Search

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.

Background/aim Optimizing treatment of early-stage Hodgkin lymphoma (HL) requires balancing cure with potential acute and late toxicities from treatment. We reviewed our institutional experience with chemotherapy alone (ChT) versus combined modality therapy (CMT). Materials and methods Patients with stage I-II classical HL in a complete response (CR) by functional imaging after chemotherapy were included. Progression-free survival (PFS) and overall survival (OS) were calculated and a multivariate analysis (MVA) was performed. Results A total of 136 patients with a CR to chemotherapy were identified. Consolidation radiation therapy (RT) was administered to 117 while 19 received no further therapy. PFS (5 years) was 97% with CMT and 84% with chemotherapy alone (p=0.02). Long-term (10 year) survival was no different (96 vs. 94%, p=0.8). On MVA, CMT improved PFS. Secondary malignancies were rare and no cardiac events were observed. Conclusion Consolidation RT results in superior PFS in early-stage Hodgkin lymphoma with minimal added toxicity.

Introduction The purpose of this study was to evaluate the role of consolidation radiation therapy (RT) in advanced Hodgkin lymphoma (HL) in the setting of a complete metabolic response (CR) to chemotherapy (ChT). Patients and Methods Patients with stage III/IV HL treated with ChT alone or combined modality therapy (CMT) between 1992 and 2012 were reviewed. Only patients in a CR according to positron emission tomography-computed tomography (PET-CT) or gallium imaging were included. Clinical end points were estimated using the Kaplan–Meier method and a multivariate analysis using the Cox proportional hazards model was performed. Results Ninety patients were identified (46 CMT; 44 ChT alone). Median follow-up was 50 months. ChT (median 6 cycles) consisted primarily of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; 74%) or an ABVD hybrid (10%). Post-ChT imaging consisted of PET-CT (71%) or gallium (29%). RT plans primarily included all initially involved sites of disease with a median dose of 21 Gy (range, 13-31 Gy). CMT was associated with improved 5-year progression-free survival (PFS; 88% vs. 65%, respectively; P P = .002) compared with ChT alone. In multivariate analysis, age younger than 45 years (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.07-0.74; P = .013) and CMT (HR, 0.32; 95% CI, 0.11-0.96; P = .04) were independently associated with improved PFS. Secondary malignancies were comparable in both cohorts (5 with CMT, 4 with ChT), whereas cardiac events were slightly more frequent with CMT (5 vs. 2). Conclusion Low-dose RT, administered to all sites of original involvement, was associated with improved PFS, even in the setting of a metabolic CR after ABVD.

From 1969 to 1982, 183 patients with previously untreated stages IIIB and IV Hodgkin's disease and relapsing Hodgkin's disease after radiation therapy were treated with combination chemotherapy plus low-dose irradiation (CRT). One hundred fifty patients who achieved a complete response (CR) were analyzed for risk of developing a second neoplasm. Median follow-up has been 8.3 years. Actuarial survival of all patients is 74% at 10 years with a relapse-free survival of 68%. An additional 24 patients with stage IIIA disease were also treated with CRT. There were 22 CRs at risk who were analyzed. Median follow-up has been 3+ years with an actuarial survival of 90% at five years and a relapse-free survival of 83%. Second neoplasms have developed in 14 of 172 patients at risk: acute nonlymphocytic leukemia (ANLL; five patients); aggressive histology non-Hodgkin's lymphoma (NHL; three patients); and a variety of solid neoplasms (six patients). Time to second neoplasm diagnosis after initial treatment ranged from 12 to 141 months. Five patients were older than 40 years. At the time of diagnosis of the second malignancy, 11 patients were free of Hodgkin's disease (for 36 to 141 months) and three were receiving therapy for recurrent Hodgkin's disease. The 10-year actuarial risk (%) of developing ANLL was 5.9 +/- 2.8; for NHL, the risk was 3.5 +/- 2.4, and for solid neoplasms, 5.8 +/- 3.0. Our results suggest that combination chemotherapy plus low-dose irradiation does not appear to significantly increase the risk of developing second neoplasms above that already reported for combination chemotherapy when administered as either initial or salvage treatment of Hodgkin's disease.

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.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Treatment of a locoregional recurrence of breast cancer after mastectomy remains a clinically challenging problem. Often these patients have undergone prior radiotherapy and chemotherapy. Therapeutic options usually include resection or additional radiation; however, the long-term control rates are often suboptimal with these approaches. Data from several randomized trials suggest that the addition of hyperthermia to radiation can increase the response rate for such local recurrences. Therefore, in settings where the available therapies are unlikely to yield local control (e.g., local/regional recurrence after prior radiation), a reasonable option to consider is radiation with hyperthermia as a radiation sensitizer. This article reviews the rationale and supporting literature for this recommendation.

