John M. Holland

Swallowing Function After Chemoradiation for Advanced Stage Oropharyngeal Cancer

OBJECTIVE: Advanced-stage oropharyngeal cancer may be treated either surgically or nonsurgically. We reported previously functional outcomes after surgical resection with free-tissue transfer. In the present study, we evaluated swallowing function after combined chemoradiation for oropharyngeal cancer. STUDY DESIGN AND SETTING: Retrospective review of 30 patients treated at a tertiary academic center for Stage III/IV oropharyngeal cancer with sequential or concurrent chemoradiation from 1994 to 2003. RESULTS: Inclusion criteria were met by 27 of 30 (90%) patients. Most patients had base of tongue lesions (67%) and Stage IV disease (93%). Gastrostomy was carried out in 22 (82%) patients either before or during treatment. Three months after chemoradiation, 33% (9/27) were consuming all nutrition orally, 22% (6 of 27) were NPO, and 45% (12 of 27) had some oral intake but still required tube feeds. One year after treatment, 53% (10 of 19) had an exclusively oral diet whereas 47% still required tube feeds including 1 patient (5%) who was NPO. In patients without recurrence and follow-up length >1 year, 69% (9 of 13) were consuming all nutrition orally whereas 31% still required gastrostomy tube (G-tube) support. A higher rate of G-tube dependence was observed in patients treated for base of tongue lesions vs tonsil lesions (67% vs 25%, P = 0.049, χ 2 analysis). CONCLUSIONS: At this institution, the short-term (3-4 months) rate of G-tube dependence was similar after surgical and non-surgical treatment of oropharyngeal cancer. One year after chemoradiation, 31% of patients without recurrence still required tube feeds. SIGNIFICANCE: These results suggest that organ-preservation protocols do not reduce the prevalence of chronic dysphagia and G-tube dependence after management of oropharyngeal cancer. EBM rating: C-4

Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice.

The tumor recurrence from residual local or micrometastatic disease remains a problem in cancer therapy. In patients with soft tissue sarcoma and the patients with inoperable nonsmall cell lung cancer, local recurrence is common and significant mortality is caused by the subsequent emergence of metastatic disease. Thus, although the aim of the primary therapy is curative, the outcome may be improved by additional targeting of residual microscopic disease. We display in a murine model that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals. Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in the control of residual disease. We further show that systemic adjuvant administration of αOX40 at surgery eliminates local recurrences. In this model, αOX40 acts to directly enhance tumor antigen-specific CD8 T-cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo. These results are also corroborated in a murine model of hypofractionated radiation therapy of lung cancer. Administration of αOX40 in combination with radiation significantly extended the survival compared with either agent alone, and resulted in a significant proportion of long-term tumor-free survivors. We conclude that αOX40 increases tumor antigen-specific CD8 T-cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant αOX40 administration may be a valuable addition to surgical and radiation therapy for cancer.

A comparison of CT scan to transrectal ultrasound-measured prostate volume in untreated prostate cancer☆

PURPOSE To compare CT and transrectal ultrasound (TRUS)-measured prostate volumes in patients with untreated prostate cancer. METHODS AND MATERIALS Between 1995 and 1999, 48 consecutive patients at the Portland Veterans Affairs Medical Center were treated with external beam radiotherapy. In 36 of these patients, TRUS and CT measurements of the prostate volume were obtained before treatment and <6 months apart. The TRUS volume was calculated using the prolate ellipsoid formula. The CT volume was calculated from the contours of the prostate drawn by one physician, who was unaware of the TRUS volume calculation, on axial CT images. RESULTS The TRUS and CT prostate volume measurements correlated strongly (Pearsons correlation coefficient = 0.925, 95% confidence interval 0.856-0.961, p < 0.0001). The CT volume was consistently larger than the TRUS volume by a factor of approximately 1.5. In men with a TRUS prostate volume less than the median (<28 cm(3)), the CT/TRUS volume ratio was 1.7, and it was 1.4 for men whose volume was greater than the median. The CT volumes were correlated similarly with the TRUS volumes regardless of the CT slice interval. CONCLUSION A strong correlation was found between CT scan and TRUS measurement of the prostate volume; however, CT consistently overestimated the prostate volume by approximately 50% compared with TRUS.

