William J. Spanos

Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522

PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). PATIENTS AND METHODS Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. RESULTS Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v. 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v. 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v. 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v. 2.0%, respectively; P = .81), 3-year PFS (61.2% v. 58.9%, respectively; P = .76), 3-year OS (72.9% v. 75.8%, respectively; P = .32), locoregional failure (19.9% v. 25.9%, respectively; P = .97), or distant metastasis (13.0% v. 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v. 49.2%, respectively; P < .001) and OS (85.6% v. 60.1%, respectively; P < .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome. CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

RTOG 96-10: Reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck

PURPOSE Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. METHODS AND MATERIALS The eligibility requirements included SCH&N presenting as a second primary or recurrence > or =6 months after definitive RT to > or =45 Gy, with > or =75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by > or =6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. RESULTS Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083). CONCLUSION Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.

Disparities in the application of adjuvant radiotherapy after breast-conserving surgery for early stage breast cancer: impact on overall survival.

Definitive local therapy of early stage breast cancer includes adjuvant radiotherapy after breast‐conserving surgery (BCS). The authors analyzed factors that influence the receipt of radiotherapy therapy and their resultant impact on outcome.

Increasing Mastectomy Rates Among all Age Groups for Early Stage Breast Cancer: A 10‐Year Study of Surgical Choice

Abstract:  First‐line surgical options for early stage breast cancer and ductal carcinoma in situ include breast conserving surgery or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. Registry analysis was carried out for 21,869 women who underwent up‐front surgical treatment for stage 0, I or II breast cancer between 1998 and 2007 using data from the Kentucky Cancer Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Overall, 54.5% of women received breast conservation and 45.5% received mastectomy over a 10‐year period (annual BCS rate range: 46.9–61.2%). The overall mastectomy rate substantially decreased from 53.1% in 1998 to 38.8% in 2005 (p < 0.0001), but then increased to 45% in 2007 (p < 0.001). Between 2005 and 2007, the increase in mastectomies in the age groups of <50 years, 50–69 years, and ≥70 years was 7.5% (p = 0.0351), 4.9% (p = 0.0132) and, 8.0% (p = 0.0283), respectively. On multivariate analysis, the rate of receiving mastectomy was drastically higher for women with stage I or II (versus in situ) disease and moderate or poorly differentiated (versus well differentiated) histology. The rate was modestly higher for uninsured and government‐insured (versus privately insured) patients, patients older than 70 years (versus younger), rural (versus urban) location, receptor negative (versus receptor positive) disease, and unusual histologies (versus ductal and lobular histology). There was no statistically significant difference in surgical choice with regard to race. Determinants of mastectomy for in situ and early stage breast cancer include stage, histology, age, insurance status, county of residence, receptor status. The rate of mastectomy declined until 2005 and is now increasing across all age groups, especially for women < 50 years and ≥70 years.

Matched-control retrospective study of the acute and late complications in patients with collagen vascular diseases treated with radiation therapy.

BACKGROUNDControversy surrounds the potential complication rate of patients with collagen vascular diseases (CVD) after radiation. We assess the acute and late complications (based on Radiation Therapy Oncology Group criteria) by a matched-control retrospective study. PATIENTS/METHODSThe charts of 12,000 patients treated with radiation therapy at the University of Louisville from 1982 to 2001 were reviewed for CVD. A total of 38 patients with documented CVD were compared with a matched-control group of 38 patients without CVD. Median follow-up for patients with CVD was 35 months. The patients were matched on the basis of site treated, age, dose, date of treatment, sex, treatment goal, follow-up, tumor site and histology, therapeutic technique, and general treatment method. The patients with CVD included 21 patients with systemic lupus erythematosus (55%), two with scleroderma (5%), four with Raynauds phenomena (11%), three with fibromyalgia (8%), three with polymyalgia rheumatica (8%), three with Sjögrens syndrome (8%), and two with polymyositis-dermatomyositis (5%). Twenty-nine patients received curative doses, and nine patients received palliative doses. RESULTSNo difference was observed in the incidence of acute or late complications between the two groups. For CVD and matched-control patients receiving curative doses, the incidence of acute reaction for grade II was 49% versus 58% and for grade III was 7% versus 7%, respectively. The incidence of late reactions for patients with CVD and the matched control patients for grade I was 3% versus 7%, for grade II was 7% versus 3%, and for grade III was 7% versus 7%, respectively. The patients treated with palliation had a similar incidence of acute reaction in the CVD and the matched-control groups. No patients in the CVD or matched-control group had fatal complications. Only patients with scleroderma had a slight increase in acute and late complications. CONCLUSIONThis is the largest matched-control study thus far in the literature. In the comparison between the patients with CVD and the matched-control patients, there was no significant difference in the incidence of acute or late complication. However, there was a higher incidence of radiation complications in patients with scleroderma. Importantly, no fatal complication was noted in any of the patients with CVD.