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.

There is growing interest in the use of preoperative (neoadjuvant) chemotherapy for patients with localized breast cancer. Originally, it was hypothesized that such early use of chemotherapy might improve survival, compared with standard postsurgical adjuvant systemic therapy, but this has not proven to be the case. Nonetheless, the primary tumor response is likely a barometer for tumor sensitivity to therapy and may be used to help guide decisions regarding additional systemic therapy. Furthermore, preoperative chemotherapy can increase the fraction of women eligible for breast-conservation therapy. A seemingly logical extension of this latter observation is the hypothesis that one can further reduce local therapies in patients responding well to initial chemotherapy. For example, studies are under way to omit (or limit) radiotherapy (RT) in patients who present with positive axillary nodes and experience pathologic complete response in the nodes to preoperative chemotherapy (eg, NSABP [National Surgical Adjuvant Breast and Bowel Project] B-51/RTOG [Radiation Therapy Oncology Group] 1304). In the NSABP/RTOG study, patients with involved axillary nodes (histologically confirmed) are treated with neoadjuvant chemotherapy. Those who are node negative at subsequent mastectomy are randomly assigned to postmastectomy RT (PMRT) to the chest wall and regional nodes. Similarly, patients who undergo subsequent breast conservation surgery and whose nodes have become negative after preoperative chemotherapy will be randomly assigned to breast RT regional nodal RT. We appreciate the importance of the question being asked in these studies and support their conduct. Defining patient subgroups that do (or do not) benefit from our therapies is an important goal. It is possible that response to preoperative chemotherapy predicts for the potential benefit of local regional RT (and hence theassociatedtherapeutic ratio).Responders topreoperativechemotherapy may have a lesser need for additional local regional RT. However, we believe the converse may be true: that the potential survival benefits of local therapies are likely highest among responders to preoperative chemotherapy. Consider the more typical clinical scenario for node-positive patients who undergo initial mastectomy, followed by adjuvant chemotherapy (Fig 1). In that setting, the addition of PMRT improves overall survival (OS) by approximately 6% to 9%. This group includes both responders and nonresponders to chemotherapy, althoughidentificationofthesesubgroupsisnotpossible,becausechemotherapy is administered postoperatively. If it is true that responders to neoadjuvant chemotherapy derive lesser survival gains with PMRT, it must follow that nonresponders derive greater gains, because the OS benefit should still be 6% to 9% (ie, sequencing of surgery and chemotherapy should not alter this; Fig 1, lower panel). An analogous situation exists for patients undergoing breast conservation. The NCIC Clinical Trials Group MA.20 study reported improvements in locoregional control and distant disease-free survival and a trend in OS with the addition of nodal RT to breast RT in patients undergoing lumpectomy followed by chemotherapy. If responders to preoperative chemotherapy derive lesser gains with nodal RT, nonresponders should derive greater gains (again, to make the math work). As we discuss here, the evidence suggests that the opposite may be true: namely, that responders to systemic therapy might derive the most survival benefit from RT. Mastectomy Chemotherapy 6%-9%

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.

BACKGROUND. Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin-containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma. METHODS. Patients with advanced cervical carcinoma were registered prospectively in the U.S., Norway, and the Netherlands. External-beam radiotherapy and brachytherapy were administered for a biologically effective dose ! 86.7 gray. At least 4 courses of weekly cisplatin (40 mg/m 2 ) and 4 sessions of weekly locoregional hyperthermia were added to radiotherapy. RESULTS. Sixty-eight patients with a median age of 45 years were enrolled. Fulldose radiotherapy was delivered to all patients according to plan. At least 4 courses of chemotherapy were received by 97% of patients, and at least 4 courses of hyperthermia treatment were received by 93% of patients. Toxicity was fully comparable to that described for chemoradiotherapy alone, and the median total treatment time was 45 days. Complete remission was achieved by 61 patients (90%). After a median follow-up of 538 days, 74% of patients remained alive without signs of recurrence, and the overall survival rate was 84%. CONCLUSIONS. The combination of full-dose radiotherapy, chemotherapy, and hyperthermia was feasible and effective in a multicenter international setting among patients with advanced cervical carcinoma. A Phase III study comparing this novel triplet with standard chemoradiation, designed to show at least a 15% improvement in overall survival, has been launched. Cancer 2005;104:763‐70. © 2005 American Cancer Society.

