Causes of death among cancer patients.

Background: The purpose of our study was to characterize the causes of death among cancer patients as a function of objectives: (i) calendar year, (ii) patient age, and (iii) time after diagnosis. Patients and methods: US death certificate data in Surveillance, Epidemiology, and End Results Stat 8.2.1 were used to categorize cancer patient death as being due to index-cancer, nonindex-cancer, and noncancer cause from 1973 to 2012. In addition, data were characterized with standardized mortality ratios (SMRs), which provide the relative risk of death compared with all persons. Results: The greatest relative decrease in index-cancer death (generally from > 60% to < 30%) was among those with cancers of the testis, kidney, bladder, endometrium, breast, cervix, prostate, ovary, anus, colorectum, melanoma, and lymphoma. Index-cancer deaths were stable (typically >40%) among patients with cancers of the liver, pancreas, esophagus, and lung, and brain. Noncancer causes of death were highest in patients with cancers of the colorectum, bladder, kidney, endometrium, breast, prostate, testis; >40% of deaths from heart disease. The highest SMRs were from nonbacterial infections, particularly among <50-year olds (e.g. SMR >1,000 for lymphomas, P < 0.001). The highest SMRs were typically within the first year after cancer diagnosis (SMRs 10-10,000, P < 0.001). Prostate cancer patients had increasing SMRs from Alzheimer's disease, as did testicular patients from suicide. Conclusion: The risk of death from index- and nonindex-cancers varies widely among primary sites. Risk of noncancer deaths now surpasses that of cancer deaths, particularly for young patients in the year after diagnosis.

Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta.

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

How do mesenchymal stromal cells exert their therapeutic benefit?

In recent years mesenchymal stromal cells (MSC) have emerged as a major new form of cell therapy. While the original perception was that MSC were stem/progenitor cells with the potential to contribute to the regeneration of tissue, more recent data suggest that the principal mechanism of MSC activity is through the release of soluble mediators that elicit the observed biologic response. Future studies are needed to identify more completely the spectrum of therapeutic applications and delineate better the associated molecular and cellular mechanisms.

Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck.

PURPOSE: To define further the role of concurrent chemoradiotherapy for patients with advanced squamous carcinoma of the head and neck. PATIENTS AND METHODS: The Radiation Therapy Oncology Group developed this three-arm randomized phase II trial. Patients with stage III or IV squamous carcinoma of the oral cavity, oropharynx, or hypopharynx were eligible. Each of three arms proposed a radiation schedule of 70 Gy in 35 fractions. Patients on arm 1 were to receive cisplatin 10 mg/m(2) daily and fluorouracil (FU) 400 mg/m(2) continuous infusion (CI) daily for the final 10 days of treatment. Treatment on arm 2 consisted of hydroxyurea 1 g every 12 hours and FU 800 mg/m(2)/d CI delivered with each fraction of radiation. Arm 3 patients were to receive weekly paclitaxel 30 mg/m(2) and cisplatin 20 mg/m(2). Patients randomly assigned to arms 1 and 3 were to receive their treatments every week; patients on arm 2 were to receive their therapy every other week. RESULTS: Between 1997 and 1999, 241 patients were entered onto study; 231 were analyzable. Ninety-two percent, 79%, and 83% of patients on arms 1, 2, and 3, respectively, were able to complete their radiation as planned or with an acceptable variation. Fewer than 10% of patients had unacceptable deviations or incomplete chemotherapy in the three arms. Estimated 2-year disease-free and overall survival rates were 38.2% and 57.4% for arm 1, 48.6% and 69.4% for arm 2, and 51.3% and 66.6% for arm 3. CONCLUSION: We have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting with high compliance rates.

Is it necessary to perform week three dosimetric analysis in low-dose-rate brachytherapy for prostate cancer when day 0 dosimetry is done? A quality assurance assessment.

