William M. Mendenhall

Squamous Cell Carcinoma of the Oropharynx Surgery, Radiation Therapy, or Both

The treatment of patients with squamous cell carcinoma (SCC) of the oropharynx remains controversial. No randomized trial has addressed adequately the question of whether surgery (S), radiation therapy (RT), or combined treatment is most effective.

Radiation optic neuropathy after megavoltage external-beam irradiation : analysis of time-dose factors

PURPOSE To investigate the risk of radiation-induced optic neuropathy according to total radiotherapy dose and fraction size, based on both retrospective and prospectively collected data. METHODS AND MATERIALS Between October 1964 and May 1989, 215 optic nerves in 131 patients received fractionated external-beam irradiation during the treatment of primary extracranial head and neck tumors. All patients had a minimum of 3 years of ophthalmologic follow-up (range, 3 to 21 years). The clinical end point was visual acuity of 20/100 or worse as a result of optic nerve injury. RESULTS Anterior ischemic optic neuropathy developed in five nerves (at mean and median times of 32 and 30 months, respectively, and a range of 2-4 years). Retrobulbar optic neuropathy developed in 12 nerves (at mean and median times of 47 and 28 months, respectively, and a range of 1-14 years). No injuries were observed in 106 optic nerves that received a total dose of < 59 Gy. Among nerves that received doses of > or = 60 Gy, the dose per fraction was more important than the total dose in producing optic neuropathy. The 15-year actuarial risk of optic neuropathy after doses of > or = 60 Gy was 11% when treatment was administered in fraction sizes of < 1.9 Gy, compared with 47% when given in fraction sizes of > or = 1.9 Gy. The data also suggest an increased risk of optic nerve injury with increasing age. CONCLUSION As there is no effective treatment of radiation-induced optic neuropathy, efforts should be directed at its prevention by minimizing the total dose, paying attention to the dose per fraction to the nerve, and using reduced-field techniques where appropriate to limit the volume of tissues that receive high-dose irradiation.

T1-T2N0 Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiation Therapy

PURPOSE The end results after radiation therapy for T1-T2N0 glottic carcinoma vary considerably. We analyze patient-related and treatment-related parameters that may influence the likelihood of cure. PATIENTS AND METHODS Five hundred nineteen patients were treated with radiation therapy and had follow-up for >or= 2 years. Three patients who were disease-free were lost to follow-up at 7 months, 21 months, and 10.5 years. No other patients were lost to follow-up. RESULTS Local control rates at 5 years after radiation therapy were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 72%. Multivariate analysis of local control revealed that the following parameters significantly influenced this end point: overall treatment time (P < .0001), T stage (P = .0003), and histologic differentiation (P = .013). Patients with poorly differentiated cancers fared less well than those with better differentiated lesions. Rates of local control with laryngeal preservation at 5 years were as follows: T1A and T1B, 95%; T2A, 82%; and T2B, 76%. Cause-specific survival rates at 5 years were as follows: T1A and T1B, 98%; T2A, 95%; and T2B, 90%. One patient with a T1N0 cancer and three patients with T2N0 lesions experienced severe late radiation complications. CONCLUSION Radiation therapy cures a high percentage of patients with T1-T2N0 glottic carcinomas and has a low rate of severe complications. The major treatment-related parameter that influences the likelihood of cure is overall treatment time.

Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications☆

One hundred thirty-four patients with advanced head and neck cancer were treated with radical surgery and postoperative radiation therapy between October 1964 and October 1984. All patients had greater than or equal to 2 years and 84% had greater than or equal to 5 years of follow-up. All patients included in the study were scheduled to receive continuous-course irradiation following a major cancer operation for previously untreated squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and began radiation treatment less than or equal to 3 months after the surgical procedure. Ninety-six percent had AJCC pathologic Stage III or IV cancer, and all were without evidence of gross disease at the start of irradiation. The majority of recurrences above the clavicles occurred in the primary field (84%) as opposed to the posterior strip (8%) or low neck (8%). Based on multivariate analysis and tabular comparisons, 4 factors were found to be significantly important for predicting disease control above the clavicles: (a) Surgical margin (5-year actuarial control with invasive cancer at the margin, 53%, versus 81% with negative margins, p = .009). Patients with close margins or in situ cancer at the margins had the same rate of control as those with negative margins. (b) Primary site (oral cavity, 64%, versus other sites, 83%; p = .029). (c) Neck Stage (N0-1 versus N2-3). (d) Number of indications for irradiation--for example, bone invasion, multiple positive nodes, perineural invasion (1-3 indications, 85%, versus greater than or equal to 4, 62%; p = .06). The rate of disease control above the clavicles did not correlate well with AJCC pathologic stage: Stage I-II, 67%; Stage III, 81%; Stage IVA (T1-3, N2-3A), 68%; Stage IVB (T4 and/or N3B), 80%. The interval between surgery and the start of irradiation (range 1-10 weeks) also was not prognostically important, even with stratification by tumor dose, surgical margin, and number of indications for irradiation. At 5 years, the actuarial survival rate was 33% for the entire group; for patients with invasive cancer at the margin, the survival rate was approximately half that of those whose margins were free of invasive cancer (17% versus 37%). Based on multivariate analysis, 2 factors were found to significantly increase the probability of death due to cancer: (a) neck Stage (N0-1 versus N2-3); (b) extension of tumor from the primary site into the skin or soft tissues of the neck.(ABSTRACT TRUNCATED AT 400 WORDS)

