Kaled M. Alektiar

Intensity-modulated radiotherapy

Intensity-modulated radiotherapy represents a recent advancement in conformal radiotherapy. It employs specialized computer-driven technology to generate dose distributions that conform to tumor targets with extremely high precision. Treatment planning is based on inverse planning algorithms and iterative computer-driven optimization to generate treatment fields with varying intensities across the beam section. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Thus far, data have demonstrated improved precision of tumor targeting in carcinomas of the prostate, head and neck, thyroid, breast, and lung, as well as in gynecologic, brain, and paraspinal tumors and soft tissue sarcomas. In prostate cancer, intensity-modulated radiotherapy has resulted in reduced rectal toxicity and has permitted tumor dose escalation to previously unattainable levels. This experience indicates that intensity-modulated radiotherapy represents a significant advancement in the ability to deliver the high radiation doses that appear to be required to improve the local cure of several types of tumors. The integration of new methods of biologically based imaging into treatment planning is being explored to identify tumor foci with phenotypic expressions of radiation resistance, which would likely require high-dose treatments. Intensity-modulated radiotherapy provides an approach for differential dose painting to selectively increase the dose to specific tumor-bearing regions. The implementation of biologic evaluation of tumor sensitivity, in addition to methods that improve target delineation and dose delivery, represents a new dimension in intensity-modulated radiotherapy research.

High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas ☆

PURPOSE Retroperitoneal sarcomas represent a formidable challenge to the treating oncologist due to their location, large size, and poor prognosis. The purpose of this study was to determine if the addition of high-dose-rate intraoperative radiation therapy (HDR-IORT) to surgery and external beam radiotherapy (EBRT) would improve the outcome in these patients. METHODS AND MATERIALS Thirty-two patients with retroperitoneal soft tissue sarcoma were prospectively treated according to a protocol that included maximal tumor resection, HDR-IORT, and postoperative EBRT when feasible. Twelve patients presented with primary and 20 with locally recurrent disease. The tumors were high-grade in 20 patients and low-grade in 12 patients. Complete gross resection was achieved in 30 patients. HDR-IORT was given to a dose of 12-15 Gy. Additional EBRT was given to 78% of patients to a dose of 45-50.4 Gy. The two patients with gross residual disease received an additional I-125 permanent implant to a median peripheral dose of 140-160 Gy. The median follow-up was 33 months (range 1-77 mo). RESULTS The 5-year actuarial local control rate for the whole group was 62%. For patients with primary disease, the local control rate was 74% compared to 54% in patients with recurrent disease (p = 0.4). The overall 5-year distant metastasis-free survival rate was 82%. In patients with high-grade tumors the rate was 70% vs. 100% in those with low-grade tumors. This difference was statistically significant, p = 0.05. The 5-year disease-free and overall survival rates were 55% and 45%, respectively. The most common type of post-treatment complication was gastrointestinal obstruction (18%) followed by fistula formation (9%), peripheral neuropathy (6%), hydronephrosis (3%), and wound complication (3%). CONCLUSIONS We are encouraged by the favorable local control rate and the acceptable morbidity with this new technique applied to a challenging patient population.

Do Radiation-Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas?

PURPOSE To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared with sporadic soft tissue sarcomas (STSs). PATIENTS AND METHODS One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH). Results Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size > 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH-the most common RAS type-the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001). CONCLUSION Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type.

Clinicopathologic analysis of 187 high-grade endometrial carcinomas of different histologic subtypes: similar outcomes belie distinctive biologic differences.

The clinical and histopathologic features of 187 high-grade endometrial cancers [FIGO grade 3 endometrioid (EC-3), serous (SC), and clear cell (CC)] were studied to determine whether clinicopathologic differences between these various histologic subtypes existed. The study group consisted of 89 EC-3s, 61 SCs, and 37 CCs. Treatment regimens were individualized. SCs and CCs were significantly more likely than EC-3s to occur in patients older than 65 years (P=0.03), and SCs tended to occur more frequently in patients of African descent than EC-3s and CCs (P=0.07), although this was not statistically significant. EC-3s had the highest rate of associated endometrial hyperplasia (P=0.05). SCs were most likely to have high-stage disease at presentation (≥stage IIB; P=0.01), with peritoneal dissemination at diagnosis being much more common compared with EC-3s and CCs (P=0.004). Median follow-up was 39 months, and median overall survival was 47 months. Five-year survivals were 45% (EC-3), 36% (SC), and 50% (CC)—differences that were not statistically significant. In contrast, the impact of stage on survival was significant (P<0.001). Among all other factors evaluated, only age greater than 65 years was a negative predictor (risk ratio, 2.23; P<0.001), whereas a family history of cancer reduced the risk of death when controlling for stage (risk ratio, 0.54; P=0.005). When controlling for stage, race, reproductive history, personal history of cancer, histologic subtype, depth of myometrial invasion, lymphovascular invasion, presence of an endometrial polyp, presence of hyperplasia, or staging adequacy did not affect prognosis. High-grade endometrial cancers of different histologic subtypes treated in an individualized manner are associated with similar clinical outcomes, but differences in age at presentation, race distribution, association with hyperplasia, stage, and sites of tumor dissemination support the idea that these represent distinct disease entities as defined by traditional histopathologic classification of endometrial cancers.

