Leonard R. Prosnitz

Hyperfractionated Irradiation with or without Concurrent Chemotherapy for Locally Advanced Head and Neck Cancer

BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck

PURPOSE Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Randomized trial of hyperthermia and radiation for superficial tumors.

PURPOSE Randomized clinical trials have demonstrated hyperthermia (HT) enhances radiation response. These trials, however, generally lacked rigorous thermal dose prescription and administration. We report the final results of a prospective randomized trial of superficial tumors (</= 3 cm depth) comparing radiotherapy versus HT combined with radiotherapy, using the parameter describing the number of cumulative equivalent minutes at 43 degrees C exceeded by 90% of monitored points within the tumor (CEM 43 degrees C T(90)) as a measure of thermal dose. METHODS This trial was designed to test whether a thermal dose of more than 10 CEM 43 degrees C T(90) results in improved complete response and duration of local control compared with a thermal dose of </= 1 CEM 43 degrees C T(90). Patients received a test dose of HT </= 1 CEM 43 degrees C T(90) and tumors deemed heatable were randomly assigned to additional HT versus no additional HT. HT was given using microwave spiral strip applicators operating at 433 MHz. RESULTS One hundred twenty-two patients were enrolled; 109 (89%) were deemed heatable and were randomly assigned. The complete response rate was 66.1% in the HT arm and 42.3% in the no-HT arm. The odds ratio for complete response was 2.7 (95% CI, 1.2 to 5.8; P = .02). Previously irradiated patients had the greatest incremental gain in complete response: 23.5% in the no-HT arm versus 68.2% in the HT arm. No overall survival benefit was seen. CONCLUSION Adjuvant hyperthermia with a thermal dose more than 10 CEM 43 degrees C T(90) confers a significant local control benefit in patients with superficial tumors receiving radiation therapy.

Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy.

ObjectiveThe authors determined whether microscopically positive surgical margins are detrimental to the outcome of early stage breast cancer patients treated with conservation surgery and radiation therapy. Summary Background DataThe optimal extent of breast surgery required for patients treated with conservation surgery and radiation therapy has not been established. To achieve breast preservation with good cosmesis, it is desirable to resect as little normal tissue as possible. However, it is critical that the resection does not leave behind a tumor burden that cannot be adequately managed by moderate doses of radiation. It is not known whether microscopically positive surgical margins are detrimental to patient outcome. MethodsThe records of 259 consecutive women (262 breasts) treated with local excision (complete removal of gross tumor with a margin) and axillary dissection followed by radiation therapy for clinical stage I and II infiltrating ductal breast cancer at Duke University Medical Center and the University of North Carolina between 1983 and 1988 were reviewed. Surgical margins were considered positive if tumor extended to the inked margins; otherwise the margins were considered negative. Margins that could not be determined, either because the original pathology report did not comment on margins, or because the original specimen had not been inked were called indeterminate. ResultsOf the 262 tumors, 32 (12%) had positive margins, 132 (50%) had negative margins, and the remaining 98 (38%) had indeterminate margins. There were 11 (4%) local failures; 3/32 (9%) from the positive margin group, 2/132 (1.5%) from the negative margin group, and 6/98 (6%) from the indeterminate group. The actuarial local failure rates at 5 years were 10%, 2%, and 10% respectively, p = 0.014 positive vs. negative, p = 0.08 positive vs. indeterminate (log rank test). Margin Status had no impact on survival or freedom from distant metastasis; 63 patients who originally had positive or indeterminate margins were re-excised, Two or 7 with positive margins after re-excision versus 1/56 rendered margin negative had a local recurrence. ConclusionsThe authors recommend re-excision for patients with positive margins because of Improvd local control of those rendered margin negative and identification of those patients at high risk for local failure (those who remain positive after re-excision). Because margin status impacts on local control, tumor margins after conservation surgery should be accurately determined in all patients.

