Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels.

BACKGROUND: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity. PATIENTS AND METHODS: Stages III-IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy. RESULTS: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027). CONCLUSIONS: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.

Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.

Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer.

PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.

Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer.

PURPOSE: To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS: Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS: The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION: T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

Radiation therapy for local-regional recurrent breast carcinoma.

One hundred seven women with recurrent breast carcinoma involving the chest wall and/or regional lymph node regions were treated with radiotherapy between 1970 and 1979. Local-regional tumor was the initial and only evidence of recurrent breast carcinoma in all cases. Forty-seven patients had their disease confined to the chest wall alone and sixty (56%) patients had chest wall involvement as some component of their local-regional recurrent disease. Within five years after the initial mastectomy, 80.5% of recurrences were manifested. All patients had radiotherapy to at least the site of involvement. Eighty-four patients (78.5%) had a complete response. The absolute 5-year survival of all patients following local-regional recurrence was 34.6%. Five year survival was 29% in those patients who had recurrence within 5 years of the original mastectomy. For those patients whose local-regional recurrence occurred after a 5-year disease-free interval, the subsequent 5-year survival was 57%. For patients with recurrence confined to the chest wall, subsequent 5-year survival was 48.9%. Patients who had supraclavicular involvement as part of their local-regional recurrence had only a 16.1% 5-year survival. The majority of patients developed distant metastasis. Twenty-two patients developed carcinoma of the contralateral breast following local-regional recurrence. Five year survival following local-regional recurrence was only 4.3% for patients whose initial treatment for their primary breast carcinoma was surgery and adjuvant chemotherapy. For those patients whose primary breast carcinoma was treated by surgery alone or surgery and post-operative radiotherapy, the 5-year survival following local-regional recurrence was over 40%.

Simultaneous localized 915 MHz external and interstitial microwave hyperthermia to heat tumors greater than 3 cm in depth.

A technique for heating superficial lesions extending to a depth greater than 3 cm using 915 MHz electromagnetic energy is described. It is well established that with external microwave applicators operating at 915 MHz, it is only possible to heat adequately up to a maximum depth of 3 cm. However, it is demonstrated that by implanting additional layers of interstitial microwave antennas (1.5 cm spacing) at required depths greater than 3 cm, and by simultaneously exciting these applicators as well as an external applicator, it is possible to extend the depth of heating at this frequency. A large neck node was successfully heated when this combined technique was used. The details of the method and the equipment used are described. Specific Absorption Rate (SAR) values and temperature distributions obtained during the four treatments delivered to the patient are also presented. This technique can be used in situations where it is not possible to perform extensive interstitial implantation, and in institutions where hyperthermia equipment for heating deeper lesions is not available.

A new radioisotope technique of splenic localization for radiation treatment.

A new technique of splenic localization, before initiating radiation therapy in patients with Hodgkin's disease, is described. We find this method of splenic localization economical and accurate.

The role of adjuvant irradiation following primary prostatectomy, based on histopathologic extent of tumor.

One hundred twenty-three patients who underwent primary prostatectomy at Northwestern Memorial Hospital during the-years 1976 to 1985 are reviewed. The patients were divided into three groups: Group 1 (50 patients) comprises patients with tumor well-contained within the prostate and without perineural, perivascular, or lymphatic (NVL) invasion; Group 2 (57 patients) comprises patients with more extensive tumor extending through or to the prostatic capsule, extending to or near the surgical margin, involving seminal vesicles, or having NVL invasion; Group 3 (16 patients) comprises those patients who received immediate postoperative irradiation. The actuarial 10-year local control rates of Group 1 (88%) and Group 3 (100%) were statistically superior to that of Group 2 (72%), p less than 0.05. The actuarial 10-year disease-free survival rate of Group 1 (72%) is statistically superior to that of Group 2 (56%), p less than 0.01; the difference in 10-year disease-free survival between Group 2 (56%) and Group 3 (64%) did not reach statistical significance. Ten-year actuarial survival statistics are 64%, 80%, and 76% for Groups 1, 2, and 3 respectively. There was no statistically significant difference in actuarial survival among any of the groups. Patients with tumor extending to or through the prostatic capsule, extending to or near the surgical margins, involving the seminal vesicles, or having NVL invasion all may benefit from adjuvant irradiation in the immediate perioperative period.

Evaluation of an ingestible telemetric temperature sensor for deep hyperthermia applications.

