Overexpression of p53 protein and outcome of patients treated with chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-04. Radiation Therapy Oncology Group.

BACKGROUND: Despite encouraging results with chemoradiation as the primary means of managing carcinoma of the anal canal, approximately 20% of patients will develop a local recurrence. This study examined the prognostic significance of p53 nuclear protein overexpression in the pretreatment biopsies of patients treated with chemoradiation for epidermoid carcinoma of the anal canal. METHODS: All patients were treated in a prospective, randomized Radiation Therapy Oncology Group trial (RTOG 87-04) in which radiotherapy to the pelvis was compared with concurrent 5-fluorouracil (5-FU) or 5-FU and mitomycin-C. Formalin fixed, paraffin embedded blocks or unstained slides from the pretreatment biopsies of 64 patients were obtained from referring institutions and evaluated immunohistochemically with the polyclonal p53 antibody CM-1. A multivariate analysis was conducted to analyze overexpression of p53 in terms of locoregional control, no evidence of disease (NED), and overall survival. RESULTS: p53 protein was overexpressed in 48.4% of the cases. Although not statistically significant, there was a trend for patients whose tumors overexpressed p53 to have inferior locoregional control (52% vs. 72%, P = 0.13), NED survival (52% vs. 68%, P = 0.27), and absolute survival (58% vs. 78%, P = 0.14). Of all the pretreatment factors analyzed, only International Union Against Cancer stage was predictive of outcome in multivariate analysis. Among those patients whose tumors overexpressed p53, there was a trend toward improved outcome in the arm that received 5-FU and mitomycin-C compared with the arm that received 5-FU only. CONCLUSIONS: Overexpression of the p53 protein may be associated with inferior outcome for patients managed with definitive chemoradiation for epidermoid carcinoma of the anal canal.

Evidence of increased failure in the treatment of prostate carcinoma patients who have perineural invasion treated with three-dimensional conformal radiation therapy.

BACKGROUND: The detection of perineural invasion (PNI) in the diagnostic transrectal biopsy of the prostate is associated with a 93% frequency of extracapsular disease extension in patients treated by prostatectomy for adenocarcinoma of the prostate. Extracapsular extension is associated with an inferior outcome compared with that of patients who have organ-confined disease. This study examined the association of PNI and treatment failure in a consecutive series of patients treated with three-dimensional conformal radiation therapy (3DCRT) alone. METHODS: The authors report actuarial biochemical no evidence of disease (bNED) survival rates for 484 consecutive patients with clinically localized prostate carcinoma diagnosed by transrectal needle biopsy who completed 3DCRT alone between May 1989 and December 1994. The median follow-up time was 28 months (range, 2-75 months), and the median dose to the center of the prostate was 7368 centigray (cGy) (range, 6316-8074 cGy). Patients were subdivided into 2 groups according to pretreatment prostate specific antigen (PSA) levels (< 20 ng/mL vs. > or = 20 ng/mL). Pathology records were reviewed for the presence or absence of PNI. bNED failure was defined as a PSA level > or = 1.5 ng/mL and rising on 2 consecutive occasions. bNED survival rates were calculated using Kaplan-Meier methodology and comparisons of survival curves were accomplished using the log rank test. RESULTS: The 3-year bNED survival for all 484 patients was 77%. The presence of PNI predicted decreased bNED survival in all patients. This detrimental effect, however, was confined to patients with pretreatment PSA values < 20 ng/mL. The bNED survival rates for patients with pretreatment PSA < 20 ng/mL demonstrated a highly significant decrease if PNI was present versus when it was absent (65% vs. 88% at 3 years, 39% vs. 65% at 5 years; P = 0.0009 for overall curve comparison). For patients with pretreatment PSA < 20 ng/mL, multivariate analysis of prognostic variables demonstrated a significant association between bNED survival and PNI (P = 0.002), palpation stage (P = 0.02), and pretreatment PSA (P = 0.006). Gleason score, age, and dose were not independent predictors of bNED survival in this group of patients. CONCLUSIONS: To the authors' knowledge, this is the first report demonstrating that PNI detected on diagnostic transrectal biopsy is a significant predictor of decreased bNED survival in patients treated with radiotherapy. The subgroup of patients affected are those with pretreatment PSA < 20 ng/mL. This result suggests that such patients may benefit from more aggressive treatment, particularly the use of larger planning target volumes or adjuvant therapies.

Bony landmarks are not an adequate substitute for lymphangiography in defining pelvic lymph node location for the treatment of cervical cancer with radiotherapy.

