogeneous dose distributions within the target area and for minimizing dose to the relevant normal structures.

A phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck

Background: Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck.Methods: Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25–0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed.Results: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3–4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT.Conclusion: The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.

Early Wound Complications in Advanced Head and Neck Cancer Treated With Surgery and Ir192 Brachytherapy

Objectives: Brachytherapy, either as primary or adjuvant therapy, is increasingly used to treat head and neck cancer. Reports of complications from the use of brachytherapy as adjuvant therapy to surgical excision have been limited and primarily follow Iodine 125 (I125) therapy. Early complications include wound breakdown, infection, flap failure, and sepsis, and late complications may include osteoradionecrosis, bone marrow suppression, or carotid injuries. The authors sought to identify the early wound complications that follow adjuvant interstitial brachytherapy with iridium 192 (Ir192).

The relationship between dose heterogeneity ("hot" spots) and complications following high-dose rate brachytherapy.

PURPOSEnIt is generally believed that hot spots should be avoided in radiotherapy because they lead to complications. Dose homogeneity within the target volume is much more difficult to achieve during brachytherapy than during external beam irradiation, and implants are rarely geometrically perfect. To not underdose some parts of the target volume, therefore, it may be necessary to accept hot spots in other parts of the target volumes, but it is not at all clear from the literature how much dose heterogeneity should be considered excessive. We undertook this study in an effort to determine just how high a dose to a hot spot is associated with clinically significant complications.nnnMETHODS AND MATERIALSnWe studied 40 patients treated by high-dose rate brachytherapy with or without external irradiation. For each patient, we calculated the minimum dose to the hottest 1 cubic centimeter (cc) volume (Dmax1) and, for 18 patients, the minimum dose to the hottest 10 cc volume (Dmax10) as well.nnnRESULTSnConsiderable dose heterogeneity existed within the target volume. The Dmax1 ranged from 150-2000% (median 320%) of the minimum target dose (MTD). The median MTD/fraction was 2.50 Gy (range 1.50-25.00), and the median Dmax1/fraction was 10.00 Gy (range 3.75-150.00). The median Dmax1 from the entire course of brachytherapy was 75.00 Gy (range 25.00-550.00). Adding the doses from planned external irradiation, plus any prior irradiation to the same area, the median total Dmax1 was 112.50 Gy (range 30.00-580.00), yet the incidence of complications, even among those in the highest quartile of this dose range, was not greater than the lowest quartile. The total median Dmax10 was 85.00 Gy (range 32.00-130.00), but the incidence of complications was, again, similar whether the dose was in the lower or the upper half of this range (32.00-85.00 Gy, or 86.00-130.00 Gy, respectively).nnnCONCLUSIONSnWe had expected to find that the patients with the highest Dmax1 and/or Dmax10 would be the ones most likely to suffer complications, but the results did not support this hypothesis. Thus, dose heterogeneity, within the scope of our study, turned out to be rather unimportant with regard to complications. This finding contradicts the conventional wisdom and suggests that concerns about hot spots need not preclude optimization to ensure adequate dosage to all parts of the target volume.

The effect of nonporous PTFE-covered stents on intimal hyperplasia following balloon arterial injury in minipigs.

Purpose: To report an experimental study investigating the ability of nonporous polytetrafluoroethylene (PTFE) covering on a metallic stent to retard the development of neointimal hyperplasia (NIH). Methods: Three groups of Hanford miniature swine underwent standardized balloon injury to both external iliac arteries. Group I animals (control) received balloon injuries only. Group II had the site of balloon injury supported by a properly sized, balloon-expandable Palmaz stent placed directly over the injury site. Group III animals received a Palmaz stent covered with PTFE graft. All animals underwent arteriography immediately after intervention and again prior to sacrifice and specimen harvest at 4 weeks. The specimens were examined grossly and histologically at the proximal, middle, and distal segments for NIH development. Results: Uncovered stents developed significantly more NIH (p < 0.0001) and greater luminal narrowing (p < 0.001) than the controls. PTFE-covered stents (group III) exhibited less NIH (p < 0.001) and luminal reduction (p < 0.01) than bare stents (group II) at the middle portion of the stent-graft, but the PTFE cover had no effect on NIH and lumen reduction at the proximal or distal ends of the prosthesis. Conclusions: PTFE-covered stents retarded NIH at 4 weeks, but only at the midportion of the devices; the covering did not prevent neointimal pannus ingrowth at the proximal and distal ends.

New barriers to ventricular invasion in paraglottic laryngeal cancer

Background. Anatomic barriers to the spread of laryngeal cancer include the conus elasticus, the quadrangular membrane, and the thyroid cartilage. It has been speculated that an elastic barrier surrounds and protects the ventricle.

PHASE I CLINICAL TRIAL OF PARENTERAL HYDROXYUREA IN COMBINATION WITH PELVIC AND PARA-AORTIC EXTERNAL RADIATION AND BRACHYTHERAPY FOR PATIENTS WITH ADVANCED SQUAMOUS CELL CANCER OF THE UTERINE CERVIX

PURPOSEnOral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix.nnnMETHODSnThis Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity.nnnRESULTSnAt dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU.nnnCONCLUSIONSnThe maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.

Loss of cervical spinal curvature during radiotherapy for head-and-neck cancers: the neck moves, too

PURPOSEnWe became concerned about our observation of the loss of the normal lordotic cervical spinal curvature during the course of radiotherapy (RT) for head-and-neck tumors. Our goal was to evaluate formally the cervical lordotic curve in 50 random patients by comparing the cervical spinal angles (CSAs) measured at the initiation of RT with the CSAs measured during the last week of RT.nnnMETHODS AND MATERIALSnFifty patients treated mono-isocentrically for head-and-neck cancer were selected randomly for review. All patients had custom-made masks, shoulder pulls, and multiple tattoos to ensure reproducibility. The CSA was defined as the angle formed by the line projected parallel to the posterior surface of C2 and the line projected parallel to C6. The measurements were done on the simulation film and the first and last port films.nnnRESULTSnThe average decrease in the CSA was 2.26 degrees (SD +/-2.19 degrees ). In patients with the isocenter placed as low as possible, the change was significantly more compared with the remaining population. (3.8 degrees vs. 1.7 degrees, p = 0.004).nnnCONCLUSIONnDespite customized immobilization, the neck position changes during the course of RT for head-and-neck tumors. Patients with the isocenter placed very low have the least long-term reproducibility and a comfortable position may be best suited to intensity-modulated RT for such head-and-neck cancer patients.