Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.

BACKGROUND: Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. PATIENTS AND METHODS: In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. RESULTS: Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). CONCLUSIONS: Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. CLINICAL TRIAL: Phase II, comparative two-arm trial (NCT00496288).

Evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for adjuvant radiotherapy in breast cancer.

BACKGROUND: The European Society of Medical Oncology (ESMO) has suggested using the ESMO-Magnitude of Clinical Benefit Scale (MCBS) to grade the magnitude of clinical benefit of cancer therapies. This approach has not been applied to radiation therapy (RT) yet. We applied the ESMO-MCBS to experiences describing the use of RT to assess (1) the 'scoreability' of the data, (2) evaluate the reasonableness of the grades for clinical benefit and (3) identify potential shortcomings in the current version of the ESMO-MCBS in its applicability to RT. MATERIALS AND METHODS: We applied the ESMO-MCBS v1.1 to a selection of studies in radiotherapy that had been identified as references in the development of American Society for Radiation Oncology (ASTRO) evidence-based guidelines on whole breast radiation. Of the 112 cited references, we identified a subset of 16 studies that are amenable to grading using the ESMO-MCBS. RESULTS: Of the 16 studies reviewed, 3/16 were scoreable with the ESMO tool. Six of 16 studies could not be scored because of shortcomings in the ESMO-MCBS v1.1: (1) in 'non-inferiority studies', there is no credit for improved patient convenience, reduced patient burden or improved cosmesis; (2) in 'superiority studies' evaluating local control as a primary endpoint, there is no credit for the clinical benefit such as reduced need for further interventions. In 7/16 studies, methodological deficiencies in the conduct and reporting were identified. CONCLUSIONS: This study represents a first step in determining the utility of the ESMO-MCBS in the evaluation of clinical benefit in radiotherapy. Important shortcomings were identified that would need to be addressed in developing a version of the ESMO-MCBS that can be robustly applied to radiotherapy treatments. Optimization of the ESMO-MCBS instrument will proceed to enable assessment of value in radiotherapy.

Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials.

The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries.

Outcomes in low-risk babies treated with half-dose chemotherapy according to the Third National Wilms' Tumor Study.

PURPOSE: To determine whether the 50% dose reduction of all chemotherapeutic agents recommended for babies (less than or equal to 12 months of age) by the Third National Wilms' Tumor Study (NWTS-3) produced acceptable toxicity without sacrificing any survival benefit. MATERIALS AND METHODS: The 365 babies enrolled in NWTS-3 had tumors of varying histologies and stages. The present analysis was restricted to the 256 infants who had tumors of favorable histology, were free of metastasis at diagnosis, and received treatment according to NWTS-3 guidelines. RESULTS: Despite the recommended attenuation of drug doses observed in 75% of the chemotherapy courses received, outcomes for these babies were comparable to those obtained in older children given full doses of chemotherapy. Four-year survival rates for 256 babies with stages I (n = 199), II (n = 38), and III (n = 19) favorable-histology tumors were 96%, 95%, and 90%, respectively. The figures for 498 stage I, 342 stage II, and 373 stage III older children with favorable-histology lesions were 92%, 94%, and 91% in that order. There were no deaths from hematologic toxicity or infection among babies who received half-dose chemotherapy. The death rates for their older NWTS-3 counterparts was 1%. CONCLUSION: Less aggressive therapies advocated for babies in NWTS-3 provide acceptable levels of morbidity without compromising the excellent results previously reported for low-risk patients of all ages.

Irradiation-related ischemic heart disease.

An expectation for long-term survival has emerged among several groups of cancer patients treated with therapeutic irradiation (eg, Hodgkin's disease, early stage breast cancer). Therefore, the cardiovascular sequelae of thoracic irradiation have recently come under scrutiny. Animal models have demonstrated that cardiac irradiation can directly damage the myocardial microvasculature and can indirectly damage the coronary macrovasculature when coupled with cholesterol feeding. A clear association between thoracic radiotherapy and ischemic heart disease was observed among older clinical studies using radiotherapeutic techniques that are no longer optimal by today's standards. Such a relationship could not be confirmed in modern studies in which treatment factors (such as dose and volume of heart irradiated) were more carefully controlled.

