Prostate-Specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes.

Prostate Specific Ets factor is a recently identified transcriptional activator that is overexpressed in prostate cancer. To determine whether this gene is overexpressed in breast cancer, we performed a virtual Northern blot using data available online at the Cancer Genome Anatomy Project website. Ninety-five SAGE libraries were probed with a unique sequence tag to the Prostate Specific Ets gene. The results indicate that Prostate Specific Ets is expressed in 14 out of 15 breast cancer libraries (93%), nine out of 10 prostate cancer libraries (90%), three out of 40 libraries from other cancers (7.5%), and four out of 30 normal tissue libraries (13%). To determine the possibility that the Prostate Specific Ets gene is a novel marker for detection of metastatic breast cancer in axillary lymph nodes, quantitative real-time RT-PCR analyses were performed. The mean level of Prostate Specific Ets expression in lymph nodes containing metastatic breast cancer (n=22) was 410-fold higher than in normal lymph node (n=51). A receiver operator characteristic curve analysis indicated that Prostate Specific Ets was overexpressed in 18 out of 22 lymph nodes containing metastatic breast cancer (82%). The receiver operator characteristic curve analysis also indicated that the diagnostic accuracy of the Prostate Specific Ets gene for detection of metastatic breast cancer in axillary lymph nodes was 0.949. These results provide evidence that Prostate Specific Ets is a potentially informative novel marker for detection of metastatic breast cancer in axillary lymph nodes, and should be included in any study that involves molecular profiling of breast cancer.

Radiotherapy for epithelial skin cancer.

PURPOSE: To retrospectively review patterns of failure, cosmesis, and outcomes according to treatment modality of patients with histologically confirmed epithelial skin cancer. METHODS AND MATERIALS: The records of 468 patients having 531 lesions were analyzed; 389 basal cell carcinomas and 142 squamous cell carcinomas were treated, 167 of which were recurrent tumors. Median follow-up was 5.8 years. Electron beam irradiation was used in 19%, superficial x-rays in 60%, a combination of electron beam and superficial x-rays in 20%, and megavoltage photons in <2%. RESULTS: The overall local tumor control rate was 89%; it was 93% for previously untreated lesions and 80% for recurrent lesions. Patients with basal cell carcinoma had a 92% overall control rate; patients with squamous cell carcinoma 80%. Multivariate analysis showed that local failure was related to the daily dose fractionation. The maximal diameter of the lesion and pathologic tumor type were also significant (p 0.01). Treatment type, patient age, and treatment duration were not significant. Overall, 92% of the treated population with cosmesis data had excellent or good results. The overall complication rate was 5.8%, consisting primarily of soft-tissue necrosis. CONCLUSIONS: Radiotherapy remains an excellent treatment modality for epithelial skin cancer. Local tumor control, cosmesis, and complications are related to the size of the primary lesion. Recurrent lesions fared worse, and therefore treatment at the earliest possible stage is strongly recommended.

Pretreatment clinical findings predict outcome for patients receiving preoperative radiation for rectal cancer.

BACKGROUND: As a sole modality, preoperative radiation for rectal carcinoma achieves a local control comparable to that of postoperative radiation plus chemotherapy. Although the addition of chemotherapy to preoperative treatment improves the pathologic complete response rate, there is also a substantial increase in acute and perioperative morbidity. Identification of subsets of patients who are at low or high risk for recurrence can help to optimize treatment. METHODS: During the period 1977-95, 384 patients received preoperative radiation therapy for localized adenocarcinoma of the rectum. Ages ranged from 19 to 97 years (mean 64.4), and there were 171 females. Preoperative treatment consisted of conventionally fractionated radiation to 3600-5040 cGy (median 4500 cGy) 6-8 weeks before surgery in 293 cases or low doses of <3000 cGy (median 2000 cGy) immediately before surgery in 91 cases. Concurrent preoperative chemotherapy was given to only 14 cases in this study period. Postoperative chemotherapy was delivered to 55 cases. RESULTS: Overall 93 patients have experienced recurrence (including 36 local failures). Local failures were scored if they occurred at any time, not just as first site of failure. For the group as a whole, the actuarial (Kaplan-Meier) freedom from relapse (FFR) and local control (LC) were 74% and 90% respectively at 5 years. Univariate analysis of clinical characteristics demonstrated a significant (p < 0.05) adverse effect on both LC and FFR for the following four clinical factors: (1) location <5 cm from the verge, (2) circumferential lesion, (3) near obstruction, (4) tethered or fixed tumor. Size, grade, age, gender, ultrasound stage, CEA, radiation dose, and the use of chemotherapy were not associated with outcome. Background of the surgeon was significantly associated with outcome, colorectal specialists achieving better results than nonspecialist surgeons. We assigned a clinical score of 0 to 2 on the basis of how many of the above four adverse clinical factors were present: 0 for none, 1 for one or two, 2 for three or four. This sorted outcome highly significantly (p < or = 0.002, Tarone Ware), with 5-year LC/FFR of 98%/85% (score 0), 90%/72% (score 1), and 74%/58% (score 2). The scoring system sorts the data for both subgroups of surgeons; however, there are substantial differences in LC on the basis of the surgeon's experience. For colorectal specialists (251 cases), the 5-year LC is 100%, 94%, and 78% for scores of 0, 1, and 2, respectively (p = 0.004). For the more mixed group of nonspecialist surgeons (133 cases), LC is 98%, 80%, and 65% for scores of 0, 1, and 2 (p = 0.008). In multivariate analysis, the clinical score and surgeon's background retained independent predictive value, even when pathologic stage was included. CONCLUSIONS: For many patients with rectal cancer, adjuvant treatment can be administered in a well-tolerated sequential fashion-moderate doses of preoperative radiation followed by surgery followed by postoperative chemotherapy to address the risk of occult metastatic disease. A clinical scoring system has been presented here that would suggest that the local control is excellent for lesions with a score of 0 or (if the surgeon is experienced) 1, and therefore sequential treatment could be considered. Cases with a clinical score of 2 should be strongly considered for protocols evaluating more aggressive preoperative treatment, such as combined modality preoperative treatment.

