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Purpose This study aimed to evaluate whether higher doses of consolidation radiation therapy (RT), which have been traditionally recommended for osseous sites in diffuse large B-cell lymphoma (DLBCL), are still necessary. Methods and materials Patients with DLBCL with osseous involvement treated with first-line chemotherapy followed by consolidation RT between 1995 and 2016 were reviewed. The primary endpoint was 5-year freedom from local recurrence, estimated using the Kaplan-Meier method. Outcomes based on the RT dose received were also assessed. Results A total of 51 patients were identified. The most common chemotherapy regimens were rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (80%) and cyclophosphamide, doxorubicin, vincristine, and prednisone (12%) with a median of 6 cycles (range, 3-8 cycles). After chemotherapy, 82% of patients achieved a complete response (CR), and 18% achieved a partial response (PR). All patients in PR were deemed appropriate for consolidation RT. The median dose was 29 Gy (24 Gy for CR; 36 Gy for PR). After a median follow-up of 86 months, 8 patients relapsed, with 2 relapses in the RT field after consolidation RT of 30 and 39.6 Gy, respectively. Overall, the 5-year freedom from local recurrence was 96% (95% confidence interval [CI], 91%-100%), disease-free survival was 76% (95% CI, 65%-89%), and overall survival was 86% (95% CI, 76%-96%). No dose-response relationship was observed. Conclusions In patients with DLBCL with osseous involvement who achieved a CR after first-line chemotherapy, 20 to 30 Gy of consolidation RT led to high rates of local control. Higher doses should be reserved for patients in PR.

Purpose To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma. Methods and Materials This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after ≥4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20 Gy. The primary endpoint was 5-year freedom from local recurrence. Results Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n = 49, 79%) and III to IV (n = 13, 21%). Bulky disease (defined as ≥7.5 cm or ≥10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and R-EPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51 months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5 years was 98% (90% lower confidence bound, 88%). Progression-free and overall survival at 5 years were 83% and 90%, respectively. Conclusions With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20 Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects.

Purpose This study is designed to validate a previously developed locoregional recurrence risk (LRR) scoring system and further define which groups of patients with breast cancer would benefit from postmastectomy radiation therapy (PMRT). Methods and Materials An LRR risk scoring system was developed previously at our institution using breast cancer patients initially treated with modified radical mastectomy between 1990 and 2001. The LRR score comprised 4 factors: patient age, lymphovascular invasion, estrogen receptor negativity, and number of involved lymph nodes. We sought to validate the original study by examining a new dataset of 1545 patients treated between 2002 and 2007. Results The 1545 patients were scored according to the previously developed criteria: 920 (59.6%) were low risk (score 0-1), 493 (31.9%) intermediate risk (score 2-3), and 132 (8.5%) were high risk (score ≥4). The 5-year locoregional control rates with and without PMRT in low-risk, intermediate-risk, and high-risk groups were 98% versus 97% ( P =.41), 97% versus 91% ( P =.0005), and 89% versus 50% ( P =.0002) respectively. Conclusions This analysis of an additional 1545 patients treated between 2002 and 2007 validates our previously reported LRR scoring system and suggests appropriate patients for whom PMRT will be beneficial. Independent validation of this scoring system by other institutions is recommended.

Purpose While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. Methods and Materials Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. Results Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). Conclusions Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

Purpose Several recent series evaluating external beam accelerated partial breast irradiation (PBI) have reported adverse cosmetic outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses. We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume would be feasible and result in a decreased dose to the uninvolved breast compared with institutional postoperative PBI historical controls. Methods and Materials A total of 17 patients with unifocal Stage T1 breast cancer were identified. Contrast-enhanced subtraction magnetic resonance images were loaded into an Eclipse treatment planning system and used to define the target volumes. A "virtual plan" was created using four photon beams in a noncoplanar beam arrangement and optimized to deliver 15 Gy to the planning target volume. Results The median breast volume was 1,713 cm 3 (range: 1,014–2,140), and the median clinical target volume was 44 cm 3 (range: 26–73). In all cases, 100% of the prescription dose covered 95% of the clinical target volume. The median conformity index was 0.86 (range: 0.70–1.12). The median percentage of the ipsilateral breast volume receiving 100% and 50% of the prescribed dose was 3.8% (range: 2.2–6.9) and 13.3% (range: 7.5–20.8) compared with 18% (range: 3–42) and 53% (range: 24–65) in the institutional historical controls treated with postoperative external beam PBI ( p = .002). The median maximum skin dose was 9 Gy. The median dose to 1 and 10 cm 3 of skin was 6.7 and 4.9 Gy. The doses to the heart and ipsilateral lung were negligible. Conclusion Preoperative PBI resulted in a substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. The skin dose appeared reasonable, given the small volumes. A prospective Phase I trial evaluating this technique is ongoing.

To develop clinical prediction models for local regional recurrence (LRR) of breast carcinoma after mastectomy that will be superior to the conventional measures of tumor size and nodal status.Clinical information from 1,010 invasive breast cancer patients who had primary modified radical mastectomy formed the database of the training and testing of clinical prognostic and prediction models of LRR. Cox proportional hazards analysis and Bayesian tree analysis were the core methodologies from which these models were built. To generate a prognostic index model, 15 clinical variables were examined for their impact on LRR. Patients were stratified by lymph node involvement (4 vs.or =4) and local regional status (recurrent vs. control) and then, within strata, randomly split into training and test data sets of equal size. To establish prediction tree models, 255 patients were selected by the criteria of having had LRR (53 patients) or no evidence of LRR without postmastectomy radiotherapy (PMRT) (202 patients).With these models, patients can be divided into low-, intermediate-, and high-risk groups on the basis of axillary nodal status, estrogen receptor status, lymphovascular invasion, and age at diagnosis. In the low-risk group, there is no influence of PMRT on either LRR or survival. For intermediate-risk patients, PMRT improves LR control but not metastases-free or overall survival. For the high-risk patients, however, PMRT improves both LR control and metastasis-free and overall survival.The prognostic score and predictive index are useful methods to estimate the risk of LRR in breast cancer patients after mastectomy and for estimating the potential benefits of PMRT. These models provide additional information criteria for selection of patients for PMRT, compared with the traditional selection criteria of nodal status and tumor size.