PURPOSE: To determine whether computed tomography/magnetic resonance imaging-based day 0 (d0) dosimetry is a meaningful predictor of day 21 (d21) dosimetry in low-dose-rate brachytherapy for localized prostate cancer. METHODS AND MATERIALS: The study population consisted of 277 men with localized (T1-2 N0 M0), low-/intermediate-risk prostate cancer treated with low-dose-rate brachytherapy. Computed tomography/magnetic resonance imaging fusion was used for postimplant dosimetry at d0 and d21. Logistic regression was used to construct receiver operating characteristic curves for achieving each constraint at d21, based on d0 D90 and V100, and Youden's index was used to evaluate cutpoints. Freedom from biochemical failure (FBCF) was estimated with the Kaplan-Meier method. RESULTS: The median d0 D90 increased from 133 to 150 Gy at d21, and median d0 V100 increased from 87% to 91%. For achieving the D90 constraint at d21, the optimal cut-point for d0 D90 was 135 Gy, with 84% of these patients maintaining a d21 D90 > 145 Gy. For achieving the D90 constraint at d21, the optimal cut-point for d0 V100 was 87%, with 83% of these patients maintained a d21 V100 > 90%. There was no improvement in FBCF in patients with a d0 D90 > 135 Gy or D90 > 145 Gy. Similarly, there was no improvement in FBCF in patients with a d0 V100 > 87% or V100 > 90%. CONCLUSIONS: Meeting dosimetric constraints on d0 does not obviate d21 dosimetric analysis. Constraints used for dose prescriptions on d0 are not the ideal predictors of d21 dosimetry.

High-efficiency transduction and long-term gene expression with a murine stem cell retroviral vector encoding the green fluorescent protein in human marrow stromal cells.

Bone marrow stromal cells (MSCs) are unique mesenchymal cells that have been utilized as vehicles for the delivery of therapeutic proteins in gene therapy protocols. However, there are several unresolved issues regarding their potential therapeutic applications. These include low transduction efficiency, attenuation of transgene expression, and the technical problems associated with drug-based selection markers. To address these issues, we have developed a transduction protocol that yields high-level gene transfer into human MSCs, employing a murine stem cell virus-based bicistronic vector containing the green fluorescent protein (GFP) gene as a selectable marker. Transduction of MSCs plated at low density for 6 hr per day for 3 days with high-titer viral supernatant resulted in a gene transfer efficiency of 80+/-6% (n = 10) as measured by GFP fluorescence. Neither centrifugation nor phosphate depletion increased transduction efficiency. Assessment of amphotropic receptor (Pit-2) expression by RT-PCR demonstrated that all MSCs expressing the receptor were successfully transduced. Cell cycle distribution profiles measured by propidium iodide staining showed no correlation with the susceptibility of MSCs to transduction by the retroviral vector. Human MSCs sequentially transduced with an adenoviral vector encoding the ecotropic receptor and ecotropic retroviral vector encoding GFP demonstrated that all MSCs are susceptible to retroviral transduction. We further showed that both genes of bicistronic vector are expressed for at least 6 months in vitro and that transgene expression did not affect the growth or osteogenic differentiation potential of MSCs. Future studies will be directed toward the development of gene therapy protocols employing this strategy.

Defining the appropriate radiation dose for pretreatment PSA < or = 10 ng/mL prostate cancer.

PURPOSE: To investigate whether a dose response exists for biochemical no evidence of disease (bNED) control in prostate cancer patients with pretreatment prostate-specific antigen (PSA) < or = 10 ng/mL and to identify the patient subgroups affected. METHODS AND MATERIALS: Between 5/89 and 10/97, 488 T1-T3 NX-0 M0 prostate cancer patients with PSA < or = 10 ng/mL were treated with three-dimensional conformal radiation therapy (3D-CRT) alone. Median and mean pretreatment PSA values were 6.3 and 6.2, respectively. Gleason scores of 2-6 and 7-10 were noted in 386 and 102 men, respectively. AJCC 1992 palpation T1-T2AB tumors were noted in 415 patients. Perineural invasion (PNI) was noted in 60 men. Mean and median age was 67 and 68 years, respectively. Dose to the center of the prostate ranged from 6260 cGy to 8409 cGy with a mean and median of 7423 cGy and 7278 cGy, respectively. Patients were stratified into three groups according to dose: <7250 cGy, 7250-7599 cGy, and > or =7600 cGy. Median dose in these three groups was 7067 cGy, 7278 cGy, and 7734 cGy, respectively. Univariate analysis was performed to determine differences in bNED control (American Society for Therapeutic Radiology and Oncology [ASTRO] Consensus Guidelines definition of failure) by dose group for the entire cohort, for 310 good prognosis patients (T1-T2A, Gleason score 2-6, absence of PNI), and for 178 poor prognosis patients (T2B-T3 or Gleason score 7-10 or presence of PNI) (1). Multivariate analysis (MVA) was performed to determine if dose was an independent predictor of bNED control. Median follow-up was 36 months. RESULTS: A dose response was not demonstrated for the entire group of patients with pretreatment PSA < or =10 ng/mL. Doses of <7250 cGy, 7250-7599 cGy, and > or =7600 cGy were associated with 5-year bNED control rates of 73%, 86%, and 89%, respectively (p = 0.12). MVA demonstrated prognosis group (p = 0. 038) to be the only independent predictor of bNED control. Good prognosis patients had a 5-year bNED of 85% and no dose response was seen. The subgroup of poor prognosis patients demonstrated a 5-year bNED control rate of 81% and a dose response was seen for those receiving > or =7600 cGy, compared to the two lower dose groups (94% vs. 75% vs. 70%; p = 0.0062). MVA for the poor prognosis subset demonstrated dose (p = 0.01) to be the only independent predictor for improved bNED control. CONCLUSIONS: The poor prognosis subset of PSA < or =10 ng/mL prostate cancer patients benefit from dose escalation. A dose response is not demonstrated for prostate cancer patients with pretreatment PSA < or =10 ng/mL and other favorable features.

Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy.

PURPOSE: The benefit of adjuvant hormones in prostate cancer patients receiving definitive radiation therapy (RT) in RTOG 85-31 and 86-10 has previously been reported. This analysis excludes those patients with positive lymph nodes or postprostatectomy to determine the benefit of adjuvant hormones in men with locally advanced nonmetastatic prostate cancer receiving definitive RT. METHODS AND MATERIALS: Nine hundred ninety-three eligible patients from RTOG 85-31 and 86-10 treated between 1987-1992 were included in this study. Five hundred seventy-five patients with T3N0M0 disease were included from RTOG 85-31 and 418 patients with T2b-T4N0M0 disease from RTOG 86-10. Patients randomized to receive long-term hormones (LTH) on 85-31 received goserelin starting the last week of RT and continued indefinitely. Patients treated with short-term hormones (STH) on 86-10 received goserelin and flutamide 2 months prior to and during RT. The median follow-up for all patients in this analysis was 71 months (range, 0.6-129 months). RESULTS: Combining both studies, statistically significant improvements in outcome were observed between the RT and hormones (I) and RT alone (II) groups for biochemical disease-free survival (bNED control) and distant metastases failure (DMF). Statistically significant improvements in bNED control, DMF and cause-specific failure (CSF) were observed for patients receiving LTH compared with STH. In those patients receiving LTH, the benefit in bNED control (p = 0.0002), DMF (p = 0.05), and CSF (p = 0.02) was limited to centrally reviewed Gleason score of 7 and 8-10 tumors. For all patients treated on 85-31, statistically significant improvements for bNED control, DMF, and CSF were observed between Group I and II. Multivariate analysis demonstrated Gleason score and the use of LTH to be independent predictors for bNED control (p < 0.0001), DMF (p < 0.0001), and CSF (p < 0.002). CONCLUSIONS: Based on this analysis, adjuvant long-term hormones compared to short-term hormones resulted in statistically significant improvements in bNED control, DMF, and CSF rates for patients with locally advanced nonmetastatic prostate cancer.

Radiotherapy options for localized prostate cancer based upon pretreatment serum prostate-specific antigen levels and biochemical control: a comprehensive review of the literature.

PURPOSE: To review all the available radiotherapy (RT) literature on localized prostate cancer treatment where serum prostate-specific antigen (PSA) levels were used to both stratify patients and evaluate outcome and determine if any conclusions can be reached regarding an optimal radiotherapeutic management for this disease. METHODS AND MATERIALS: A MEDLINE search was conducted to obtain all articles in English on prostate cancer treatment employing RT from 1986-1997. Studies were considered eligible for review only if they met all the following criteria: 1) pretreatment PSA values were recorded and grouped for subsequent evaluation, 2) posttreatment PSA values were continuously monitored, 3) definitions of biochemical control were stated, and 4) the median follow-up was given. RESULTS: Of the 246 articles identified, only 20 met the inclusion criteria; 4 using conformal external beam RT, 8 using conventional external beam RT, and 8 using interstitial brachytherapy (4 using a permanent implant alone, 3 combining external beam RT with a permanent implant, and 1 combining a conformal temporary interstitial implant boost with external beam RT). No studies using neutrons (with or without external beam RT) or androgen deprivation (combined with external beam RT) were identified where patients were stratified by pretreatment PSA levels. Results for all therapies were extremely variable with the 3-5-year rates of biochemical control for patients with pretreatment PSA levels < or = 4 ng/ml ranging from 48 to 100%, for PSA levels >4 and < or = 10 ng/ml ranging from 44 to 90%, for PSA levels >10 and < or = 20 ng/ml ranging from 27 to 89%, and for PSA levels >20 ranging from 14 to 89%. The median Gleason score, T-stage, definition of biochemical control, and follow-up were substantially different from series to series. No RT option consistently produced superior results. CONCLUSIONS: When data are reviewed from studies using serum PSA levels to stratify patients and to evaluate treatment outcome, no consistently superior RT technique was identified. These data suggest that standard definitions of disease stage (combining clinical, pathologic, and biochemical criteria) and a common definition of biochemical cure (as developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel) need to be adopted to evaluate treatment efficacy and advise patients on the most appropriate radiotherapeutic option for their disease.

