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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.

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.

For patients with primary CNS lymphoma who achieve complete response (CR) after induction methotrexate-based chemotherapy with rituximab, low-dose whole brain radiation therapy (LD-WBRT) appears effective and is well tolerated. For patients who respond to induction methotrexate-based chemotherapy with or without rituximab but have unifocal residual disease less than 3 cm in size, we hypothesized that LD-WBRT combined with radiosurgery would be effective at controlling residual disease and well tolerated.Four adult patients with primary CNS lymphoma with a favorable response to induction chemotherapy but had residual disease less than 3 cm were identified. Induction chemotherapy consisted of methotrexate with or without additional agents including rituximab. LD-WBRT comprised 2340 cGy in 13 fractions. This was immediately preceded or followed by a single radiosurgery treatment of 12 12.5 Gy to the focus of residual disease defined on contrast enhanced T1 weighted MRI.The median follow-up was 17.1 months (range 10-23 months). All patients had residual disease after induction chemotherapy but achieved complete response (CR) following LD-WBRT and radiosurgery. Three patients remained free of disease. One patient developed distant brain recurrence 12 months after radiation but remained alive at last follow-up (17 months). No treatment-related neurotoxicity was observed.The combination of induction methotrexate-based chemotherapy with or without rituximab, LD-WBRT and radiosurgery appears effective and well tolerated in patients with primary CNS lymphoma who achieve a partial response (PR) to chemotherapy with minimal residual disease. Longer follow-up and larger patient numbers are clearly needed for confirmation.

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.

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.

The study was designed to determine the maximum tolerated dose (MTD) of IP cisplatin [CDDP] combined with intravenous thiosulphate and concurrent whole abdomen hyperthermia for advanced, recurrent or progressive ovarian carcinoma. Between September 1991 and November 1998, 41 patients with advanced epithelial ovarian cancer received escalating doses of IP (IP) cisplatin (six cycles given every 3-4 weeks) and whole abdomen hyperthermia with intravenous thiosulphate as second line treatment. Whole abdomen hyperthermia was administrated using a BSD-2000 annular phased array system. Forty-one patients were enrolled in the phase I/II portions of the study. Forty-four per cent (18/41) had undergone sub-optimal cytoreductive surgery and 15% (6/41) had been optimally debulked of their disease. Ninety per cent (37/41) had platinum-resistant disease and 10% (4/41) had platinum-sensitive disease. No DLTs occurred in the phase I testing and the recommended dose for this combination schedule was 180 mg m-2 of IP cisplatin with thiosulphate and whole abdomen hyperthermia. The overall response rate was 44% (10 CR, 8 PR) and the median survival for all patients from protocol entry was 30 months (range 2-107 months). Median duration and survival of those achieving a pathologic CR was 14 months (range 2-27 months) and 35 months (range 14-71 months, 95% CI 16-54 months), respectively. Salvage platinum based IP cisplatin with hyperthermia did achieve pathologic CR in selected patients and was well tolerated. These promising results suggest a role for the use of adjuvant whole abdomen hyperthermia as a means of augmenting chemosensitization.

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.

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.

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.

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.

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.

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.

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

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.

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.

Background: 2-[fluorine-18]fluoro-2-deoxy-D-glucose‐positron emission tomography (PET) and gallium-67 citrate (gallium) response after chemotherapy are powerful prognostic factors in diffuse large B-cell lymphoma (DLBCL). However, clinical outcomes when consolidation radiation therapy (RT) is administered are less defined. Patients and methods: We reviewed 99 patients diagnosed with DLBCL from 1996 to 2007 at Duke University who had a post-chemotherapy response assessment with either PET or gallium and who subsequently received consolidation RT. Clinical outcomes were estimated using the Kaplan‐Meier method and compared using the log-rank test. Results: Median follow-up was 4.4 years. Stage distribution was I‐II in 70% and III‐IV in 30%. Chemotherapy was R-CHOP or CHOP in 88%. Median RT dose was 30 Gy. Post-chemotherapy PET (n = 79) or gallium (n = 20) was positive in 21 of 99 patients and negative in 78 of 99 patients. Five-year in-field control was 95% with a negative PET/gallium scan versus 71% with a positive scan (P < 0.01). Five-year event-free survival (EFS; 83% versus 65%, P = 0.04) and overall survival (89% versus 73%, P = 0.04) were also significantly better when the post-chemotherapy PET/gallium was negative. Conclusions: A positive PET/gallium scan after chemotherapy is associated with an increased risk of local failure and death. Consolidation RT, however, still results in long-term EFS in 65% of patients.