In a prior study, the combination of (31)P magnetic resonance spectroscopy (MRS)-based intracellular pH (pHi) and T2 relaxation time was highly predictive of the pathologic complete response (pCR) rate in a small series of patients with soft tissue sarcomas (STSs) treated with thermoradiotherapy. Changes in the magnetic resonance metabolite ratios and pO(2) were related to the pCR rate. Hypoxia also correlated with a greater likelihood for the development of metastases. Because of the limited number of patients in the prior series, we initiated this study to determine whether the prior observations were repeatable and whether (31)P MRS lipid-related resonances were related to a propensity for metastasis.Patients with high-grade STSs were enrolled in an institutional review board-approved Phase II thermoradiotherapy trial. All tumors received daily external beam radiotherapy (1.8-2.0 Gy, five times weekly) to a total dose of 30-50 Gy. Hyperthermia followed radiotherapy by1 h and was given two times weekly. Tumors were resected 4-6 weeks after radiotherapy completion. The MRS/MRI parameters included (31)P metabolite ratios, pHi, and T2 relaxation time. The median pO(2) and hypoxic fraction were determined using pO(2) histography. Comparisons between experimental endpoints and the pCR rate and metastasis-free and overall survival were made.Of 35 patients, 21 and 28 had reportable pretreatment MRS/MRI and pO(2) data, respectively. The cutpoints for a previously tested receiver operating curve for a pCR were T2 = 100 and pHi = 7.3. In the current series, few tumors fell below the cutpoints so validation was not possible. The phosphodiester (PDE)/inorganic phosphate (Pi) ratio and hypoxic fraction correlated inversely with the pCR rate in the current series (Spearman correlation coefficient -0.51, p = 0.017; odds ratio of percentage of necrosisor =95% = 0.01 for a 1% increase in the hypoxic fraction; Wald p = 0.036). The pretreatment phosphomonoester (PME)/Pi ratio also correlated inversely with the pCR rate (odds ratio of percentage of necrosisor =95% = 0.06 for pretreatment PME/Pi ratio0.8 vs.or =0.8, Wald p = 0.023). The pretreatment PME/PDE ratio correlated strongly with metastasis-free survival and overall survival (p = 0.012 and hazard ratio = 5.8, and p = 0.038 and hazard ratio = 6.75, respectively).The dual parameter model containing pHi and T2 to predict the pCR in STSs treated with thermoradiotherapy was not verified. However, other parameters were statistically significant, including the PDE/Pi ratio and hypoxic fraction. These relationships may have interfered with our ability to obtain the pCR rate predicted by thermal doses achieved in these patients. The relationship between the PME/PDE ratio and metastasis-free and overall survival was provocative, but requires additional study to verify its predictive capability. Currently, 50% of all STS patients with high-grade tumors develop distant metastasis even when excellent local control is achieved. Parameters that could help select for patients who need adjuvant chemotherapy could have significant clinical benefit.

For almost 5 years, the March 1998 issue of The Journal of Clinical Oncology has been sitting on my desk as a reminder to write a rebuttal to “A Meta-Analysis of Chemotherapy Versus Combined Modality Treatment Trials in Hodgkin’s disease” (1). That analysis concluded that combined modality therapy (CMT) was of little value overall in advanced Hodgkin’s disease (HD). Thanks to the editors of the International Journal of Radiation Oncology, Biology, Physics for inviting this editorial and overcoming my inertia. Apologies to those readers who have seen similar thoughts in a recent prior editorial. Let’s set the stage with a brief historical review. HD was considered generally incurable until the 1960s, when the pioneering work of Vera Peters, Henry Kaplan, and Eric Easson all independently demonstrated long-term survival without disease for early stage HD treated with radiotherapy (RT) alone. This was followed in the 1970s by the introduction of combination chemotherapy (CT) for advanced disease. Although RT cured the majority of patients with localized disease, CT had a 40–50% success rate in advanced HD. It was therefore logical to attempt to combine the two in advanced HD to improve results. The rationale was fourfold: (1) HD is exquisitely sensitive to RT (the best drug for HD to paraphrase Richard Hoppe); (2) after CT, HD tends to relapse at sites of initial involvement (note the original articles reporting this never distinguished between bulk and nonbulk disease in this regard); (3) CT works best against small numbers of malignant cells; and (4) when a complete response (CR) is obtained with CT, one cannot distinguish at present between cure (all cells killed) and a two log kill with persistence of subclinical disease. We therefore proposed, a number of years ago, a treatment program whereby, after a CT-induced CR, RT would be administered to the sites at greatest risk for relapse, namely all the clinically involved sites of diagnosis and only those sites. Only a modest dose was thought to be necessary (15–25 Gy), because CT was having some effect (the patients were in CR). Additionally, this dose could be safely administered to parenchymal organs and to nodal areas and was unlikely to have significant long-term toxicity. A number of Phase II trials followed, by us and other groups, which demonstrated a reduction in relapse rate of CR patients from 30–50% with CT alone to 10–15% with the addition of RT and a corresponding modest improvement in survival (2). The next step was confirmatory Phase III trials; here is where difficulties began. The treatment protocol was complex and the concepts foreign to many radiation oncologists. The notion of using such low doses was against conventional wisdom of the time, and whole-organ irradiation was worrisome. The resultant Phase III trial designs varied widely—often only nodal RT was used, fields were not limited to involved sites, and RT doses were higher (35–40 Gy). Quality assurance was highly variable, often with little review of the RT to be certain the doses and field designs were appropriate and administered as intended. An additional variable was the chemotherapy. When testing the value of consolidation RT, it would seem selfevident that one should pick the best CT program and then compare that best program alone to the same with the addition of RT (call this design A). Many studies, however, decided to compare one chemotherapy program plus RT to a different CT program, either more cycles of the same drugs or the addition of other drugs (call this design B), making interpretation of results problematic. Consider now the 1998 meta-analysis referred to previously, published by the International Database on Hodgkin’s Disease Overview Study Group (1). Data on 1740 patients treated on 14 Phase III trials were analyzed. These 14 trials included 16 comparisons: 8 compared the same CT program with and without consolidation RT, whereas 8 compared one CT program plus RT vs. a different CT program alone. These two design types were referred to by the authors as the additional RT design and the parallel

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.

Purpose The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile. Methods and Materials Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achieve a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated. Results A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field. Conclusions Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.