Purpose: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO2) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy. Experimental Design: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m2) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60–65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment. Results: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO2 = 4.7 ± 1.2 mmHg). Five patients had well-oxygenated tumors (pO2 = 27.6 ± 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses. Conclusions: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.

Rituximab in combination with chlorambucil or radiation therapy may be an effective and less-toxic therapeutic alternative for patients with lymphocyte predominance Hodgkin's disease (LPHD). We treated 6 patients with LPHD with weekly rituximab at 375 mg/m2 for 4 weeks, followed by either radiation therapy or chlorambucil. Four patients had previously untreated disease and 2 had relapsed LPHD. All patients had no evidence of disease progression at a median follow-up time of 12.5 months after receiving rituximab therapy (range, 6-39 months) and a median follow-up time of 6.5 months after completion of chlorambucil or radiation therapy (range, 3-25 months). Further follow-up is warranted to evaluate response duration and late toxicity of this novel treatment strategy

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

Major advances in the treatment of locally advanced cervical carcinoma were reported in 1999-2000 in five studies from the Gynecologic Oncology Group, Radiation Therapy Oncology Group and Southwestern Oncology Group. Collectively these trials reported a decrease in the risk of recurrence or death from cervical cancer ranging from 30-50% with the use of concurrent chemoradiation, as compared with radiation alone. On the basis of these trials the National Cancer Institute in 1999 issued a clinical alert concluding 'Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.' Concurrently with these publications there appeared the publication in the Lancet in 2000 of the Dutch Deep Hyperthermia Group trial of radiotherapy alone versus combined radiation and hyperthermia for locally advanced pelvic tumors including carcinoma of the cervix. This multi-center phase III trial demonstrated an approximate doubling of the three year survival from 27 to 51% for the addition of hyperthermia to radiotherapy in patients with locally advanced cervical carcinoma. Additional trials to test the value of hyperthermia in patients with cervical carcinoma treated with concurrent chemotherapy and radiation are imperative and take precedence over a trial to investigate the value of chemotherapy in patients treated with hyperthermia and radiation.

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.

We prospectively evaluated whether delivering a thermal dose of10 cumulative equivalent minutes at 43 degrees C to90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patientsor = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T900.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate ofor = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

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.

The role of postmastectomy radiotherapy (PMRT) has been controversial for decades, accounting for countless presentations, debates, and papers. It was reasonably clear from the beginning that PMRT improved locoregional control. Much of the controversy has had to do with whether PMRT improved survival. The evidence is now strong that PMRT does indeed improve survival, both from individual studies and from reviews and meta-analyses. The Gebski et al analysis is particularly significant because, unlike many meta-analyses, this study controlled for the quality of the radiotherapy. The more recent studies demonstrate an absolute survival benefit of approximately 5% to 10% and approximately 66% to 75% relative reduction in locoregional recurrence. There should no longer be much doubt in the minds of oncologists as to the value of PMRT. Controversy continues to exist, however, as to the clinical characteristics of patients who would benefit significantly from PRMT. Because the risk of locoregional recurrence increases with the number of positive axillary lymph nodes, a widely adopted approach has been to apply PMRT only in patients with four or more positive axillary nodes, and not to those with one to three positive nodes. The rationale for this approach is nicely summarized in a prior Journal of Clinical Oncology editorial. If one believes that the ratio between locoregional failures avoided and breast cancer deaths prevented is approximately four to one, the group with four or more positive node group will enjoy the largest benefits in both locoregional control and survival. We have a number of concerns with this thesis, however. First, though this approach seems logical, it is not supported by the available data. In the Overgaard and Ragaz studies (Table 1), the absolute magnitude of the overall survival benefit afforded by PMRT is similar in the patients with one to three versus four or more positive lymph nodes. Many have criticized these studies for the degree of axillary surgery (median number of recovered nodes, seven in Overgaard and 11 in Ragaz), compared with a larger number of recovered nodes in some other studies. To address this criticism, a recent analysis from the Danish trials considered the subset of 1,152 node-positive patients with eight or more nodes removed (ie, median). The overall 15-year survival rate was increased by 9% in patients with either one to three positive nodes or four or more positive nodes, with a disconnect between improvement in local control and survival. Although the patients with four or more positive nodes had a far greater improvement in local control with RT than did the group with one to three nodes, the survival benefits were similar in both groups. The explanation advanced by the authors seems plausible. Improvements in locoregional control will yield survival benefits only if there is systemic tumor control as well. Because patients with four or more positive axillary nodes are likely, on average, to harbor a higher systemic subclinical disease burden than those with one to three positive nodes, improvements in locoregional control will be less likely to translate into a survival benefit in the four or more node group. Thus, the ratio between locoregional failures avoided and breast cancer deaths prevented may not be constant across patient subgroups. Further, as the efficacy of systemic therapy increases, the impact of PMRT on survival may also increase. In this regard, local and systemic therapies are synergistic rather than competitive. Second, some argue that a more complete axillary dissection would have moved most of the patients with one to three positive nodes in the Overgaard and Ragaz studies into the group with four or more positive nodes. This issue has been studied by several investigators. Danforth et al and Saha et al found that 64% to 71% of patients with one to three positive nodes after limited level I dissection (median, 10 nodes) would remain in the group with one to three positive nodes with a more complete dissection. Using mathematical models based on clinical data, Kiricute et al and Iyer et al computed that approximately 50% of patients with two positive nodes after limited dissection will remain in the group with one to three positive nodes with a more complete dissection. Thus, approximately 50% to 70% of the patients in the group with one to three positive nodes from the original Overgaard and Ragaz studies would likely remain in the same group with a more complete dissection. Thus, the often-heard suggestion that most of the patients with one to three nodes in the Overgaard and Ragaz studies would have had four or more nodes with a more complete dissection is not consistent with the data. Third, the subsetting of patients into groups with one to three versus four or more positive nodes is an artificial distinction originating in the early days of adjuvant systemic therapy for breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) was perhaps the first to do this, with initial benefits from adjuvant chemotherapy observed only in those with four or more positive lymph nodes. Later studies demonstrated the utility of systemic therapy in patients with one to three, or even zero, involved nodes. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 13 MAY 1 2008

