Jimmy T. Efird

Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.

A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.

Radical Radiation Therapy in the Management of Prostatic Adenocarcinoma: The Initial Prostate Specific Antigen Value as a Predictor of Treatment Outcome

We studied 161 prostate cancer patients treated by radical irradiation alone without endocrine therapy in whom pretreatment and posttreatment prostate specific antigen (PSA) values were measured, and who had a minimum followup of 2 years. Outcome was analyzed in an actuarial fashion using clinical disease-free survival and biochemical disease-free survival (freedom from an increasing PSA level or a PSA level of greater than 1.0 ng./ml. 2 years following irradiation) as end points. Of the patients 54% achieved a post-irradiation nadir value in the range 0 to 1.0 ng./ml. and 29% had a nadir value that was undetectably low (less than 0.5 ng./ml.). The likelihood of achieving these values was greater among patients with early stage than locally advanced tumors. For all T stages the likelihood of being disease-free at 4 years was substantially and significantly lower when PSA was used as an end point than when clinical evaluation alone was used: stages T1 and T2 (85 patients) 41% versus 71%, and stages T3 and T4 (76 patients) 15% versus 61%. For the whole group at 4 years clinical control was 67% but biochemical control was only 26% (p < 0.05). The likelihood of being free of biochemical evidence of persistent disease at 4 years was a function of the initial PSA value (PSA less than 4.0 in 81% of the cases, 4.1 to 10.0 in 43%, 10.1 to 20.0 in 31%, 20.1 to 50.0 in 6% and greater than 50.0 in 0%). For stages T1 and T2 cancer patients with an initial PSA level of less than 15 ng./ml. (67% of all early stage cases) this value was 65% and it was even higher (73%) when poorly differentiated tumors were excluded. When the initial PSA level for stages T1 and T2 tumors was greater than 15 ng./ml. the projected 4-year rate of freedom from biochemical failure was only 7%. For stages T3 and T4 cancer patients the corresponding figures were 39% for those with an initial PSA level of less than 15 ng./ml. and 0% for those with an initial PSA level of greater than 15 ng./ml. The prognostic power of the initial PSA level was independent of stage, grade, patient age and prior transurethral resection of the prostate in a multivariate analysis. An initial serum PSA level of more than 15 ng./ml. is, therefore, a powerful predictor of probable failure with conventional radiation therapy. Serum PSA monitoring is a sensitive detector of early relapse.(ABSTRACT TRUNCATED AT 400 WORDS)

INDIVIDUALIZING MANAGEMENT OF AGGRESSIVE FIBROMATOSES

PURPOSE To examine prognostic indicators in aggressive fibromatoses that may be used to optimize case-specific management strategy. METHODS AND MATERIALS One hundred and seven fibromatoses presenting between 1971 and 1992 were analyzed. The following treatment modalities were utilized: (a) surgery alone for 51 tumors; (b) radiation alone for 15 tumors; and (c) radiation and surgery (combined modality) for 41 tumors. Outcome analysis was based on 5-year actuarial local control rates. RESULTS Control rates among surgery, radiation therapy, and combined modality groups were 69%, 93%, and 72%. Multivariate analysis identified age < 18 years, recurrent disease, positive surgical margins, and treatment with surgery alone as predictors for failure. Patients treated with surgery alone had control rates of 50% (3 of 6) for gross residual, 56% for microscopically positive margins, and 77% for negative margins. Radiation and surgery resulted in rates of 59% for gross residual, 78% for microscopically positive margins, and 100% (6 of 6) for negative margins. For recurrent vs. primary tumors, control was achieved in 48% vs. 77%, 90% vs. 100% (5 of 5), and 67% vs. 79% in the Surgery, Radiation, and Combined modality Groups, respectively. Patients presenting with multiple disease sites tended to have aggressive disease. A radiation dose-control relation to > 60 Gy was seen in patients with unresected or gross residual disease. Of the patients, 23 with disease involving the plantar region had a control rate of 62%, with significantly worse outcomes in children. CONCLUSIONS These results are consistent with those found in the relevant literature. They support primary resection with negative margins when feasible. Radiation is a highly effective alternative in situations where surgery would result in major functional or cosmetic defects. When negative surgical margins are not achieved in recurrent tumors, radiation is recommended. Perioperative radiation should be considered in other high-risk groups (recurrent disease, positive margins, and plantar tumors in young patients). Doses of 60-65 Gy for gross disease and 50-60 Gy for microscopic residual are recommended. Observation may be considered for primary tumors with disease remaining in situ when they are located such that progression would not cause significant morbidity. Although plantar lesions in children may represent a group at high risk for recurrence or aggressive behavior, the greater potential for radiation-induced morbidity in this group must also temper its use. Given the inconsistent nature and treatment response of this tumor, it is fundamental that treatment recommendations should be made based on the risk:benefit analysis for the individual patient, dependent on tumor characteristics and location, as well as patient characteristics and preferences.