Localized prostate cancer treated by external-beam radiotherapy alone: serum prostate-specific antigen--driven outcome analysis.

PURPOSE: To determine the 5-year rate of survival with no evidence of disease (NED) using strict biochemical criteria in men with prostate cancer treated by external-beam radiotherapy alone and to examine possible clinical and treatment factors that predict the likelihood of NED survival. MATERIALS AND METHODS: Five hundred men with clinically localized prostate cancer consecutively treated with external-beam radiotherapy alone with no prior, concomitant, or adjuvant endocrine therapy were identified. All patients had serial serum prostate-specific antigen (PSA) values determined after treatment and 451 patients had pretreatment PSA values determined. The median follow-up duration is 20 months (range, 2 to 72; mean, 36). RESULTS: The 5-year rate of overall survival in this group of patients was 80%. The 5-year rate of survival without clinical evidence of disease (cNED) was 72%. The 5-year rate of survival without evidence of clinical, radiographic, or biochemical relapse (bNED) was 51%. Multivariate analysis demonstrated that a pretreatment serum PSA level < or = 15 ng/mL was the most important predictor of bNED survival (P < .0001). Patients with early-stage (T1, T2a/b) tumors and a pretreatment serum PSA less than 15 ng/mL had a 3-year rate of bNED survival of 86%. The rate of bNED survival for patients with a pretreatment PSA level greater than 15 ng/mL was 38% at 3 years. CONCLUSION: Pretreatment serum PSA level is the most important predictor of treatment outcome in this group of patients treated with definitive radiotherapy alone. External-beam radiation alone can produce acceptable early rates of bNED survival in patients with clinically organ-confined tumors and a pretreatment PSA level < or = 15 ng/mL. To produce acceptable results in those patients with pretreatment PSA levels more than 15 ng/mL, effective adjuvant treatments in addition to aggressive local treatments are necessary.

Impact of improved irradiation technique, age, and lymph node sampling on the severe complication rate of surgically staged endometrial cancer patients: a multivariate analysis.

PURPOSE: Limited information is available regarding factors that predispose to complications following postoperative pelvic radiotherapy (RT) for endometrial cancer. To address this issue, patients with clinically staged I/II endometrial cancer who received postoperative RT following total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) with or without lymph node sampling (LNS) were studied. PATIENTS AND METHODS: From 1960 through 1990, 235 patients with adenocarcinoma of the endometrium received postoperative RT after surgical staging. Multiple factors were evaluated to determine associations with severe complications. Pretreatment factors included age, stage, comorbidities. Treatment-related factors consisted of LNS, total RT dose, volume of RT fields, dose per fraction, total number of RT fields, number of RT fields treated per day, machine energy, and addition of vaginal implant. RESULTS: The 5-year actuarial risk of a severe complication was 5.5%. Factors associated with an increased risk of complications in univariate analysis included age more than 65 years (11% v 2%), use of only one portal per day (40% v 3%), use of anteroposterior/posteroanterior fields (23% v 4%), total dose > or = 50 Gy (8% v 2%), and LNS (11% v 3%). In a multivariate analysis, only older age, LNS, and the use of one field per day were significant. Increased risks associated with a total dose > or 50 Gy and the anteroposterior/posteroanterior technique were entirely attributable to the use of one field per day. A subanalysis among patients who had adequate RT techniques (eg, multiple fields treated per day) showed a significant increase in complications (7% v 1%) for those with and without LNS, respectively. CONCLUSIONS: Severe complications associated with adjuvant RT for endometrial cancer were increased among patients who were older or underwent LNS or received suboptimal RT technique. Pelvic RT using proper methods can be delivered with acceptable risks.

Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients.

PURPOSE: Metastatic deposits are the most common intraocular malignancies. We evaluated the efficacy of external-beam radiotherapy (EBRT) in the palliation of posterior uveal metastases in terms of clinically relevant outcomes: functional vision, tumor control, and globe preservation. PATIENTS AND METHODS: Four hundred eighty-three consecutive patients (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972 and 1995. Of these, 233 eyes (188 patients) had lesions of the posterior uveal tract and received EBRT. Best-corrected visual acuity (VA) was documented pre- and post-EBRT. Visual function was considered excellent if VA < or = 20/50, navigational if 20/60 to 20/200, and legally blind if > or = 20/400. Most patients received 30 to 40 Gy in 2- to 3-Gy fractions to the posterior or entire globe. RESULTS: Fifty-seven percent of all assessable eyes had improved visual function or maintained at least navigational vision following EBRT. Thirty-six percent of legally blind eyes regained useful vision. Ninety-three percent experienced no clinical evidence of tumor progression and the globe preservation rate was 98%. The following characteristics independently predicted improvement to or maintenance of excellent vision on multivariate analysis: excellent vision pre-EBRT (P = .001), age less than 55 years (P = .004), white race (v black/Hispanic) (P = .003), and tumor base diameter less than 15 mm (P < .001). CONCLUSION: EBRT effectively restores and maintains useful vision in patients with choroid metastases, with a globe preservation rate of 98%. Patients less than 55 years with pretreatment VA better than 20/60 and tumor diameter less than 15 mm are most likely to benefit from this therapeutic intervention.

Apoptosis as a predictor of paclitaxel-induced radiosensitization in human tumor cell lines.

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.

Effects of radiation therapy on adult brain behavior: evidence for a rebound phenomenon in a phase 1 trial.

Although radiotherapy (XRT) is a necessary course of treatment to prolong life expectancy in patients with many types of brain neoplasms, it has damaging effects that are little understood. We used a comprehensive neuropsychological battery to evaluate five patients with low-grade brain tumors prior to XRT and then at 3-month intervals up to 9 months postcompletion of XRT. We matched patients by age and education with six normal control subjects to assess baseline impairment. In intrasubject comparisons, we examined change over time postcompletion of XRT. In spite of varying locations of tumors, all patients showed deterioration in long-term memory at a mean of 1.5 months postcompletion of XRT. Patients also consistently demonstrated a rebound effect between means of 4.7 and 7.6 months post-XRT. We found no changes over time in working memory, attention, visuospatial processes, or on any other neuropsychological test with the exception of information-processing speed, which quickened over time. Functional measures of fatigue and mood did not correlate significantly with the long-term memory scores. Long-term memory appears sensitive to the proposed white matter changes thought to be the mechanism for the early-delayed effects of XRT. Our findings suggest a neurobehavioral model for studying the effects of XRT on brain functioning.

Stereotactic radiosurgery and radiotherapy: new developments and new directions.

Stereotactic irradiation is a precise method for the delivery of focused radiation beams to small intracranial targets. Treatment can be administered in single or multiple fractions (radiosurgery or stereotactic radiotherapy, respectively). The technology has evolved rapidly because of advances in both hardware and software design. Clinical indications are unfolding through the prospective trial mechanism.

Postoperative radiation therapy for surgically staged endometrial cancer: impact of time factors (overall treatment time and surgery-to-radiation interval) on outcome.