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.

Purpose: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS). Methods and Materials: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180–200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10–100 CEM 43° T 90 . Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4–6 weeks after the completion of radiation and hyperthermia. Results: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5–10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor. Conclusions: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

The role of locoregional radiation therapy after mastectomy is controversial. It reduces the risk of tumor relapse, improves breast cancer-specific survival and possibly overall survival, but has potential morbidity. This article reviews the technical aspects of postmastectomy radiation therapy and its associations with treatment-related morbidity. We consider common problems that arise in the technical setup of radiation fields. Adverse effects of postmastectomy radiation therapy may be reduced or prevented by careful radiation treatment planning.

Purpose: To assess the cost-effectiveness of postmastectomy local-regional radiation therapy (RT) for patients with breast cancer with regard to local-regional relapse (LRR) and quality-adjusted life years (QALY). Methods and Materials: Data from the literature are used to estimate the risk of LRR, and the impact of RT on the risk of LRR and survival. The risk of LRR is related linearly to the number of positive axillary nodes [% rate of LRR = 10 + (4 × number of positive nodes)]. RT reduces the risk of LRR by 67%. LRRs are treated with excision or biopsy followed by RT; half being controlled locally and half receiving additional salvage surgery and chemotherapy. Absolute improvements in 10-year overall survival due to RT are assumed to vary between 1 and 12%; and accrue linearly during the initial 10-year follow-up period. Professional and technical charges are used as a surrogate for costs. Money spent and benefits recognized in future years are discounted to 1997 values using a 3% annual rate. Quality factors are used to adjust for treatment, disease, and toxicity status. Results: The cost per LRR prevented with the addition of routine postmastectomy RT is highly dependent upon the number of positive axillary nodes and ranges from $100,000–$200,000 for patients with 0–2 nodes, and $25,000–$75,000 for ≥ 4 nodes. The cost per QALY gained at 10 years is $10,000–$110,000 for survival benefits ≥ 3%. Conclusions: The cost per LRR prevented decreases with increasing numbers of positive axillary nodes. There is not a sharp cutoff at the ≤3 vs. ≥4 lymph node number, suggesting that using this cutoff for recommending or not recommending RT following mastectomy is not economically logical. The cost per QALY of $10,000–$100,000 compares favorably to that of other accepted medical procedures. Modest changes in the quantitative assumptions do not qualitatively alter the results. Concerns regarding costs should not generally preclude the use of postmastectomy RT.

Purpose : To assess acute and late effects of radiation therapy in women with breast cancer treated with a breast positioning ring. Materials and methods : Fifty-six patients with large and/or pendulous breasts were irradiated using a breast positioning ring. The incidence of acute morbidity was correlated with patient weight and breast ‘size'. Cosmesis was scored at ≥1 year following radiation therapy by the patients. Dose changes in the buildup region under the ring were measured using a computer-controlled scanning system. Results : Moist desquamation (MD) occurred in 60.7% (34/56) of patients treated with the breast ring. The incidence of MD was more common in patients with larger breasts ( P =0.08), the severity necessitating a treatment interruption in 5 out of 56 (9%) patients. Cosmesis at ≥1 year following radiation therapy was scored as ≥ good by all patients. The surface dose under the ring was approximately 85% of the D max dose. Conclusions : The incidence or severity of acute MD in patients treated with a breast positioning ring appears high in patients with large pendulous breasts, and might be related in part, to the increased skin dose due to the positioning ring. To date, there appears to be no significant late normal tissue effects in patients treated with the positioning ring. Additional follow up is needed to assess the long-term consequences of the ring on cosmesis.

This article reviews radiation techniques including field arrangements, anatomic borders, and doses for the treatment of Hodgkin's disease when radiotherapy is being used as the sole treatment and when it is part of a planned combined modality program with chemotherapy. We describe the techniques currently in use at Duke University Medical Center. Particular emphasis is placed on the evidence regarding the appropriate extent of the treatment field and the doses of radiation necessary to achieve local control. These issues assume increasing importance as we attempt to maintain high cure rates for Hodgkin's disease but lower the frequency of serious long-term complications.

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 evalaute the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of th ehead and neck (SCCHN). Methods and Materials: Pretreatment tumor pO2 was assessed polagographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measureemnt taken from locally advanced primaries (T3 or T4) or neck nodes ≥ 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66–70 Gy) or twice daily irradiation 91.25 Gy B.I.D. to 70–75 Gy) +/- planned neck dissection (for ≥N2A disease) according to institutiional 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 tmor 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 = 0.07). Conclusion: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relatiosnhip between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Purpose: To better understanding the dose and time dependence of radiation therapy (RT)-induced regional lung dysfunction as assessed by changes in regional lung perfusion. Methods and Materials: Patients who were to receive RT for tumors in and around the thorax, wherein portions of healthy lung would be incidentally irradiated, were prospectively studied. Regional function was assessed pre- and post-RT with single photon emission computed tomography (SPECT) lung perfusion scans, obtained following the intravenous administration of ∼4 mCi of technetium-99m macroaggregated albumin. Pre-RT computed tomography (CT) scans were used to calculate the three-dimensional (3D) dose distribution, reflecting tissue density inhomogeneity corrections. Each SPECT scan was correlated with the pre-RT CT scan, and the 3D dose distribution. Changes in regional lung perfusion were correlated with regional Rt dose, at various time intervals following radiation. Results: The data from 20 patients (7 breast cancer, 5 lymphoma, 1 esophagus, 1 sarcoma, and 6 lung cancer) have been analyzed. Patients with gross intrathoracic lung cancers causing obstruction of regional pulmonary arteries were not included. For most patients, there is a statistically significant dose-dependent reduction in regional blood flow at all time points following radiation. While a time dependence is suggested in the high dose range, the limited amount of data prevents meaningful statistical evaluation. Conclusions: Radiation therapy-induced regional lung dysfunction occurs in a dose-dependent manner and develops within 3–6 months following radiation. In contrast to classical "sigmoid" dose-response curves, desribed mainly for changes following whole lung irradiation, these data suggest a more gradual relationship between regional dysfunction and RT dose. Retraction of irradiation lung with secondary movement of unirradiated lung into the "3D-defined irradiated volume" may have introduced inaccuracies into this analysis. Additional studies are currently underway to asses this possibility and better refine this dose-response curve. Studies are underway to determine if changes in assessment of whole lung function, such as pulmonary function tests, can be predicted by summing the regional changes observed.