Predictors of survival in recurrent rectal cancer after resection and intraoperative radiotherapy

AbstractPURPOSE: This study was designed to determine predictors of survival after surgery and intraoperative radiotherapy for recurrent rectal cancer. METHODS: From a prospective database, 634 patients undergoing resection for recurrent rectal cancer between January 1990 and June 2000 were identified. Of these, 111 received intraoperative radiotherapy with curative intent, and 100 were available for follow-up. Clinicopathologic variables from both the primary and recurrent operations were evaluated as predictors of disease-free and disease-specific survival by multivariate Cox regression and log-rank test. RESULTS: There were 54 males and 46 females, with a median age of 57 (range, 37–83) years. With a median follow-up of 23.2 months, 60 patients (60 percent) recurred: 20 (33 percent) locally, 27 (45 percent) distantly, and 13 (22 percent) at both sites. Of all variables analyzed, only complete resection with microscopically negative margins and the absence of vascular invasion in the recurrent specimen predicted improved disease-free and disease-specific survival (P < 0.01 for all). Median disease-free survival and median disease-specific survival were 31.2 and 66.1 months, respectively, for complete resection compared with 7.9 and 22.8 months for resection with microscopic or grossly positive margins (P < 0.01 for both). Median disease-free survival and median disease-specific survival were 6.4 and 16.1 months, respectively, in the presence of vascular invasion in the recurrent specimen compared with 23.3 and 57.3 months in the absence of vascular invasion (P < 0.01 and P < 0.05, respectively). Complete resection and the absence of vascular invasion were the only predictors of improved local control as well (P < 0.05 and P < 0.01, respectively). CONCLUSION: Resection with negative microscopic margins and absence of vascular invasion are independent predictors of local control and improved survival after resection and intraoperative radiotherapy for recurrent rectal cancer.

High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer.

PURPOSE Management of locally recurrent colorectal adenocarcinoma represents a significant challenge. Many of these tumors adhere to or invade into vital pelvic structures rendering surgery or external beam radiotherapy (EBRT) as palliative treatment. Therefore, a treatment approach was developed to evaluate the role of high-dose-rate intraoperative brachytherapy (HDR-IORT) and surgery as a component of therapy in the management of locally recurrent colorectal cancer. This is an update of our preliminary report with longer follow-up and larger patient numbers. METHODS AND MATERIALS Between January 1992 and September 1998, 74 patients with locally recurrent rectal cancer were treated with surgery and HDR-IORT. Additional EBRT was given to 29 patients, and 33 patients received 5-fluorouracil based chemotherapy. All patients underwent complete gross resection, and 21 of 74 had positive microscopic margin. The dose of HDR-IORT ranged from 10 to 18 Gy. RESULTS With a median follow-up of 22 months, the 5-year local control, distant metastasis disease-free, disease-free, and overall survival rates were 39%, 39%, 23%, and 23%, respectively. The only predictor of improved local control was a negative margin of resection with a 5-year local control rate of 43%, compared to 26% in those with positive margin (p = 0.02). For overall survival, a negative microscopic margin (p = 0.04) and the use of IORT + EBRT (p = 0.04) were significant predictors of improved survival. The incidence of peripheral neuropathy was 16%. CONCLUSION The results with HDR-IORT in this group of patients are encouraging. Further improvements in local and distant control are still needed.

Adult Spermatic Cord Sarcomas: Management and Results

Background: We present a 20-year surgical experience with spermatic cord sarcoma, describe prognostic features, and evaluate the results of surgical and adjunctive treatments.Methods: Forty-seven patients were identified from an institutional database. Disease-free survival was calculated, and prognostic factors such as tumor grade, size, extent of operation, and adjuvant therapy were analyzed.Results: The median patient age was 58 years (range, 16–83 years), and the median follow-up was 51 months (range, .5–226 months). The most common tumor types included liposarcoma (51%), leiomyosarcoma (19%), embryonal rhabdomyosarcoma (13%), and malignant fibrous histiocytoma (11%). Twenty-nine (62%) patients had high-grade tumors, 21 (45%) were treated with adjuvant radiation, and 9 (19%) received chemotherapy. The overall 5- and 10-year disease-specific survival was 75% and 55%, respectively. No specific prognostic factors were identified for recurrence or disease-free survival. In 21 patients who underwent reoperative wide resection after a prior incomplete resection, a trend toward improved disease-free survival was noted (P < .059). Of these, six (29%) had residual viable sarcoma. We could not demonstrate a therapeutic effect of adjuvant radiation or chemotherapy.Conclusions: We demonstrated that aggressive surgical strategies, including reoperative wide resection, significantly decrease local recurrence and may improve disease free-survival in select patients with spermatic cord sarcoma.