PURPOSE: To evaluate the impact of prolonged overall radiation treatment (RT) time and surgery-to-radiation interval on local control (LC) and disease-specific survival (DSS) of surgically staged endometrial cancer patients in relation to known prognostic factors. METHODS AND MATERIALS: Between 1971 and 1993, 195 endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. All patients underwent total abdominal hysterectomy (TAH), with 38% also having lymph node sampling. All patients received whole pelvic external beam RT to a median dose of 45 Gy (range 40 to 60 Gy). Sixty-nine percent received a vaginal cuff boost with either low dose rate or high dose rate brachytherapy. Tumor and treatment factors were analyzed for impact on LC and DSS. Median follow-up was 47 months (range: 6 to 187 months). RESULTS: The overall actuarial 5-year LC rate was 85%. In multivariate analysis, tumor grade, pathologic stage, external radiation dose, and surgical lymph node evaluation were independent prognostic variables for improved LC. Surgery-to-radiation interval of greater than 6 weeks was a marginally significant factor for decreased LC (p = 0.06). Overall RT time and external beam treatment time did not appear to impact LC rates. The overall actuarial 5-year DSS rate was 86%. In multivariate analysis, depth of myometrial invasion, tumor grade, and pathologic stage were independent prognostic variables for DSS. In addition, a surgery-to-radiation interval of greater than 6 weeks was significantly associated with decreased DSS (p < 0.005). CONCLUSIONS: Surgery-to-radiation interval of greater than 6 weeks is a significant independent prognostic variable for decreased DSS and a marginally significant variable for decreased LC in patients irradiated postoperatively for endometrial cancer. Other time factors (overall RT time and external beam treatment time) did not appear to impact outcome. Based on this analysis, postoperative radiation therapy for endometrial cancer should be initiated within 6 weeks following surgery.

Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on post-implant dosimetry: an analysis based on serial CT acquisition.

PURPOSE: To characterize the magnitude and duration of post-implant edema following the implantation of I-125 or Pd-103 seeds into the prostate and to investigate its effect on the CT-based calculation of the total dose delivered by the implant. MATERIALS AND METHODS: A pre-implant CT scan and 3 to 5 serial post-implant CT scans were obtained on 10 patients who received either I-125 or Pd-103 seed implants. None of the patients received hormone therapy. The magnitude and duration of edema were determined from the change in the spatial distribution of the implanted seeds as the edema resolves. Dose volume histograms were compiled to determine the percentage of the prostate volume that received a dose equal to, or greater than, the prescribed dose. RESULTS: The magnitude of the edema, expressed as the ratio of the post- to pre-implant volume on the day of the procedure, ranged from 1.33 to 1.96 (mean 1.52). The edema decreased exponentially with time; however, the edema half-life (time for the edema to decrease by 1/2) varied from 4 to 25 days (mean 9.3 days). As the edema resolved, the percentage of the prostate that received a dose equal to or greater than the prescribed dose increased by at least 7% in 7 of the 10 patients and increased by more than 15% in 2. In those patients in whom dose coverage was unaffected by the resolution of edema, more than 90% of the prostate was covered by the prescribed dose in the initial CT scan. CONCLUSION: Post-implant edema increased the prostate volume by factors which ranged from 1.33 to 1.96 (mean: 1.52). The edema resolved exponentially with an edema half-life which varied from 4 to 25 days (mean: 9.3 days). Edema had a significant effect on the post-implant dosimetry in 7 of 10 cases. Factors that affect the impact of edema on the dosimetry are the magnitude of the edema and the planned margin between the prescribed isodose line and the periphery of the prostate.

Results of the 1989 Association of Residents in Radiation Oncology survey.

To assess a variety of issues concerning physician-trainees in radiation oncology, a survey was conducted by the Association of Residents in Radiation Oncology (ARRO). Ultimately, 70% of residents responded to the survey. The survey identified perceived strengths as well as shortcomings in training programs. We conclude that residents are generally satisfied with their training. Future surveys are planned to expand this important database.

Positional stability of sources during low-dose-rate brachytherapy for cervical carcinoma.