We have investigated the potential of an ingestible thermometric system (ITS) for use with a deep heating system. The ingestible sensor contains a temperature-sensitive quartz crystal oscillator. The telemetered signal is inductively coupled by a radiofrequency coil system to an external receiver. The sensors, covered with a protective silicon coating, are 10 mm in diameter and 20 mm long and are energized by an internal silver-oxide battery. Experimental studies were carried out to investigate the accuracy of the system and the extent of reliable operation of these sensors in an electromagnetic environment. Different measurements were repeated for five sensors. Calibration accuracy was verified by comparison with a Bowman probe in the temperature range 30 degrees C to 55 degrees C. Linear regression analysis of individual pill readings indicated a correlation within +/- 0.4 degrees C at 95% prediction intervals in the clinical temperature range of 35 degrees C to 50 degrees C. Further work is required to improve this accuracy to meet the quality assurance guidelines of +/- 0.2 degrees C suggested by the Hyperthermia Physics Center. Response times were determined by the exponential fit of heat-up and cool-down curves for each pill. All curves had correlation coefficients greater than 0.98. Time (mean +/- SE) to achieve 90% response during heat-up was 115 +/- sec. Time to cool-down to 10% of initial temperature was 114 +/- 4 sec. The effect of the external antenna and sensor spacing and the angle of orientation of the sensor relative to the antenna plane were also studied. Electromagnetic interference effects were studied by placing the sensor with a Bowman probe in a cylindrical saline phantom for the tests in an annular phase array applicator. Different power levels at three frequencies--80, 100, and 120 MHz--were used. Accurate temperature readings could not be obtained when the electromagnetic power was on because of interference effects with the receiver. However, the temperatures read with the ITS immediately after the electromagnetic power was switched off correlated well with the Bowman probe readings across the power categories and the three frequencies used. The phantom was heated to steady state, with a Bowman probe placed at the central axis of the cylinder used as control. During the heat-up period and the steady state, the mean difference (+/- SE) between the ITS and Bowman probe was 0.12 degrees C (+/- 0.05 degrees C).(ABSTRACT TRUNCATED AT 400 WORDS)

Local graft irradiation after failure of modern immunosuppression in acute cellular and vascular graft rejection.

PURPOSE: With improved chemical immunosuppressive agents, approximately 90% of rejection episodes can be reversed. However, in situations of failed immunosuppression, graft loss becomes inevitable. Our objective is to assess the efficacy of local graft irradiation (LGI) as an effort of last resort in a contemporary group of patients in whom graft failure to irreversible cellular and vascular rejection is imminent. METHODS AND MATERIALS: A total of 308 renal transplantations were performed at our institution from 1992 to 1995, and an overall 1-year graft survival rate of 90% has been seen as a result of improvement in chemical immunosuppression. However, 6 patients were referred for LGI when all other measures failed to reverse the rejection crisis. Parameters that were studied in these patients included graft function and postirradiation graft histology. RESULTS: Irradiation was associated with reversal of the rejection crisis and resulted in documented histological long-term graft survival in 1 of the 6 patients (17%). Two of the six patients (33%) had reversal of the rejection episode based on postirradiation biopsy of the renal allograft. Three of the six patients showed some level of clinical improvement of graft function for varying periods of time. One patient maintained stable allograft function without deterioration and with continued independence from hemodialysis. One recipient died from sepsis despite histologic improvement after irradiation. CONCLUSIONS: Our impression is that LGI is indicated when all other measures have failed to reverse an acute rejection episode in the transplanted renal allograft. The role of radiation in this setting should be studied further.

Transbronchial radioactive implantation using a Flexible Injector System. An improved technique for endobronchial brachytherapy.

A new implantation device for endobronchial brachytherapy is described. This implantation system is flexible and can be easily passed through the suction channel of a flexible bronchofiberscope (FBF) for radionuclide implantation of the tumor. All four patients implanted using this system, experienced excellent palliation of their symptoms. We think that the flexible system described is an improvement over the rigid system for endobronchial implantation in most patients.

Outpatient total body irradiation prior to bone marrow transplantation in pediatric patients: a feasibility analysis.