Purpose: To determine the safety and efficacy of combined external beam irradiation and external regional hyperthermia in the treatment of adenocarcinoma of the prostate. Methods and Materials: From 1987 to 1994,30 patients received combined external beam irradiation and external regional hyperthermia for locally advanced prostate cancer. The results of the 21 patients with newly diagnosed (n = 18) or locally recurrent (n = 3) adenocarcinoma are reported herein. No patient had evidence of distant metastases. Total radiotherapy doses of 65-70 Gy to the prostate were planned using a four-field box technique. Hyperthermia treatments were delivered using an annular phased array microwave device. The treatment goal was to achieve temperatures 2 42°C in all measured points wlthln the prostate. Results: Of the newly diagnosed patients, 16 out of 18 (89%) had T3 or T4 tumors, 11 out of 18 (61%) had Gleason scores of 7-9, and the mean pretreatment Prostate Specific Antigen (PSA) was 69 rig/ml. The median follow-up of all 21 patients was 36 months. None of the patients achieved the treatment goal of all intratmnoral temperatures 2 42°C. The mean CEM 43 T90 was 2.34 min. The disease-free survival at 36 months is 25%; 12 out of 18 (67%) of the patients have relapsed. The only significant predictor of relapse was pretreatment PSA. There were no complications > Grade 3. Conclusions: In spite of the inability to achieve high tumor temperatures, the relapse-free survival rate in this population of patients with very advanced localized prostate cancer treated with radiation therapy plus hyperthermia compares favorably with most series using radiation therapy alone. Further studies aimed at improving the ability to deliver hyperthermia to the prostate are warranted. 0 1997 Elsevier Science Inc. Prostate cancer, Hyperthermia, Radiation therapy.

The treatment for advanced stage Hodgkin's disease was revolutionized approximately 30 years ago with the introduction of combination chemotherapy. This approach has resulted in the cure of approximately 50% of patients with advanced disease. In an effort to improve these results, consolidation radiotherapy (RT) was introduced approximately 25 years ago. The rationale for adjuvant RT comes from several observations: significant numbers of patients relapse following combination chemotherapy alone, these relapses occur predominantly at initially involved sites, and successful salvage following relapse can be quite difficult to achieve. Data from numerous phase II trials have demonstrated that adjuvant RT significantly reduces the relapse rate compared with what is seen following chemotherapy alone and appears to increase survival as well. Phase III trials have confirmed the reduction in relapse but, as yet, have failed to demonstrate survival benefits. Because definitive phase III trials are lacking, the use of consolidation radiotherapy has gained only partial acceptance and remains controlversial. There have been numerous methodological difficulties with the execution of the reported phase III trials, most notably the failure of a substantial portion of patients randomly allocated to the radiotherapy group to actually receive radiation. This review presents updated results of studies using chemotherapy alone including patterns of failure analyses, summarizes the available literature pertaining to both retrospective and prospective trials of combined modality therapy, discusses toxicity issues, and attempts to provide guidelines regarding patient selection, sequencing of chemotherapy and radiotherapy, and radiation dose and field size. It is our conclusion that the available evidence supports the routine use of combined modality therapy for patients with advanced stage Hodgkin's disease.

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 tumors. 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.

Purpose : The validity of tumor pO 2 measurement as a predictive outcome assay depends upon demonstrating that intrapatient pO 2 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 (% pO 2 s

Purpose: Tumor oxygenation is thought to influence the radiocurability of many malignancies. Advances in polarographic electrode technology have facilitated the in situ measurement of human tumor pO 2 . The optimal method of defining a "hypoxic" tumor is not known. Characterization of intra-tumor and intertumor PO 2 heterogeneity could help with this process. This study was performed to evaluate pretreatment tumor oxygenation status and PO 2 heterogeneity in patients with soft tissue sarcoma. Methods and Materials: Nine patients with soft tissue sarcomas underwent pretreatment PO 2 measurements with the Eppendorf PO 2 histograph. Two grossly distinct anatomic sites within each tumor were measured in all but one patient; these were localized under computerized tomography guidance to ensure that all measurements were obtained from tumor tissue. Multiple probe tracks were studied at each site. Measurements were performed in resting, awake patients. Results: A total of 1588 PO 2 readings was obtained (mean = 176/patient). Measurement path lengths ranged from 22–36 mm. The average hypoxic fraction (pO 2 2 was positively correlated with mean and median tumor pO 2 . Tumor hypoxic fraction increased with increasing tumor volume. Linear PO 2 profiles and frequency histograms provided similar estimates of the extent of hypoxia in individual tumors. Marked variation in oxygenation existed both within and between individual tumors. The intertumor variation was greater than the intertumor variation. Conclusion: Radiobiologic hypoxia exists in human soft tissue sarcomas. The PO 2 variation within individual tumors is less than the variation between tumors. Further study is necessary to identify the best parameter for defining tumor hypoxia and to discern the relationship between tumor PO 2 and treatment outcome.

Purpose To evaluate treatment results and prognostic factors, especially margin status and molecular subtype, in early-stage breast cancer patients treated with breast conservation therapy (BCT). Methods and Materials The records of 1,058 Stage I or II breast cancer patients treated with BCT (surgical excision plus radiotherapy) at Duke University Medical Center, Durham, North Carolina, from 1985–2005 were retrospectively reviewed. Conventional receptor analyses were used as surrogate markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal like). Actuarial estimates of overall survival (OS), cause-specific survival (CSS), failure-free survival, and locoregional control (LRC) were computed by use of Kaplan-Meier plots. We analyzed prognostic variables for significance using Cox proportional hazards univariate and multivariate analysis. The study was approved by the Duke University Medical Center Institutional Review Board. Results The median age of the patients was 56 years (range, 18–89 years). Of the patients, 80% had T1 disease and 66% N0 disease pathologically. With a median follow-up of 9.8 years, an in-breast recurrence developed in 53 patients and 10 patients had nodal failure. For all patients, the 10-year CSS rate was 94%; LRC rate, 94%; and failure-free survival rate, 88%. Luminal A patients had a CSS rate of 95% and LRC rate of 99%. Basal-type patients appeared to do worse, with regard to both CSS rate (74%) and LRC rate (76%), but the numbers were small and the difference was not statistically significant. LRC rates of patients with negative margins (widely negative, close, and extent of margin not known) were virtually identical (93%, 96%, and 94%, respectively). Those with positive margins appeared to fare slightly worse based on LRC rate (88%), but again, the numbers were small and the difference was not statistically significant. Conclusions BCT remains the treatment of choice for early-stage breast cancer patients irrespective of molecular subtype. Negative margins of excision are desirable, but the width of the negative margin does not influence outcome.

