Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report.

PURPOSE: In 1990 we published the results of an intensive 3-week preoperative chemoradiation regimen for locoregional esophageal cancer that suggested improved survival compared with historical controls. We now report the long-term results at a median follow-up of 78.7 months. PATIENTS AND METHODS: Forty-three patients with locoregional squamous cell carcinoma or adenocarcinoma of the esophagus or cardia were treated with fluorouracil (5-FU), cisplatin, and bolus vinblastine concurrent with radiation administered over 21 days. Transhiatal esophagectomy was performed on day 42. RESULTS: Forty-one patients (95%) completed the preoperative treatment, and 36 (84%) had a potentially curative resection. Ten of 41 (24%) had no tumor in the resected esophagus and nodal tissues (path-negative group). The median survival duration of all 43 patients registered on study was 29 months; 34% were alive at 5 years. By histology, median survival durations were 32 months for 21 adenocarcinoma patients and 23 months for 22 squamous cell patients, with corresponding 5-year survival rates of 34% and 31%, respectively. Analysis of the 36 patients who underwent a potentially curative resection demonstrated median survival durations of 32 and 44 months and 5-year survival rates of 36% and 43%, respectively, for adenocarcinoma and squamous cell histologies. Path-negative (complete response [CR]) patients had a median survival duration of 70 months and 60% were alive at 5 years, while those patients with residual tumor in the resected esophagus had a median survival duration of 26 months and 32% were alive at 5 years (P = .114 by the log-rank test and P = .04 by the Wilcoxon test). CONCLUSION: The results of this regimen appear improved over those reported with surgery alone, with an approximate doubling of the 5-year survival rate. Thirty-two percent of patients with residual tumor in the esophageal specimen are long-term survivors, which suggests a benefit from esophagectomy. A randomized trial is in progress to compare this preoperative regimen with immediate surgery.

Primary treatment of stage III ovarian carcinoma with sequential chemotherapy and whole abdominal radiation therapy.

A prospective phase II clinical treatment trial of 13 patients with previously untreated optimal surgically resected (< or = 1 cm stage III ovarian carcinoma was conducted at the University of Michigan Hospitals. The treatment regimen after surgical resection consisted of chemotherapy followed by whole abdomen and pelvic radiation therapy. Chemotherapy consisted of four cycles of 50 mg/m2 cisplatin and 1000 mg/m2 cytoxan. This was followed by whole abdomen radiation therapy with a planned total dose of 30 Gy to the whole abdomen and then a 20-Gy boost to the pelvis. Six of 13 patients received a paraaortic radiation boost. There was minimal acute toxicity, but delayed toxicity was encountered with 38% of patients developing a bowel obstruction. Nine patients had reassessment laparotomy: 5 second-look laparotomies and 4 laparotomies for bowel obstruction. Two of these 9 patients died of septic complications after surgery. Nine patients died with disease, 1 patient is alive with advanced disease, and only 3 patients are alive with no evidence of disease. Actuarial 3-year survival and progression-free interval was 26 and 20%, respectively. Primary treatment consisting of sequential chemotherapy and whole abdomen radiation in the dose and scheme utilized did not improve the survival over what could be expected utilizing one of these treatments alone. It was associated with increased delayed toxicity.

Treatment of T3a bladder cancer with iridium implantation.

A total of 7 patients with high grade, T3a (Stage B2) bladder cancer were treated with external radiation therapy and interstitial iridium implantation from May 1986 through March 1988. Follow-up has ranged from nineteen to sixty-one months with a median of forty months. One patient has required a cystectomy and is currently free of disease, and 1 patient has had recurrence of his cancer and metastatic carcinoma has developed; 5 are free of disease and have maintained their usual state of bladder function. Iridium implantation maintains bladder function and is effective therapy for selected individuals with localized, muscle-invading bladder cancer.

Continuous infusion of low-dose 5-fluorouracil and radiation therapy for poor-prognosis squamous cell carcinoma of the uterine cervix.

Ten patients with squamous cell carcinoma of the cervix metastatic to periaortic lymph nodes were treated with external-beam radiation therapy and synchronous infusion of intravenous 5-fluorouracil (5-FU) chemotherapy at doses of 350 mg/m2/day. The overall response rate was 90% with four complete responses (CR) and five partial responses (PR). The median duration of response was 11.8 months for CRs and 3.6 months for PRs. Toxicity was tolerable, with gastrointestinal symptoms and myelosuppression being noted most frequently. No patient experienced life-threatening toxicity. Median survival was 7.6 months, with only one patient being alive and free of disease at 2 years. In this pilot study we were unable to demonstrate a beneficial effect of continuous infusion of low doses of 5-FU chemotherapy concurrent with radiation therapy when compared to conventional radiotherapy in patients with advanced squamous cell carcinoma of the cervix.