The treatment of nonpalpable PSA-detected adenocarcinoma of the prostate with 3-dimensional conformal radiation therapy.

PURPOSE: We reviewed our institution's experience treating patients with nonpalpable PSA-detected prostate cancer with three-dimensional conformal radiation therapy (3DCRT) to determine prognostic factors that predict for biochemical-free survival (bNED) control and present the bNED control rates. METHODS AND MATERIALS: Between May 1, 1990 and November 30, 1994, 160 patients with nonpalpable PSA-detected prostate cancer received 3DCRT at Fox Chase Cancer Center (median total dose 73 Gy; range: 67-78 Gy). bNED failure was defined as three consecutive increases in posttreatment PSA after achieving a nadir. bNED failure was recorded as the time midway between the nadir and the first consecutive rising PSA. Five-year actuarial rates of bNED control were calculated for pretreatment PSA (0-9.9 vs. 10-19.9 vs. > or = 20 ng/ml), Gleason score (2-6 vs. 7-10), treatment field size (prostate vs. small pelvis), age (<65 vs. > or = 65), and dose (< or = 73 vs. >73 Gy) using Kaplan-Meier methods and compared using the Log rank test. The Cox model was used to multivariately establish independent predictors based on significant univariate factors. Median follow-up was 39 months (range: 2-84 months). RESULTS: The 5-year actuarial rate of bNED control was 86% for the entire group of patients. The Cox Proportional Hazards model demonstrated that pretreatment PSA was an independent predictor of bNED control. Treatment field size was marginally predictive. There was no difference in bNED control when patients were stratified by the number of lobes positive for disease. Statistically different rates of bNED control were seen when the patients with nonpalpable disease were univariately compared to T2b and T2c patients. Three patients experienced Grade 3-4 genitourinary (GU) toxicity and 3 patients experienced Grade 3-4 gastrointestinal (GI) toxicity. CONCLUSIONS: Patients with nonpalpable PSA-detected prostate cancer can be effectively treated with 3DCRT with minimal morbidity and high rates of bNED control at 5 years. Pretreatment PSA level is an independent predictor of bNED control.

Patterns and fate of PSA bouncing following 3D-CRT.

PURPOSE: The goals of this study were to quantify the frequency of post-treatment prostate-specific antigen (PSA)-level bouncing following three-dimensional conformal radiation therapy (3D-CRT) for prostate cancer and to identify any relationships that may exist between bouncing activity and biochemical control (bNED). METHODS: Between May 1989 and July 1995, 306 patients were treated with 3D-CRT alone. All patients had 6 or more post-treatment PSA levels and at least 5 years of PSA follow-up. The median total follow-up and total dose to the center of prostate was 79 months and 74 Gy, respectively. A bounce was defined by a minimum rise in PSA of 0.4 ng/mL over a 6-month period, followed by a drop in PSA of any magnitude. Estimates of bNED control rates were made using Kaplan-Meier methodology and comparisons were made using the log-rank test. Multivariate analysis of bNED control predictors was accomplished using a stepwise Cox proportional hazards model. RESULTS: Nearly one third of the patients experienced at least one bounce. Bouncers were found to present with higher pretreatment PSA levels and were treated with lower dose levels to the center of prostate. Five-year bNED control estimates for nonbouncers vs. bouncers were 69% and 52%, respectively (p = 0.0024). After controlling for dose and pretreatment PSA level, total number of bounces emerged as a significant predictor of bNED control (p = 0.02). CONCLUSIONS: Bouncing PSA levels occur in approximately one third of the patients treated with 3D-CRT alone, with bouncing occurring at a constant rate from 2 to 5 years post-treatment. Bouncing is associated with lower radiation dose levels, higher pretreatment PSA levels, and decreased bNED control. Nearly half of the bouncers are bNED controlled; thus, clinicians should not use bouncing as a sole indicator of relapse.

The cost effectiveness of 3D conformal radiation therapy compared with conventional techniques for patients with clinically localized prostate cancer.