Benign meningiomas: primary treatment selection affects survival.

PURPOSE To examine the effect of primary treatment selection on outcomes for benign intracranial meningiomas at the University of Florida. METHODS AND MATERIALS For 262 patients, the impact of age, Karnofsky performance status, pathologic features, tumor size, tumor location, and treatment modality on local control and cause-specific survival was analyzed (minimum potential follow-up, 2 years; median follow-up, 8.2 years). Extent of surgery was classified by Simpson grade. Treatment groups: surgery alone (n = 229), surgery and postoperative radiotherapy (RT) (n = 21), RT alone (n = 7), radiosurgery alone (n = 5). Survival analysis: Kaplan-Meier method with univariate and multivariate analysis. RESULTS At 15 years, local control was 76% after total excision (TE) and 87% after subtotal excision plus RT (SE+RT), both significantly better (p = 0.0001) than after SE alone (30%). Cause-specific survival at 15 years was reduced after treatment with SE alone (51%), compared with TE (88%) or SE+RT (86%) (p = 0.0003). Recurrence after primary treatment portended decreased survival, independent of initial treatment group or salvage treatment selection (p = 0.001). Atypical pathologic features predicted reduced 15-year local control (54 vs. 71%) and cause-specific survival rates (57 vs. 86%). Multivariate analysis for cause-specific survival revealed treatment group (SE vs. others; p = 0.0001), pathologic features (atypical vs. typical;p = 0.0056), and Karnofsky performance status (> or = 80 vs. < 80; p = 0.0153) as significant variables. CONCLUSION Benign meningiomas are well managed by TE or SE+RT. SE alone is inadequate therapy and adversely affects cause-specific survival. Atypical pathologic features predict a poorer outcome, suggesting possible benefit from more aggressive treatment. Because local recurrence portends lower survival rates, primary treatment choice is important.

Prophylactic glutamine protects the intestinal mucosa from radiation injury.

Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine‐enriched elemental diet, administered before whole‐abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine‐enriched or glutamine‐free for 4 days. The animals were then subjected to a single dose of 1000 cGy x‐radiation to the abdomen. After irradiation, all animals received the glutamine‐free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine‐fed rats. Rats receiving the glutamine‐enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine‐free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine‐free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation which may accelerate healing of the acutely radiated bowel.

RADIATION RETINOPATHY AFTER EXTERNAL-BEAM IRRADIATION: ANALYSIS OF TIME-DOSE FACTORS

PURPOSE To investigate the risk of radiation-induced retinopathy according to total radiation dose and fraction size, based on both retrospective and prospectively collected data. METHODS AND MATERIALS Between October 1964 and May 1989, 68 retinae in 64 patients received fractionated external-beam irradiation during the treatment of primary extracranial head and neck tumors. All patients had a minimum of 3 years of ophthalmologic follow-up (range, 3 to 26 years; mean, 9 years; median, 8 years). RESULTS Twenty-seven eyes in 26 patients developed radiation retinopathy resulting in visual acuity of 20/200 or worse. The mean and median times to the onset of symptoms attributable to retinal ischemia were 2.8 and 2.5 years, respectively. Fourteen of the injured eyes developed rubeosis iridis and/or neovascular glaucoma. Radiation retinopathy was not observed at doses below 45 Gy, but increased steadily in incidence at doses > or = 45 Gy. In the range of doses between 45 and 55 Gy, there was an increased risk of injury among patients who received doses per fraction of > or = 1.9 Gy (p = .09). There was also a trend toward increased risk of injury among patients who received chemotherapy (two of two vs. four of ten in the 45-51 Gy range; p = .23). The lowest dose associated with retinopathy was 45 Gy delivered to a diabetic patient by twice-a-day fractionation. The data did not suggest an increased risk of radiation retinopathy with increasing age. CONCLUSION The current study suggests the importance of total dose as well as dose per fraction, and adds support to a small body of literature suggesting that patients with diabetes mellitus or who receive chemotherapy are at increased risk of injury. A sigmoid dose-response curve is constructed from our current data and data from the literature.

