Aaron H. Wolfson

The importance of postoperative radiation therapy in multimodality management of locally advanced breast cancer: a phase II trial of neoadjuvant MVAC, surgery, and radiation.

PURPOSEnTo determine the impact of postoperative radiation on locoregional relapse and overall survival rate in a multimodality protocol for locally advanced breast cancer (LABC).nnnMATERIAL AND METHODSnOf the patients entered in the protocol, 55 were evaluable. Treatment consisted of: neoadjuvant MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) until a maximum response had been achieved; modified radical mastectomy; 6 courses of postoperative adjuvant MVAC chemotherapy, and chest wall irradiation (CWXRT). Multivariate analysis of locoregional response and overall survival was done.nnnRESULTSnOf the total, 42 patients received chest wall radiation; 28 of these also received radiation to regional lymph nodes. Chest wall doses ranged from 45 Gy to 50.4 Gy to the whole chest wall, with 31 patients receiving an additional chest-wall boost. The incidence of locoregional relapse with and without radiation was 7% vs. 31%, respectively (p = 0.026). An overall survival benefit was seen in those receiving radiation, with a mean overall survival of 50 months vs. 20 months, and a 3-year overall survival of 88% vs. 46% with and without radiation, respectively (p = 0.003). Multivariate analysis showed that overall survival was affected by the presence of pathological CR (p = .047), the number of pre-operative chemotherapy cycles (p = .036) and whether or not they received radiation (p = 0.003). Neither the interval between surgery and radiation, technique of radiation, nor radiation modality significantly affected local control.nnnCONCLUSIONnThe significant improvement in local regional control and overall survival with the addition of radiation suggests that radiation should be an integral part of multimodality management of locally advanced breast cancer.

The role of steroids in the management of metastatic carcinoma to the brain : a pilot prospective trial

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.

The role of hyperfractionated re-irradiation in metastatic brain disease: A single institutional trial

Progression of brain metastases after brain irradiation has prompted several studies on retreatment of the brain. Increased durations of survival and improved quality of life have been reported. Fifteen patients with previously treated brain metastases were entered into this pilot study between May 1990 and January 1994. All patients had neurologic and/or radiologic evidence of progression of brain metastases. The lung was the primary site in 60% of cases. The remaining 40% had breast, ovarian, and skin primaries. The median interval between the first treatment and retreatment was 10 months. All patients received whole-brain irradiation with or without a boost for their initial treatment course. Doses ranged from 3,000 to 5,500 cGy for initial treatments (median, 3,000). Retreatment consisted of limited fields with a median side equivalent square of 8.8 cm. Patients were retreated with a median dose of 3,000 cGy (range, 600-3,000 cGy). A median cumulative dose of 6,000 cGy was achieved. Retreatment consisted of twice-daily fractions (150 cGy/fraction). Retreatment was tolerated without serious complications. Of the 15 patients treated, nine (60%) experienced improvement, and five (27%) had stabilization of neurologic function and/or radiographic parameters. Median survival was 3.2 months; two of the reirradiated patients survived > or = 9 months. In conclusion, reirradiation is a viable option in patients with recurrent metastatic lesions of the brain, and the use of a limited retreatment volume makes this a well-tolerated, low-morbidity treatment that leads to clinical benefits and, in some instances, enhanced survival. The influence of hyperfractionation on the outcome needs to be investigated further in large series.

High-dose-rate remote afterloading intracavitary brachytherapy for the treatment of extrahepatic biliary duct carcinoma.

PURPOSEThe purpose of this study was to determine whether a dose response exists for extrahepatic bile duct carcinoma (EBDC) when treated with increasingly higher radiation doses delivered via a combination of external beam radiation (EBRT) and high dose rate intracavitary brachytherapy (HDRIB). To establish the best tolerated dose of HDRIB. METHODS AND MATERIALSEighteen patients with pathologically proven, locoregional but unresectable or incompletely resected EBDC were studied from 1991–1998 in this phase I/II trial. All patients received EBRT, delivered via megavoltage photons at standard fractionation schedules, for a total dose of 45 Gy. The HDRIB was delivered using the nucleotron HDR remote afterloading unit with a 10 Ci Ir192 source. Each treatment of HDRIB delivered 7 Gy at 1 cm depth. The first group of eight patients received one treatment of HDRIB (Group 1, total dose = 52 Gy). The second group of six patients received two weekly treatments (Group 2, total dose = 59 Gy). The last group of four patients received three weekly treatments of HDRIB (Group 3, total dose = 66 Gy). HDRIB was delivered once weekly concomitant with the EBRT. Acute adverse reactions were evaluated after for each group of patients before escalating to the next higher dose level of HDRIB. RESULTSThe median follow up time for all 18 patients was 15 months. The median survival for all 18 patients was 12.2 months (range 2 to 79.6 months). Overall two-year survival was 27.8%. Three patients (16.7%) had survival of more than 5 years. Dose response is suggested by the median survival of the three groups (9, 12.2, and 20.3 months for Group 1, 2, and 3, respectively), although this did not reach statistical significance. Complete or partial response (>50% reduction in tumor size) was seen in 25% of patients receiving total of 52 Gy compared to 80% of patients (5 patients in Group 2 and 3 patients in Group 3) receiving greater than 59 Gy (P = 0.05). No patients developed Grade 4 complications. One patient in Group 2 developed Grade 3 toxicity after second treatment of HDRIB. CONCLUSIONHigh dose rate brachytherapy of 21 Gy in three divided weekly treatments, plus 45 Gy of external beam radiation is well tolerated. A dose response is shown with significant increase of PR and CR rate for dose >59 Gy. This modality of treatment appears to be safe and effective for inoperable extrahepatic biliary duct carcinoma.