Background and purpose Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. Methods Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45Gy). Patients were followed up every 1.5–3months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. Results Twenty-three (85%) patients were previously irradiated (median 60.4Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1year LPFS was 76%. Overall survival was 23months for patients with CR, and 5.4months in patients achieving a partial response (PR) ( p =0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. Conclusions ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Between 287 and 291, 49 women with operable breast cancer involving ≥ 10 axillary nodes were treated following mastectomy, with four cycles of Cyclophosphamide, Adriamycin, 5FU, followed by high doses of Cyclophosphamide, Cisplatin, Carmustine (HDCT) with autologous bone marrow transplant support. Forty patients received local regional radiotherapy (generally to the chest wall, internal mammary, supraclavicular, axillary nodal areas; minimum 44–50 Gy, 1.8–2 Gy/fraction, ±10–15 Gy scar boost; standard radiation techniques). The first nine patients did not receive local-regional radiotherapy. Three developed a local-regional failure (6–12 months after HDCT); six are without evidence of disease. Local-regional radiotherapy (LR XRT) was delivered to the subsequent 40 patients following HDCT + autologous bone marrow transplant. Six received < 44 Gy of the planned local regional radiotherapy due to significant toxicity and one of these failed locally. Only one local failure was observed among the 34 patients who received ? 44 Gy. Two additional patients developed distant metastases. None of these 40 patients have failed in the axilla despite the fact that the axilla was irradiated in only 18 cases. Overall, 3640 (90%) of these patients are without evidence of disease 4–30 months following HDCT (approximately 10–36 months after mastectomy, median 22 months). Radiotherapy was interrupted or discontinued because of progressive dyspnea, thrombocytopenia, or neutropenia in nine patients. Further studies to determine the roles of local-regional radiotherapy and HDCT in the development of these toxicities are underway. These encouraging results suggest that HDCT + autologous bone marrow transplant + local-regional radiotherapy may improve the survival rate in these high risk patients. A national randomized study to test the efficacy of this HDCT regimen is currently underway (Cancer and Leukemia Group B #9082 and Southwest Oncology Group #9114).

A recent meta-analysis published in Lancet suggests that postoperative radiotherapy is detrimental to patients with non‐ small-cell lung cancer (1). This meta-analysis includes 2128 patients from 9 randomized trials conducted since 1965. Overall, the meta-analysis suggests that RT reduces the risk of local regional recurrence but has a detrimental effect on overall survival ( p 5 0.001). There was no identifiable subgroup for whom there was an improved survival with RT. The authors conclude that postoperative RT should not be used in completely resected non‐small-cell lung cancer. Approximately 25% of the patients in this study had Stage I disease, while an additional approximate 33% of patients had Stage II disease. Less than half of the patients had Stage III disease. The data show a clear trend for the largest detrimental effect in patients with Stage I disease. The effect in Stage II disease was smaller. There was no difference in survival amongst those with Stage III disease. As the extent of nodal disease parallels the stage, findings were similar regarding the degree of nodal involvement. Radiation therapy, like all cancer therapies, has the potential to cause serious toxicity and should not be indiscriminately delivered. Chest irradiation can impair cardiopulmonary function, cause esophagitis with secondary dehydration and weakness. The cure rate with surgical resection in node negative patients exceeds 50%. Presently, such patients are not generally considered for postoperative RT, since the predominant mode of failure is systemic. The rationale for thoracic RT increases with advancing disease stage, because the risk of intrathoracic recurrence increases. The risk of systemic recurrence, however, remains dominant, minimizing the potential impact of RT on survival. It is interesting to note that the detrimental effect of thoracic RT on survival was not demonstrated in the patients with Stage III (or mediastinal node positive) disease. It seems unlikely that radiation-induced morbidity/mortality would be less in this group than in earlier stage patients. In fact, patients with higher stage disease probably had larger radiation fields than patients with lower stage disease. We would interpret this observation to mean that radiation therapy in higher stage patients did improve lung cancer-specific survival. It is likely that the

Purpose To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and complete the planned course of local–regional radiotherapy (RT) for women with breast cancer involving ≥10 axillary nodes. Methods and Materials From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed. Results Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients ( p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio [OR] = 0 .38, p p = 0.005), African American ( p = 0.003), postmastectomy ( p = 0.02), or estrogen receptor positive ( p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR=2.05), modification (29% vs. 14%, p = 0.001, OR=2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR=5.35), compared with ID. Conclusion Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non–African Americans warrants further study.

Between 1970 and 1983, 273 patients underwent radical surgery (radical prostatectomy—261, radical cystoprostatectomy—12) for newly diagnosed adenocarcinoma of the prostate at Duke University Medical Center and received no adjuvant radiotherapy. A total of 46 patients developed local recurrence. Forty developed local relapse only and six developed simultaneous local and distant failure. The crude local relapse rate was 17 (46273). The actuarial local failure rate at 5, 10, and 15 years was 12%, 32%, and 35%, respectively. Univariate and multivariate analyses were performed to identify factors predictive of local relapse after radical surgery. Possible prognostic factors analyzed were: age, type of biopsy, use of adjuvant hormonal therapy, histologic grade, histologic involvement of seminal vesicles, positive surgical margins, clinical stage, and elevated acid phosphatase. Factors identified as significant predictors of local relapse by univariate analysis were: poorly differentiated histology ( p = 0.0001), seminal vesicle involvement ( p = 0.0009), and positive surgical margins ( p = 0.0001). An elevated preoperative acid phosphatase was of borderline significance ( p = 0.06). On multivariate analysis, poorly differentiated histology ( p = 0.0007), positive margins ( p = 0.0015), and elevated acid phosphatase ( p = 0.0273) were significant predictors of local failure. Seminal vesicle involvement was no longer a significant predictor of local failure. However, on subsequent univariate and multivariate analyses, seminal vesicle involvement was the only significant predictor for the development of distant metastases ( p = 0.0019, multivariate). Thus, patients with poorly differentiated tumors, positive surgical margins, or elevated preoperative acid phosphatase are at high risk for local relapse after radical prostatectomy. These patients should be included in future clinical trials studying the role of adjuvant radiotherapy after radical prostatectomy, or offered adjuvant radiotherapy if they cannot or will not participate in such trials.