Second malignancies in early stage laryngeal carcinoma patients treated with radiotherapy

A retrospective review of 240 patients with T1/T2 squamous cell carcinomas of the larynx was performed. Seventy-two per cent had glottic primaries, 27 per cent had supraglottic tumours and one per cent had subglottic disease. Sixty-nine per cent presented with T1 disease and 31 per cent had T2 staged tumours. All patients were treated with definitive radiotherapy between 1973 and 1997. With a median follow-up of 68 months, 68 patients (28 per cent) have developed 72 other cancers. Ten of 68 presented with synchronous primaries (15 per cent). Thirty per cent of glottic patients and 25 per cent of the supraglottic/subglottic patients developed second cancers. The most frequent second malignancy was lung cancer: 28/72 (39 per cent). Fifteen patients developed second head and neck cancers (21 per cent). Other second primary sites included oesophagus (eight), prostate (six), colorectal (five), breast (two) and others (eight). The median time from radiotherapy until the development of a second cancer was 31 months. The Kaplan-Meier survival estimate at five years was significantly less for those patients developing second cancers (55 per cent) compared to those not developing second malignancies (70 per cent), (p<0.05). The median survival from the development of a second cancer was 14 months. More died as a result of a second cancer (41 patients) than their primary laryngeal cancer (40 patients). Second cancers are common and deadly in patients with early stage laryngeal carcinoma.

Does neoadjuvant chemoradiation downstage esophageal carcinoma

BACKGROUND Neoadjuvant chemoradiotherapy is administered to patients with esophageal carcinoma with the belief that this will both downstage the tumor and improve survival. Endoscopic ultrasound (EUS) is currently the most accurate method of staging esophageal cancer for tumor (T) and lymph node (N) status. Because both EUS and neoadjuvant therapy for esophageal carcinoma are relatively new, there are few data examining the relationship between EUS stage and histological stage (the stage after resection) in patients receiving neoadjuvant therapy. METHODS To determine the effect of neoadjuvant chemoradiotherapy on T and N stage as determined by EUS, we retrospectively compared two groups of patients with esophageal cancer staged by EUS. One group (33 patients) underwent neoadjuvant therapy (Walsh protocol: 5-fluorouracil, cisplatin, and 4000 rads of external beam radiation) followed by resection. The second group (22 patients), a control group, underwent resection without neoadjuvant therapy. We then compared histological stage to determine if there was a downstaging in the patients receiving neoadjuvant therapy. Survival was evaluated as well. RESULTS EUS accurately predicted histologic stage. In the control group EUS overestimated T stage in 3 of 22 (13%), underestimated N stage in 2 of 22 (9%), and overestimated N stage in 2 of 22 (9%) of patients. Preoperative radiochemotherapy downstaged (preoperative EUS stage versus pathologic specimen) 12 of 33 (36%) of patients whereas only 1 of 22 (5%) of patients in the control group was downstaged. Complete response (no tumor found in the surgical specimen) was observed in 5 of 33 (15%) of patients receiving radiochemotherapy. Survival was prolonged significantly in patients receiving radiochemotherapy: 20.6 months versus 9.6 months for those (stage II or III) patients not receiving radiochemotherapy (P <0.01). Operative time, operative blood loss, and length of stay were not significantly different between groups. Perioperative mortality was higher in the radiochemotherapy group (13%) compared with the no radiochemotherapy group (5%) but did not achieve statistical significance. CONCLUSIONS EUS accurately stages esophageal carcinoma. Neoadjuvant radiochemotherapy downstages esophageal carcinoma for T and N status. In our nonrandomized study, neoadjuvant therapy conferred a significant survival advantage. Operative risk appears to be increased in patients receiving neoadjuvant radiochemotherapy prior to esophagectomy.