Chemical disease-free survival in localized carcinoma of prostate treated with external beam irradiation: comparison of American Society of Therapeutic Radiology and Oncology Consensus or 1 ng/mL as endpoint.

PURPOSE: To compare postirradiation biochemical disease-free survival using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus or elevation of postirradiation prostate-specific antigen (PSA) level beyond 1 ng/mL as an endpoint and correlate chemical failure with subsequent appearance of clinically detected local recurrence or distant metastasis. METHODS AND MATERIALS: Records of 466 patients with histologically confirmed adenocarcinoma of the prostate treated with irradiation alone between January 1987 and December 1995 were analyzed; 339 patients were treated with bilateral 120 degrees arc rotation and, starting in 1992, 117 with three-dimensional conformal irradiation. Doses were 68--77 Gy in 1.8 to 2 Gy daily fractions. Minimum follow-up is 4 years (mean, 5.5 years; maximum, 9.6 years). A chemical failure was recorded using the ASTRO Consensus or when postirradiation PSA level exceeded 1 ng/mL at any time. Clinical failures were determined by rectal examination, radiographic studies, and, when clinically indicated, biopsy. RESULTS: Six-year chemical disease-free survival rates using the ASTRO Consensus according to pretreatment PSA level for T1 tumors were: < or = 4 ng/mL, 100%; 4.1--20 ng/mL, 80%; and > 20 ng/mL, 50%. For T2 tumors the rates were: < or = 4 ng/mL, 91%; 4.1--10 ng/mL, 81%; 10.1--20 ng/mL, 55%; 20.1--40 ng/mL, 63%; and > 40 ng/mL, 46%. When postirradiation PSA levels higher than 1 ng/mL were used, the corresponding 6-year chemical disease-free survival rates for T1 tumors were 92% for pretreatment PSA levels of < or = 4 ng/mL, 58--60% for levels of 4.1--20 ng/mL, and 30% for levels > 20 ng/mL. For T2 tumors, the 6-year chemical disease-free survival rates were 78% in patients with pretreatment PSA levels of 4--10 ng/mL, 45% for 10.1--40 ng/mL, and 25% for > 40 ng/mL. Of 167 patients with T1 tumors, 30 (18%) developed a chemical failure, 97% within 5 years from completion of radiation therapy; no patient has developed a local recurrence or distant metastasis. In patients with T2 tumors, overall 45 of 236 (19%) had chemical failure, 94% within 5 years of completion of radiation therapy; 4% have developed a local recurrence, and 10%, distant metastasis. In patients with T3 tumors, overall, 24 of 65 (37%) developed a chemical failure, 100% within 3.5 years from completion of radiation therapy; 4% of these patients developed a local recurrence within 2 years, and 12% developed distant metastasis within 4 years of completion of irradiation. The average time to clinical appearance of local recurrence or distant metastasis after a chemical failure was detected was 5 years and 3 years, respectively. CONCLUSION: There was a close correlation between the postirradiation nadir PSA and subsequent development of a chemical failure. Except for patients with T1 tumors and pretreatment PSA of 4.1--20 ng/mL, there is good agreement in 6-year chemical disease-free survival using the ASTRO Consensus or PSA elevations above 1 ng/mL as an endpoint. Although the ASTRO Consensus tends to give a higher percentage of chemical disease-free survival in most groups, the differences with longer follow-up are not statistically significant (p > 0.05). It is important to follow these patients for at least 10 years to better assess the significance of and the relationship between chemical and clinical failures.

Outcome of patients with rectal adenocarcinoma and localized pelvic non-nodal metastatic foci.

PURPOSE: The aim of this study was to evaluate the outcome of patients with primary rectal adenocarcinoma and soft tissue metastatic foci restricted to the pelvis and to determine whether this entity, which is considered N1 disease in the American Joint Committee on Cancer staging system, behaves like completely replaced nodal disease or the first sign of M1 disease. The clinical course for patients with this finding is not well-described in the literature. METHODS: The authors retrospectively reviewed the medical records of 395 patients with rectal adenocarcinoma who received radiation treatment. Eighteen patients had pelvic soft tissue metastatic foci. Exclusions from this study included 1) cases without metastatic pelvic foci; 2) cases of recurrent cancer; 3) cases with known distant metastatic disease as defined by American Joint Committee on Cancer criteria; and 4) cases with extrapelvic metastatic foci. All patients received adjuvant radiotherapy. Thirteen cases received preoperative radiotherapy. Four cases received postoperative radiotherapy. One case received both preoperative and postoperative radiotherapy. Eight cases received chemotherapy. RESULTS: All eighteen patients had T3 or T4 lesions. Thirteen patients had lymph nodes that contained metastatic disease and would therefore have been scored N1 or N2 even without the pelvic tumor implants. Sixteen of 18 (89 percent) patients died of disease after a survival time of 12 to 37 (mean, 25) months. Only 1 of 18 (6 percent) patients was disease free at five years. The other remaining survivor was undergoing palliative therapy for metastatic disease to the lung. This is significantly worse than our institution's experience with T3,4N+ disease after preoperative radiation (5-year survival, 11 vs. 56 percent; P = 0.0002, Generalized Wilcoxon of Breslow). There was a high incidence of local (9/18) and distant (14/18) failure. No other factor, including radiation dose, margin status, chemotherapy, T stage, and number of involved nodes or soft tissue implants, correlated independently with outcome. CONCLUSIONS: Pelvic metastatic foci confer a significantly worse prognosis than other T3,4N+ disease. Such cases should be excluded from prospective trials for localized disease. Although this entity probably represents M1 disease for most patients, survival can be long, and aggressive locoregional and systemic treatment is warranted.