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.

Purpose Low rates of breast conservation therapy (BCT) are reported in the southern United States. We evaluated the influence on BCT rates of opening a radiotherapy (RT) clinic at a community hospital in North Carolina. Before opening, RT was available 5 miles away at a tertiary care center. Methods and materials A review of the pathology database of the community hospital identified patients who underwent definitive surgery for invasive breast malignancy or ductal carcinoma in situ between 1994 and 1995, and 1997 and 1998, before and after the opening of the RT clinic in 1996. From these data, the mode of therapy, mastectomy or BCT, was determined. The results were compared using logistic regression analysis. Surgical and RT physician staffing were unchanged throughout the study period. Results A total of 586 patients was evaluated. The BCT rate at the community hospital for 1994–1995 and 1997–1998 was 29% and 44%, respectively. On both univariate and multivariate logistic regression analysis, the era of treatment was statistically significant in its impact on the procedure performed ( p Conclusion The use of BCT increased at a community hospital after the opening of an on-site RT facility, even though RT was available 5 miles away previously.

Radiation oncologists routinely make treatment decisions based, in part, on the perceived risk of normal tissue injury. Accurate assessments of the risk of normal tissue damage, however, are often elusive. Almost all of our knowledge of radiation tolerance of normal tissues was developed prior to the era of 3-dimensional (3-D) treatment planning and dose calculation and is therefore lacking in precision (5). There is a need to use the new technology to quantitatively study and better understand the physical and biological parameters related to the development of radiation-induced organ injury. The group at the University of Michigan is aggressively applying their extensive 3-D treatment planning tools to this topic. They previously reported the results of an analysis relating the risk of hepatic toxicity to the 3-D dose distribution within the liver (9). In this issue, Martel et al. quantitatively relate the 3-D radiation dose distribution within the lungs of 63 patients to the development of clinical pneumonitis (15). Their results suggest that it may be possible to calculate realistic estimates of the risk of normal tissue injury based on the 3-D dose distribution. This a very important paper and is one of the first attempts to meticulously apply 3-D technology to this important subject. Radiation-induced symptomatic pulmonary injury is common following treatment of tumors in and around the thorax and remains a major obstacle to aggressive local therapy for lung cancer (3, 4, 7, 10, 17). The study also serves to highlight many of the difficulties of applying 3-D tools to determine normal tissue complication probabilities (NTCP). Estimating the risk of organ injury requires that the radiation dose distribution be both known and interpretable. While modern radiation treatment planning tools, such as those used in this study, dramatically improve our ability to know the detailed 3D dose distribution, interpretation remains difficult. (DVH) used to display the 3-D dose information are commonly used as aids in assessing 3-D treatment plans. Dose-volume histograms may not, however, in themselves provide a clinically useful endpoint. The NTCP model used by Martel et al. is a mathematical manipulation to derive a NTCP from the DVH (11). Given the complexity of 3-D radiation dose distributions, there is great appeal in attempts to reduce this vast information into a single numerical value. This may not, however, be a realistic goal because these mathematical models ignore patient-specific biological risk factors that are likely to be important determinants of the clinical outcome. For example, the risk of developing dyspnea following thoracic irradiation must be related to the pretreatment pulmonary status. In fact, one of the patients in Martel’s study who developed grade 4 pneumonitis had a very low NTCP value of 2.2%, but had severe preexisting pulmonary disease. Therefore, clinicians should use extreme care when these models are applied in patient-care situations. Another weakness of DVHs are that they discard spatial information. It is assumed that irradiation of X% of an organ to Y Gy will result in a clinical outcome that is independent of which specific volume of the organ is irradiated. This may be true for some organs in which the function is uniformly distributed throughout the organ. It is not likely to be true for organs such as the brain, eye, or heart where the function is heterogenously distributed. This concept is well supported by radiosurgery data suggesting that the development of clinical symptoms is dependent not only on the dose-volume parameters, but on the location of the treated volume (6, 16). Even in the liver and lung where different regions of the organ normally have similar and independent functions, functional heterogeneities may be present in the diseased state. For example, our group has used single photon emission computed tomography (SPECT) lung scans to demonstrate functional heterogeneities within the lungs of patients with lung cancer or chronic obstructive pulmonary disease ( 14). These SPECT scans provide a 3-D map of functioning vascular/alveolar complexes. Pretreatment scans can be used to design radiation treatment fields that

cured of their Hodgkin’s disease. Of the 20%–25% who do relapse, the majority of these are cured with subsequent salvage programs employing either chemotherapy alone or combined modality therapy. The problem, of course, is what happens beyond 10 years. Patients treated with full-dose subtotal nodal radiotherapy, i.e., doses in the range of 40 Gy, will experience an increased frequency of both cardiac disease and second malignancies, the relative risk for each of these entities being approximately 4. In actuarial terms, the risk of any second malignancy is approximately 1% per year. When one examines survival curves for Hodgkin’s disease patients treated with subtotal nodal radiotherapy beyond 10 years, death due to causes other than Hodgkin’s disease becomes predominant.

Purpose: To assess the distance from a clinically recognized anatomic landmark to the different costocondral interspaces in female patients to facilitate the design of radiation fields intended to include specific internal mammary nodal areas. Methods and Materials: The distance from the suprasternal notch (SSN) to the caudal portion of the first through fourth interspace was measured on a computer display of the chest skeleton of 65 female patients with left-sided breast cancer. The relationship between these distances and bone size (sternal length and standing height) was assessed via linear regression. In 21 of the 65 patients where myocardial perfusion imaging of the heart was available, the relationship between the location of the 3rd costochondral interspace and the left ventricle was assessed. Results: In 90% of patients (59/65), the first, second, third, and fourth interspace were within 5, 8.5, 11, and 14 cm of the SSN, respectively. The SSN-interspace distances did not correlate well with sternal length ( r = 0.28) or standing height ( r = 0.31). In 20 of 21 patients (95%), the third interspace "shadowed" the cephalad aspect of the left heart ventricle. Median "shadowing" was 3 cm (range 0.5–6 cm). Conclusion: The caudal portion of the third costochondral interspace is ≤ 11 cm caudal to the SSN in 90% of patients. These measurements can be used to clinically design radiation therapy fields intended to treat the upper three interspaces. The distance from the SSN to the 1st through 4th interspaces is not related to sternal length or to standing height. In patients with left-sided breast cancer, radiation treatment fields designed to include the internal mammary lymph nodes in the upper three interspaces may incidentally include a portion of the heart.