Dose escalation for stage C (T3) prostate cancer: minimal rectal toxicity observed using conformal therapy.

The treatment of stage C (T3) adenocarcinoma of the prostate using external beam radiation therapy (RT) reportedly achieves clinical local control of approximately 70-80%. A dose relationship to local control has been demonstrated in prostate cancer, although a dose-related increase in complications has also been observed. To determine the maximum dose deliverable to the prostate gland while maintaining an acceptable complication rate, a prospective dose-escalation trial using a conformational planning and dose-delivery technique was initiated for patients with stage C (T3) disease. Initial results reported here are encouraging.

Concurrent preoperative chemotherapy and radiation therapy in localized esophageal adenocarcinoma.

Twenty-four patients with localized, potentially resectable adenocarcinoma of the esophagus were enrolled in this study to evaluate the use of preoperative chemotherapy and radiation therapy, followed by transhiatal esophagectomy. The patients were newly diagnosed and had received no prior treatment. Radiation therapy consisted of 4900 cGy, administered as 350-cGy fractions 5 days a week for 14 fractions. The chemotherapy consisted of 5-fluorouracil 300 mg/m2/day administered as a continuous 24-hour intravenous infusion for 96 hours each week, concomitantly with the radiation therapy. After a 3-week rest, patients underwent transhiatal esophagectomy. Twenty-two patients could be observed for their responses to the chemotherapy and radiation regimen. Radiographically, 41% showed improvement, 36% had stable disease, and 23% had progression. Nineteen patients underwent surgery; all patients had total gross removal of disease, and two patients had a complete histologic response. All 24 patients could be examined for toxicity assessment. There were three deaths during the treatment period: one patient died of a perioperative complication, one of pneumonia, and one of a myocardial infarction. Eleven patients eventually had pleural and/or pericardial effusions, and six of these were symptomatic. All 24 patients could be examined for survival analysis. The median follow-up for all patients was 12.5 months, with 32.5 months for all surviving patients. Median survival was reached at 11 months. Disease-free survival was 9.5 months. It was concluded that the radiation-fractionation schedule in this preoperative regimen was associated with marked toxicity in the form of pleural and pericardial effusions. There was no improvement in survival compared with historic controls. The role of combined preoperative treatment in this patient population has yet to be determined.

Treatment planning issues related to prostate movement in response to differential filling of the rectum and bladder.

Conventional stimulation for patients with localized prostatic carcinoma often includes opacification of the dose limiting adjacent normal tissues. However, CT-based treatment planning is performed with the bladder and the rectum naturally filled or emptied. These latter conditions more closely approximate those in place at treatment Comparison of these CT-based treatment plans to simulator films taken with the rectum and bladder opacified yielded indirect evidence of movement of the prostate gland by 0.5 cm or more in 31 of 50 consecutive patients. The range of motion was 0 to 2 cm with an average of 0.5 cm (1.0 cm in the 31 patients). Six additional patients (five with local recurrence following I-125 seed implantation) were analyzed separately using CT scans. Registered CT images (3 mm slices) taken with the rectum and bladder full and/or empty provided direct evidence of prostate movement in 3 of the 6 patients. The dosimetric consequences of this movement are demonstrated using 3-dimensional dose distributions.

Chemotherapy and radiation therapy before transhiatal esophagectomy for esophageal carcinoma.

Recent efforts to improve survival in patients with esophageal carcinoma have combined both systemic and local therapy. From October 1985 to October 1987, 43 patients with local-regional esophageal cancer (adenocarcinoma in 21, squamous cell in 22) were treated with cisplatin, vinblastine, and 5-fluorouracil chemotherapy concurrent with 4,500 cGy radiation therapy for 21 days before transhiatal esophagectomy 3 weeks later. Two patients died of chemotherapy/radiation therapy toxicity. Forty-one completed preoperative chemotherapy/radiation therapy. At operation, 2 patients had incurable metastatic disease; 39 underwent transhiatal esophagectomy. Eleven patients had no residual tumor in the resected specimen for a 27% (11 of 41) pathological complete response rate. Preoperative chemotherapy/radiation therapy resulted in no increased perioperative morbidity as compared with our historical controls. One patient died postoperatively of an unrecognized brain metastasis (2% operative morbidity). At a median follow-up of 27 months, 20 patients (47%) are alive and clinically disease-free and 21 have died, 19 from progression of their carcinoma. The median survival time for all 43 patients is 29 months (Kaplan-Meier estimate), and cumulative survival is 72% at 12 months, 60% at 24 months, and 46% at 36 months. All 11 patients with a complete response are alive at a median follow-up of 36 months, and all are disease-free. The 2-year survival of 60% of this group as compared with 32% in our earlier patients treated with transhiatal esophagectomy alone suggests that intensive combined modality therapy improves survival in these patients. A randomized prospective trial is now in progress.

Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.

A CT-compatible version of the Fletcher system intracavitary applicator: clinical application and 3-dimensional treatment planning.

A new acrylic version of the familiar Fletcher intracavitary applicator, the Ann Arbor (AA) applicator, has been developed. This new device eliminates the problem of "streak" artifacts on CT images, but unlike other plastic applicators the ability to shield portions of the bladder and rectum is retained through the use of tungsten alloy shields which are afterloaded with the radioactive sources. To minimize changes in placement geometry and to take advantage of the wide clinical experience with the Fletcher system, the new applicator nearly duplicates the physical dimensions of the Fletcher applicator. With the Ann Arbor applicator in place, dummy sources are easier to locate on standard radiographic simulations. CT scans are free of artifact and provide clear, detailed visualizations of cross-sectional anatomy. The new applicator thus allows CT images to be used to their potential in evaluating crucial anatomic relationships and in performing 3-D dosimetry with dose volume analysis. Using a treatment planning system with 3-D capabilities, solid surface graphic display of applicator, cervix, rectum, bladder, and treatment isodose volume has been performed. In addition, dose volume histograms can be generated to obtain precise measurements of the volume of cervix, rectum, or bladder receiving specified doses.

Optimal coverage of peritoneal surface in whole abdominal radiation for ovarian neoplasms.

Patterns of failure in ovarian carcinoma include early seeding of the entire peritoneal cavity. Inability to encompass the anatomic extent of the peritoneal cavity is a possible factor leading to relapse. However, little has been published regarding technical advances in optimal coverage of the peritoneal surface in whole abdominal radiation. In the Department of Radiation Oncology at the University of Michigan, 21 consecutive patients were analyzed prospectively in regard to adequate coverage of peritoneum in the treatment of advanced ovarian carcinoma. Simulation and focused blocks were designed to treat the whole abdomen. CT treatment planning studies were obtained with the entire peritoneum identified as the target volume. Simulator designed blocks were projected over the CT scans throughout the treatment volume. Dose volume histograms were used to calculate the amount of target volume missed for each treatment plan. All treatment plans demonstrated different degrees of volume miss, ranging from 1 cm3 to 837.3 cm3 with a median of 137.9 cm3 overall. Volume missed directly correlated with increasing patient weight and flatter pelvic shape, but poorly with AP separation. This was especially evident for patients requiring treatment at extended distances in both the supine and prone positions. We conclude that bony landmarks are poor guidelines in designing pelvic blocks, especially in heavy patients and patients requiring treatment in both prone and supine positions. CT treatment planning is helpful to ensure optimal peritoneal coverage.

Boost treatment of the prostate using shaped, fixed fields.

Using a CT-based, 3-D treatment planning system and Beam's Eye-View (BEV) displays, shaped fixed-field techniques have been developed for external beam boost treatment of Stage C carcinoma of the prostate. The basic technique comprises three sets of opposing beams (laterals and +/- 45 degrees with respect to the lateral) into a 6-field arrangement. Target volumes together with bladder and rectal wall volumes are outlined on axial CT slices and combined to form 3-D volumes. For each field, an interactive BEV display is produced showing the target volume in its correct 3-D geometrical perspective and an auto-block routine is used to design focused blocks which conform to that volume. Full 3-D volume calculations computed for those plans on 17 patients were analyzed along with similar calculations for more traditional unblocked 4-field box and bilateral arc techniques. Compared to the 95% isodose volume for the 6-field conformational technique, traditional open beam full target coverage techniques typically produce high dose volumes which cover up to five times as much uninvolved tissue. Dose volume histograms illustrate that typically half as much bladder and rectal tissue is treated to high dose using the conformational boost techniques. From the dosimetric perspective of sparing normal tissues, shaped fixed-field boost techniques are shown to be clearly superior to traditional full coverage bilateral arc techniques. Smaller 8 cm X 8 cm arc techniques are shown to be quantitatively unacceptable for treatment of this advanced stage disease, as they typically misses 20-35% of the target volume.