Effect of rest interval on tumor and normal tissue response—A report of phase III study of accelerated split course palliative radiation for advanced pelvic malignancies (RTOG-8502)☆

From August 1985 through September 1989, 284 patients with advanced pelvic malignancies were entered into a trial (RTOG 8502) of palliative split course radiation (4440 cGy in three courses of 1480 cGy/2 days/4 fractions with a rest of 2-4 weeks between courses). The initial 148 patients were part of a Phase II acceptable response rate and minimal acute or late toxicity (IJRBP 17:659-662, 1989). The present analysis is a report of the subsequent 136 patients randomized between rest intervals of 2 weeks versus 4 weeks to determine if length of rest would influence tumor response or patient toxicity. The patients were stratified for performance status (Karnofsky Performance Status) and histology. The patients were evenly matched for age and sex. There was a trend toward increased acute toxicity incidence in patients with shorter rest interval (5/68 versus 0/68; p = .07). Late toxicity was not significantly different between the two groups. Decreasing the interval between courses did not result in a significant improvement in tumor response (CR+PR = 34% vs. 26%, p = n.s.). More patients in the 2 week groups completed all three courses (72% vs. 63%). Not surprisingly, patients completing cell three courses had a significantly higher overall response rate than for patients completing less than three courses (42% vs. 5%) and higher complete response rate (17% vs. 1%). A multivariate analysis indicated performance status as the significant predictor for number of courses completed. For Karnofsky Performance Status greater than or equal to 80, the survival at 12 months was 40% for the 2 week interval and 25% for the 4 week interval. Performance status and histology were the only significant variables in a multivariate analysis of survival.

Age as a prognostic factor in carcinoma of the cervix

The influence of age on prognosis for carcinoma of the cervix was evaluated for a population of 218 patients treated at Loma Linda University between 1972 and 1982. Treatment methods were consistent over this time interval and were tailored according to age and extent of disease. Minimum follow-up is 5 years. The age groups were less than 35, 35-55, 55-75, and greater than or equal to 75. There was a significantly higher percentage of stages IIB and III in the older (greater than 55) age groups. The age groups were subdivided by stage for analysis of local-regional and distant failures. No significant age differences in local-regional or distant failures were found. Actuarial analysis of disease-free survival demonstrated no significant difference by age group. Age could not be verified as a prognostic factor in this study population.

Commissioning of a mobile electron accelerator for intraoperative radiotherapy

Radiation performance characteristics of a dedicated intraoperative accelerator were determined to prepare the unit for clinical use. The linear accelerator uses standing wave X‐band technology (wavelength approximately 3 centimeters) in order to minimize the mass of the accelerator. The injector design, smaller accelerator components, and low electron beam currents minimize radiation leakage. The unit may be used in a standard operating room without additional shielding. The mass of the accelerator gantry is 1250 Kg (weight approximately 2750 lbs) and the unit is transportable between operating rooms. Nominal electron energies are 4, 6, 9, and 12 MeV, and operate at selectable dose rates of 2.5 or 10 Gray per minute. Dmax depths in water for a 10 cm applicator are 0.7, 1.3, 1.7, and 2.0 for these energies, respectively. The depths of 80% dose are 1.2, 2.1, 3.1, and 3.9 cm, respectively. Absolute calibration using the American Association of Physicists in Medicine TG‐51 protocol was performed for all electron energies using the 10 cm applicator. Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30° beveled applicators. Output factors were determined for all energies relative to the 10 cm flat applicator. Central axis depth dose profiles and isodose plots were determined for every applicator and energy combination. A quality assurance protocol, performed each day before patient treatment, was developed for output and energy constancy. PACS number(s): 87.53.–j, 87.52.–g

Evaluation of unplanned interruptions in radiotherapy treatment schedules

One of the major radiobiological interests has been to maximize the effectiveness of the time-dose relationship in the clinical setting. Current explorations include altered fractionation schedules, multiple daily fractions and hypofractionation. Patient compliance to standard radiotherapy treatment schedules is taken for granted. To evaluate the true rate of compliance, the charts of all new patients treated from July 1, 1984 through June 30, 1985 were reviewed. The overall incidence of unplanned interruptions was 54% (361/668). The frequency of interruptions is significantly higher in patients treated to the primary site as compared to those treated for metastasis (59.8% and 35.6% respectively). The duration of the interruptions varied: 12.7% of the patients missed only 1 day, 25% missed 2 to 5 days, 38% had interruptions totalling 6-15 days, and in 24% the total exceeded 15 days. The most frequent cause of the unplanned interruptions was a rest resulting from unusually adverse tissue reactions (46.8%-169/361). Although this study has documented that unplanned interruptions are a major problem, the impact on local control and survival cannot be determined from our data. A retrospective review of multi-institutional studies such as those conducted by the Patterns of Care or RTOG might show that one of the major causes of failure is unplanned interruptions.

Phase I-II study of multiple daily fractions for palliation of advanced head and neck malignancies.

PURPOSE To assess palliation of advance head and neck malignancies with the use of rapid hyper fractionation studies similar to the RTOG 85-02. MATERIALS AND METHODS 37 patients with 39 lesions were entered into the non-randomized Phase I-II protocol, between 1984 and 1991. Previously untreated malignancies were present in 24 lesions, primary recurrent diseases in six patients, metastasis to the head and neck in five patients and skin primaries in the remaining two cases. At presentation 15 of 37 patients (or 17 of 39 lesions) were in operable due to poor medical status, eight patients were considered technically in operable due to extent of disease, 10 patients had distant metastasis and four patients refused surgery. The protocol uses twice a day fraction (370 cGy per fraction) for 2 consecutive days totalling 1,480 cGy per course. Three courses were given at 3-week intervals for a final tumor dose of 4,440 cGy in twelve fraction over 8-9 weeks. RESULTS Eleven of 39 lesions had complete response; 19 lesions had partial response; 4 lesions had no response; 3 lesions progressed under treatment. Response could not be assessed in two patients. The average survival after completion of therapy was 4.5 months ranging from 2 weeks to 31 months. Palliation was achieved in 33 of 39 lesions. The acute reactions were minimal and no late or long term complications were noted. CONCLUSION The absence of significant complications with reasonable response in the high rate of palliation suggests that this rapid hyper fractionation palliation study should be studied for further evaluation.