Three-dimensional conformal therapy or standard irradiation in localized carcinoma of prostate: preliminary results of a nonrandomized comparison.

PURPOSE: We present preliminary results of a nonrandomized comparison of three-dimensional conformal radiation therapy (3D CRT) and standard radiation therapy (SRT) in localized carcinoma of the prostate in two groups of patients with comparable prognostic factors treated during the same period. METHODS AND MATERIALS: Between January 1992 and December 1997, 146 patients were treated with 3D CRT and 131 with SRT alone for clinical stage T1c or T2 histologically confirmed carcinoma of the prostate. None of these patients received hormonal therapy. Mean follow-up for all patients is 3 years (range, 1-6 years). For 3D CRT, 7 intersecting fields were used (Cerrobend blocking or multileaf collimation) to deliver 68-73.8 Gy to the prostate; 3D dose distributions and dose-volume histograms (DVHs) of the planning target volume, bladder, and rectum were obtained. SRT consisted of bilateral 120 degrees rotational arcs, with portals with 2-cm margins around the prostate to deliver 68-70 Gy to the prostate. The criterion for chemical disease-free survival was a postirradiation prostate-specific antigen (PSA) (Tandem-R, Hybritech) value following the American Society for Therapeutic Radiology and Oncology guidelines. Symptoms during treatment were quantitated weekly, and late effects were assessed every 4-6 months. RESULTS: DVHs showed a two-thirds reduction in normal bladder or rectum receiving 70 Gy or more with 3D CRT. Higher 5-year chemical disease-free survival was observed with 3D CRT (91% for T1c and 96% for T2 tumors) compared with SRT (53% and 58%, respectively). There was no statistically significant difference in chemical disease-free survival in patients with Gleason score of 4 or less (p = 0.83), but with Gleason score of 5-7, the 5-year survival rates were 96% with 3D CRT and 53% with SRT (p < or = 0.01). In 111 patients with pretreatment PSA of 10 ng/mL or less, treated with 3D CRT, the chemical disease-free rate was 96% vs. 65% in 94 patients treated with SRT (p < or = 0.01). In patients with PSA of 10. 1-20 ng/mL, the chemical disease-free survival rate for 26 patients treated with 3D CRT was 88% compared with 40% for 20 patients treated with SRT (p = 0.05). The corresponding values were 71% and 26%, respectively, for patients with PSA levels of greater than 20 ng/mL (p = 0.30). On multivariate analysis, the most important prognostic factors for chemical failure were pretreatment PSA (p = 0. 023), nadir PSA (p = 0.001), and 3D CRT technique (p = 0.033). Moderate dysuria and difficulty in urinating were reported by 2-5% of patients treated with 3D CRT in contrast to 6-9% of patients treated with SRT; moderate urinary frequency and nocturia were reported by 18-24% treated with 3D CRT and 18-27% of patients in the SRT group. The incidence of moderate loose stools/diarrhea, usually after the 4th week of treatment, was 3-5% in the 3D CRT patients and 8-19% in the SRT group. Late intestinal morbidity (proctitis, rectal bleeding) was very low (1.7%) in the 3D CRT group in contrast to the SRT patients (8%). CONCLUSION: Three-dimensional CRT spares more normal tissues, yields higher chemical disease-free survival, and results in less treatment morbidity than SRT in treatment of Stage T1-T2 prostate cancer. Longer follow-up is needed to confirm these preliminary observations.

New trends in prostatic cancer research. Three-dimensional conformal radiation therapy (3-D CRT), brachytherapy, and new therapeutic modalities.

In prostatic cancer research three-dimensional conformal radiation therapy (3-D CRT), brachytherapy and new therapeutic modalities have been applied. Treatment planning and delivery of radiation therapy have substantially evolved in the past 20 years. The treatment of localized carcinoma of the prostate with 3-D CRT is described, preliminary clinical results are presented and compared with those with standard radiation therapy (SRT). The benefit of 3-D CRT hypothetically could be linked to improved local tumor control because of a better coverage of the target volume with a specific dose of irradiation, less acute and late toxicity, possibility of carrying out dose-escalation studies. Intensity modulated radiation therapy (IMRT) may be particularly useful in some cases. Further efforts are necessary with collaboration of urologists and radiation oncologists to continue to explore approaches to optimally select and manage patients with localized prostate cancer. A reliable assessment of the impact of 3-D CRT and IMRT on outcome should come from prospective randomized long-term studies. As for brachytherapy, standardized protocols should be developed to objectively evaluate brachytherapy in localized prostatic cancer. Recently a great deal of interest has been focused on new therapeutic modalities with chemotherapeutic agents, a new agent named prostate specific enhancer, a regulatory element of the PSA gene is being tested. Laboratory and animal studies of the viral construct have been reported. A phase I human clinical trial is being initiated in the U.S.A. in patients with postirradiation hormone refractory prostate cancer.

Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)

PURPOSE: To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy. METHODS AND MATERIALS: Between January 1991 and October 1995, 99 patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment. RESULTS: Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V20), the effective volume (Veff) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > or = Grade 2 pneumonitis. Multivariate analysis revealed the V20 to be the single independent predictor of pneumonitis. CONCLUSIONS: The V20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.

Radiation therapy morbidity in carcinoma of the uterine cervix: dosimetric and clinical correlation.

PURPOSE: To quantitate the impact of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in patients treated with irradiation alone for cervical cancer. METHODS AND MATERIALS: Records were reviewed of 1456 patients (Stages IB-IVA) treated with external-beam irradiation plus two low-dose rate intracavitary insertions to deliver 70 to 90 Gy to point A. Follow-up was obtained in 98% of patients (median, 11 years; minimum, 3 years; maximum, 30 years). The relationships among various dosimetry parameters and Grade 2 or 3 sequelae were analyzed. RESULTS: In Stage IB, the frequency of patients developing Grade 2 morbidity was 9%, and Grade 3 morbidity, 5%; in Stages IIA, IIB, III, and IVA, Grade 2 morbidity was 10% to 12% and Grade 3 was 10%. The most frequent Grade 2 sequelae were cystitis and proctitis (0.7% to 3%). The most common Grade 3 sequelae were vesicovaginal fistula (0.6% to 2% in patients with Stage I-III tumors), rectovaginal fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In the bladder, doses below 80 Gy correlated with less than 3% incidence of morbidity and 5% with higher doses (p = 0.31). In the rectosigmoid, the incidence of significant morbidity was less than 4% with doses below 75 Gy and increased to 9% with higher doses. For the small intestine, the incidence of morbidity was less than 1% with 50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall (p = 0.04). When the ratio of dose to the bladder or rectum in relation to point A was 0.8 or less, the incidence of rectal morbidity was 2.5% (8 of 320) vs. 7.3% (80 of 1095) with higher ratios (p < or = 0.01); bladder morbidity was 2.3% (7 of 305) and 5.8% (64 of 1110), respectively (p = 0.02). The incidence of Grade 2 and 3 bladder morbidity was 2.9% (10 of 336) when the dose rate was less than 0.80 Gy/h, in contrast to 6.1% (62 of 1010) with higher dose rates (p = 0.07). Rectal morbidity was 2% to 5% in Stage IB, regardless of dose rate to the rectum; in Stages IIA-B and III, morbidity was 5.2% (28 of 539) with a dose rate of 0.80 Gy or less and 10.7% (37 of 347) with higher dose rates (p < 0.01). Multivariate analysis showed that dose to the rectal point was the only factor influencing rectosigmoid sequelae, and dose to the bladder point affected bladder morbidity. CONCLUSIONS: Various dosimetric parameters correlate closely with the incidence of significant morbidity in patients treated with definitive irradiation for carcinoma of the uterine cervix. Careful dosimetry and special attention to related factors will reduce morbidity to the lowest possible level without compromising pelvic tumor control.

Primary T-cell and activated macrophage response associated with tumor protection using peptide/poly-N-acetyl glucosamine vaccination.

The mode of peptide-based cancer vaccine administration critically affects the ability to achieve a clinically relevant tumor-specific response. We have previously shown (Cole et al., Clin. Cancer Res., 3: 867-873, 1997) that a specific formulation of the polysaccharide poly-N-acetyl glucosamine (p-GlcNAc, designated as F2 gel) is an effective vehicle for sustained cytokine and peptide delivery in vitro. The purpose of this study was to evaluate the efficacy of F2 gel/peptide vaccination in the murine EG.7-OVA tumor model and to elucidate potential mechanisms involved in the observed cell-mediated response. C57BL/6 mice were given injections of 200 microl in the base of tail/footpad using either F2 gel alone or 200 microg of: SIINFEKL minimal peptide (OVA) in PBS, OVA peptide/endoplasmic reticulum insertion signal sequence fusion (ESOVA) in PBS, OVA in F2 gel, or ESOVA in F2 gel. Splenocytes were tested 10 days later for a secondary response using a Cr51 assay as well as a primary CTL response using the lactate dehydrogenase cytotoxicity assay. Splenocytes from immunized mice were harvested at specific time points and assayed for cell surface and intracellular markers. On day 10 postvaccination, animals were challenged with EG.7-OVA murine thymoma cells. Tumor size and appearance were recorded. Vaccination with F2 gel/peptide (either OVA or ESOVA) resulted in a primary T-cell response (up to 25% tumor cell-specific lysis) and no tumor growth in 69% of the mice. By 48 h, the proportion of splenic T cells had increased 4-fold compared with B cells. Presence of an increased Th1 CD4 helper population was demonstrated by IFN-gamma production. CD4 cells were activated at 24 and 48 h as shown by IL-2 receptor alpha chain expression (from 2% basal expression to 15.4% at 48 h). Activated splenic macrophages increased from 3 to 8% within 10 h, and their level of B7-2 expression doubled. Depletion of macrophages before vaccine injection abolished any tumor-specific primary CTL response. F2 gel/peptide tumor vaccine can prime the immune system in an antigen-specific manner by generating a measurable primary T-cell response with minimal peptide; this process involves macrophage presence and activation as well as induction of Th1 CD4 cells. This is the first demonstration of a primary CTL response generated with minimal peptide vaccination using a noninfectious delivery system. These results justify additional studies to better define the mechanisms involved in F2 gel/peptide vaccination in preparation for clinical trials.