BACKGROUND: We previously demonstrated the advantages of three-dimensional conformal radiation therapy (3DCRT) in improved rates of biochemical (bNED) control in certain subsets of patients with clinically localized prostate cancer. However, in this era of cost consciousness and limited resources, the cost effectiveness of 3DCRT compared with conventional external beam irradiation (CRT) remains unexamined. METHODS AND MATERIALS: Between October 1, 1987 and November 30, 1991, 193 patients with clinically localized prostate cancer received definitive external beam irradiation at Fox Chase Cancer Center. The 1998 Medicare fee schedule was used to determine treatment charges and to provide a reference for a national comparison. Complete charges for pretreatment work-up, treatment, and follow-up were tabulated for each patient. The mean total charges (MTC) using the Lin method of estimating medical costs was used to analyze and compare costs between groups. A matched case/control analysis was performed to further evaluate the effect of cost between techniques. The median follow-up was 72 months (range 3-118). RESULTS: The overall 5-year actuarial rate of bNED control was 41% and 53%, respectively, for the CRT and 3DCRT patients (p = 0.03). The MTC for the CRT patients was $10,544.53. For the 3DCRT patients, the MTC was $8,955.48. The sample mean of the total costs from the observed deaths for the two patient groups by follow-up interval ranged from $9,800.63 to $59,635.01 for the CRT patients to $17,259.00 to $24,250.38 for the 3DCRT patients. No statistically significant difference in cost was observed between groups using the matched case/control analysis. CONCLUSION: Initial work-up and treatment costs were greater for patients treated with 3DCRT compared with patients treated with conventional techniques. However, with longer follow-up, the mean total cost of treatment was not statistically different between the two treatment groups. Because of improved rates of bNED control for these patients and the increased costs associated with the treatment of a greater fraction of patients with recurrent disease following CRT, 3DCRT was cost effective for patients with clinically localized prostate cancer.

The role of regional nodal irradiation in the management of patients with early-stage breast cancer treated with breast-conserving therapy.

PURPOSE: To determine the incidence of regional nodal failure (RNF) and indications for regional nodal irradiation (RNI) in patients with Stage I and II breast cancer treated with breast-conserving therapy (BCT). METHODS AND MATERIALS: Four hundred fifty-six patients with Stage I/II breast cancer were treated with BCT at William Beaumont Hospital. All patients underwent excisional biopsy and 288 (63%) were reexcised. A Level I/II ipsilateral axillary lymph node dissection was performed on 431 patients (95%). Pathologically involved nodes were found in 106 (23%) cases (69 with one to three nodes and 37 with > or = four nodes involved). All patients received whole breast irradiation (median dose 50 Gy) and 415 (91%) were boosted to the tumor bed (median total dose 60.4 Gy). Three hundred and sixty (79%) patients received breast alone irradiation and 96 (21%) also received RNI. The median axilla/supraclavicular fossa dose was 50 Gy. RESULTS: With a median follow-up of 83 months, 15 patients developed a RNF for a 5- and 8-year actuarial rate of 3 and 4%, respectively. The 5- and 8-year actuarial rates of axillary failure (AF) were 0.7 and 1.0%, respectively. The incidence of RNF or AF was not affected by the use of RNI in N0 or N1 patients with one to three positive nodes. Only in patients with four or more positive nodes was there a trend towards improved regional control with RNI (p = 0.09). However, patient numbers were extremely small, and this improvement was limited to a reduction in the rate of failure in the supraclavicular fossa (SCF) (20 vs. 0%, p = 0.04). Multiple clinical, pathologic, and treatment related factors were analyzed for an association with AF. On univariate analysis, AF was associated with the number of lymph nodes excised (p < 0.0001) estrogen receptor status (p = 0.0016), and pathologic node status (p = 0.0021). CONCLUSIONS: Regional nodal failure as the first site of failure is uncommon in patients with early-stage breast cancer treated with BCT with < or = three positive lymph nodes and appears unaffected by RNI. For patients with four or more positive lymph nodes, a trend towards improved RNF was noted with RNI, primarily in the SCF. However, patient numbers were extremely small in all subsets analyzed. Additional studies are needed to further define the need for RNI in these patients and help determine other factors associated with RNF.

The correlation between the ASTRO Consensus Panel definition of biochemical failure and clinical outcome for patients with prostate cancer treated with external beam irradiation. American Society of Therapeutic Radiology and Oncology.

