Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer.

This review examined the 60 years of progress made in treating breast cancer from the unique perspective of the reader of Cancer, with a specific emphasis on the evolution of radiation therapy, constituting a survey of the published articles in each decade, and the standards of treatment and controversies of their times that they portray, in 3 major areas: radiation as an adjuvant therapy to mastectomy, radiation for internal mammary lymph node treatment, and radiation with breast-conserving surgery as an alternative to mastectomy.

Clinical implementation of intensity-modulated tangential beam irradiation for breast cancer.

A Monte Carlo based intensity-modulated radiation therapy (IMRT) treatment planning system has been developed and used for breast treatment. An iterative method was used for optimization to generate IMRT plans and a step-and-shoot technique was used for beam delivery. The patient setup and incident beam directions were the same as those for conventional tangential photon treatment. The weights for the opposed beamlets in the two tangential beams were determined first by the doses at the depths of the maximum dose at both sides to minimize hot spots. The intensity of an individual beamlet pair was then optimized based on the dose at the midplane. Fine tuning was made to achieve optimal target dose uniformity and to reduce the dose to the heart when necessary. The final dose calculations were performed using the Monte Carlo method and the plans were verified by phantom measurements. The dose distributions and dose-volume-histograms of IMRT plans were compared with those of conventional plans that were generated using a commercial treatment planning system and recalculated using an in-house Monte Carlo system for the first 25 patients. The dose comparisons showed that the percentage volume receiving more than 95% of the prescription dose (V95) and the percentage volume receiving more than 100% of the prescription dose (V100) for the clinical target volume (CTV) of IMRT plans were about the same as those of conventional plans. The percentage volume receiving more than 105% of the prescription dose (V105) for the CTV was reduced from 23.1% to 7.9% on average. The percentage volume of the lung receiving more than 20 Gy dose (V20 Gy) during the entire treatment was reduced by about 10%. The percentage volume of the heart receiving more than 30 Gy dose (V30 Gy) is reduced from 3.3% to 0.3%. Further studies revealed that a less than 5 degrees change in couch angle and collimator angle at patient setup had no significant effect on the dose coverage of CTV but had significant effect on the dose to the lung and heart. The study on the effect of beam spoiler showed that it increased the dose at the buildup region by 0- 13% that varies with location. The machine output linearity and stability for small monitor unit delivery of Siemens accelerators used for this study was checked and found to be suitable for breast IMRT. The total effect of variations was calculated to be less than 1% for typical breast treatments. The beam delivery time was increased by about 2 min compared with conventional tangential treatments. The whole treatment including patient setup and beam delivery can be completed in a 15 min slot. The IMRT technique has been proven practical for breast treatment clinically. The results showed that tangential IMRT improved the dose homogeneity in the breast and reduced the dose to the lung and heart.

Recursive partitioning identifies patients at high and low risk for ipsilateral tumor recurrence after breast-conserving surgery and radiation.

PURPOSE: Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer. PATIENTS AND METHODS: Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years. RESULTS: Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P =.03). For patients

Local recurrence after mastectomy or breast-conserving surgery and radiation.

Approximately 10% to 15% of patients with stage I/II invasive breast cancer will develop a clinically isolated local recurrence. The standard management of an ipsilateral breast tumor recurrence following breast-conserving surgery and radiation is salvage mastectomy, while local excision and radiation are optimal treatment of a chest wall recurrence following initial mastectomy. Although there are few data regarding the efficacy of systemic therapy after isolated local relapse, chemotherapy and/or hormonal therapy should be considered for most patients because of the high risk of subsequent distant relapse. However, local relapse does not always herald distant metastases. A prolonged interval between initial treatment and local recurrence is the most important prognostic factor for subsequent outcome, and when combined with other favorable characteristics, can predict 5-year survival rates of 70% or higher.

Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13.

PURPOSE: To determine if Biafine compared to Best Supportive Care (BSC) is effective in minimizing or preventing radiation-induced dermatitis in women undergoing breast irradiation. METHODS AND MATERIALS: Patients were randomized between Biafine (n = 83) vs. BSC (n = 89). The institutions identified preference for BSC at the time of randomization. A no-treatment arm was allowed (16% received no treatment). Patients were instructed to apply randomized product three times a day, but not within 4 h of their daily RT session. Application began following their first radiation treatment and continued 2 weeks postradiation. Skin dermatitis was scored weekly utilizing the RTOG and ONS (Oncology Nursing Society) skin toxicity scales, a weekly patient satisfaction and quality-of-life questionnaire. RESULTS: Using the RTOG toxicity scale there was no overall difference for maximum dermatitis during RT between Biafine and BSC (p = 0.77). There was no difference in maximum toxicity by arm or breast size. There was an interaction between breast size and toxicity, with large-breasted women exhibiting more toxicity. Large-breasted women receiving Biafine were more likely to have no toxicity 6 weeks post RT. CONCLUSION: There was no overall difference between BSC and Biafine in the prevention, time to, or duration of radiation-induced dermatitis.