Postoperative Radiotherapy for Patients with Carcinoma of the Prostate Undergoing Radical Prostatectomy with Positive Surgical Margins, Seminal Vesicle Involvement and/or Penetration Through the Capsule

AbstractBetween 1970 and 1983, 442 patients were treated for carcinoma of the prostate at our university medical center. Of the patients 319 underwent radical prostatectomy and 159 (50 per cent) had positive surgical margins and/or seminal vesicle involvement. Of these 159 patients 46 received postoperative irradiation and the actuarial survival was 96, 90 and 90 per cent at 5, 10 and 15 years, respectively. Among the remaining 113 patients who were treated with an operation alone the corresponding figures were 82, 62 and 21 per cent, respectively (p equals 0.02). Considering deaths only of cancer, the surgery only patients had a 15-year actuarial survival of 25 per cent compared to 90 per cent for those who underwent postoperative radiotherapy (p equals 0.07). Actuarial survival free of disease for the surgery plus postoperative irradiation group at 15 years was 40 per cent compared to 28 per cent for the surgery only group (p equals 0.34). Actuarial local control in the irradiated patients was 96 per ce...

Adjuvant radiotherapy for pathologic stage T3 4 adenocarcinoma of the prostate: Ten-year update

PURPOSE To determine the role of adjuvant postoperative radiotherapy (RT) following radical prostatectomy (RP) in a group of patients with pathologic Stage T3/4 adenocarcinoma of the prostate followed for a median of 10 years after treatment. METHODS AND MATERIALS Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have pathologic Stage T3/4. Forty-six received adjuvant RT and 113 did not. Radiotherapy usually consisted of 45-50 Gy to the whole pelvis followed by a boost to the prostate bed of 10-15 Gy, to a total dose of 55-65 Gy. Patients were analyzed with respect to survival, disease-free survival, local control, and freedom from distant metastases. A rising prostate-specific antigen in the absence of other evidence of relapse was scored as a separate category of recurrence. RESULTS Both groups of patients have been followed for a median of 10 years. The actuarial survival at 10 and 15 years was 62% and 62% for the RT group compared to 52% and 37%, respectively, for the RP group (p = 0.18). The disease-free survival for the Rt group was 55% and 48% at 10 and 15 years, respectively, compared to 37% and 33% for the RP group (p = 0.16). Similarly, there was no difference in the rate of distant metastases between the two groups. In contrast, the local relapse rate was significantly reduced by the addition of postoperative radiotherapy. The actuarial local control rate at 10 and 15 years was 92% and 82%, respectively, for the RT group vs 60% and 53% for the RP group (p = 0.002). CONCLUSIONS While postoperative pelvic RT significantly improves local control compared to RP alone for pathologic Stage T3/4 prostate cancer, it has no impact on distant metastases and consequently does not improve survival. These data are consistent with the conclusion that many patients with pathologic Stage T3/4 prostate cancer have occult metastases at presentation and will not be cured by local therapies alone. The optimal treatment for this patient population remains to be established.

Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: preliminary results

PURPOSE To determine the incidence and dose dependence of regional cardiac perfusion abnormalities in patients with left-sided breast cancer treated with radiation therapy (RT) with and without doxorubicin (Dox). METHODS Twenty patients with left-sided breast cancer underwent cardiac perfusion imaging using single photon emission computed tomography (SPECT) prechemotherapy, pre-RT, and 6 months post-RT. SPECT perfusion images were registered onto 3-dimensional (3D) RT dose distributions. The volume of heart in the RT field was quantified, and the regional RT dose was calculated. A decrease in regional cardiac perfusion was assessed subjectively by visual inspection and objectively using image fusion software. Ten patients received Dox-based chemotherapy (total dose 120-300 mg/m(2)), and 10 patients had no chemotherapy. RT was delivered by tangent beams in all patients to a total dose of 46-50 Gy. RESULTS Overall, 60% of the patients had new visible perfusion defects 6 months post-RT. A dose-dependent perfusion defect was seen at 6 months with minimal defect appreciated at 0-10 Gy, and a 20% decrease in regional perfusion at 41-50 Gy. One of 20 patients had a decrease in left ventricle ejection fraction (LVEF) of greater than 10% at 6 months; 2/20 patients had developed transient pericarditis. No instances of myocardial infarction or congestive heart failure (CHF) have occurred. CONCLUSIONS RT causes cardiac perfusion defects 6 months post-RT in most patients. Long-term follow-up is needed to assess whether these perfusion changes are transient or permanent and to determine if these findings are associated with changes in overall cardiac function and clinical outcome.

Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas

The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000-5040 cGy at 180-200 cGy per fraction. Hyperthermia was delivered 30-60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4-6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors Tmin and Tmax. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors Tmin and Tmax. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than Tmin and Tmax (such as T90, T50, and T10) be tested prospectively along with other important thermal variables in Phase II trials in further efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.

Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases.

PURPOSE The validity of tumor pO2 measurement as a predictive outcome assay depends upon demonstrating that intrapatient pO2 variation is less than interpatient variation. No consensus exists regarding the appropriate distance between individual measurements. This distance could affect the calculation of the hypoxic fraction (% pO2s < 5 mm Hg) and the assessment of intra/interpatient heterogeneity. This study was performed to evaluate tumor oxygenation and to assess the effects of two different measurement intervals on pO2 heterogeneity in three different sets of patients. MATERIALS AND METHODS Fifteen patients with soft tissue sarcoma, nine patients with cervical carcinoma, and eight patients with squamous carcinoma metastatic to lymph nodes underwent pretreatment polarographic pO2 measurements. Two grossly distinct sites were studied in each tumor, and 2-3 linear tracks were measured at each site. Track lengths varied from 20-36 mm. Distance between measured points was either 0.7-0.8 mm or 0.4 mm. Mean pO2, median pO2, and hypoxic fraction were calculated for each track. Data for each patient were also averaged across all tracks obtained for that patient. Track-specific data were used to evaluate intrapatient variation. The range of average values for each patient was used to assess interpatient heterogeneity. The ratio of these measures provided an assessment of within- vs. between-patient heterogeneity. RESULTS The median number of pO2 measurements/patient was 200 (range: 88-356). The average length of hypoxic regions varied from 4.5-5.6 mm. Median tumor pO2s for the cervix, lymph node, and sarcoma patients were 4.5 mm Hg, 12.6 mm Hg, and 18.0 mm Hg, respectively (p = 0.07). Median hypoxic fractions were 0.61, 0.36, and 0.31, respectively (p = 0.07). Intrapatient heterogeneity was less than interpatient heterogeneity for all parameters in all patients, except for mean pO2 for the cervix patients measured at 0.7-mm increments (1.51). Assessment of oxygenation was not affected by the distance between samples. CONCLUSIONS Heterogeneity of tumor oxygenation within tumors is less than that between tumors. Both 0.4 mm and 0.7-0.8 mm sampling increments provide similar data. Longer term follow-up of large numbers of uniformly treated patients is required to define the value of tumor oxygen measurement as a predictor of treatment outcome.

Technical factors associated with radiation pneumonitis after local ± regional radiation therapy for breast cancer

PURPOSE To assess the incidence of, and clinical factors associated with, symptomatic radiation pneumonitis (RP) after tangential breast/chest wall irradiation with or without regional lymph node treatment. METHODS AND MATERIALS The records of 613 patients irradiated with tangential photon fields for breast cancer with >6 months follow-up were reviewed. Clinically significant RP was defined as the presence of new pulmonary symptoms requiring steroids. Data on clinical factors previously reported to be associated with RP were collected, e.g., tamoxifen or chemotherapy exposure and age. The central lung distance (CLD) and the average of the superior and inferior mid lung distance (ALD) in the lateral tangential field were measured on simulator films as a surrogate for irradiated lung volume. Many patients were treated with partly wide tangential fields that included a heart block shielding a part of the lower lung. RESULTS RP developed in 15/613 (2.4%) patients. In the univariate analysis, there was an increased incidence of RP among patients treated with local-regional radiotherapy (RT) (4.1%) vs. those receiving local RT only (0.9%) (p = 0.02), and among patients receiving chemotherapy (3.9%) vs. those not treated with chemotherapy (1.4%) (p = 0.06). According to multivariate analysis, only the use of nodal RT remained independently associated with RP (p = 0.03). There was no statistically significant association between ranked CLD or ALD measurements and RP among patients treated with nodal irradiation with tangential beams. However, there was a statistically nonsignificant trend for increasing rates of RP with grouped ALD values: below 2 cm (4% RP rate), between 2 and 3 cm (6%), and above 3 cm (14%). CONCLUSIONS RP was an uncommon complication, both with local and local-regional RT. The addition of regional lymph node irradiation slightly increased the incidence of RP among patients treated with the partly wide tangential field technique. Concern for RP should, however, not deter patients with node-positive breast cancer from receiving local-regional RT.