PURPOSE: We reviewed our institution's experience treating patients with external beam irradiation (RT) to determine if the ASTRO Consensus Panel definition of biochemical failure (BF) following radiation therapy correlates with clinical distant metastases free survival (DMFS), disease-free survival (DFS), cause-specific survival (CSS), and local control (LC). METHODS AND MATERIALS: Between 1/1/87 and 12/31/92, 568 patients with clinically localized prostate cancer received external beam irradiation (RT) using localized prostate fields at William Beaumont Hospital (median total dose 66.6 Gy; range: 60-70.4 Gy). Biochemical failure was defined as three consecutive increases in post-treatment prostate specific antigen (PSA) after achieving a nadir. Biochemical failure was recorded as the time midway between the nadir and the first rising PSA. Five-year actuarial rates of clinical DMFS, DFS, CSS, and LC were calculated for patients who were biochemically controlled (BC) versus those who failed biochemically. Median follow-up was 56 months (range: 24-118 months). RESULTS: Five-year actuarial rates of DMFS, DFS, CSS, and LC were significantly greater in patients who were biochemically controlled versus those who were not (p < 0.001). In patients who were BC, the 5-year actuarial rates of DMFS, DFS, CSS, and LC were 99%, 99%, 98%, and 99% respectively. For patients who failed biochemically, the 5-year actuarial rates of DMFS, DFS, CSS, and LC were 74%, 64%, 89%, and 86% respectively. When stratifying by pretreatment PSA, Gleason score, and T stage these differences remained significant for DMFS, DFS, and CSS. The Cox proportional hazards model demonstrated that BC was the single most important predictor of clinical outcome for DMFS, DFS, CSS, and LC. Pretreatment PSA and Gleason score were also independent predictors of outcome for DMFS and DFS. CONCLUSIONS: The ASTRO Consensus Panel definition of BF following radiation therapy correlates well with clinical DMFS, DFS, and CSS. These findings suggest that the Consensus Panel definition may be a surrogate for clinical progression and survival and should be considered a valid endpoint for separating successful versus unsuccessful treatment. Additional studies with longer follow-up will be needed to corroborate these findings.

Implementation of 3D-virtual brachytherapy in the management of breast cancer: a description of a new method of interstitial brachytherapy.

PURPOSE: We present the initial description of a new technique of interstitial breast brachytherapy in which a computer-generated image of an implant template is applied virtually to serial-computed tomography (CT) scan images of a patient's breast. Optimal placement of the virtual template around the CT images of the proposed target volume provides the physician with a preplan for improved positioning of implant needles around the actual target volume intraoperatively. METHODS AND MATERIALS: Since March of 1993, 110 patients with early-stage breast cancer were entered onto a protocol of low or high dose rate brachytherapy as the sole radiation modality for part of their breast-conserving therapy. To improve the accuracy and reproducibility of target volume coverage in patients with a closed lumpectomy cavity, 11 of these implants were performed using the virtual brachytherapy technique. The virtual implant procedure was performed by first placing radiopaque skin markers on the breast surface for reference on the CT image and ultimately as intraoperative landmarks for the placement of implant needles. A CT scan of the breast was then performed and the target volume outlined on each CT scan slice by the physician. A virtual image of the brachytherapy template was then positioned around the CT image of the target volume to achieve an idealized implant with optimal coverage. The projected entrance and exit points of all needles on the skin of the breast (from the idealized virtual implant) were then identified (by perspective rendering of multiple 3D views) and hard-copy images taken to the operating room. The implant was then constructed by referencing the virtual implant images (needle entrance and exit points) to the radiopaque skin markers on the breast. After the implant was completed, a CT scan of the breast with the template catheters or needles in position was taken for comparison of the actual target volume coverage with the virtual implant generated preoperatively. RESULTS: Intraoperative ultrasound was used to check the real-time position of the afterloading needles in reference to the chest wall and posterior border of the target volume. No adjustment of needles was required in any of the 11 patients. Assessment of target volume coverage between the virtual implant and the actual CT image of the implant showed excellent agreement. In each case, all target volume boundaries specified by the physician were adequately covered. The total number of implant planes, intertemplate separation, and template orientation were identical between the virtual and real implant. CONCLUSION: We conclude that 3D virtual brachytherapy may offer an improved technique for accurately performing interstitial implants of the breast with a closed lumpectomy cavity in selected patients. Although preliminary results show excellent coverage of the desired target volume, additional patients will be required to establish the reproducibility of this technique and its practical limitations.

Dose selection for prostate cancer patients based on dose comparison and dose response studies.

