Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.

Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.

High-dose-rate brachytherapy for primary carcinomas of the oral cavity and oropharynx.

OBJECTIVE: Local control for patients treated with primary radiation therapy for tumors of the oral cavity is improved using low-dose-rate brachytherapy. Oropharyngeal carcinomas have also been treated with brachytherapy. The few reports in the literature regarding high-dose-rate brachytherapy (HDRBT) for head and neck cancer involve small numbers of patients and often contain a mix of palliative and curative cases. The purpose of this study is to evaluate the feasibility of HDRBT in the largest reported cohort of primary head and neck cancer patients treated with primary radiation therapy. STUDY DESIGN: This is a prospective nonrandomized study. METHODS: Fifty-five patients with primary untreated squamous cell carcinomas of the oral cavity and oropharynx were analyzed. There were 16 patients with T1, 26 with T2, 8 with T3, and 5 with T4 tumors. All patients received external-beam radiotherapy (EBRT) followed by HDRBT. Thirty-eight patients received hyperfractionated (twice daily) EBRT followed by HDRBT two or three times daily. Patients with cervical adenopathy also received hyperthermia and an electron boost to the site(s) of positive nodes. Median follow-up was 2.7 years. Toxicity and local control were analyzed. Data were analyzed by the Kaplan-Meier life-table method with statistical significance determined by the X2 and log-rank tests. RESULTS: High-dose-rate brachytherapy was extremely well tolerated. Only 9 patients (16%) developed a complication. Four patients developed osteoradionecrosis, and five developed soft tissue necrosis, all of which healed with conservative medical management. No complication required surgical intervention or hospitalization. Actuarial 2-year local control for the entire cohort was 79%. Local control was 87% for patients with T1 (15/16) and T2 (22/26) tumors versus 47% for T3 (5/8) and T4 (2/5) tumors (P < .01). CONCLUSIONS: High-dose-rate brachytherapy is feasible as a boost for patients with primary squamous cell carcinomas of the oral cavity and oropharynx. Patients with T1 and T2 tumors fared exceptionally well; those with advanced tumors may require more aggressive treatment, such as higher radiation doses, surgical resection, or systemic chemotherapy. The use of HDRBT both shortens the overall treatment time and limits the volume of tissue exposed to high doses of radiation therapy. In the future, as more patients treated with HDRBT are evaluable, we hope to identify potential factors that predict for local control so that we may select patients optimally for this treatment.

Significance of pretreatment hemoglobin level in patients with T1 glottic cancer.

Recent reports have suggested that pretreatment hemoglobin level (Hgb) is significantly associated with local control (LC) and overall survival (OS) in patients with T1 and T2 squamous cell carcinoma of the glottic larynx. To further evaluate the association of pretreatment Hgb level and other factors with outcome, we performed a retrospective review limited to patients with T1 squamous cell carcinoma of the glottic larynx treated with external beam radiation therapy. One-hundred thirty-nine patients with T1 squamous cell carcinoma of the glottic larynx were analyzed. Median follow-up was 5 years (range 2-22). Median pretreatment Hgb was 14.4 gm/dl (range 8.2-17.2). The following parameters were analyzed for their impact on LC, OS, and disease specific survival (DSS): age; gender; pretreatment Hgb; tumor grade; anterior commissure involvement; field size; total dose; dose per fraction; and overall treatment time. Five-year actuarial LC was 84%. Pretreatment Hgb was not a significant predictor for LC when assessed as a continuous variable (P = 0.38), nor as a dichotomous variable with a cutoff at 13 gm/dl. Local control was 82% for patients with Hgb >13 vs. 92% for Hgb < or = 13 (P= 0.13). No other factor was significant for LC. Five-year actuarial OS was 74%. Univariate analysis revealed that, pretreatment Hgb, total dose, and patient age were significant factors for OS. Overall survival was 78% for patients with pretreatment Hgb > 13 gm/dl vs. 68% for patients with Hgb < or = 13 gm/dl (P = 0.004). Overall survival was 77% for patients treated with > 66 Gy vs. 67% for those treated with < or =66 Gy (P = 0.0013), and 80% for patients < or =61 years as opposed to 69% for patients older than 61 years (P = 0.017). Multivariate analysis revealed that only age (P = 0.014) and Hgb concentration (P = 0.001) retained significance. Five-year actuarial DSS was 92%. Pretreatment Hgb was not a prognostic factor for DSS, nor were any other analyzed factors. Pretreatment Hgb is not a significant prognostic factor for LC in patients with T1 squamous cell carcinoma of the glottic larynx, but it does predict for a poorer OS without affecting DSS. This suggests that patients with lower pretreatment Hgb may have confounding medical problems that detract from their overall survival.