Geriatric pain management. The anesthesiologist's perspective.

Geriatric patients have a unique physiology that makes their pain management problematic. This article reviews the issue of geriatric pain management from the perspective of the anesthesiologist. It looks at the main causes of geriatric chronic pain and emphasizes the different analgesic modalities available that can provide maximum relief and minimal potential side effects.

Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist?

PURPOSE: The elective treatment of internal mammary lymph nodes (++IMNs) in breast cancer is controversial. Previous randomized trials have not shown a benefit to the extended radical mastectomy or elective IMN irradiation overall, but a survival benefit has been suggested by some for subgroups of patients with medial tumors and positive axillary lymph nodes. The advent of effective systemic chemotherapy and potential for serious cardiac morbidity have also been factors leading to the decreased use of IMN irradiation during the past decade. The recent publishing of positive trials testing postmastectomy radiation that had included regional IMN irradiation has renewed interest in their elective treatment. The purpose of this study is to critically review historical and new data regarding IMNs in breast cancer. METHODS AND MATERIALS: The historical incidence of occult IMN positivity in operable breast cancer is reviewed, and the new information provided by sentinel lymph node studies also discussed. The results of published randomized prospective trials testing the value of elective IMN dissection and/or radiation are analyzed. The data regarding patterns of failure following elective IMN treatment is studied to determine its impact on local-regional control, distant metastases, and survival. A conclusion is drawn regarding the merits of elective IMN treatment based on this review of the literature. RESULTS: Although controversial, the existing data from prospective, randomized trials of IMN treatment do not seem to support their elective dissection or irradiation. While it has not been shown to contribute to a survival benefit, the IMN irradiation increases the risk of cardiac toxicity that has effaced the value of radiation of the chest wall in reducing breast cancer deaths in previous randomized studies and meta-analyses. Sentinel lymph node mapping provides an opportunity to further evaluate the IMN chain in early stage breast cancer. Biopsy of "hot" nodes may be considered in the future to select patients who are most likely to benefit from additional regional therapy to these nodes. CONCLUSIONS: Irradiation of the IMN chain in conjunction with the chest wall and supraclavicular region should be considered only for those with pathologically proven IMNs with the goal of improving tumor regional control.

Preliminary results of a bone marrow magnetic resonance imaging protocol for patients with high-risk prostate cancer.

OBJECTIVES: To compare the accuracy of a bone marrow magnetic resonance imaging (MRI) protocol in patients at high risk of metastatic disease with radioisotopic bone scans, the standard method for detection of bony metastases in patients with prostate cancer. METHODS: The study group consisted of 19 men with prostate cancer who underwent a bone marrow MRI between November 1993 and February 1996. This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and femurs. Indications for MRI included an equivocal bone scan and/or staging of locally advanced or recurrent disease. The findings on MRI and bone scan were compared and the results correlated with the subsequent clinical patient outcome. RESULTS: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13 patients with negative bone scans. Four patients had an indeterminate bone scan: 2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on the basis of subsequent clinical follow-up. Two patients with positive bone scans had true-positive MRIs. CONCLUSIONS: Although not recommended for routine staging, MRI was useful in this study for clarifying an equivocal bone scan. The bone marrow MRI protocol images a high yield volume of the bony skeleton and is fast and economical compared with obtaining many focused MRI scans of these areas separately. These preliminary data suggest that further investigation of its clinical utility for staging locally advanced or recurrent disease is justified.

Histopathologic review of prostate biopsies from patients referred to a comprehensive cancer center: correlation of pathologic findings, analysis of cost, and impact on treatment.