Outpatient total body irradiation (TBI) prior to bone marrow transplantation has been accomplished in a total of 68 pediatric patients. The TBI regimen was fractionated with a total dose of 12 Gy in eight fractions twice daily. Antiemetic therapy consisted of oral ondansetron three times daily throughout the TBI course. Eight patients experienced mild nausea without vomiting, and four patients experienced mild nausea and vomiting. One patient required intravenous hydration after severe nausea and vomiting. Another patient experienced intractable diarrhea and dehydration which required inpatient management. Outpatient TBI prior to bone marrow transplantation is feasible in pediatric patients.

Role of radiation therapy in the management of carcinoma in situ of the larynx.

Twenty-one patients with carcinoma in situ of the larynx were treated with definitive irradiation from 1959 to 1987. The in situ changes were limited to 1 vocal cord in 19 patients, and to both vocal cords in 1 patient. One patient demonstrated extensive in situ changes involving the vocal cords bilaterally, as well as the anterior commissure, with both supraglottic and infraglottic extension. The mean follow-up from completion of treatment was 6.2 years, with a median of 50 months. Definitive irradiation resulted in a local control rate of 95%. The patient with extraglottic spread of in situ changes experienced a local failure 7 months after completion of treatment and, despite surgical salvage, died of local recurrence. This patient represents the only recurrence in our series. Our data suggest that radiation therapy can provide excellent control in carcinoma in situ limited to the true vocal cord.

Swallowing disorders in head and neck cancer patients treated with radiotherapy and adjuvant chemotherapy.

The nature of swallowing problems was examined in nine patients treated primarily with external-beam radiation and adjuvant chemotherapy for newly diagnosed tumors of the head and neck. All subjects underwent videofluorographic examination of their swallowing. Three analyses were completed, including the following: observations of motility disorders, residue, and aspiration; temporal analyses; and biomechanical analyses. Oropharyngeal swallow efficiency was calculated for the first swallow of each bolus. Swallow motility disorders were observed in both the oral and pharyngeal stages. Seven of the nine patients demonstrated reduced posterior tongue base movement toward the posterior pharyngeal wall and reduced laryngeal elevation during the swallow. Oropharyngeal swallow efficiency measures were significantly lower in the nine irradiated patients than in age-matched normal subjects. Between patients and normal subjects, significant differences were found in the measures of timing and distance of pharyngeal structural movements during the swallow, as well as in the measures of coordination during the swallow. Although treatment of head and neck cancer with external-beam radiation is designed to provide cancer cure and preserve organ functioning, oral and pharyngeal motility for swallow can become compromised if external-beam radiation treatment is provided to either the larynx or tongue base regions.

Intraoperative radiation of canine carotid artery, internal jugular vein, and vagus nerve. Therapeutic applications in the management of advanced head and neck cancers.

As a step in the application of intraoperative radiotherapy (IORT) for treating advanced head and neck cancers, preliminary information was obtained on the radiation tolerance of the canine common carotid artery, internal jugular vein, and vagus nerve to a single, high-dose electron beam. Both sides of the neck of eight mongrel dogs were operated on to expose an 8-cm segment of common carotid artery, internal jugular vein, and vagus nerve. One side of the neck was irradiated, using escalating doses of 2500, 3500, 4500, and 5500 cGy. The contralateral side of the neck served as the unirradiated control. At 3 and 6 months after IORT, one dog at each dose level was killed. None of the dogs developed carotid bleeding at any time after IORT. Light microscopic investigations using hematoxylin-eosin staining on the common carotid artery and internal jugular vein showed no consistent changes that suggested radiation damage; however, the Masson trichrome stain and hydroxyproline concentration of irradiated common carotid artery indicated an increase in the collagen content of the tunica media. Marked changes in the irradiated vagus nerve were seen, indicating severe demyelination and loss of nerve fibers, which appeared to be radiation-dose dependent. Four patients with advanced recurrent head and neck cancer were treated with surgical resection and IORT without any acute or subacute complications. The role of IORT as a supplement to surgery, external beam irradiation, and chemotherapy in selected patients with advanced head and neck cancer needs further exploration.

Radiotherapy of lymphoproliferative diseases of the orbit. Surveillance of 65 cases.

