Faculty Bibliography

Although resection is the standard of care for liver metastasis, 80-90% of patients are not resectable at diagnosis. Advances in combination chemotherapy, particularly with targeted agents, have increased tumour response and survival in patients with unresectable metastatic colorectal cancer, but these techniques have limitations and may be associated with high recurrence rates. Some autopsy series have shown that as many as 40% of patients with metastatic colorectal cancer have disease confined to the liver; aggressive local therapy may improve overall survival in such patients. Local control of liver metastases can also ease hepatic capsular pain to improve quality of life. Stereotactic body radiation therapy (SBRT) offers an alternative, non-invasive approach to the treatment of liver metastasis through precisely targeted delivery of radiation to the tumours while minimising normal tissue toxicity. Early applications of SBRT to liver metastases have been promising with the reports of 2-year local control rates of 71-86% and other studies reporting 18-month local control rates of 71-93%. While these data establish the safety of SBRT for liver metastases, more rigorous phase II clinical studies are needed to fully evaluate long-term efficacy and toxicity results. In the interim, this review stresses that SBRT of liver must be performed cautiously given the challenges of organ motion and the low toxicity tolerance of the surrounding hepatic parenchyma.

BACKGROUND:A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS:Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m(2)) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks. RESULTS:Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy-dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted. CONCLUSIONS:Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. Amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen.

The epidemiology and natural history of adult gliosarcomas (GSMs), as well as patient and treatment factors associated with outcome, are ill defined. Patients over 20 years of age with GSM diagnosed from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and Cox models were used to examine outcomes. Similar analyses were conducted for patients diagnosed with glioblastoma (GBM) over the same time period. GSM represented 2.2% of the 16,388 patients identified with either GSM or GBM. No significant differences between GSM and GBM were identified with respect to age, gender, race, tumor size, or use of adjuvant radiation therapy (RT). Patients with GSM were more likely to have temporal lobe involvement and undergo some form of tumor resection. The most important analyzed factors influencing GSM overall survival were age, extent of resection, and use of adjuvant RT. After adjusting for factors impacting overall survival, the prognosis for GSM appears slightly worse than for GBM (HR = 1.17, 95% CI, 1.05-1.31). GSM is a rare malignancy that presents very similarly to GBM with a slightly greater propensity for temporal lobe involvement. Optimal treatment remains to be defined. However, these retrospective findings suggest tumor excision, as opposed to biopsy only, and adjuvant RT may improve outcome. Despite therapy, prognosis remains dismal and outcomes may be inferior to those seen in GBM patients.

PURPOSE/OBJECTIVE:Cancer cachexia is a common problem among advanced cancer patients. A mixture of beta-hydroxyl beta-methyl butyrate, glutamine, and arginine (HMB/Arg/Gln) previously showed activity for increasing lean body mass (LBM) among patients with cancer cachexia. Therefore a phase III trial was implemented to confirm this activity. MATERIALS AND METHODS/METHODS:Four hundred seventy-two advanced cancer patients with between 2% and 10% weight loss were randomized to a mixture of beta-hydroxyl beta-methyl butyrate, glutamine, and arginine or an isonitrogenous, isocaloric control mixture taken twice a day for 8 weeks. Lean body mass was estimated by bioimpedance and skin-fold measurements. Body plethysmography was used when available. Weight, the Schwartz Fatigue Scale, and the Spitzer Quality of Life Scale were also measured. RESULTS:Only 37% of the patients completed protocol treatment. The majority of the patient loss was because of patient preference (45% of enrolled patients). However, loss of power was not an issue because of the planned large target sample size. Based on an intention to treat analysis, there was no statistically significant difference in the 8-week lean body mass between the two arms. The secondary endpoints were also not significantly different between the arms. Based on the results of the area under the curve (AUC) analysis, patients receiving HMB/Arg/Gln had a strong trend higher LBM throughout the study as measured by both bioimpedance (p = 0.08) and skin-fold measurements (p = 0.08). Among the subset of patients receiving concurrent chemotherapy, there were again no significant differences in the endpoints. The secondary endpoints were also not significantly different between the arms. CONCLUSION/CONCLUSIONS:This trial was unable to adequately test the ability of beta-hydroxy beta-methylbutyrate, glutamine, and arginine to reverse or prevent lean body mass wasting among cancer patients. Possible contributing factors beyond the efficacy of the intervention were the inability of patients to complete an 8-week course of treatment and return in a timely fashion for follow-up assessment, and because the patients may have only had weight loss possible not related to cachexia, but other causes of weight loss, such as decreased appetite. However, there was a strong trend towards an increased body mass among patients taking the Juven compound using the secondary endpoint of AUC.

PURPOSE/OBJECTIVE:Respiratory motion presents a significant challenge in stereotactic body radiosurgery. Respiratory tracking that follows the translational movement of the internal fiducials minimizes the uncertainties in dose delivery. However, the effect of deformation, defined as any changes in the body and organs relative to the center of fiducials, remains unanswered. This study investigated this problem and a possible solution. METHODS AND MATERIALS/METHODS:Dose delivery using a robotic respiratory-tracking system was studied with clinical data. Each treatment plan was designed with the computed tomography scan in the end-expiration phase. The planned beams were applied to the computed tomography scan in end-inspiration following the shift of the fiducials. The dose coverage was compared with the initial plan, and the uncertainty due to the deformation was estimated. A necessary margin from the clinical target volume to the planning target volume was determined to account for this and other sources of uncertainty. RESULTS:We studied 12 lung and 5 upper abdomen lesions. Our results demonstrated that for lung patients with properly implanted fiducials a 3-mm margin is required to compensate for the deformation and a 5-mm margin is required to compensate for all uncertainties. Our results for the upper abdomen tumors were still preliminary but indicated a similar result, although a larger margin might be required. CONCLUSION/CONCLUSIONS:The effect of body deformation was studied. We found that adequate dose coverage for lung tumors can be ensured with proper fiducial placement and a 5-mm planning target volume margin. This approach is more practical and effective than a recent proposal to combine four-dimensional planning with respiratory tracking.