BACKGROUND: Clinicians at the Fox Chase Cancer Center (FCCC) base prostate carcinoma treatment decisions regarding need to treat, field size, total dose, and adjuvant hormonal therapy on known prognostic factors including clinical stage, Gleason score (GS), perineural invasion (PNI), and pretreatment prostate specific antigen levels. The pathology of every patient is reviewed at FCCC to confirm a diagnosis of malignancy. The objective of this study was to define differences between pathologic reviews and their impact on treatment between outside institutions and FCCC. METHODS: The authors reviewed 538 pathology reports of prostate biopsies performed at both outside pathology departments and FCCC on patients evaluated between January 1993 and December 1996. The outside pathology reviews represented 107 community hospitals, academic institutions, and private pathology laboratories. Patients who had received hormonal therapy, cryosurgery, or radical prostatectomy prior to prostate biopsy were excluded from analysis. Final FCCC pathology determinations were compared with pathology reports from outside institutions. Reports then were analyzed to determine whether differences in interpretation would have resulted in different treatment strategies. Differences in percentages according to institutional type were evaluated using the chi-square statistic. The cost was assessed and cost per change in treatment estimated. RESULTS: The 538 pathology reviews identified a nearly 40% change in GS and a 13% change in > or =2 GS between the FCCC pathology review and 107 outside academic institutions. The results of this study showed that 22% of community hospitals, 10% of private laboratories, and 8% of academic institutions demonstrated at least 2 GS changes compared with the FCCC pathology review (p = 0.001). There was no significant difference observed between types of institutions in the incidence of PNI. CONCLUSIONS: This analysis provides evidence of a significant difference in the pathologic reviews of prostate biopsies conducted at FCCC and outside pathology departments. There was a nearly 40% change in GS and a 13% change in > or =2 GS between the FCCC pathology review and 107 outside institutions. The second pathology review added approximately $104 per case for a total of $55,952 to review all 538 cases. Overall, the savings in health care dollars resulting from the second pathologic review totaled $12,997. This second review of outside pathology in prostate cancer appears to be justified based on the treatment changes and on cost.

A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged fifty or younger.

INTRODUCTION: Indications for postmastectomy radiation include primary tumor size > or = 5 cm and/or > or = 4 positive axillary nodes. In clinical practice, patients with a close or positive margin after mastectomy are also often treated with postmastectomy radiation. However, there is little data regarding the risk of a chest wall recurrence in patients with close or positive margins who otherwise would be considered low risk (tumor size <5 cm and/or 0-3 positive nodes). To address this issue, we assessed the risk of a chest wall recurrence in women with Stage I-II breast cancer who underwent mastectomy and were found to have primary tumor size <5 cm and 0-3 positive nodes with a close or positive deep margin. METHODS AND MATERIALS: The pathologic reports from 789 patients treated by mastectomy between 1985 and 1994 at our institution were retrospectively reviewed. Of these, 136 (17%) had tumor within 1 cm of the deep resection margin. The study population consists of 34 of these patients with close or positive margins whose primary tumor size was <5 cm with 0-3 positive axillary nodes and who received no postoperative radiation. The median age was 43 years (range 29-76). Of these, 44% had T1 tumors and 56% T2 tumors. Pathologic axillary nodal status was negative in 65% and positive in 35%. The median number of positive nodes was 1. The deep margin was positive in 2 patients, < or = 2 mm in 17 patients, 2.1-4 mm in 7 patients and 4.1-6 mm in 8 patients. Of the 34 patients, 67% received adjuvant chemotherapy +/- tamoxifen and 21% received tamoxifen alone. The median follow-up was 59 months (range 7-143). RESULTS: There were 5 chest wall recurrences at a median interval of 26 months (range 7-127). One was an isolated first failure, one occurred concurrent with an axillary recurrence, and three were associated with distant metastases. The 5- and 8-year cumulative incidences of a chest wall recurrence were 9% and 18%. Patient age correlated with the cumulative incidence of chest wall recurrence at 8 years; age < or = 50 years had a rate of 28% vs. 0% for age >50 (p = 0.04). There was no correlation with chest wall failure and number of positive nodes, ER status, lymphovascular invasion, location of primary, grade, family history, or type of tumor close to the margin. Of 5 chest wall failures, 4 were in patients who had received adjuvant systemic chemotherapy +/- tamoxifen. Chest wall failures occurred in 1 patient with a positive deep margin, 3 patients with margins within 2 mm, and 1 patient with a margin of 5 mm. The estimated cumulative incidence probability of chest wall recurrence at 8 years by margin proximity was 24% < or = 2 mm vs. 7% 2.1-6 mm (p = 0.36), and by clinical size 24% for T2 tumors vs. 7% for T1 (p = 0.98). CONCLUSIONS: A close or positive margin is uncommon (< or = 5%) after mastectomy in patients with tumor size <5 cm and 0-3 positive axillary nodes but, when present, it appears to be in a younger patient population. The subgroup of patients aged 50 or younger with clinical T1-T2 tumor size and 0-3 positive nodes who have a close (< or = 5 mm) or positive mastectomy margin are at high risk (28% at 8 years) for chest wall recurrence regardless of adjuvant systemic therapy and, therefore, should be considered for postmastectomy radiation.