Pharmacological Elevation of Blood Pressure in Acute Stroke Clinical Effects and Safety

BACKGROUND AND PURPOSE Lowering of blood pressure can adversely affect ischemic symptoms in acute stroke. The aim of our study was to determine whether induced hypertension in stroke is safe and to examine its effects on neurological deficits in patients presenting with acute cerebral ischemia. METHODS We retrospectively reviewed all patients admitted to our neurological intensive care unit with the diagnosis of ischemic stroke over a 2.5-year period. Thirty-three patients were not given a pressor agent (Ph- group), while 30 were treated with phenylephrine (Ph+ group) in an attempt to improve cerebral perfusion. RESULTS Baseline characteristics showed few differences between the Ph+ and Ph- groups. Intracerebral hemorrhage, brain edema, cardiac morbidity, and mortality were not increased in the Ph+ group. In 10 of 30 Ph+ patients, a systolic blood pressure threshold was identified below which ischemic deficits worsened and above which deficits improved. The mean threshold was 156 mm Hg (range, 120 to 190 mm Hg). The mean number of stenotic/occluded cerebral arteries was greater in those Ph+ patients with an identified clinical blood pressure threshold (mean, 2.1 per patient) than in Ph+ patients without a threshold (mean, 1.2 per patient; P < .05). CONCLUSIONS The results suggest that careful use of phenylephrine induced hypertension is not associated with an increase in morbidity or mortality in acute stroke. Although based on a retrospective analysis of clinical practice, this report suggests that a subset of patients, particularly those with multiple stenosis of cerebral arteries, may improve neurologically upon elevation of the blood pressure.

Novel Extracellular Matrix Structures in the Neural Stem Cell Niche Capture the Neurogenic Factor Fibroblast Growth Factor 2 from the Extracellular Milieu

The novel extracellular matrix structures called fractones are found in the lateral ventricle walls, the principal adult brain stem cell niche. By electron microscopy, fractones were shown to contact neural stem and progenitor cells (NSPC), suggesting a role in neurogenesis. Here, we investigated spatial relationships between proliferating NSPC and fractones and identified basic components and the first function of fractones. Using bromodeoxyuridine (BrdU) for birth‐dating cells in the adult mouse lateral ventricle wall, we found most mitotic cells next to fractones, although some cells emerged next to capillaries. Like capillary basement membranes, fractones were immunoreactive for laminin β1 and γ1, collagen IV, nidogen, and perlecan, but not laminin‐α1, in the adult rat, mouse, and human. Intriguingly, N‐sulfate heparan sulfate proteoglycan (HSPG) immunoreactivity was restricted to fractone subpopulations and infrequent subependymal capillaries. Double immunolabel for BrdU and N‐sulfate HSPG revealed preferential mitosis next to N‐sulfate HSPG immunoreactive fractones. To determine whether N sulfate HSPG immunoreactivity within fractones reflects a potential for binding neurogenic growth factors, we identified biotinylated fibroblast growth factor 2 (FGF‐2) binding sites in situ on frozen sections, and in vivo after intracerebroventricular injection of biotinylated FGF‐2 in the adult rat or mouse. Both binding assays revealed biotinylated FGF‐2 on fractone subpopulations and on infrequent subependymal capillaries. The binding of biotinylated FGF‐2 was specific and dependent upon HSPG, as demonstrated in vitro and in vivo by inhibition with heparatinase and by the concomitant disappearance of N‐sulfate HSPG immunoreactivity. These results strongly suggest that fractones promote growth factor activity in the neural stem cell niche.

Thymoma : histologic subclassification is an independent prognostic factor

Background. Several histologic classifications of thymomas have been proposed, and attempts have been made to correlate the different histologic subtypes to clinical behavior and prognosis. Recently, Marino and Müller‐Hermelink and Kirchner et al. proposed a new morphologic classification of thymomas based on the resemblance of the neoplastic cells to subtypes of the normal thymic epithelial cells. In this classification, six categories of thymic epithelial tumors are recognized, They define four categories of thymoma: medullary, mixed, organoid (predominantly cortical), and cortical, and two subgroups of thymic carcinomas: well differentiated thymic carcinoma and high grade carcinomas.

Selective Bladder Preservation by Combination Treatment of Invasive Bladder Cancer

BACKGROUND For patients with invasive bladder cancer the usual recommended treatment is radical cystectomy, although transurethral resection of the tumor, systemic chemotherapy, and radiotherapy are each effective in some patients. We sought to determine whether these treatments in combination might be as effective as radical cystectomy and thus might allow the bladder to be preserved and the cancer cured. METHODS We enrolled 53 consecutive patients with muscle-invading bladder cancer (stages T2 through T4, NXM0) in a trial of transurethral surgery, combination chemotherapy, and irradiation (4000 cGy) with concurrent cisplatin administration. Urologic evaluation of the tumor response directed further therapy: radical cystectomy in the 8 patients who had incomplete responses, additional chemotherapy and radiotherapy (6480 cGy) in the 34 patients who had complete responses or who were unsuited for cystectomy, and alternative care in the 11 patients who could not tolerate either irradiation or chemotherapy. RESULTS After a median follow-up of 48 months, 24 of the 53 patients (45 percent) were alive and free of detectable tumor. In 31 patients (58 percent) the bladder was free of invasive tumor and functioning well, even though in 9 (17 percent) a superficial tumor recurred and required further transurethral surgery and intravesical drug therapy. Of the 28 patients who had complete responses after initial treatment, 89 percent had functioning tumor-free bladders. CONCLUSIONS Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial that included a group for simultaneous comparison would be required to produce definitive results.