Factors affecting long-term outcome of irradiation in carcinoma of the vagina.

OBJECTIVE: This report evaluates prognostic and technical factors affecting outcome of patients with primary carcinoma of the vagina treated with definitive radiation therapy. METHODS AND MATERIALS: A retrospective analysis was performed on records of 212 patients with histologically confirmed carcinoma of the vagina treated with irradiation. RESULTS: Tumor stage was the most significant prognostic factor; actuarial 10-year disease-free survival was 94% for Stage 0 (20 patients), 80% for Stage I (59 patients), 55% for Stage IIA (63 patients), 35% for Stage IIB (34 patients), 38% for Stage III (20 patients), and 0% for Stage IV (15 patients). All in situ lesions except one were controlled with intracavitary therapy. Of the patients with Stage I disease, 86% showed no evidence of vaginal or pelvic recurrence; most of them received interstitial or intracavitary therapy or both, and the addition of external-beam irradiation did not significantly increase survival or tumor control. In Stage IIA (paravaginal extension) and IIB (parametrial involvement) 66% and 56% of the tumors, respectively, were controlled with a combination of brachytherapy and external-beam irradiation; 13 of 20 (65%) Stage III tumors were controlled in the pelvis. Four patients with Stage IV disease (27%) had no recurrence in the pelvis. The total incidence of distant metastases was 13% in Stage I, 30% in Stage IIA, 52% in Stage IIB, 50% in Stage III, and 47% in Stage IV. The dose of irradiation delivered to the primary tumor or the parametrial extension was of relative importance in achieving successful results. In patients with Stage I disease, brachytherapy alone achieved the same local tumor control (80-100%) as in patients receiving external pelvic irradiation (78-100%) as well. In Stage II and III there was a trend toward better tumor control (57-80%) with combined external irradiation and brachytherapy than with the latter alone (33-50%) (p = 0.42). The incidence of grade 2-3 complications (12%) correlated with the stage of the tumor and type of treatment given. CONCLUSION: Radiation therapy is an effective treatment for patients with vaginal carcinoma, particularly Stage I. More effective irradiation techniques, including optimization of dose distribution combining external irradiation and interstitial brachytherapy in tumors beyond Stage I, are necessary to enhance locoregional tumor control. The high incidence of distant metastases emphasizes the need for earlier diagnosis and effective systemic cytotoxic agents to improve survival in these patients.

Five fractions of preoperative radiotherapy for selected cases of rectal carcinoma: long-term tumor control and tolerance to treatment.

BACKGROUND: Randomized Swedish studies demonstrate the efficacy of a 5-fraction course of preoperative radiotherapy for rectal carcinoma. The present study evaluates the results in a single U.S. institution over a 20-year period with a similar regimen. METHODS AND MATERIALS: During the period of 1975-1995, 83 patients received pelvic radiotherapy of 20 Gy/5 fractions, followed by immediate surgery for rectal cancer. These patients represented 21% of cases receiving preoperative treatment; the remainder received 45-50 Gy preoperatively. The 5-fraction course was used for lesions deemed readily resectable but too bulky for conservative endocavitary treatment. Since 1990, it has been our policy to administer postoperative chemotherapy to medically fit patients who prove to have pathologic Stage II or III disease. Patient characteristics including age (mean 65 years, range 23-90), gender (45% male), and location within the rectum were comparable to our previously reported cases that received 45 Gy/25 fractions preoperatively. However, the group selected for 5 fractions preoperatively had relatively fewer lesions that were tethered (20% vs. 61%), circumferential (11% vs. 20%), or near obstructing (1% vs. 16%). RESULTS: With a post treatment follow-up of 1-15 years (mean 4.7), there have been 3 local failures and 12 distant failures, with an actuarial local control of 95%, and disease-specific survival of 77% at 5 and 10 years. Grade > or = 3 perioperative or late toxicity occurred in 11 cases (13%), including 3 (3.5%) late bowel obstructions. Stage II or III disease was found in 56% of the cases, 74% of which were free of disease at last follow-up. However, patients with Stage II or III lesions that were significantly tethered or fixed had a 40% greater likelihood of recurring than similar stage lesions that were, at most, slightly tethered. Sphincter-preserving surgery was possible in 60% of the patients. In recent years, postoperative chemotherapy has been administered to 16 patients with Stage II or III disease; this has been well tolerated, with only 1 late toxicity (cystitis managed medically). When compared with a matched group of cases receiving conventionally fractionated preoperative radiation, there were no significant differences in perioperative morbidity and nonradiotherapeutic cost generating factors (length of hospital stay, duration of postoperative antibiotics, blood loss at surgery). CONCLUSION: Patients with resectable rectal cancer who received 20 Gy/5 fractions preoperative radiotherapy to the pelvis had excellent local and distant control of disease. These patients were able to undergo sphincter-preserving surgery and postoperative chemotherapy. It would be of interest to conduct a randomized trial comparing short course with longer course (45 or 50 Gy) preoperative radiotherapy for resectable T3 lesions. The results of this study suggest that, in general, differences in toxicity, local control, and disease-free survival would probably be < 10%. However, since the results of this study suggest that patients with significantly tethered lesions may be better served with the higher dose and longer duration course of radiation, clinical degree of fixation should be included as a stratification parameter, and stopping criteria should be included for tethered lesions.