PURPOSE: To better define the appropriate dose for individual prostate cancer patients treated with three-dimensional conformal radiation therapy (3D CRT). METHODS AND MATERIALS: Six hundred eighteen patients treated with 3D CRT between 4/89 and 4/97 with a median follow-up of 53 months are the subject of this study. The bNED outcomes were assessed by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. The patients were grouped into three groups by prostate-specific antigen (PSA) level (<10 ng/ml, 10-19.9 ng/ml, and 20+ ng/ml) and further subgrouped into six subgroups by favorable (T1, 2A and Gleason score < or =6 and no perineural invasion) and unfavorable characteristics (one or more of T2B, T3, Gleason 7-10, perineural invasion). Dose comparisons for bNED studies were made for each of the six subgroups by dividing patients at 76 Gy for all subgroups except the favorable <10 ng/ml subgroup, which was divided at 72.5 Gy. Five-year bNED rates were compared for the median dose of each dose comparison subgroup. Dose response functions were plotted based on 5-year bNED rates for the six patient groupings, with the data from each of the six subgroups divided into three dose groups. The 5-year bNED rate was also estimated using the dose response function and compares 73 Gy with 78 Gy. RESULTS: Dose comparisons show a significant difference in 5-year bNED rates for three of the six subgroups but not for the favorable <10 ng/ml, the favorable 10-19.9 ng/ml, or the unfavorable > or =20 ng/ml subgroups. The significant differences ranged from 22% to 40% improvement in 5-year bNED with higher dose. Dose response functions show significant differences in 5-year bNED rates comparing 73 Gy and 78 Gy for four of the six subgroups. Again, no difference was observed for the favorable <10 ng/ml group or the unfavorable > or =20 ng/ml group. The significant differences observed in 5-year bNED ranged from 15% to 43%. CONCLUSIONS: Dose response varies by patient subgroup, and appropriate dose can be estimated for up to six subdivisions of prostate cancer patients. The appropriate use of high dose with 3D CRT results in 5-year cure rates that equal or exceed other treatments. The national practice must be upgraded to allow the safe administration of 75-80 Gy with 3D CRT.

P105 as a prognostic indicator in patients irradiated for locally advanced head-and-neck cancer: a clinical/laboratory correlative analysis of RTOG-9003.

PURPOSE: In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy. METHODS AND MATERIALS: Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival. RESULTS: Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival. CONCLUSION: p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.

Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control.

PURPOSE: Biochemical control using serial posttreatment serum prostate specific antigen (PSA) levels is being increasingly used to assess treatment efficacy for localized prostate cancer. However, no standardized definition of biochemical control has been established. We reviewed our experience treating patients with localized prostate cancer and applied three different commonly used definitions of biochemical control to determine if differences in therapeutic outcome would be observed. METHODS AND MATERIALS: Between January 1987 and December 1991, 480 patients with clinically localized prostate cancer received external beam irradiation (RT) using localized prostate fields at William Beaumont Hospital. The median dose to the prostate was 66.6 Gy (range 58-70.4) using a four-field or arc technique. Pretreatment and posttreatment serum PSA levels were recorded. Over 86% (414 of 480) of patients had a pretreatment PSA level available. Three different definitions of biochemical control were used: (a) PSA nadir < 1 ng/ml within 1 year of treatment completion. After achieving nadir, if two consecutive increases of PSA were noted, the patient was scored a failure at the time of the first increase; (b) PSA nadir < 1.5 ng/ml within 1 year of treatment completion. After achieving nadir, if two consecutive increases of PSA were noted, the patient was scored a failure at the time of the first increase; (c) Posttreatment PSA nadir < 4 ng/ml without a time limit. Once the nadir was achieved, if it did not rise above normal the patient was considered to be biochemically controlled. Clinical local control was defined as no palpable prostate nodularity beyond 18 months, no new prostate nodularity, or a negative prostate biopsy. RESULTS: Median follow-up was 48 months (range 3-112). Pretreatment PSA values were correlated with treatment outcome using the three definitions of biochemical control as well as clinical local control. Pretreatment PSA values were stratified into five groups (Group 1: PSA < 4; Group 2: PSA 4-10; Group 3: PSA 10-15; Group 4: PSA 15-20; and Group 5: PSA > 20), and 5-year actuarial rates of biochemical control were calculated using the three biochemical control and one clinical local control definitions. For Group 1, 5-year actuarial rates of biochemical control were 84%, 90%, 91%, and 96% for Definitions 1-3 and clinical local control, respectively. For Group 2, 5-year actuarial control rates were 45%, 54%, 74%, and 92% for the four definitions, respectively. For Group 3, 5-year actuarial control rates were 26%, 31%, 63%, and 100% for the four definitions, respectively. For Group 4, 5-year actuarial control rates were 24%, 24%, 50%, and 100% for the four definitions, respectively. Finally, for Group 5, 5-year actuarial control rates were 5%, 14%, 15%, and 89% for the four definitions, respectively. Depending on the definition used, statistically significant differences overall in outcome rates were observed. Differences between all four definitions for all pairwise comparisons ranged from 5 to 53% (p < 0.001). CONCLUSION: When different definitions of biochemical control are used in assessing treatment outcome, significantly different rates of success are noted. Until a standardized definition of biochemical control is adopted, differences in treatment outcome cannot be meaningfully compared.