Prognostic factors and survival in patients with spinal cord gliomas after radiation therapy.

The purpose of this study was to determine the impact of various prognostic factors on survival in spinal cord gliomas treated with radiation. Fifty-three patients with spinal cord gliomas irradiated at three major institutions were studied. Fifty-one patients were classified as having ependymoma, astrocytoma, or both. Two patients were classified as having gliomas (otherwise unspecified). Eleven patients had complete resection of their tumor. Biopsy or partial resection was done in the remaining patients. All patients received external beam radiation. Information on these patients was placed in a central database file and analyzed for the effect of several prognostic factors on survival. Overall survival of the entire group was 76.9% and 61.5% at 5 and 10 years, respectively. Pathologic status significantly affected survival (p = 0.03). Patients with ependymomas had a 5-year survival of 93.8% and a 10-year survival of 67.5%. Patients with astrocytoma had a 5-year survival of 64.2% and a 10-year survival of 54%. Univariate analysis showed pathology and the presence of cysts (p = 0.038) to significantly affect survival. Age, sex, location of the primary, extent of surgery radiation dose, and number of involved segments did not affect survival. On multivariate analysis, astrocytic pathology, involvement of more than five segments, male sex, and the absence of cysts (in or adjacent to the tumor) were associated with a significantly inferior survival. This study confirms the importance of pathology and number of segments involved in determining outcome or survival. The presence of cysts adjacent to or within the tumor was found to be associated with an improvement in survival.

Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: Report of a single institutional phase II trial

&NA; Prophylactic cranial irradiation (PCI) has been demonstrated to significantly reduce the incidence of brain relapse from limited disease small‐cell lung cancer (LD SCLC), but concerns about neurologic toxicity remain. The purpose of this report was to update a phase II institutional trial that explored the impact of twice‐daily PCI on neurologic toxicity as well as outcome for this group of patients. All eligible subjects had documented complete response to induction chemotherapy and consolidative chest irradiation. The whole brain was treated with twice‐daily fractions of 1.5 Gy with megavoltage irradiation to an approximate total dose of 30.0–36.0 Gy. Although not devised as a randomized study, approximately half of the eligible patients declined the protocol enrollment of their own volition and were retrospectively evaluated as a “historical” control group regarding the incidence of brain metastases. Fifteen patients accepted twice‐daily PCI, with 12 deferring treatment. Median follow‐up was 20 months. Disease‐free survival at 2 years was 54% with twice‐daily PCI versus 0% without any PCI (p = 0.013). Overall survival at 2 years was 62% with twice‐daily PCI versus 23% without PCI (p = 0.032). No statistically significant neurologic deterioration was detected in the PCI group posttreatment. Thus, twice‐daily PCI should be considered for patients with LD SCLC who achieve a complete response to chemoirradiation. A multiinstitutional randomized trial would be necessary before making definitive recommendations.

Does a Radiation Dose-response Relation Exist Concerning Survival of Patients Who Have Soft-tissue Sarcomas of the Extremities?: Radiation Dose-response Relation for Soft-tissue Sarcomas

This study analyzes a single-institution experience by evaluating the impact on survival of increasing total dose of adjunctive irradiation in patients who had extremity soft-tissue sarcoma (ESTS). A retrospective review of the tumor registry at a university medical center from January 1984 through December 1992 yielded a total of 59 surgical patients of ESTS. With follow-up ranging from 30 to 135 months (median, 65 months), the 2-, 5-, and 8-year overall and disease-free survival for all patients was 86%, 71%, 58% and 76%, 70%, 56%, respectively. Multivariate analyses using the Cox proportional hazards model revealed that total radiation dose (p = 0.02), American Joint Committee on Cancer stage (p = 0.04), and tumor size (p = 0.006) were all significant prognostic factors of overall survival; however, only tumor size was predictive of disease-free survival (p = 0.02). When the effect of tumor size and disease stage were controlled in the Cox model, a dose-response curve between increasing total radiation dose and improved overall patient survival was indicated. This study demonstrates the significance of tumor size on predicting both overall and disease-free survival in patients who have soft-tissue sarcomas of the extremity. It also suggests, however, that a radiation dose-response relation may exist for overall survival. Future investigations should consider evaluating the minimal total radiation dose needed to optimize patient survival after limb-sparing surgery.