Second malignant neoplasia in patients with T1 glottic cancer treated with radiation.

OBJECTIVE/HYPOTHESIS: To evaluate incidence, site of occurrence and outcome of second malignant neoplasia (SMN) in patients with T1 glottic cancer treated with radiation. STUDY DESIGN: Retrospective. METHODS: Between February 1964 and May 1993, 158 patients with T1 squamous carcinoma of the larynx were treated with definitive radiation. Incidence, site (aerodigestive tract or not) and outcome of SMN were analyzed. Median follow-up was 63 months (range, 12-245 mo). RESULTS: Thirty-four patients developed SMN, for an overall incidence of 22%. Twenty-four (67%) SMNs occurred in an aero-upper-digestive-tract site compared with nine (25%) occurring in a non-aero-upper-digestive tract site. The incidence of SMN observed was higher than would be expected for the general population at risk. The observed-to-expected ratios (OER) for all SMN, aero-upper-digestive SMN and non-aero-upper-digestive SMNs were 1.73, 5.53, and 0.62, respectively. Overall 5- and 10-year survivals were 76% and 57%, respectively, for those who did not develop SMN, as compared with 68% and 26%, for those who developed SMN (P = .003). Overall, 13 patients (8.2%) have died from laryngeal cancer, while 23 (15%) died from SMN (P = .001). CONCLUSION: This study confirms a higher incidence of SMN in T1 glottic cancer patients, compared with the general population. The majority of cases occur in aero-upper-digestive sites. These patients are more likely to die from their SMN than from glottic cancer. Patients with T1 squamous cell carcinoma of the glottic larynx represent a group of head and neck cancer patients who should be targeted in studies evaluating the potential benefits of chemoprevention, and aggressively counseled for social and/or behavioral modifications.

Multiple causes of cerebrovascular events in children with tumors of the parasellar region.

Cerebrovascular arterial occlusion is a rare but devastating event causing long-term morbidity in children with tumors in the parasellar region. While usually associated with radiation therapy, there are a variety of host, tumor and treatment factors which predispose patients to significant vasculopathy. Case reports of 5 patients from St. Jude Children's Research Hospital with tumors in the parasellar region who presented with or developed vascular occlusive disease are summarized. Multiple factors are identified in these cases which probably impacted on the development of cerebral arterial occlusion with or without moyamoya syndrome. These include, but are not limited to, neurofibromatosis, tumor encasement of major cerebral vessels, surgical alterations, and radiation therapy. The literature supports multiple, potentially interactive etiologies for the development of vascular events in these patients, suggesting that their development is not simply a phenomenon related to radiation therapy.

The molecular regulation of apoptosis and implications for radiation oncology.

One of the major goals of cancer research is to identify and understand the causes of cellular proliferation. The role of cell death, or lack thereof, in carcinogenesis, tumour growth, metastatic spread and response to treatment has been largely overlooked even though the morphology of apoptosis (programmed cell death) was clearly described over 20 years ago, and its importance in cancer speculated on at that time. Over the last 5 years, however, an explosion of research has focused on delineating the molecular components of the apoptotic pathways and examining the role of apoptosis in a tumour's growth and response to treatment. This review highlights the aspects of apoptosis most relevant to radiation oncologists and radiobiologists. The apoptotic pathways will be described, with attention to the stimuli that initiate apoptosis, the oncogenes and tumour suppressor genes that mediate apoptosis, and the effector enzymes (proteases and endonucleases) responsible for the execution of apoptosis. In addition, we review the effect of classically described radiobiology cell survival parameters-cell cycle stage, dose rate, linear energy transfer, oxygen, total dose, and fractionation-on radiation induced apoptosis.