PURPOSE: A presumed advantage of high dose rate gynecologic applicators is the fixed relationship maintained between applicator and anatomic structures during the brief exposure. However, it has never been demonstrated that movement of applicators during low dose rate procedures is significant. Therefore, we assessed the magnitude of changes in positioning and attendant alterations in dosimetry which occur during LDR applications. METHODS AND MATERIALS: Fifteen consecutive cervix cancer patients who were treated with combined external beam and brachytherapy (Fletcher-Suit-Delclos applicator), agreed to have orthogonal pelvic radiographs prior to after-loading and following removal of Cesium-137 sources. RESULTS: The median duration of the insertion was 56.5 hours. The average shift was 3.0 mm. Detailed analysis of source movement showed the following changes in median dose (external plus implant): point A, 1.4%; point B, 1.7%; point P, 0.9%; bladder point, 1.9%; rectal point, 2.6%. CONCLUSION: The geometric relationships between the intracavitary gynecologic applicator and the target tissue as well as the critical structures can be adequately maintained throughout the course of a low dose rate implant. Source movement does not result in significant dose changes in terms of decreased cure rates or added complications. Thus, while rationale for high dose rate applicators continues to be proposed, maintenance of a fixed geometric relationship should not be an impetus for the selection of high dose rate intracavitary applicators when treating cervical tumors.

Observations of pretreatment prostate-specific antigen doubling time in 107 patients referred for definitive radiotherapy.

PURPOSE: To determine pretreatment prostate-specific antigen doubling times (PSADT) in patients referred for definitive radiotherapy. METHODS AND MATERIALS: One hundred and seven patients with histologically proven nonmetastatic prostate cancer and an elevated prostate-specific antigen (PSA) who were referred for radiation therapy had three serum PSA values obtained prior to the start of definitive therapy. Prostate-specific antigen doubling times were calculated by linear regression. RESULTS: Prostate-specific antigen values increased during the period of observation in 78 patients (73%). Forty-three patients (40%) had calculated PSADT of less than 2 years and of those patients with pretreatment serum PSA values of greater than 10 ng/mL more than 50% has calculated PSADT of less than 2 years. CONCLUSIONS: A significant minority of patients referred for radiotherapy have calculated PSADT of less than 2 years. The significance of this relatively fast growth rate is as yet undetermined, but suggests that patients referred for radiotherapy may have aggressive disease prior to treatment.

Effect of edema on the post-implant dosimetry of an I-125 prostate implant: a case study.

PURPOSE: To investigate the effect of post-implant edema on the CT-based calculation of the total dose delivered by an I-125 prostate implant. MATERIALS AND METHODS: CT scans of a transperineal I-125 prostate implant were obtained 1 and 39-days post-implant. Changes in the prostate dimensions were determined from changes in the spatial distribution of the I-125 seeds. The total dose delivered to the target volume was computed from each CT scan, and the results compared. RESULTS: The volume of the prostate decreased by approximately 17% during the 38-day interval between the first and second CT scans. As a result, the radiation dose computed from the second CT scan was 13% higher. CONCLUSION: Post-implant edema can cause a significant underestimation of the radiation dose delivered by an I-125 prostate implant. Similar analysis should be carried out among a larger cohort of patients to confirm or refute these observations.

The influence of lymphangiography on the development of hypothyroidism in patients irradiated for Hodgkin's disease.