Potency following high-dose three-dimensional conformal radiotherapy and the impact of prior major urologic surgical procedures in patients treated for prostate cancer

PURPOSE To assess the impact of high-dose three-dimensional conformal radiotherapy (3DCRT) on potency in patients treated for clinically localized prostate cancer and to identify factors that might predict the outcome of sexual function following treatment. METHODS AND MATERIALS One hundred twenty-four consecutive patients treated with 3DCRT for localized prostate cancer at UCSF between 1991-1993 were included in this retrospective analysis. Patient responses were obtained from a mailed questionnaire, telephone interviews, or departmental records. Medial follow-up was 21 months. RESULTS Sixty patients reported having sexual function prior to 3DCRT, including 47 who were fully potent and 13 who were marginally potent. Of the remaining 64 patients, 45 were impotent, 7 were on hormones, 1 was status-postorchiectomy, and 11 were not evaluable. Following 3DCRT, 37 of 60 patients (62%) retained sexual function sufficient for intercourse. Of those with sexual function before irradiation, 33 of 47 (70%) of patients fully potent and 4 of 13 (31%) of patients marginally potent maintained function sufficient for intercourse (p < 0.01). Potency was retained in 6 of 15 (40%) patients with a history of a major urologic surgical procedure (MUSP) and in 31 of 45 (69%) with no history of a MUSP (p < 0.04). Transurethral resection of the prostate was the MUSP in eight of these patients, with four (50%) maintaining sexual function. CONCLUSIONS Patients who receive definitive 3DCRT for localized prostate cancer appear to maintain potency similar to patients treated with conventional radiotherapy. However, patients who are marginally potent at presentation or who have a history of a MUSP appear to be at increased risk of impotence following 3DCRT.

Prevention of local recurrence after surgical debulking of nodal and subcutaneous melanoma deposits by hypofractionated radiation

Background: Local recurrence (LR) after surgical debulking of nodal or subcutaneous melanoma deposits defeats the purpose of operation and may worsen prognosis if the procedure was performed for stage III disease. To decrease LR rates in this setting, we extended the previously described role of hypofractionated radiation for melanoma deposits of the neck to all situations where the patient was felt to be at high risk for postoperative relapse after resection of bulky disease.Methods: Hypofractionated external beam radiation was administered in 6-Gy doses for 5 fractions (total dose 30 Gy, given over a median of 15 elapsed days) to 42 resected melanoma deposit sites in 41 patients.Results: Stages of the 41 patients at the time of treatment were: 22 stage III and 19 stage IV. All patients had complete gross resection of disease at the radiation site before radiation. Mean time between operation and initiation of radiation was 4 weeks. The 42 sites of treatment included 27 neck, 9 axilla, 3 groin, and 3 subcutaneous deposits. There were no treatment-related deaths; side effects were minimal and self-limited. Transient erythema, desquamation, fibrosis, telangiectasias, and mucositis, parotiditis, and xerostomia (for head and neck radiation) were reported, but no patient required interruption of therapy for these events. Of the 42 treated sites, only 2 recurred in the treatment field (one neck, one axilla) during the mean follow-up time of 22.4 months, for a treatment failure rate of 4.8%. This represents improved local control compared with patients treated with surgery alone at our institution and with published recurrence rates.Conclusions: The addition of hypofractionated radiation therapy after resection of nodal and subcutaneous melanoma deposits at a variety of sites is a rapid and well-tolerated method of providing excellent local control.

Metabolic Tumor Volume as a Prognostic Imaging-Based Biomarker for Head-and-Neck Cancer: Pilot Results From Radiation Therapy Oncology Group Protocol 0522

PURPOSE To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting. METHODS AND MATERIALS Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes. RESULTS Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited. CONCLUSION High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early‐stage non–small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single‐institution reports. The current multi‐institutional study reported outcomes evaluating the largest such population reported to date.

Cranial neuropathy following curative chemotherapy and radiotherapy for carcinoma of the nasopharynx

Cranial nerve damage following head and neck radiotherapy is an unusual event. Cranial neuropathy following concurrent chemotherapy and radiotherapy is unreported. The authors report a case of a 54-year-old man treated with curative chemotherapy and radiotherapy for a stage III nasopharyngeal carcinoma who developed an unilateral hypoglossal nerve palsy five years after therapy. Follow-up examination and magnetic resonance imaging (MRI) show no evidence of recurrent disease. Hypoglossal nerve injury occurring after head and neck radiotherapy is an indirect effect due to progressive soft tissue fibrosis and loss of vascularity. This process develops over years leading to nerve entrapment and permanent damage. Cranial nerve palsies, including damage to the hypoglossal nerve, can develop years after therapy with no evidence of tumour recurrence. Chemotherapy and radiotherapy have improved progression-free and overall survival in advanced nasopharyngeal cancer. As more patients achieve long-term tumour control following chemotherapy and radiotherapy, we must be cognizant of potential late injury to cranial nerves.