Carcinoma of the tonsillar fossa: prognostic factors and long-term therapy outcome.

PURPOSE: To identify prognostic parameters and evaluate the therapeutic outcomes for patients with carcinoma of the tonsillar fossa treated with three treatment modalities. METHODS AND MATERIALS: The results of therapy are reported in 384 patients with histologically proven epidermoid carcinoma of the tonsillar fossa; 154 were treated with irradiation alone (55-70 Gy), 144 with preoperative radiation therapy (20-40 Gy), and 86 with postoperative irradiation (50-60 Gy). The operation in all but four patients in the last two groups consisted of an en bloc radical tonsillectomy with ipsilateral lymph node dissection. RESULTS: Treatment modality and total irradiation doses had no impact on survival. Actuarial 10-year disease-free survival rates were 65% for patients with T1 tumors, 60% for T2, 60% for T3, and 30% for T4 disease. Patients with no cervical lymphadenopathy or with a small metastatic lymph node (N1) had better disease-free survival (60% and 70%, respectively) at 5 years than those with large or fixed lymph nodes (30%). Primary tumor recurrence (local, marginal) rates in the T1, T2, and T3 groups were 20-25% in patients treated with irradiation and surgery and 31% for those treated with irradiation alone (difference not statistically significant). In patients with T4 disease treated with surgery and postoperative irradiation, the local failure rate was 32% compared with 86% with low-dose preoperative irradiation and 47% with irradiation alone (p = 0.03). The overall recurrence rates in the neck were 10% for N0 patients, 25% for N1 and N2, and 35-40% for patients with N3 cervical lymph nodes, without significant differences among the various treatment groups. The incidence of contralateral neck recurrences was 8% with the various treatment modalities. On multivariate analysis the only significant factors for local tumor control and disease-free survival were T and N stage (p = 0.04-0.001). Fatal complications were noted in 7 of 144 (5%) patients treated with preoperative irradiation and surgery, 2 of 86 (2%) of those receiving postoperative irradiation, and 2 of 154 (1.3%) patients treated with radiation therapy alone. Other moderate or severe nonfatal sequelae were noted in 30% of the patients treated with preoperative irradiation and surgery, in 53% treated with postoperative irradiation, and in 19% receiving radiation therapy alone. CONCLUSION: Primary tumor and neck node stage are the only significant prognostic factors influencing locoregional tumor control and disease-free survival. Treatment modality had no significant impact on outcome. Radiation therapy remains the treatment of choice for patients with stage T1-T2 carcinoma of the tonsillar fossa. In patients with T3-T4 tumors and good general condition, combination surgery and postoperative irradiation offers better tumor control than single-modality and preoperative irradiation procedures, but with greater morbidity.

Irradiation in carcinoma of the vulva: factors affecting outcome.

PURPOSE: This report reviews the increasing role of radiation therapy in the management of patients with histologically confirmed vulvar carcinoma, based on a retrospective analysis of 68 patients with primary disease (2 in situ and 66 invasive) and 18 patients with recurrent tumor treated with irradiation alone or combined with surgery. METHODS AND MATERIALS: Of the patients with primary tumors, 14 were treated with wide local excision plus irradiation, 19 received irradiation alone after biopsy, 24 were treated with radical vulvectomy followed by irradiation to the operative fields and inguinal-femoral/pelvic lymph nodes, and 11 received postoperative irradiation after partial or simple vulvectomy. The 18 patients with recurrent tumors were treated with irradiation alone. Indications and techniques of irradiation are discussed in detail. RESULTS: In patients treated with biopsy/local excision and irradiation, local tumor control was 92% to 100% in Stages T1-3N0, 40% in similar stages with N1-3, and 27% in recurrent tumors. In patients treated with partial/radical vulvectomy and irradiation, primary tumor control was 90% in patients with T1-3 tumors and any nodal stage, 33% in patients with any T stage and N3 lymph nodes, and 66% with recurrent tumors. The actuarial 5-year disease-free survival rates were 87% for T1N0, 62% for T2-3N0, 30% for T1-3N1 disease, and 11 % for patients with recurrent tumors; there were no long-term survivors with T4 or N2-3 tumors. Four of 18 patients (22%) treated for postvulvectomy recurrent disease remain disease-free after local tumor excision and irradiation. In patients with T1-2 tumors treated with biopsy/wide tumor excision and irradiation with doses under 50 Gy, local tumor control was 75% (3 of 4), in contrast to 100% (13 of 13) with 50.1 to 65 Gy. In patients with T3-4 tumors treated with local wide excision and irradiation, tumor control was 0% with doses below 50 Gy (3 patients) and 63% (7 of 11) with 50.1 to 65 Gy. In patients with T1-2 tumors treated with partial/radical vulvectomy and irradiation, local tumor control was 83% (14 of 17), regardless of dose level, and in T3-4 tumors, it was 62% (5 of 8) with 50 to 60 Gy and 80% (8 of 10) with doses higher than 60 Gy. The differences are not statistically significant. There was no significant dose response for tumor control in the inguinal-femoral lymph nodes; doses of 50 Gy were adequate for elective treatment of nonpalpable lymph nodes, and 60 to 70 Gy controlled tumor growth in 75% to 80% of patients with N2-3 nodes when administered postoperatively after partial or radical lymph node dissection. Significant treatment morbidity included one rectovaginal fistula, one case of proctitis, one rectal stricture, four bone/skin necroses, four vaginal necroses, and one groin abscess. CONCLUSIONS: Irradiation is playing a greater role in the management of patients with carcinoma of the vulva; combined with wide local tumor excision or used alone in T1-2 tumors, it is an alternative treatment to radical vulvectomy, with significantly less morbidity. Postradical vulvectomy irradiation in locally advanced tumors improves tumor control at the primary site and the regional lymphatics in comparison with reports of surgery alone.