Purpose: To determine the effective dose of consolidation radiation in Hodgkin's disease (HD) patients with large mediastinal adenopathy (LMA) treated with combined modality therapy (CMT). Methods and Materials: Eighty-three HD patients with LMA receiving CMT between 1983 and 1997 at Duke University and Yale University were identified. Patients underwent complete clinical staging. The staging breakdown was: IA, 4 patients; IB, 1 patient; IIA, 25 patients; IIB, 33 patients; IIIA, 3 patients; IIIB-6 patients; IVA, 2 patients; and IVB, 9 patients. All patients received induction chemotherapy (CT) as follows: MOPP/ABV(D), 31 patients; BCVPP, 15 patients; ABVD, 24 patients; MOPP, 3 patients; and other regimens, 10 patients. Following 6 cycles of CT, patients were restaged and classified as having either complete response (CR) or induction failure (IF). Post-CT gallium scans were obtained in 52 patients. Patients with residual radiographic abnormalities were classified as having CR if they were gallium-negative and clinically well otherwise. Following induction CT, 78 patients had a CR. There were 5 IFs. Consolidation irradiation was administered to all sites of initial involvement in patients who had achieved CR. RT dose varied. Patients were grouped into the following dose ranges: ≤ 20 Gy, 12 patients; 20–25 Gy, 24 patients; 25–30 Gy, 30 patients; ≥ 30 Gy, 12 patients. Results: Overall survival and failure-free survival were both 76% at 10 years. Of the 78 CR patients, 15 failed. Patterns of failure were in-field alone, 8 patients; out of field alone, 2 patients; and combined, 5 patients. Failure patterns by RT dose were: ≤ 20 Gy, 0/12; 20–25 Gy, 7/24; 25–30 Gy, 5/30; ≥ 30 Gy, 3/11. There was no apparent correlation between RT dose and subsequent failure. Post chemotherapy gallium scans were helpful in predicting for failure. Of 48 patients in whom the gallium was negative after chemotherapy, there were 6 failures, compared with 9 failures among 30 patients in whom gallium was not done after chemotherapy ( p = 0.066). Additionally, patients receiving adriamycin-based chemotherapy regimens had improved outcomes compared to those not receiving adriamycin ( p = 0.03.) Conclusions: These retrospective data suggest that low-dose radiotherapy following CR achieved with induction chemotherapy (particularly when documented with gallium scanning) may be as effective as higher doses for bulky HD at presentation. Phase III trials are necessary for confirmation of this hypothesis.

Purpose: To determine the variability of the depth of supraclavicular (SC) and axillary (AX) lymph nodes in patients undergoing radiation therapy for breast cancer and to relate this variability with the patient's anterior/posterior (A/P) diameter. The dosimetric consequences of the variability in depth are explored and related to the need for a posterior axillary boost field. Method and Materials: In 49 patients undergoing treatment-planning computed tomography (CT) scanning in the treatment position, the maximum depth of the SC and AX lymph nodes was measured on CT images. The A/P diameter was measured at the location of the SC and AX, respectively. The relationship between the SC/AX lymph node depth and patient diameter was determined using linear regression. For an anterior SC and AX field, the relative dose to the SC and AX lymph nodes were calculated for a 6 MV photon beam. Results: The maximum depth of the SC lymph nodes ranged from 2.4 to 9.5 cm (median, 4.3 cm). The depth was less than 3 cm in 4 patients, 3–6 cm in 39 (80%), and greater than 6 cm in 6 patients. There was a linear relationship between the SC lymph node depth and the A/P diameter. The depth of the SC lymph nodes in cm equals approximately one-half of the A/P diameter minus 3.5 ( r 2 = 0.69). In 94% (46 of 49) of patients, the SC lymph node depth was between one-fifth and one-half of the A/P diameter. The depth of the axillary lymph nodes ranged from 1.4 to 8 cm (median, 4.3 cm). The depth was less than 3 cm in 8 patients, 3–6 cm in 32 (65%), and greater than 6 cm in 9 patients. The AX lymph node depth in cm equals approximately one-half of the A/P diameter minus 3 ( r 2 = 0.81). In all patients, the AX lymph nodes were shallower than mid-depth. The depth of the SC and AX lymph nodes was within ± 1 cm in 53% (26 of 49) of patients. The AX lymph nodes were located at ≥ 1 cm shallower or greater depth than the SC in 24.5% (12 of 49) and 22.5% (11 of 49) of patients, respectively. If an anterior 6-MV beam only is used to treat the SC and AX lymph nodes in these 49 patients, the dose to the AX is within ± 5% of the SC dose in 53% (26 of 49) patients and is 90% or more of the dose delivered in the SC in 90% (44 of 49) of patients. Conclusion: The maximum depth of the SC and AX lymph nodes varies widely and is related to the patient's size represented by the A/P diameter. In most patients, the AX lymph nodes lie at approximately the same depth or shallower than the SC. Therefore, the rationale for a posterior axillary boost field needs to be further assessed. When the AX and SC lymph nodes are deep, opposed supraclavicular and axillary fields and/or the use of a higher energy beam might be reasonable.