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.

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.

Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used.To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment.A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging.The contrast agent in all tumours typically peaked in the first 1-4 min. The tumours' WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002.This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.

The risk of any second malignancy was determined for all patients treated for a primary cancer of the breast without evidence of distant metastasis at Duke University Medical Center between 1970 and 1981. The incidence, 10-year actuarial risk (AR), and relative risk (RR) of a second malignancy developing were calculated for the 407 patients who were treated with surgery alone, 226 who were treated with surgery followed by adjuvant chemotherapy (CT), 140 who were treated with surgery plus adjuvant radiation therapy (RT), and 308 who received all three modalities (CRT). The AR of a subsequent cancer (8.4% for CRT, 8.7% for CT, 8.7% for RT, and 11.7% for surgery only patients) did not differ significantly between treatment groups. The overall second cancer RR was 1.0% after CRT, 1.3% after RT, 1.6% after CT, and 1.7% after surgery alone. Contralateral breast cancers (RR of 4.2%; 95% CI, 2.7 to 6.3) account for the statistically significant excess of second malignancies among the surgery alone patients. The AR for contralateral breast cancer in the surgery group was higher than in either group receiving CT (P less than 0.01), but was not significantly different from the RT group. The RR for solid tumors othermore » than breast cancer was not significantly different from unity in any of the treatment groups. The RR for acute leukemia was 16.7% in the CRT group (95% CI, 0.2 to 92.7), 11.1% in the CT group (95% CI, 0.1 to 61.8), 10.0% in the surgery alone group (95% CI, 1.1 to 36.1), and 0.0% in the RT group (95% CI, 0.0 to 61.1). This study indicated that inclusion of RT and/or CT in the initial treatment of breast cancer did not impact negatively on patients' overall risk for a subsequent malignancy during the first decade after therapy, and that adjuvant CT with or without RT may decrease their risk of a contralateral breast cancer.« less

The risk of a second malignancy was determined for 999 patients given primary treatment using chemotherapy only, radiation therapy only, or both for Hodgkin's Disease or a non-Hodgkin's lymphoma at Duke University Medical Center between 1970 and 1981. The incidence, 10-year actuarial risk, and relative risk of developing an acute leukemia, solid tumor, or second lymphoma were determined by treatment modality and initial lymphoma type. Among the 313 Hodgkin's disease patients, the acute leukemia actuarial risk was 2.0% after chemotherapy, 1.4% after radiation therapy, and 0.9% after combined treatment with chemotherapy and radiation therapy. Their relative risk for acute leukemia was 51.3 overall (95% confidence interval [CI] 13.8 to 131.8) and was elevated in each treatment group. Among the 686 non-Hodgkin's lymphoma patients, the acute leukemia actuarial risk was zero after radiation therapy, 4.6% after chemotherapy, and 4.5% after the combined treatment, again not significantly different between treatment groups. The leukemia relative risk was 10.6 (95% CI 3.4 to 24.8) in the chemotherapy and 11.9 (95% CI 3.2 to 30.6) in the combined treatment group. Among both the Hodgkin's disease and non-Hodgkin's lymphoma populations, the combined treatment group had a lower actuarial risk for solid tumors than either the chemotherapy or radiation therapy group (P less than 0.02). Solid tumor actuarial risk did not differ significantly between the chemotherapy and radiation therapy groups. Hodgkin's disease patients had a solid tumor relative risk that was elevated significantly after radiation therapy (6.5; 95% CI 2.4 to 14.0) and to a lesser extent after chemotherapy (2.6; 95% CI 0.8 to 6.1) or combined treatment (1.7; 95% CI 0.2 to 6.0). Solid tumor relative risk among non-Hodgkin's lymphoma patients was 0.3 for the combined treatment, 0.8 for the chemotherapy, and 1.0 for the radiation therapy group. None of the Hodgkin's disease patients developed a non-Hodgkin's lymphoma. This study found no significant difference in leukemia risk among lymphoma patients treated with chemotherapy and the combined treatment. It also found that the overall risk of a second malignancy is no higher after treatment with the combined therapy than with chemotherapy or radiation therapy alone.