PURPOSE: Curative radiotherapy (RT) for carcinoma of the cervix requires adequate irradiation of regional lymph node groups. The best nonsurgical method of defining lymph node anatomy in the pelvis remains the lymphangiogram (LAG). This study was designed to determine if bony landmarks could accurately substitute for LAG as a means of determining lymph node position for the purpose of pelvic RT treatment planning. METHODS AND MATERIALS: The post-LAG simulation films of 22 patients treated at the Fox Chase Cancer Center for cervical cancer were examined. On anterior/posterior (A/P) simulation films, the distance of lymph nodes was determined from the top, middle, and bottom of the sacroiliac joint, and at the pelvic rim, 1 and 2 cm above the acetabulum. On lateral (LAT) simulation films, lymph node position was measured at points 0, 4, and 8 cm along a line from the bottom of L5 to the anterior aspect of the pubic symphysis. Positive values represent lateral and anterior distances relative to the reference point on A/P and LAT films, respectively. Negative values represent distances in the opposite direction. The adequacy of standard pelvic fields as defined by the Gynecologic Oncology Group (GOG) (A/P: 1.5 cm margin on the pelvic rim; LAT field edge is a vertical line anterior to the pubic symphysis) was also examined. Data are expressed as the mean +/- two standard deviations, (i.e. 95% confidence level). RESULTS: On A/P simulation films, the distance of visualized lymph nodes had mean values of -1.6 +/- 1.7 cm (range -4.1 to -0.4 cm), -1.3 +/- 1.5 cm (range -3.4 to 0.0 cm), and 1.2 +/- 1.8 cm (range -1.0 to 2.6 cm) from the sacro-iliac (SI) joint at the superior, middle, and inferior points, respectively. The mean distance of the nodes from the pelvic rim at points 1 and 2 cm above the acetabulum was 0.3 +/- 1.2 cm (range -0.6 to 1.8 cm) and 0.2 +/- 1.8 cm (range -1.6 to 2.1 cm), respectively. On LAT simulation films, the distance of lymph nodes from points 0, 4, and 8 cm from the previously described reference line had mean values of 2.0 +/- 1.0 cm (range 1.3 to 3.0 cm), 0.9 +/- 3.9 cm (range -1.9 to 5.1 cm), and 1.8 +/- 2.1 cm (range -0.8 to 3.5 cm), respectively. Ten of 22 (45%) patients would have had inadequate nodal irradiation if their fields had been designed according to standard GOG parameters. In all cases, these incompletely irradiated lymph nodes were from the lowest of the lateral external iliac group. CONCLUSION: Great variability in pelvic lymph node location is demonstrated when LAG is used to directly visualize their location. Bony structures are inaccurate landmarks for pelvic lymph node position. The GOG standard pelvic fields are not consistently adequate to cover all lateral external iliac lymph nodes, although the clinical significance of this subgroup of lymph nodes is not known. At this time, LAG remains the ideal radiographic modality to define anatomic location of regional lymph nodes for pelvic RT treatment planning. The clinical importance of the most lateral group of external iliac lymph nodes in various stages of cervical cancer represents a potential area of future research.

Treatment-related myelodysplastic syndrome following abdominopelvic radiotherapy for endometrial cancer.

A patient with grade II endometrial adenocarcinoma underwent TAH/BSO. The tumor penetrated 50% of the myometrium. A lesion from the serosa of the sigmoid colon was removed and contained metastatic adenocarcinoma. Metastatic tumor was also found in the common iliac lymph nodes. Postoperatively the patient was treated with abdominopelvic radiotherapy to 30 Gy. The pelvis was boosted to a dose of 46.2 Gy. The vaginal apex was then treated with three applications of high-dose-rate brachytherapy to a total dose of 12 Gy. The patient was doing well with no evidence of recurrence 52 months following treatment when she was diagnosed with a myelodysplastic syndrome. Cytogenetic analysis revealed aberrations of chromosomes 5 and 7, which is highly suggestive of a treatment-related process. Myelodysplasia induced by radiotherapy alone is an unusual but recognized event.

Prostate specific antigen density is not an independent predictor of response for prostate cancer treated by conformal radiotherapy.

Although prostate specific antigen (PSA) density appears to be an important discriminator between benign and malignant prostatic disease, conflicting data exist concerning its prognostic value. The present study was undertaken to confirm whether PSA density represents a new prognostic indicator of disease-free survival for prostate cancer treated with conformal radio-therapy. Between April 1989 and December 1992, 186 patients with organ confined prostate cancer were treated with definitive irradiation according to previously published conformal guidelines. The PSA density was defined as the ratio of the pretreatment serum PSA (ng./ml.) to the prostate volume (ml.) as determined from treatment planning computerized tomography. The median PSA density was 0.15 with a range of 0.02 to 2.12. A statistically significant advantage in actuarial freedom from biochemical relapse was noted for patients with pretreatment PSA levels less than 15 ng./ml. when compared to those with higher pretreatment PSA levels (3-year freedom from biochemical relapse 85% versus 28%, p < 0.001). Also, patients with PSA density of 0.15 or less had statistically superior freedom from biochemical relapse compared to their counterparts with higher PSA density (3-year freedom from biochemical relapse 88% versus 28%, p < 0.001). In a multivariate analysis only the baseline PSA (p < 0.002) and the Gleason score (p < 0.002) emerged as significant predictors of prolonged freedom from biochemical relapse. The PSA density had no impact on freedom from biochemical relapse whether it was entered into this multivariate model as a continuous or a dichotomous variable. In our data base baseline PSA levels remain the most powerful independent discriminant of response to conformal irradiation. PSA density is only a surrogate for baseline PSA levels and does not refine the ability to predict prolongation of freedom from biochemical relapse following conformal radiotherapy.

The effect of arachidonic acid metabolites on the ciliary beat frequency of human nasal mucosa in vitro.

Using computerized microphotometry, we studied the effects of prostaglandin E2 (PGE2), the prostacyclin analog Iloprost, and the thromboxane A2 analog U46619 on the ciliary beat frequency (CBF) of human nasal mucosa. Thirty-two normal subjects underwent nasal cytologic brushing of the inferior meatus to obtain ciliary samples, and a total of 5,640 ciliated cell clusters were analyzed. Each subject served as their own control. PGE2, 10(-10) to 10(-6) M, produced a significant dose dependent increase in CBF of up to 12% versus control. This increase was not significantly inhibited by the addition of the cyclooxygenase inhibitor indomethacin (10(-6) M). Iloprost, 10(-12) to 10(-6) M, also significantly increased CBF by 12.7% at 10(-8) M. This ciliostimulatory effect, however, was abolished by indomethacin. The thromboxane A2 analog, 10(-10) to 10(-6) M, did not significantly effect CBF. The present study demonstrates that a thromboxane A2 analog has no effect on ciliary motility, PGE2 has a direct ciliostimulatory effect, and a prostacyclin analog has a ciliostimulatory effect likely mediated by stimulation of the cyclooxygenase pathway within human cells.