The use of ultrasonography in the localization of the lumpectomy cavity for interstitial brachytherapy of the breast.

PURPOSE: To determine the value of breast ultrasonography (US) in defining the lumpectomy cavity for patients treated with interstitial brachytherapy. METHODS AND MATERIALS: In March 1993, a protocol of low dose rate (LDR) interstitial brachytherapy as the sole radiation modality in selected patients with early breast cancer was initiated at William Beaumont Hospital. To date, 60 patients have been entered in this protocol, and 38 have undergone US assisted placement of interstitial brachytherapy needles. The lumpectomy cavity was outlined in all dimensions and corresponding skin marks were placed for reference at time of implantation. These US dimensions were compared to the physician's clinical estimate of the location of the lumpectomy cavity, the patient's presurgical mammogram, and the position of the surgical scar. In the intraoperative setting, the dimensions of the lumpectomy cavity were also obtained and the placement of the deep plane of interstitial needles was verified by US. RESULTS: The full extent of the lumpectomy cavity was underestimated by clinical examination (physical exam, operative report, mammographic information and location of the surgical scar) in 33 of 38 patients (87%). The depth to the chest wall was also incorrectly estimated in 34 (90%) patients when compared to US examination. Intraoperatively, US was performed in nine patients and was useful in verifying the accurate placement of the deepest plane of interstitial brachytherapy needles. In 7 of 9 patients (75%), clinical placement of needles did not ensure adequate coverage of the posterior extent of the lumpectomy cavity as visualized by intraoperative US. CONCLUSIONS: In breast cancer patients considered for interstitial brachytherapy, US appears to be a more accurate means of identifying the full extent of the lumpectomy cavity when compared to clinical estimates. In addition, US allows real-time verification of needle placement in the intraoperative setting.

Ductal carcinoma in situ detected in the mammographic era: an analysis of clinical, pathologic, and treatment-related factors affecting outcome with breast-conserving therapy.

PURPOSE: We reviewed our institution's experience treating predominantly mammographically detected ductal carcinoma in situ (DCIS) with breast-conserving therapy (BCT) to determine if any clinical, pathologic, or treatment-related factors affected outcome. METHODS AND MATERIALS: From January 2, 1980 to January 6, 1992, 107 breasts in 105 patients were treated with BCT at William Beaumont Hospital, Royal Oak, MI. All patients underwent at least an excisional biopsy and 70 patients (65%) were reexcised. All patients received whole-breast irradiation to a median dose of 50.4 Gy (range 43.1 to 56.0 Gy). Ninety-nine patients (93%) received a supplemental boost to the tumor bed for a median total dose of 60.4 Gy (range 59.1 to 71.8 Gy) using either photons (2 patients), electrons (69 patients), or an interstitial implant (28 patients). RESULTS: With a median follow-up of 78 months, 10 patients have failed in the treated breast for a 5- and 10-year actuarial local control rate of 91.2 and 89.8%, respectively. Thirteen percent of the population have been followed for 10 years or more. Three recurrences were pure DCIS, and seven were invasive. All patients were salvaged with mastectomy. Nine patients remain without evidence of disease a median of 30.6 months after surgery. One patient failed distantly 36 months after local recurrence for an ultimate cause specific survival of 99%. Potential clinical (age, mammographic findings, method of detection, etc.), pathologic (nuclear grade, margins, etc.), and treatment-related factors (dose, boost technique, reexcision status, etc.) affecting outcome were analyzed. No variable was found to be associated with an ipsilateral breast tumor recurrence. However, when only recurrences that occurred within or immediately adjacent to the lumpectomy cavity were analyzed, both margin status and the extent of cancerization of lobules (COL) near the surgical margin were associated with the development of a local recurrence. CONCLUSIONS: Patients treated with BCT for predominantly mammographically detected DCIS achieve excellent rates of local control and overall survival. Both margin status and the extent of COL near the surgical margin appear to be associated with recurrences within or immediately adjacent to the lumpectomy cavity. These data suggest that careful attention to the completeness of surgical resection of DCIS is an important determinant of outcome.