Mucosal Melanomas of the Head and Neck: The Role of Postoperative Radiation Therapy

Objectives. Mucosal melanomas are rarer than their cutaneous counterparts and are associated with a poorer prognosis. We report the clinical outcomes of patients with mucosal melanomas of the head and neck region generally treated with definitive surgery followed by postoperative radiation therapy (RT). Methods. We reviewed the records of 17 patients treated at the University of Miami in 1990–2007. Patients generally received conventionally fractionated RT regimens to the postoperative bed. Elective nodal RT was not routinely delivered. Eight patients received adjuvant chemotherapy or immunotherapy. Results. Median followup was 35.2 months (range 5–225). As the first site of failure: 3 patients recurred locally, 2 regionally and 2 distantly. All 3 patients who recurred locally had not received RT. Of the 5 locoregional recurrences, 4 were salvaged successfully with multimodality therapy with no evidence of disease at last followup. Overall survival was 64.7% at 2 years and 51.5% at 5 years. Conclusions. Patients with mucosal melanoma of the head and neck are best treated with surgery to achieve negative margins, followed by postoperative RT to optimize local control. Elective nodal irradiation may not be indicated in all cases, as regional failures were not predominant. Distant metastases were fewer when compared to historical data, potentially due to advancements in adjuvant therapies as well as aggressive multi-modality salvage at time of failure.

Management of Stage I-B, II-A, and II-B Carcinoma of the Cervix with High-Dose-Rate Brachytherapy: Initial Results of an Institutional Clinical Trial

In 1989, the University of Miami began a program incorporating high-dose-rate (HDR) brachytherapy into the definitive treatment of patients with invasive carcinoma of the cervix. Patients received an average total dose to point A of 5,511 cGy (range 4,280-6,360 cGy) in an average of 57 days (range 39-84 days). An analysis of the first 24 cases found 11 FIGO Stage I-B, four Stage II-A, and nine Stage II-B tumors. At the end of all radiation therapy, 19/24 patients tumors (79.2%) had undergone a clinical complete response (CR). With median follow-up of 26 months (range 14-63 months), three have relapsed locally, two regionally, and six in extrapelvic sites. Almost two-thirds of all failures occurred in patients with tumors >4 cm, who also took more than 8 weeks to complete their treatment. Overall 2-year actuarial survival for the entire study group is approximately 74%. A univariate analysis determined that clinical stage (P = 0.02), overall treatment time (P = 0.03), tumor size (P = 0.05), and response at the end of therapy (P = 0.005) were significant prognostic factors. Multivariate analysis showed that tumor response to therapy was the most important prognosticator of outcome (P = 0.001). Besides five cases of apical vaginal stenosis, there have been no reported chronic complications in this cohort of patients. A prospectively randomized trial is recommended to compare the efficacy of HDR vs. low-dose-rate brachytherapy in cervical carcinoma.

The impact of perioperative chemotherapy timing in conjunction with postoperative external-beam radiation therapy on extremity soft-tissue sarcomas outcome

Purpose:The perioperative management of primary extremity soft-tissue sarcomas (ESTS) is multidisciplinary including radiation therapy and chemotherapy (CT). The interplay between these modalities and the relative importance of each remain unclear. Our study aims to determine the relative impact of CT and radiotherapy on the outcome of ESTS patients treated with limb-sparing surgery. Materials and Methods:A retrospective review of ESTS registry yielded 97 patients who received neoadjuvant chemotherapy (NCT) and/or adjuvant CT with or without external-beam radiation therapy (EBRT) from January 1, 1999 through December 31, 2009. The cohort comprised 56 males and 41 females whose age at surgery ranged from 17 to 83 years (median, 56 y). Tumor characteristics included the following: 73 lower ESTS; 70 grade 3 lesions; 63 American Joint Committee on Cancer stage III tumors; and 27 lesions with positive microscopic margins. The following outcome parameters were evaluated for the patients’ subgroups: overall survival (OS), locoregional control (LRC), and disease-free survival (DFS). Results:EBRT was delivered postoperatively to 81 patients and 49 received CT. Median EBRT dose was 63 Gy (range, 50 to 72 Gy). At median follow-up of 54.6 months, the 5-year OS, LRC, DFS was 68.9%, 87.1%, 66.5%, respectively. On multivariate analysis, positive surgical margins negatively impacted LRC, DFS, and OS (hazard ratio [HR]=10.43, P=0.004), (HR=2.37, P=0.03), (HR=2.26, P=0.038), respectively. EBRT use improved LRC (HR=0.24, P=0.018) and DFS (HR=0.36, P=0.021). The impact of EBRT on DFS was retained (HR=0.28, P=0.006) in the high-grade ESTS subgroup who received CT. The 5-year local failure rate was 6.5%, 28.6%, and 22.2% (P=0.019) for patient receiving NCT, adjuvant chemotherapy, and no CT, respectively. Conclusion:Our data support the use of NCT followed by limb-sparing surgery and adjuvant EBRT in ESTS for local failure reduction with a trend toward improved DFS.