The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes

OBJECTIVE To describe the incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. METHODS Using a prospectively maintained database we identified all cases of endometrial cancer that had both pelvic and aortic nodal dissection and determined the rate of isolated paraaortic nodal metastasis in the setting of negative pelvic nodes. For this report a satisfactory pelvic node dissection meant the identification of 8 or more pelvic nodes on final pathology. RESULTS 1942 endometrial cancer patients were surgically treated at our institution from 1/93 to 1/08. 847 had both pelvic and paraaortic nodes removed during surgery and identified by pathology. 734 had negative pelvic nodes with at least one paraaortic node identified. Only 12 (1.6%) had positive paraaortic nodes with negative pelvic nodes. Seven (1%) of 640 cases with 8 or more negative pelvic nodes had positive paraaortic nodes. Final grade for these cases included: G1 (2), G2 (2), G3 (1), papillary serous (1), and undifferentiated (1). Of the 570 cases with a final diagnosis of grade 1 endometrial cancer, 187 had both pelvic and aortic node dissection during the same operation, and 2/187 (1%) had a positive paraaortic node with negative pelvic nodes. CONCLUSIONS Isolated paraaortic nodal metastasis in the setting of negative pelvic nodes occurs in approximately 1% of surgically staged endometrial cancer cases. This low rate seems consistent for low- and high-grade lesions. Future studies looking at the incidence of isolated paraaortic nodal metastasis in the setting of negative sentinel pelvic nodes are warranted.

Colorectal cancer pelvic recurrences: determinants of resectability.

PURPOSEThis study was designed to identify preoperative and intraoperative features of locally recurrent colorectal cancer that predict R0 resection in patients scheduled for attempted complete resection followed by intraoperative radiation therapy.METHODSReview of a prospective data base identified 119 patients brought to the intraoperative radiation therapy suite for planned complete resection of locally recurrent rectal (n = 101) and colon (n = 18) cancer between January 1994 and November 2000. R0 resection was achieved in 61 patients. This group was compared with patients in which an R1 (n = 38), R2 (n = 7), or palliative procedure (n = 13) was performed. Variables evaluated included: tumor location, features of the primary tumor, and preoperative findings on computed tomography, magnetic resonance imaging, and history/physical. Tumor location was established by review of operative/pathologic reports and classified as axial (anastomotic/perineal), anterior (bladder/genitourinary organs), posterior (presacral), or lateral (pelvic sidewall).RESULTSWhen recurrence was confined to the axial location only, or axial and anterior locations, R0 resection was achieved significantly more often than when other locations were involved (P < 0.001, P = 0.003, respectively). When a lateral component was present, R0 resection was achieved significantly less often than when there was no lateral component (P = 0.002). For patients with available preoperative computed tomography and/or magnetic resonance imaging results (n = 70), the finding of lateral tumor involvement was associated with R0 resection significantly less often than when lateral disease was not identified (P = 0.004).CONCLUSIONSPelvic recurrences confined to the axial location, or axial and anterior locations, are more likely to be completely resectable (R0) than those involving the pelvic sidewall. Efforts to enhance preoperative identification and imaging of these patients are clearly justified.

Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity

Background: We reviewed single-institution experience using brachytherapy alone for primary high-grade soft tissue sarcoma of the extremity.Methods: Between July 1982 and September 1997, 202 adult patients with primary high-grade soft tissue sarcoma of the extremity were treated with limb-sparing surgery and adjuvant brachy-therapy. All patients underwent complete gross resection, but the margin of resection was micro-scopically positive in 18% of patients. The median dose of brachytherapy was 45 Gy delivered over 5 days. Tumors located in the shoulder or groin were defined as central location. Complications were assessed in terms of wound complications, bone fracture, and peripheral nerve damage.Results: With a median follow-up of 61 months, the 5-year local control, distant relapse-free survival, and overall survival rates were 84%, 63%, and 70%, respectively. On multivariate analysis, poor local control correlated with shoulder location, positive microscopic margins of resection, and nonshoulder upper extremity site. The 5-year actuarial rates of wound complications requiring reoperation, bone fracture, and grade ≥3 nerve damage were 12%, 3%, and 5%, respectively.Conclusions: Adjuvant brachytherapy provides adequate local control and acceptable morbidity that compares favorably with data reported for external beam radiation. Shoulder tumor location was identified as an independent prognostic factor for poor local control, mandating further improvement in the local management of these tumors.