Purpose: To determine the feasibility of combining external beam radiotherapy, continuous infusion 5-fluorouracil (5-FU), and external microwave hyperthermia in patients with locally advanced, unresectable, or recurrent adenocarcinoma of the rectum. Methods and Materials: From 7/95 through 2/99, 15 patients were enrolled in the study. The treatment regimen consisted of continuous infusion 5-FU 250 mg/m 2 /d 7 days/week beginning on day 1, external beam radiotherapy to the pelvis, 4500 cGy, 180 cGy/d 5 days/week using a 3 or 4-field technique, and external microwave hyperthermia on days 3, 8, 15, 22, and 29. Chemotherapy was stopped on the last day of radiotherapy. Surgical resection, if feasible, was scheduled 3–6 weeks after completing thermochemoradiotherapy. For this regimen to be considered feasible, no more than 2 of the 15 patients should fail to complete therapy due to life-threatening toxicity. Toxicity was scored using National Cancer Institute Criteria. Results: All patients completed the chemoradiotherapy portion of the protocol. Eleven of the 15 patients completed all 5 hyperthermia treatments. Of the 4 patients who did not receive the full course of hyperthermia, only 1 patient had treatment stopped due to life-threatening toxicity. The other 3 patients did not complete hyperthermia due to scheduling errors ( n = 2) or patient request ( n = 1). Five of 15 patients required a treatment interruption due to toxicity ≥ Grade 3. Seven patients experienced lesser degrees of toxicity which did not require treatment interruption. Three patients experienced no side effects. The most common toxicities were dermatitis and diarrhea. Of the 14 patients in whom surgery was planned, 11 (79%) were resectable. There was one pathologic complete response. Conclusions: It is feasible to deliver thermochemoradiotherapy, as prescribed in this study, to patients with locally advanced, unresectable, or recurrent rectal cancer. The therapy is moderately toxic, with one-third of patients requiring temporary treatment interruptions. The regimen appears active against rectal cancer, and appears to warrant further consideration as a treatment option for this patient population.

Purpose: To determine the variability of position of internal mammary vessels (IMV) and glandular breast tissue (GBT) in patients undergoing breast-conserving radiation therapy. To assess the frequency and magnitude of tangential field border shifts based on preradiation therapy (RT) computed tomography (CT) imaging in breast cancer patients. Methods and Materials: Five hundred and ninety breast cancer patients irradiated between 9/94 and 3/98 underwent routine CT-based treatment planning. Two analyses were performed. First, the position of IMV and GBT, outlined on the central axis CT image, was determined relative to the midsternum in 111 patients irradiated during a 12-month period. In the second analysis, the difference between anticipated (pre-CT) and actual (CT-based) tangential field borders was assessed in 254 patients irradiated during a 2-year period. Results: In the first analysis, the depth of the IMVs varied from 1 to 6 cm (median 2.4 cm). The lateral distance from the midsternum also varied widely (range 1.7 to 3.7 cm, median 2.5 cm). Similar variability was found in the position of the GBT. In the second analysis, CT information led to changes of anticipated field borders in 65% of patients. The lateral border was shifted in 56% of patients (anteriorly 18%, posteriorly 38%). When the patients were segregated based on internal mammary node (IMN) treatment, the medial border was shifted in 49% of patients when the IMNs were treated in the tangential fields and in 24% when the GBT only was treated. The frequency of lateral field border shifts was similar in both groups. Conclusions: The position of IMVs and GBT varies widely in breast cancer patients. Tangential field borders based on surface anatomy may not be ideal. Among 254 breast cancer patients, the field borders were shifted in 65% of patients when CT information was available. Thus, in most breast cancer patients, field borders are shifted when CT-based treatment planning is used.

Purpose: To review our experience treating clinical Stage I non-small–cell lung carcinoma with radiotherapy alone using modern techniques and staging. The effect of dose and volume on outcome is to be analyzed. Methods: Between January 1980 and December 1995, 156 patients with Stage I medically inoperable non-small–cell lung cancer were irradiated at Duke University Medical Center and the Durham Veterans Administration Medical Center. Fifteen patients were excluded from analysis (7 treated with palliative intent, and 8 lost to follow-up immediately following radiation). Characteristics of the 141 evaluable patients were as follows: Median age 70 years (range 46–95); gender: male 83%, female 17%; institution: DUMC 65%, DVAMC 35%; T1N0 54%, T2N0 46%; median size 3 cm (range 0.5 to 8); pathology: squamous cell carcinoma 52%, adenocarcinoma 18%, large cell carcinoma 19%, not otherwise specified 11%; presenting symptoms: weight loss 26%, cough 23%, none (incidental diagnosis) 57%. All patients underwent simulation prior to radiotherapy using linear accelerators of ≥4 MV. No patients received surgery or chemotherapy as part of their initial treatment. The median dose of radiotherapy (not reflecting lung inhomogeneity corrections) was 64 Gy (50 to 80 Gy) given in 1.2 bid to 3 Gy qid fractionation. The majority of cases included some prophylactic nodal regions (73%). Results: Of the 141 patients, 108 have died; 33% of intercurrent death, 35% of cancer, and 7% of unknown causes. At last follow-up, 33 patients were alive (median 24 months, range 7–132 months). The 2- and 5-year overall survival was 39% and 13%, respectively (median 18 months). The corresponding cause-specific survival was 60%, and 32% (median 30 months). On multivariate analysis, significant factors influencing overall and/or cause-specific survival were age, squamous cell histology, incidental diagnosis, and pack-years of smoking. There was a nonsignificant trend towards improved cause-specific survival with higher radiotherapy doses and larger treatment volumes. On patterns of failure analysis, 42% of failures were local-only and 38% were distant-only. Regional-only failure occurred in 4 patients (7%), 3 of whom failed solely in an unirradiated nodal site. Analysis of factors correlating with local failure at 2 years was performed using a multinominal logistic regression analysis. Significant factors associated with a lower local failure included incidental diagnosis and absence of cough with a strong trend toward significance for higher radiotherapy dose ( p = 0.07) and larger treatment volume ( p = 0.08). Patients who were locally controlled had an improved cause-specific survival at 5 years over those who were not controlled (46% vs. 12%, p = 0.03). Grade III–V complications occurred in 2 patients (1.5%). Conclusion: Patients with clinical Stage I medically inoperable non-small–cell lung cancer treated with contemporary radiotherapy alone achieved a 5-year cause-specific survival of 32%. Uncontrolled lung cancer was the primary cause of death in these patients, and local failure alone represented the most common mode of failure (42%). Patients who were locally controlled had a significantly improved cause-specific survival over those who failed locally. Because higher doses of radiotherapy appear to provide improved local control, studies of dose escalation are warranted until dose-limiting toxicity is observed.