Regulation of radiation-induced apoptosis in oncogene-transfected fibroblasts: influence of H-ras on the G2 delay.

Primary fibroblasts, after serum withdrawal or after irradiation, do not undergo apoptosis. Myc-transfected fibroblasts, in contrast, undergo apoptosis upon serum withdrawal and after irradiation. We have studied the relationship of apoptosis induction to effects on the G2 phase cell cycle in a series of rat embryo cells transformed by rasH plus myc or immortalized by myc alone. In this system, while the presence of rasH had little effect on the extent of apoptosis induction by serum withdrawal, rasH greatly suppressed the apoptotic response of myc-transfected cells to X-rays. The cells into which rasH had been introduced showed a profound G2 arrest associated with suppression of cyclin B1 mRNA expression. In contrast, cells with myc alone had a minimal G2 delay after irradiation and no suppression of cyclin B1 mRNA expression. We hypothesize that rasH, by influencing the G2 response of cells to X-rays, exerts an anti-apoptotic effect. In support of this hypothesis; we found that treatment of cells with caffeine, an agent that relieves the G2 delay after irradiation resulted in increased apoptosis in the irradiated cells, but not in control cells.

Radiotherapy for Merkel cell carcinoma of the skin of the head and neck.

BACKGROUND: Merkel cell carcinoma is a relatively rare neuroendocrine carcinoma of the skin. It arises in the head and neck region in approximately 50% of cases. Its aggressive behavior predisposes patients to local-regional recurrence and distant metastases after surgical excision alone. In this article, we describe our experience with Merkel cell carcinoma of the head and neck. METHODS: Of 18 patients with Merkel cell carcinoma treated in the Department of Radiation Oncology at the University of Florida, 12 patients who had primary tumors in the head and neck region are reported. Eight patients were treated at initial diagnosis (group A), and four were treated at the time of local-regional recurrence (group B). RESULTS: Local-regional control was achieved in seven of eight patients in group A and all four patients in group B. One patient in group A and all patients in group B developed distant metastases and eventually died of their disease. Bone exposure developed in one patient, requiring surgical debridement and hyperbaric oxygen treatment. CONCLUSION: Patients with Merkel cell carcinoma of the head and neck should be treated aggressively. Our data suggest that local-regional recurrence is a harbinger of distant metastases. We recommend that these patients receive treatment to both the primary site and draining lymphatics at initial presentation. The role of chemotherapy remains unclear.

Does pathologic node status affect local control in patients with carcinoma of the head and neck treated with radical surgery and postoperative radiotherapy?

PURPOSE: To evaluate the effect of pathologic lymph node status and nodal stage on local control at the primary site in patients with advanced squamous cell carcinomas of the head and neck, treated with radical surgery and postoperative irradiation. METHODS AND MATERIALS: Fifty-seven patients with advanced squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, larynx, and supraglottic larynx were analyzed. All patients underwent resection of the primary lesion, neck dissection, and postoperative radiotherapy. Minimum follow-up was 2 years. The median dose to the primary tumor bed was 60.4 Gray (range 39.7-72.0). Besides pathologic nodal status (pN0 vs. pN+) and nodal stage, the following factors were analyzed for their impact on local control: age, gender, T stage, tumor grade, resection margins, interval from surgery to irradiation, dose to the primary site, and overall treatment time. RESULTS: The 3-year actuarial local control rate was 78%. When all patients were analyzed, nodal status (pN0 vs. pN+) did not affect control at the primary site (71% vs. 82%, p = 0.42). Nodal stage (pN0-N2a va. pN2b-N2c) was also not a significant factor for local control (74% vs. 82%, p = 0.57). When only patients with negative margins were analyzed, nodal status again did not impact on local control (79% vs. 90% for pN0 vs. pN+, p = 0.39). On univariate analysis, only tumor grade, margin status, and elapsed days were significant factors for local control. Local control was 85% for patients with negative margins vs. 60% for those with positive margins (p = 0.016). For patients with moderately and poorly differentiated tumors, local control was 86% as compared to 50% for patients with well-differentiated tumors (p = 0.007). When radiotherapy was completed within 50 days, local control was 93% as opposed to 63% for > 50 days (p = 0.016). On multivariate analysis, only margin status (p = 0.002) and tumor grade (p = 0.007) remained significant. CONCLUSION: We conclude that neither the presence of pathologically positive nodes nor nodal stage is a prognostically significant factor for local control in patients who have undergone radical surgery and postoperative radiotherapy for advanced squamous cell carcinomas of the head and neck. We do not recommend a change in treatment philosophy, such as an increase in dose to the primary site, based on the pathologic status of the neck.