A review of randomized trials suggesting an improvement in overall patient survival with postmastectomy radiation therapy revealed that most patients in these studies had three or fewer positive axillary lymph nodes. Therefore, it is logical to consider using postmastectomy radiation therapy in all lymph node positive patients, not just those with four or more positive lymph nodes.

Prospective assessment of quality of life (QoL) in patients with refractory, residual or recurrent ovarian cancer receiving whole abdomen hyperthermia and intravenous liposomal doxorubicin chemotherapy.Treatment consisted of six cycles of intravenous liposomal doxorubicin at 40 mg m2 followed by whole abdomen hyperthermia with each cycle delivered every 4 weeks. QoL assessment was performed at baseline, prior to each cycle of chemotherapy and every 3 months during follow-up using self-administered questionnaires. Global QoL was rated on a seven-point scale and specific domains of QoL, disease related symptoms and treatment related toxicity were rated on a four-point scale.Thirty-two patients were enrolled on the study and 129 QoL questionnaires were completed. Average age was 57.9 (range 45-76); nine patients had persistent and 23 recurrent disease. Ten patients completed six cycles of therapy. Three patients returned follow-up surveys. Subjects rated their overall QoL and health at baseline as above average with mean scores 5.10 (95% CI=4.62-5.58) and 4.66 (95% CI=4.23-5.08), respectively. No significant change in overall QoL was found between baseline and cycles 4-6 of therapy. Mean ratings of overall health and subject reported differences in QoL between cycles were not significantly changed during therapy. Limited follow-up data were available, but scores suggest possible improvement in QoL for patients completing all therapy. Subjects rated the greatest negative impact on QoL in areas of role functioning and social functioning, where the mean (SD) over all cycles was 2.00 (0.67) and 1.98 (0.70), respectively. For physical symptoms, fatigue and sleep disturbance had the most negative impact on QoL with means (SD) of 2.26 (0.62) and 1.91 (0.70). The moderate treatment related toxicity seen in this study did not significantly impact patients reported QoL.Patients with unfavourable ovarian cancer responding to intravenous liposomal doxorubicin and whole abdomen hyperthermia maintained above average QoL during therapy. Limited data on patients completing protocol therapy demonstrated possible improvement in QoL.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO210 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

BACKGROUND Five randomized studies have demonstrated a benefit derived from adding cisplatin (CDDP)-based chemotherapy to radiotherapy (RT) for treatment of cervical carcinoma. The Dutch Phase III pelvic tumor trial demonstrated a survival and local control benefit due to the addition of hyperthermia (HT) to RT. The authors evaluated response and toxicity in patients with locally advanced cervical carcinoma (LACC) who were treated with concurrent weekly CDDP, HT, and RT (whole pelvis [n = 7] and whole pelvis and paraaortic nodes [n = 5]). METHODS From August 1998 through December 2000, 12 patients with LACC or locally recurrent cervical carcinoma (LRCC) following hysterectomy were enrolled on a pilot study combining weekly CDDP, HT, and RT. RESULTS Ten patients were treated at initial diagnosis. All achieved clinical complete response and durable local control. Two of the 10 experienced recurrence outside the pelvis; 1 of these patients had pulmonary metastasis, and the other had isolated paraaortic nodal involvement. Two patients treated for LRCC experienced local and systemic progression and died of disease within 6 months. CONCLUSIONS In this small series, trimodality therapy resulted in an excellent clinical response and was well tolerated. The addition of HT to chemoradiotherapy represents a promising new strategy that warrants multiinstitutional collaborative efforts to confirm its efficacy. Cancer 2003;98:277–82. © 2003 American Cancer Society. DOI 10.1002/cncr.11475

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.