PURPOSE: There is no consensus in the literature regarding the role of lymphangiography in promoting hypothyroidism in individuals with Hodgkin's disease irradiated with a mantle field. We sought to analyze the onset and rate of developing clinical or chemical hypothyroidism as well as possible factors related to its development in patients who received irradiation to the thyroid gland during treatment of Hodgkin's disease. METHODS AND MATERIALS: One hundred and forty-two patients with Hodgkin's disease were treated at the Fox Chase Cancer Center between June 1967 and October 1993. All patients were treated with curative intent with radiation therapy using a mantle field. After exclusion of patients without available thyroid function tests, < 200 days of follow-up, or no radiation to the thyroid, 104 patients were eligible for analysis. Follow-up ranged from 7-170 months (median: 43 months). Sixty-seven patients had a lymphangiogram. Seventy-three patients were treated with radiation alone and 31 with radiation plus chemotherapy. RESULTS: The actuarial 2-, and 5-year rates of biochemical hypothyroidism for all 104 patients were 18 and 37%, respectively. Forty patients developed hypothyroidism: 9 (23%) at < or = 1 year, 18 (45%) at < or = 2 years, and 33 (83%) at < or = 5 years. The actuarial 2-, and 5-year rates of biochemical hypothyroidism for patients who underwent a lymphangiogram were 23 and 42%, respectively, compared to 9 and 28%, respectively, for patients who received mantle irradiation without a lymphangiogram (p = 0.05). The effects of lymphangiogram, total thyroid dose, stage, chemotherapy, dose per fraction, energy, and age were evaluated for all patients by Cox proportional hazards regression analysis. The use of a lymphangiogram (p = 0.05) was the only variable that significantly influenced hypothyroidism. CONCLUSIONS: This paper demonstrates in a multivariate analysis accounting for other potentially important variables the significant effect of lymphangiography and subsequent radiation therapy on the development of hypothyroidism. This information must be balanced with the fact that lymphangiograms remain a useful aid in assessing lymph node involvement, staging patients, and planning treatment fields.

Strong correlation between imaging response and survival among patients with primary central nervous system lymphoma: a secondary analysis of RTOG studies 83-15 and 88-06.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is the brain tumor with the most rapidly increasing incidence, yet little is known about its radiographic response to cranial irradiation. If traditionally used doses of radiotherapy ( approximately 60 Gy) are associated with low rates of complete response and poor survival, then an argument can be made to consider dose escalation of radiotherapy. Alternatively, if poor survival rates are associated with high rates of complete response, there would be no reason to subject patients to higher radiation doses with increased risks of treatment-related morbidity. The purpose of this analysis is to provide a detailed review of response following cranial irradiation. Based on these findings, recommendations are offered for future protocol design. METHODS AND MATERIALS: Patients were treated on either RTOG 83-15 (whole brain irradiation to 40 Gy followed by a 20 Gy boost to the tumor plus 2-cm margin) or RTOG 88-06 (induction cyclophosphamide, doxorubicin, vincristine, dexamethasone [CHOD] followed by whole brain irradiation to 41.4 Gy and an 18 Gy tumor boost). Imaging surveillance (CT, MR) was required following surgery, prior to the initiation of RT and following completion of RT. Complete response referred to the absence of enhancement on follow-up scans in comparison to the pretherapy study. A tumor size reduction of at least 50% in the product of the largest cross-sectional diameter and its largest perpendicular diameter was scored as a partial response. RESULTS: Seventy-nine patients had scans available for central review. Complete response was achieved in 83% and 85% of patients treated on RTOG 83-15 and 88-06, respectively. The rates of partial response (14%, 11%) and radiographic progression (3%, 4%) also were comparable between the studies. For survival analyses, data were aggregated from the two studies. The 4-year survival rates were 24% for complete responders versus 11% for other patients (p = 0.0006). In multivariate analysis, only complete radiographic response (p < 0.0007), and high Karnofsky performance status (KPS >/= 70) (p < 0.005) were independently associated with increased rates of 4-year survival. CONCLUSION: A high rate of complete radiographic response was observed following moderate doses of cranial irradiation (alone or in combination with CHOD chemotherapy). Although complete responders had a statistically significant survival advantage at 4 years when compared with partial responders and nonresponders, the majority of patients who achieved complete response were dead of disease by 4 years following treatment. Based on this analysis of the RTOG database, there is no rationale for radiation dose escalation as a therapeutic strategy to combat PCNSL. Consequently, the radiotherapy component of the current RTOG Phase II trial (RTOG 93-10) now includes relatively low total doses of hyperfractionated irradiation for patients without residual disease (36 Gy/1.2 Gy, twice a day) as well as a more aggressive chemotherapy regimen.