Prognostic factors for local control and survival in T1 squamous cell carcinoma of the glottis.

PURPOSE: To evaluate the effect of host, tumor, and treatment-related variables on local control and survival in patients with T1N0M0 squamous cell carcinoma of the glottis. MATERIALS AND METHODS: Ninety-one patients with T1N0M0 squamous cell carcinoma of the glottic larynx were analyzed. Median follow-up was 9 years (range 2-25). Patients were treated with daily fractions of 180 cGy to 220 cGy to doses of 5925-7000 cGy (median 6400). The following factors were analyzed: age, sex, histologic grade, disease extent, beam energy, field size, total dose, dose per fraction, and elapsed treatment days. RESULTS: The 5-year actuarial local control was 80%. On univariate analysis, only elapsed treatment days and dose per fraction were significant factors for local control. Local control was 100% if treatment was completed within 42 days, 91% for 43-46 days, 74% for 47-50 days, 65% for 51-54 days, and 50% for 55-66 days (p = 0.0001). In patients treated at < 200 cGy per fraction, local control was 62% as compared to 87% for > or = 200 cGy per fraction (p = 0.006). On multivariate analysis, only elapsed treatment days was a significant factor for local control (p = 0.0001). The 5-year actuarial survival for the whole group was 92%. Elapsed treatment days was the only variable affecting survival. Survival was 100% if treatment was delivered within 42 days, 96% for 43-46 days, 94% for 47-50 days, 91% for 51-54 days, and 67% for 55-66 days (p = 0.02). The 5-year actuarial disease-specific survival was 95%, with treatment duration again being the only significant prognostic factor. Disease-specific survival was 97% for treatment completed within 39-54 days versus 80% for 55-66 days (p = 0.02). Only three (3.3%) patients experienced moderate or severe complications. None of the evaluated parameters impacted significantly on complications. CONCLUSION: We conclude that elapsed days is the most prognostically significant factor for local control and survival in patients treated with radiotherapy for T1 squamous cell carcinoma of the glottis. We recommend that these patients be treated with 210 cGy daily fractions to 6300 cGy.

Application of magnetic resonance imaging and three-dimensional treatment planning in the treatment of orbital lymphoma.

Radiotherapy for lymphoma of the orbit must be individualized for each patient and clinical setting. Most techniques focus on optimizing the dose to the tumor while sparing the lens. This study describes a technique utilizing magnetic resonance imaging (MRI) and three dimensional (3D) planning in the treatment of orbital lymphoma. A patient presented with an intermediate grade lymphoma of the right orbit. The prescribed tumor dose was 4050 cGy in 18 fractions. Three D planning was carried out and tumor volumes, retina, and lens were subsequently outlined. Dose calculations including dose volume histograms of the target, retina, and lens were then performed. Part of the retina was outside of the treatment volume while 50% of the retina received 90% or more of the prescribed dose. The patient was clinically NED when last seen 2 years following therapy with no treatment-related morbidity. Patients with lymphomas of the orbit can be optimally treated using MRI based 3D treatment planning.

Crosslinked polyether/polysiloxane networks for blood-interfacing applications.

The interaction of blood with new artificial surfaces is an area of continual medical interest. In this study, a series of polyether/polysiloxane networks were synthesized, characterized in terms of both bulk and surface compositions, and evaluated for blood compatibility. The crosslinked networks were produced by reacting the epoxy groups of polyglycidoxy propyl methyl siloxane (PGPMS) with the hydroxyl end groups of polypropylene glycol (PPG). Blood compatibility was evaluated using an in vitro platelet retention test and fibrinogen adsorption experiments from human plasma and buffered saline. The PPG/PGPMS networks exhibit low fibrinogen adsorption and low platelet activation. Such properties make the networks potentially attractive as materials for blood-interfacing applications.