Sixty-five patients with lymphoproliferative disease of the orbit were treated at the Joint Radiation Oncology Center of the University of Pittsburgh. An analysis of these patients was stratified by their initial tumor histopathology: benign lymphoid hyperplasia (BLH) in 28, malignant lymphoma (ML) in 20, and lymphoid infiltrate of indeterminate histology (IH) in 17. The median follow-up was 42 months. Radiation treatment was efficacious in all three groups of patients. The actuarial local recurrence-free survival rate is 84%. Treatment programs usually consisted of 20 to 30 Gy delivered in 10 to 15 fractions. ML patients had significantly lower overall and disease-specific survival rates than IH and BLH patient (p less than or equal to 0.02). BLH patients had a significantly lower local recurrence-free survival than patients with IH and BLH (p = 0.03). There was no significant difference between the three groups of patients with regard to the subsequent development of systemic lymphoma. There were no significant differences in local (16%) or systemic (36%) relapse between patients irradiated with less than 30 Gy or greater than or equal to 30 Gy. Cataracts were detected in 46% of the patients treated with anterior-posterior fields, but none were detected in those treated with other techniques. The results of this study emphasize the importance of long-term follow-up and careful treatment planning for patients with lymphoproliferative diseases of the orbit.

Management of early-stage Hodgkin's lymphoma. The radiation oncology experience at Northwestern University/Northwestern Memorial Hospital.

Early-stage Hodgkin's lymphoma patients treated with radiotherapy alone or combined modality therapy were retrospectively analyzed for survival, patterns of failure, salvage, and toxicity. Of 75 evaluable patients, 47 were given radiotherapy alone and 28 were given combination radiotherapy and chemotherapy. Of the patients studied, 26 were clinical stage I and 49 were clinical stage II, with nine patients upstaged at laparotomy. Minimum follow-up was 2 years, with a median of 81 months. Complete response rate was 95%. Relapse-free survival and overall survival were 89% and 96%, respectively, at 2 years; 78% and 86% at 5 years; and 76% and 82% at 10 years. Of 16 patients who relapsed (21%), 13/47 patients were treated with radiotherapy and 3/28 were treated with combined modality therapy. Salvage rates were higher in those treated with radiotherapy alone. There were 13 deaths: six from disease, two from treatment-related complications, and five from second primary malignancies. There was a higher incidence of second malignancies and deaths due to complication in patients treated with combined modality therapy. Radiotherapy alone or with chemotherapy is an effective modality in the treatment of Hodgkin's lymphoma. Treatment should be selected properly to optimize results and decrease complications.

Initial results for automated computational modeling of patient-specific electromagnetic hyperthermia.

Developments in finite-difference time-domain (FD-TD) computational modeling of Maxwell's equations, super-computer technology, and computed tomography (CT) imagery open the possibility of accurate numerical simulation of electromagnetic (EM) wave interactions with specific, complex, biological tissue structures. One application of this technology is in the area of treatment planning for EM hyperthermia. In this paper, we report the first highly automated CT image segmentation and interpolation scheme applied to model patient-specific EM hyperthermia. This novel system is based on sophisticated tools from the artificial intelligence, computer vision, and computer graphics disciplines. It permits CT-based patient-specific hyperthermia models to be constructed without tedious manual contouring on digitizing pads or CRT screens. The system permits in principle near real-time assistance in hyperthermia treatment planning. We apply this system to interpret actual patient CT data, reconstructing a 3-D model of the human thigh from a collection of 29 serial CT images at 10 mm intervals. Then, using FD-TD, we obtain 2-D and 3-D models of EM hyperthermia of this thigh due to a waveguide applicator. We find that different results are obtained from the 2-D and 3-D models, and conclude that full 3-D tissue models are required for future clinical usage.

Re-irradiation and external hyperthermia in locally advanced, radiation recurrent, hormone refractory prostate cancer: a preliminary report.

The purpose of this report is to present the preliminary results of re-irradiation and external hyperthermia in patients with locally advanced, previously irradiated, hormone refractory prostate cancer. Three consecutive patients with symptomatic, locally advanced, previously irradiated and hormone refractory prostate cancer were treated with further irradiation (30.6-50 Gy) and external hyperthermia (5-8 treatments). All patients had complete resolution of symptoms lasting for 12-24 months. Significant tumour shrinkage, including complete tumour response, was demonstrated by CT and endoscopy. In one case, at 2 years after re-treatment, there is continued tumour regression and bone regeneration in the pelvis. Two patients had local control of tumour, which continued until most recent follow-up at 12 months and more than 24 months, respectively. Another case developed local recurrence at 17 months. At most recent follow-up, no patient has experienced significant treatment-related side effects. In these patients with no other therapeutic alternatives, re-irradiation and hyperthermia can provide durable tumour response for more than a year, resulting in significant improvement in quality of life. Further clinical studies are warranted.