BACKGROUND Axillary lymph node dissection is commonly performed as part of the primary management of breast carcinoma. Its value in patient management, however, has recently been questioned. Few studies exist that document long term complications. METHODS Four hundred thirty-two patients with Stage I or II breast carcinoma who were free of recurrence 2-5 years after surgery were identified. A cross-sectional survey was conducted to determine the prevalence of long term symptoms and complications as perceived by the patient, and patient and treatment factors that may have predicted complications were determined. Three hundred thirty of the 432 (76%) completed a mailed, self-administered questionnaire. In addition, the medical records of the 330 patients were reviewed. Patient and treatment factors were analyzed with logistic regression. RESULTS Numbness was reported by 35% of patients at the time of the survey. Pain was noted in 30%, arm swelling in 15%, and limitation of arm movement in 8%. Eight percent reported episodes of infection or inflammation at some point since the diagnosis of breast carcinoma. The majority of symptoms were mild and interfered minimally with daily activities. Younger age (P = 0.001) was associated with more frequent reporting of pain. Numbness was more common in younger patients (P = 0.004) as well as in those with a history of smoking (P = 0.012). There was a positive association of limitation of arm motion with adjuvant tamoxifen therapy (P = 0.016). Arm swelling was associated with both younger age (P = 0.004) and greater body surface area (P = 0.008). Radiation therapy was associated with a higher frequency of infection or inflammation in the arm and/or breast (P = 0.001). CONCLUSIONS Mild symptoms, especially pain and numbness, are common 2-5 years after axillary lymph node dissection. The frequency of inflammation or infection in patients treated with radiation to the breast or chest wall after an axillary lymph node dissection may be greater than previously appreciated. Severe complications or symptoms that have a major impact on daily activities are uncommon. These findings should help health care providers and their patients with breast carcinoma weigh the pros and cons of axillary lymph node dissection. Cancer 1998;83:1362-1368. © 1998 American Cancer Society.

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.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.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.Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