Squamous cell carcinoma of the head and neck treated with radiation therapy the role of neck dissection for clinically positive neck nodes

This is an analysis of 161 patients with squamous cell carcinoma of the head and neck treated with irradiation to the primary site and neck followed by a neck dissection(s) for clinically positive neck nodes. Patients were treated between October 1964 and December 1982; there was a minimum 2-year follow-up. Fifty-two patients were deleted from analysis of neck disease control because they died of intercurrent disease or cancer less than 2 years from treatment with the neck continuously disease-free. All patients are included in the analysis of complications. Neck disease control rate was the same for radiation plus neck dissection or radiation therapy alone for solitary nodes less than 3 cm. As the size and number of nodes increased, there was a higher rate of neck disease control for combined treatment as compared with irradiation alone. The neck disease control rate, size for size, was lower for patients with fixed nodes and for those with residual tumor in the pathologic specimen. There was no difference in neck disease control as a function of the interval between irradiation and neck dissection. For nodes less than or equal to 6 cm, a minimum node dose of 5000 rad appeared to be sufficient for control, whereas for nodes greater than 6 cm, at least 6000 rad appeared to be required for optimal control. Fixed nodes required a higher dose compared to mobile masses. The incidence of postoperative complications was increased with maximum subcutaneous doses of greater than or equal to 6000 rad. There was also an increased incidence of postoperative complications for patients undergoing simultaneous, as compared with staged, bilateral neck dissection.

Malignant tumors of the nasal cavity and paranasal sinuses.

To evaluate the role of radiation therapy in patients with nasal cavity and paranasal sinus tumors.

Radiotherapy for pituitary adenoma: Long-term outcome and sequelae☆

PURPOSE To review outcome and treatment sequelae in patients treated with external beam radiotherapy for pituitary adenomas. METHODS AND MATERIALS One hundred forty-one patients with pituitary adenomas received radiotherapy at the University of Florida and had 2-year minimum potential follow-up. One hundred twenty-one had newly diagnosed adenomas, and 20 had recurrent tumors. Newly diagnosed tumors were treated with surgery and radiotherapy (n = 98) or radiotherapy alone (n = 23). Patients with recurrent tumors received salvage treatment with surgery and radiotherapy (n = 10) or radiotherapy alone (n = 10). The impact of age, sex, presenting symptoms, tumor extent, surgery type, degree of resection, hormonal activity, primary or salvage therapy, and radiotherapy dose on tumor control was analyzed. Tumor control is defined by the absence of radiographic progression and stable or decreased hormone level (in hormonally active tumors) after treatment. Effect of therapy on vision, hormonal function, neurocognitive function, life satisfaction, and affective symptoms were examined. A Likert categorical scale survey was used for assessment of neurocognitive, life satisfaction, and affective symptom status. Survey results from the radiotherapy patients were compared with a control group treated with transsphenoidal surgery alone. Multivariate analysis used the forward step-wise sequence of chi squares for the log rank test. RESULTS At 10 years, tumor control for the surgery and radiotherapy group (S + RT) was 95% and not statistically different (p = 0.58) than for patients treated with radiotherapy alone (RT) (90%). Patients with prolactin- and ACTH-secreting tumors had significantly worse tumor control, as did patients treated for recurrent tumors. Multivariate analysis for tumor control revealed that only young age was predictive of worse outcome (p = 0.0354). Visual function was either unaffected or improved in most patients, although four patients developed visual loss due to treatment. Hormonal function was affected adversely in 46 of the 93 patients for whom detailed hormonal information was available. Neurocognitive function evaluation revealed that patients in the S + RT group were more likely (p = 0.005) to report difficulty with memory than those in the RT-alone or S-alone groups. No significant difference in life satisfaction or affective symptoms was evident. CONCLUSIONS Pituitary adenomas are well controlled by external beam radiotherapy, either alone or in combination with surgery. Visual symptoms often improve after treatment. Hormonal sequelae require medical intervention in many patients. Neurocognitive sequelae may be different among treatment groups.