Carcinomatous encephalitis is a rapidly fatal form of metastasis caused by miliary spread of systemic cancer into the brain parenchyma. The diagnostic criteria and optimal treatment for this disease are not well defined. We report a patient with rapid neurologic deterioration from carcinomatous encephalitis from lung adenocarcinoma. She was treated with gefitinib and high-dose fractionated whole brain radiotherapy, and eventually improved neurologically and was discharged home on hospital day 48. Gefitinib and high-dose fractionated radiotherapy may have synergistic activity in patients with carcinomatous encephalitis from non-small cell lung cancer having favorable prognostic factors. More importantly, timely recognition of this disease and the use of large fraction radiation therapy are necessary to control rapid neurologic deterioration.

The Cyberknife delivers frameless image-guided stereotactic radiosurgery to intracranial and extracranial tumors. We report our use of Cyberknife radiosurgery on a medullary plasmacytoma in the clivus extending into the foramen magnum. No acute toxicity was seen during or within 24 hours of treatment, and the subject had a complete and durable radiographic response on MRI 12+ months after treatment. To our knowledge, this is a first case of successful Cyberknife radiosurgery of a medullary plasmacytoma.

PURPOSE/OBJECTIVE:In a Phase I/II trial, we investigated concurrent weekly docetaxel and concomitant boost radiation in patients with locally advanced squamous cell cancer of the head and neck (SCCHN) after induction chemotherapy. PATIENTS AND METHODS/METHODS:Patients presented with American Joint Committee on Cancer Stage III/IV and were treated initially with induction chemotherapy using cisplatinum/5-fluorouracil (PF), carboplatinum-5-FU, or docetaxel-PF. Patients then received docetaxel four times weekly with concomitant boost (CB) radiation (1.8 Gy once-daily X20, 1.8/1.5 Gy twice a day). Fifteen patients each received 20 mg/M2 and 25 mg/M2. RESULTS:Thirty-one patients were enrolled and 30 were evaluable for response and toxicity. Median follow-up was 42 months (range, 27-63 months). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, and unknown primary 4. Eighty-seven percent of patients had N2/N3 disease; 60% had T3/T4 disease. Twenty percent of patients had a complete response (CR) to induction chemotherapy. After chemoradiotherapy, 21 of 30 patients had a CR, 2 had progressive disease, and 7 had partial response (PR). Nineteen of 26 patients presenting with neck disease had neck dissections, and 7 of 19 were positive. Ninety-three percent of all patients were rendered disease-free after all planned therapy. Treatment failed in 8 patients, and 7 have died of disease. An additional patient died with no evidence of disease. Twenty-one patients (70%) are currently alive with no evidence of disease. No acute dose-limiting toxicity was observed at either dose level. CONCLUSIONS:This intensive treatment regimen of concurrent docetaxel/concomitant boost radiation and surgery after induction chemotherapy in poor prognosis patients yields good local regional control and survival. Docetaxel/CB chemoradiotherapy represents an aggressive alternative regimen to platinum-based chemoradiotherapy or surgery in patients who have a poor response to induction chemotherapy.

OBJECTIVES/OBJECTIVE:Chemoradiation-induced xerostomia affects approximately 40,000 head and neck cancer patients annually in the United States. No human histopathologic or immunohistochemical data exist that characterize chemoradiation-related salivary gland damage. The objective of this study was to describe the histopathologic and immunohistochemical features of the non-acute phase of human submandibular gland damage after chemoradiation therapy. METHODS:Pathologic materials were retrieved from patients who had undergone neck dissection after protocol-driven chemoradiotherapy for stage IV head and neck cancer at a tertiary head and neck cancer institute. Histologic and immunohistochemical analyses were performed on representative sections of chemoradiated submandibular glands, and findings were compared to age- and sex-matched, untreated control glands. RESULTS:Forty patients were identified who had undergone neck dissection an average of 11 weeks after treatment with induction chemotherapy and chemoradiation therapy for non-oral head and neck cancer. In the chemoradiated glands, light microscopic findings included pronounced acinar cell loss with accompanying ductal metaplasia and ductal proliferation and increased fibrosis, chronic inflammation, nuclear atypia, and cytoplasmic vacuolization when compared with controls. Microvascular density was marginally affected by chemoradiation; cytokeratin staining showed preservation of ductal epithelium when compared to controls. CONCLUSIONS:Nonacute changes seen in human submandibular glands after chemoradiation therapy are compared to those seen in previously described irradiated animal and human models. Primary dysfunction in humans appears to be related to a reduction in function and number of submandibular gland acinar cells. The ductal system appears to be preserved after chemoradiation therapy. Implications for management of xerostomia are discussed.