BACKGROUND The purpose of this study was to determine risk factors that affect locoregional control of nasopharyngeal carcinoma (NPC) after radiotherapy. Computed tomography (CT) is utilized for radiotherapy planning and for identifying high risk anatomic areas. METHODS Between April 1990 and December 1993, 40 consecutive patients (1 in Stage I, 3 in Stage II, 5 in Stage III, and 31 in Stage IV) who had locoregional NPC were given definitive radiotherapy at the Koo Foundation Sun Yat-Sen Cancer Center in Taipei, Taiwan. All patients had individualized CT treatment planning. The dimension of each tumor as shown on the treatment planning CT were mapped on conventional simulation films. The extent of each tumor was further affirmed by magnetic resonance imaging (MRI) and the tumor map revised as necessary. The primary radiation fields were designed to include the primary tumor and potential spread areas with appropriate margins. Concurrent chemotherapy was also given to 35 patients (87.5%) who had positive cervical lymph nodes or primary tumors extending beyond the nasopharynx. RESULTS By the end of December 1995, after a median follow-up of 42 months and minimal follow-up of 24 months, the locoregional control rate at 4 years was 84.8% (95% confidence interval [CI], 72.3-97.3), disease free survival 68.4% (95% CI, 52. 1-84.7), and overall survival 76.7% (95% CI, 63.4-90.0). The radiation field margin near the sphenoid sinus averaged 1.9 cm, the clivus margin 1.1 cm, the pterygoid fossa margin 2.0 cm, and the oral cavity margin 1.7 cm. Risk factor analysis revealed that T classification and the radiation field margin at the clivus were the most important factors for locoregional control of the tumor. The locoregional control rates were 92.6% (25/27) for T1-T3 patients and 76.9% (10/13) for T4 patients (P = 0.03). The locoregional control rates were 71.4% (5/7) for patients with a clivus margin < 1 cm and 90.6% (29/32) for patients with a clivus margin ≥ 1 cm (P = 0.08). CONCLUSIONS The excellent locoregional control observed in this series may be attributed to the concurrent chemotherapy and radiotherapy as well as meticulous treatment planning with CT and MRI. The precise delineation of the involved area with the aid of CT, which is taken while the patient is in the position for irradiation, serves to define the necessary safety margin of the radiation field. T classification and clivus margin are the most important factors in determining locoregional control of radiotherapy of NPC. The statistical trend observed in this study indicated that the clivus margin should be adequate to reduce the failure around the clivus, as all local recurrences were observed in this area. Cancer 1998;82:261-7. © 1998 American Cancer Society.

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.

Data from randomized and nonrandomized studies demonstrate that the addition of breast irradiation after local excision of invasive and noninvasive breast cancers markedly reduces the breast failure rate. Local excision with breast irradiation remains the standard approach for breast-conserving therapy for both invasive and noninvasive cancers. Some data suggest that there might be patient subgroups that could be treated with local excision without radiotherapy, but additional studies are necessary to better define these groups.

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.

(1996). The Case for Adjuvant Radiation Therapy in Advanced Hodgkin's Disease. Cancer Investigation: Vol. 14, No. 4, pp. 361-370.

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.

Background. Forty patients with Stage 11-111 breast cancer with 10 or more positive axillary nodes were treated with mastectomy followed by four cycles of standard dose CAF (cytoxan, Adriamycin, 5-FU), followed by high dose cytoxan, cisplatin, carmustine (HDCT) with autologous bone marrow transplant support (ABMT), and local-regional radiotherapy (LR XRT). During LR XRT, the hematologic toxicity experienced by these patients appeared more severe than that usually seen in patients not heavily pretreated with chemotherapy. Radiation therapy was interrupted in four patients (10%) because of thrombocytopenia and leukopenia. This observation prompted a comparison of the hematologic changes seen in this group with those seen in patients not treated previously with chemotherapy. Methods. A detailed analysis of changes in hematologic parameters during LR XRT was performed in 33 evaluable patients who received CAF-HDCT/ABMT and compared with a “control” group of 17 women who did not receive prior chemotherapy. Results. The mean pretreatment leukocyte, platelet, and hematocrit counts were lower in the CAF-HDCT/ ABMT group than in the control group, with the differences indicating statistical significance for the latter two (P = 0.17, P < 0.001, and P = 0.001, respectively). None of the control patients required a treatment interruption because of hematologic toxicity, whereas four of the CAFHDCT/ABMT patients did. Among the CAF-HDCT/ ABMT patients, a leukocyte count nadir of less than 2.0, a platelet nadir of less than 50,000, and a hematocrit nadir of less than 25 occurred in 12%, 19%, and 9%, respectively. The corresponding rates of control patients were 6%, 0%, and 0’70, respectively. Relative to their pretreatment levels, however, both groups experienced similar declines in platelet and leukocyte counts. Conclusion. The higher rate of hematologic toxicity observed in the patients who previously received conventional chemotherapy plus HDCT/ABMT appears to have been due primarily to lower preradiotherapy blood counts. Cancer 1994; 74:2964-71.

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.

BACKGROUND Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. METHODS This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. RESULTS Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. CONCLUSIONS The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.

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.

Objective The 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 data The 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. Methods The 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. Results Of 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 of 7 with positive margins after re-excision versus 1/56 rendered margin negative had a local recurrence. Conclusions The authors recommend re-excision for patients with positive margins because of improved 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.