Conformal external beam treatment of prostate cancer.

OBJECTIVES: This study reports the 5-year outcomes of treatment for patients with prostate cancer treated largely with conformal three-dimensional radiation therapy. METHODS: Results are presented for 456 consecutive patients treated prior to December 31, 1993 whose pretreatment prostate-specific antigen (PSA) levels are known. Biochemical failure was defined as two consecutive rises in the PSA that equals or exceeds 1.5 ng/mL. Kaplan-Meier product limit methods, the log-rank test, and Cox regression models were used in evaluating the data. No patient was lost to follow-up. RESULTS: The 5-year biochemically free of failure (bNED) rate for all patients was 61% and 57% at 7 years. In the group with pretreatment PSA less than 10 ng/mL, the 5-year bNED rate for patients with localized disease (T1,2AB disease, Gleason sum of 6 or less) was 85% and for those with locally advanced disease (T2C,3), 70%. In the group with pretreatment PSA of 10 to 19.9 ng/mL, the 5-year bNED rate for patients with localized disease was 66% and for those with locally advanced disease, 44%. In the group with pretreatment PSA of 20 ng/mL or above, the patients with localized or locally advanced disease had 5-year bNED rates of 31% and 21%, respectively. CONCLUSIONS: The results of largely conformal three-dimensional external beam treatment of localized prostate cancer produced 5-year bNED results that are comparable to recent reports of nerve-sparing prostatectomy. Preliminary 7-year bNED results in all patients and in patients with localized tumors indicated a modest decrease in the cancer-free rate from that observed at 5 years, suggesting the results are durable.

Young patients with prostate cancer have an outcome justifying their treatment with external beam radiation.

PURPOSE: The majority of young patients with early stage prostate cancer in the United States are treated with radical prostatectomy. To determine whether this preference for surgical care is justified, we analyzed by patient age the survival without biochemical evidence of disease (bNED) of men with clinically organ-confined prostate cancer treated with external beam irradiation. METHODS AND MATERIALS: One hundred and sixty-nine men with clinical stages T1-2 adenocarcinoma of the prostate received external beam radiation therapy alone at Fox Chase Cancer Center. All patients had serum prostate-specific antigen (PSA) values less than 10 ng/ml prior to initiation of treatment. Out of 169 patients, 167 had unstaged regional nodes (NX) and all had no evidence for distant metastasis (M0). The median age was 69 years. Criteria for bNED survival were posttreatment serum PSA < or = 1.5 ng/ml and not rising on two consecutive values. The median follow-up is 35 months. RESULTS: The actuarial 5-year bNED survival of all 169 patients was 85%. The bNED survival of patients less than 65 was not significantly different than that of patients 65 and older (89 vs. 84%, respectively). Patient age, American Joint Committee on Cancer (AJCC) stage, palpation stage, Gleason score, and dose to the center of the prostate were not found to be significant predictors of bNED survival on multivariate analysis. CONCLUSION: Our results using strict biochemical endpoints are comparable to reported series of similarly staged men treated with prostatectomy. In addition, the patient age of less than 65 is not a prognostic factor for worse outcome after radiation therapy. Young patients with clinically organ-confined prostate cancer who are fully informed of their treatment options can be appropriately accepted for external beam treatment.

Improving patient-controlled analgesia: adding droperidol to morphine sulfate to reduce nausea and vomiting and potentiate analgesia.

Opioid-related side effects, including nausea and vomiting, are common in patients using morphine in patient-controlled analgesia for postoperative pain relief. The purpose of this study was to determine if the addition of droperidol to a morphine sulfate delivery system could decrease the incidences of nausea and vomiting without increasing droperidol-related side effects. Forty ASA 1 and 2 patients scheduled to undergo peripheral orthopedic surgery were randomized to receive either morphine sulfate (2 mg/mL), or morphine sulfate (1.9 mg/mL) plus droperidol (0.125 mg/mL) for postoperative self-controlled analgesia. Visual analogue scores for pain, nausea, and sedation were obtained from each patient immediately after surgery and each morning and evening until patient-controlled analgesia was discontinued approximately 48 hours later. Total patient-controlled use of morphine sulfate was recorded at each visual analogue rating. The patients who used morphine sulfate plus droperidol had significantly less nausea and vomiting and used significantly less morphine. No patient experienced droperidol-related side effects. We conclude that the routine addition of droperidol to morphine sulfate in self-controlled analgesia improves the comfort of patients following peripheral orthopedic surgery.