The management of vaginal melanoma.

Between 1964 and 1987 ten patients with vaginal melanoma were treated at The University of Michigan Hospital. Five of the six patients who underwent radical surgery had adequate information concerning the first site of relapse, and in four of these five, pelvic sites or locoregional lymph nodes were the first sites of recurrent disease. One of these patients developed a 17-cm pelvic recurrence, which responded with a 75% reduction in size 3 months after completion of radiotherapy given in high individual fractions (400 cGy X 11). Three patients were managed with local resection, and all developed recurrent locoregional disease. One patient presented with metastatic disease. We conclude that locoregional control of vaginal melanoma is difficult to achieve with surgery alone. We hypothesize that preoperative radiotherapy to the pelvis (500 cGy X 6 given 3 days a week to the whole pelvis with subsequent consideration for a vaginal boost field) may improve the poor rate of locoregional control of vaginal melanoma that is seen when surgery alone is used.

Primary carcinoma of the distal male urethra: a case treated with lymphadenectomy and interstitial radiation therapy.

We report a case of primary squamous cell carcinoma of the distal male urethra with a single inguinal node metastasis. Treatment consisted of unilateral pelvic and inguinal lymphadenectomy, and a combined course of external beam and interstitial radiation therapy to the distal urethra and penis by the Henschke modification of the Paris technique.

Brain metastasis in patients with superior sulcus tumors.

During a 20-year period, from 1963 to 1983, 68 patients were treated for carcinoma of the lung presenting in the superior sulcus. Their ages ranged from 41 to 79 years (median, 56 years). Thirty-six patients had squamous cell carcinoma, 13 had adenocarcinoma, 14 had large cell carcinoma, two had small cell carcinoma, and three had clinical diagnosis only. All tumors were considered to be inoperable or unresectable and were treated with external irradiation alone. The 3-year disease-free survival was 25%. Brain metastasis developed in 23 patients (34%); the brain was the first site of metastasis in 16 patients (24%), five of whom eventually developed other sites of metastasis. The cumulative probability of brain metastasis was 53% at 3 years. Brain metastases were seen in ten patients (28%) with squamous cell carcinoma, five patients (38%) with adenocarcinoma, seven patients (50%) with large cell carcinoma, and one patient without a histocytologic diagnosis. The proportion of patients younger than 60 years (19/41, 46%) who developed brain metastasis was significantly greater than that for patients 60 years or older (4/27, 15%) (P less than or equal to 0.01). Nine of 11 patients with metastasis only to the brain died as a consequence of the intracranial disease 1 to 13 months (median, 6 months) after the diagnosis of brain metastases. The other two patients received therapeutic irradiation to the entire brain and survived longer than 5 days after the whole-brain irradiation: one died at 62 months of intercurrent disease, and the other is alive and well 129 months after diagnosis. The high probability of brain metastasis from superior sulcus tumors, regardless of histopathologic type and the frequency with which the brain is the only site of clinical failure, suggest that systematic prophylactic cranial irradiation could reduce the morbidity and perhaps even contribute favorably to the survival of these patients.

Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung.

Between January, 1971 and August, 1978, 410 patients with histologically or cytologically confirmed inoperable or unresectable carcinoma of the lung of all cell types were treated with curative intent. Forty-five patients lived a minimum of 3 years and 32 patients lived 5 or more years. The 3-year survival rate increased from 7.6% (15/197) between January, 1971 and June, 1975 to 14.1% (30/213) for the interval from July, 1975 to August, 1978 (p less than 0.01). Factors associated with long-term survival were performance status (p less than 0.01), early stage (p less than 0.001), high total dose of radiation (p less than 0.02), large cell carcinoma (p less than 0.01), inoperable for medical reasons (p less than 0.001), and thoracotomy to determine unresectability (p less than 0.04). The difference in survival rates between the two time periods was not related to different patient factors. Survival rates were most improved in the second time period for patients with Stage II or Stage III carcinoma of the lung. Eight patients died from cancer between 36 and 54 months of initial treatment. Five patients died of intercurrent disease without evidence of cancer of the lung after 3 years. An increasing proportion of long-term survivors of inoperable carcinoma of the lung can be expected to result from a better understanding of these diseases, more technically sophisticated external irradiation, and the use of combination chemotherapy for small cell carcinoma.