Brainstem tolerance to conformal radiotherapy of skull base tumors

PURPOSE The aim of this study was to analyze the long-term incidence of brainstem toxicity in patients treated for skull base tumors with high dose conformal radiotherapy. METHODS AND MATERIALS Between 1974 and 1995, 367 patients with chordomas (n = 195) and chondrosarcomas (n = 172) of the base of skull have been treated with combined megavoltage photon and 160 MeV proton radiotherapy. Following 3D treatment planning with delineation of target volumes and critical nontarget structures dose distributions and dose-volume histograms were calculated. Radiotherapy was given an 1.8 Gy or CGE (=Cobalt Gray Equivalent) dose per fraction, with prescribed target doses ranging from 63 CGE to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to < or = 64 CGE and to the brainstem center to < or = 53 CGE. RESULTS Follow-up time ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem toxicity was observed in 17 of 367 patients attributable to treatment, resulting in death of three patients. Actuarial rates of 5 and 10-year high-grade toxicity-free survival were 94 and 88%, respectively. Increased risk of brainstem toxicity was significantly associated with maximum dose to brainstem, volume of brainstem receiving > or = 50 CGE, > or = 55 CGE, and > or = 60 CGE, number of surgical procedures, and prevalence of diabetes or high blood pressure. Multivariate analysis identified three independent factors as important prognosticators: number of surgical procedures (p < 0.001), volume of the brainstem receiving 60 CGE (p < 0.001), and prevalence of diabetes (p < 0.01). CONCLUSIONS Tolerance of brainstem to fractionated radiotherapy appears to be a steep function of tissue volume included in high dose regions rather than the maximum dose of brainstem alone. In addition, presence of predisposing factors as well as extent of surgical manipulation can significantly lower brainstem tolerance in the individual patient.

Late rectal bleeding following combined x-ray and proton high dose irradiation for patients with stages T3–T4 prostate carcinoma

PURPOSE Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity. METHODS We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2). RESULTS With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding. CONCLUSIONS Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse

PURPOSE To determine the patterns of failure and outcome following relapse of chordomas of the base of skull and cervical spine. METHODS AND MATERIALS Between November 1975 and October 1993, 204 patients were treated for chordoma of the base of skull or cervical spine, of which 63 have developed relapse. These 63 patients constitute the main focus of this study. Forty-five patients presented with base of skull and 18 with cervical spine tumors. All patients received combined proton and photon beam radiation. The median prescribed dose was 70.1 cobalt-Gray equivalent (CGE) (range 66.6-77.4). There were 25 males and 38 females, with a median age of 41 years (range 7-66). Median follow-up was 54 months (range 8-158). RESULTS Sixty-three of the 204 patients treated (31%) had treatment failure. Among the 63 patients who relapsed, 60 (95%) experienced local recurrence, and in 49 patients (78%), this was the only site of failure. Two of 63 patients (3%) developed regional lymph node relapse and 3 of 63 (5%) developed surgical pathway recurrence (1 left neck, 1 palate and 1 nasal cavity). Thirteen of 204 patients relapsed in distant sites, accounting for 20% (13 of 63) of all patients with recurrence in this series. The most common metastatic sites were lungs and bones presenting in 7 of 13 and 6 of 13 patients, respectively. Only 2 of 13 patients failed with isolated distant metastasis. The actuarial 3- and 5-year survival rates after local relapse (60 patients) were 44 and 5%, respectively. Following distant failure (13 patients), the 3- and 5-year survival rates were 25 and 12%, respectively. After any relapse (63 patients) the corresponding survival rates were 43 and 7%. Following local relapse, 49 of 60 patients underwent salvage therapy consisting of subtotal resection in most patients (46 of 49). The remaining 11 of 60 patients received supportive care only. Salvage therapy resulted in stable or improved status without subsequent disease progression in 26 of 49 (53%), and progressive disease in 16 of 49 patients (33%). The actuarial 2- and 5-year overall survival rates following relapse for the 49 patients who underwent salvage treatment were 63 and 6%, which favorably compared to the 2-year survival rate of 21% for those who received supportive care only (p = 0.001). CONCLUSION Local relapse is the predominant type of treatment failure for chordomas of the base of skull and cervical spine. Salvage treatment may relieve symptoms; however, most patients will ultimately succumb to their disease. Poor long-term survival rates following relapse emphasize the importance of a combined treatment approach with experienced surgeons and radiation oncologists at the time of primary treatment. For most patients, only permanent local tumor control will offer a chance of cure.