Detection of occult breast cancer micrometastases in axillary lymph nodes using a multimarker reverse transcriptase-polymerase chain reaction panel.

BACKGROUND: Axillary lymph node status in breast cancer patients remains the single most important predictor of outcomes. Current methods of histopathologic analysis may be inadequate because 30% of node-negative patients recur. The purpose of this study was to test the hypothesis that a multigene reverse transcriptase-polymerase chain reaction (RT-PCR) panel provides a more sensitive method to detect axillary lymph node metastases than routine pathologic examination. STUDY DESIGN: Sixty-one consecutive breast cancer patients were evaluated, with nine normal control patients. Nodes > 1 cm were bisected for histopathologic and RT-PCR analysis. Nodal tissue was homogenized, and total RNA was converted into cDNA with reverse transcriptase. Reverse transcriptase-polymerase chain reaction analysis was performed with primers specific for keratin-19, c-myc, prolactin inducible protein (PIP), and beta-actin using ethidium bromide gel electrophoresis. Reverse transcriptase-polymerase chain reaction positive/ pathology negative axillary lymph nodes were reevaluated using step sectioning and immunohistochemical staining. RESULTS: Thirty-seven patients had pathologically negative axillary lymph nodes, of which 15 (40%) were positive by RT-PCR analysis. Two RT-PCR negative results (one probably from tissue processing error and the other secondary to sampling error) among the 24 histologically positive specimens were detected (8%). The number of patients in each pathologic stage was 26 patients in stage I; 18, stage IIA; 7, stage IIB; 7, stage IIIA; 3, stage IIIB; and 0 patients in stage IV. By RT-PCR staging, 8 of 26 patients went from stage I to IIA (30%), and 7 of 18 from stage IIA to IIB (39%). Of the RT-PCR positive individuals who were stage I by pathologic analysis, 100% were found to be c-myc positive, 0% keratin-19 positive, and 0% PIP positive; for stage IIIB patients these markers were 50%, 100%, and 100% respectively. Additionally, an increasing number of positive markers per specimen appeared to correlate with larger primary tumor size (p < 0.01) and decreased predicted 5-year survival (r = 0.950, p < 0.002). CONCLUSIONS: Multimarker RT-PCR analysis appears to be a readily available and highly sensitive method for the detection of axillary lymph node micrometastases. Longterm followup of RT-PCR positive patients will be required to determine its clinical relevance. If validated as a predictor of disease recurrence, this method would provide a powerful complement to routine histopathologic analysis of axillary lymph nodes.

Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix.

PURPOSE: To assess the impact of tumor size and extent, and dose of irradiation on pelvic tumor control, incidence of distant metastases, and disease-free survival in carcinoma of the uterine cervix. METHODS AND MATERIALS: Records were reviewed of 1499 patients (Stages IA-IVA) treated with definitive irradiation (combination of external beam plus two intracavitary insertions to deliver doses of 65-95 Gy to point A, depending on stage and tumor volume). Follow-up was obtained in 98% of patients (median 11 years, minimum 3 years, maximum 30 years). The relationship between outcome and tumor size was analyzed in each stage. Pelvic tumor control was correlated with total doses to point A and to the lateral pelvic wall. RESULTS: The 10-year actuarial pelvic failure rate in Stage IB was 5% for tumors <2 cm, 15% for 2.1-5 cm, and 35% for tumors >5 cm (p = 0.01); in Stage IIA, the rates were 0%, 28%, and 25%, respectively (p = 0.12). Stage IIB unilateral or bilateral nonbulky tumors <5 cm had a 23% pelvic failure rate compared with 34% for unilateral or bilateral bulky tumors >5 cm (p = 0.13). In Stage IIB, pelvic failures were 18% with medial parametrial involvement only, compared with 28% when tumor extended into the lateral parametrium (p = 0.05). In Stage III, unilateral parametrial involvement was associated with a 32% pelvic failure rate versus 50% for bilateral extension (p < 0.01). Ten-year disease-free survival rates were 90% for IB tumors <2 cm, 76% for 2.1-4 cm, 61% for 4.1-5 cm, and 47% for >5 cm (p = 0.01); in Stage IIA, the rates were 93%, 63%, 39%, and 59%, respectively (p < or = 0.01). Patients with Stage IIB medial parametrial involvement had better 10-year disease-free survival (67%) than those with lateral parametrial extension (56%) (p = 0.02). Stage III patients with unilateral tumor extension had a 48% 10-year disease-free survival rate compared with 32% for bilateral parametrial involvement (p < or = 0.01). The presence of endometrial extension or tumor only in the endometrial curettings had no significant impact on pelvic failure. However, in patients with Stage IB disease, the incidence of distant metastases was 31% with positive curettings, 15% with negative curettings, and 22% with admixture (p < or = 0.01). In Stage IIA, the corresponding values were 51%, 33%, and 18% (p = 0.05). The 10-year disease-free survival rates in Stage IB were 67% with positive curettings, 81% for negative curettings, and 77% for admixture (p = 0.02); in Stage IIA, the rates were 45%, 66%, and 67%, respectively (p = 0.14). Because this is not a prospective Phase II dose-escalation study, the correlation of doses of irradiation with pelvic tumor control in the various stages and tumor size groups is not consistent. Nevertheless, with Stage IB and IIA tumors <2 cm in diameter, the pelvic failure rate was under 10% with doses of 70-80 Gy to point A, whereas for larger lesions even doses of 85-90 Gy resulted in 25% to 37% pelvic failure rates. In Stage IIB with doses of 70 Gy to point A, the pelvic failure rate was about 50% compared with about 20% in nonbulky and 30% in bulky tumors with doses > 80 Gy. In Stage III unilateral lesions, the pelvic failure rate was about 50% with < or =70 Gy to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses. CONCLUSIONS: Clinical stage and size of tumor are critical factors in prognosis, therapy efficacy, and evaluation of results in carcinoma of the uterine cervix. The doses to point A suggest that for lesions <2 cm, doses of 75 Gy result in < or =10% pelvic failures, whereas in more extensive lesions, even with doses of 85 Gy, the pelvic failure rate is about 30%; and in Stage IIB-III tumors, doses of 85 Gy result in 35-50% pelvic failures. Refinements in brachytherapy techniques and/or use of agents to selectively sensitize the tumors to irradiation will be necessary to improve the present results in invasive carcinoma of t

Efficacy of reverse transcriptase-polymerase chain reaction screening for micrometastic disease in axillary lymph nodes of breast cancer patients.

Pathologic examination of axillary lymph nodes (ALNs) may miss micrometastases in 30 per cent of breast cancer patients. We have developed a multimarker reverse transcriptase-polymerase chain reaction (RT-PCR)-based screening method that detects histopathologically positive ALNs with a 5 per cent false-negative rate. The purpose of this study was to compare this RT-PCR methodology with histopathology with regard to sensitivity and cost. Pathologically negative ALNs from 35 breast cancer patients were re-evaluated by a single pathologist in a blinded fashion using serial sectioning with immunohistochemical staining. Histopathologic results were then compared with those of RT-PCR. Cost analysis was performed based on standard charges for these methods. RT-PCR identified micrometastases in 14 of 35 pathologically negative nodes. Serial sectioning and immunohistochemical staining identified micrometastases in two cases, with RT-PCR positive for one of these. The charge per specimen for performing routine histopathologic examination was $380, serial sectioning and immunohistochemical staining $787, and RT-PCR $125. RT-PCR appears to be more sensitive at detecting ALN micrometastasis than histopathologic examination even with serial sectioning and immunohistochemical staining. If micrometastatic breast cancer detected by RT-PCR proves to be clinically relevant, it could be a more effective screening methodology with significant cost savings as compared to currently available pathologic examinations.

Superficial hyperthermia and irradiation for recurrent breast carcinoma of the chest wall: prognostic factors in 196 tumors.

PURPOSE: To correlate patient-, tumor-, and treatment-related factors with subsequent local tumor control. METHODS AND MATERIALS: From 1977 to 1990, 196 subcutaneous/superficial lesions (179 measurable, 17 microscopic) in 151 patients with recurrent breast carcinoma of the chest wall were treated with superficial 915-MHz microwave hyperthermia and irradiation. The definition of min t43 > or = 10 min is that all monitored tumor catheters had a minimum of 1 hyperthermia session with temperatures > 43 degrees C for at least 10 min. RESULTS: Factors correlating with local control on univariate analysis included length of survival (> or = 1 year vs. < 1 year) (p < 0.0001), specific absorption rate (SAR) (> or = 25% vs. < 25%) (p = 0.0001), minimum t43 > 10 min (p < 0.0001), tumor volume (p < 0.0001), tumor surface area (p < 0.0001), tumor depth (p = 0.0002), number of hyperthermia sessions (p = 0.0003), and current radiation dose (p = 0.0012). On multivariate analysis, the factors best correlated with ultimate local control were SAR (p < 0.001) and number of hyperthermia sessions (p = 0.003). CONCLUSIONS: Multivariate analysis supports the importance of adequate specific absorption rate (SAR) coverage as a better predictor of local control than tumor volume, surface area, or depth. The explanation is that SAR can be correlated with the tumor surface area and depth, depending on the hyperthermia applicator characteristics. It is recommended that future clinical trials stratify study lesions into either SAR > or = 25% or < 25% because this can be readily estimated prior to initiating treatment. It is also recommended that future clinical trials attempt to have adequate lengths of follow-up after therapy to assess the results in long-term survivors.

Postoperative radiation therapy in non-small cell lung cancer.

One hundred seventy-three patients with the diagnosis of non-small cell lung cancer (NSCLC) were treated with surgery and postoperative radiation therapy (RT) at the Radiation Oncology Center, Washington University, St. Louis. All patients had been retrospectively reviewed and restaged according to the new American Joint Committee (AJC) staging classification. Seventeen patients were stage I, 69 were stage II, 74 were stage IIIA, and 2 patients were stage IIIB. In 11 patients, accurate staging could not be determined. Indications for postoperative RT were positive surgical margins (32 patients), metastatic hilar nodes (78 patients), and metastatic mediastinal nodes (62 patients). Locoregional control for stages I, II, and IIIA was 85, 75, and 85%, respectively. Five-year actuarial survival was 35% for stage I and 20% for stages II and IIIA. Patients with N0 disease (positive margins) had 5-year survival of 25%, whereas patients with N1 and N2 disease had a 5-year survival of 20%.