Bruce J. Walz

Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications

A retrospective analysis was carried out on 811 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. A correlation was made of the doses of irradiation delivered to the pelvic organs with external beam and intracavitary insertions. Approximately 3% of the patients exhibited grade 2 gastrointestinal complications, and 2% developed grade 2 urinary complications; 5% of the patients developed grade 3 gastrointestinal complications, and 3% developed grade 3 urinary complications. Other types of complications, primarily grade 2, such as vaginal necrosis, pelivic abscess, thrombophlebitis, etc, were seen in approximately 5% of the patients. Thus, the total percentage of patients developing grade 2 complicatins was 10% and grade 3 complications, approximately 8%. About 25% of the patients who had complications showed more than one sequela. The most frequently observed grade 2 complications were proctitis, cystitis, vaginal stenosis, and partial small bowel obstruction which were treated with conservative management. Grade 3 complications required surgical treatment and consisted most frequently of ureteral stricture, vesicovaginal fistula, rectovaginal fistula, sigmoid stricture, small bowel obstruction, proctitis, and large rectal ulcers. The most significant factor affecting the appearance of complications was the total dose of irradiation delivered to the pelvic organs by the whole pelvis external irradiation and intracavitary insertions. With maximum total doses up to 8000 rad the incidence of grade 2 and 3 complications was less than 5%. However, with higher doses the incidence of complications increased to 10% to 15%. In patients receiving total doses of 6000 rad to the bladder or rectum, more complications were noted when only one intracavitary insertion was performed, as compared with two or three. Eighty percent of the rectosigmoid complications occurred within 30 months of initial therapy, in contrast to 48 months for the urinary complications. Patients who developed complications had survival rates comparable to those without complications. This underscores the need to rapidly institute treatment on patients who have severe injury after radiation therapy. Even though it is difficult to determine the exact total dose delivered to a specific volume within the pelvis, the current study strongly indicates that dose calculations to specific anatomical points may be reliable parameters to use in modifying treatment techniques to deliver doses of irradiation that will not exceed tolerance limits for the pelvic structures, when treating patients with carcinoma of the uterine cervix with irradiation alone.

Radiation therapy alone in the treatment of carcinoma of uterine cervix I. Analysis of tumor recurrence

This is a retrospective analysis with emphasis on the patterns of failure in 849 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. In 281 patients with Stage IB tumors, the total incidence of pelvic failure was 6.4% (two without and 16 combined with distant metastasis). In 88 patients with Stage IIA, 12.5% failed in the pelvis (one without and ten combined with distant metastasis). The total pelvic failure rate in Stage IIB was 17.4% (22 without and 22 combined with distant metastasis). In 212 patients with Stage III, the overall pelvic failure rate was 35.8% (31 without and 45 combined with distant metastasis). Approximately 25% of the pelvic recurrences were central (cervix or vagina) and 75% parametrial. The overall incidence of distant metastasis was 13.5% for Stage IB, 27.3% for Stage IIA, 23.8% for Stage IIB, and 39.6% in Stage III. Higher doses of irradiation delivered to the medial and lateral parametrium with external beam irradiation and intracavitary insertions were correlated with a lower incidence of parametrial failures in all stages, except IB. In Stage IIA, medial parametrial doses below 9000 rad resulted in 10/78 = 12.8% pelvic failures, in contrast to one recurrence in 10 patients treated with doses over 9000 rad. In Stage IIB, doses below 9000 rad yielded a pelvic recurrence rate of 36/203 (17.7%) compared to 5/49 (10.2%) with higher doses. In Stage III there were 66/167 (39.5%) recurrences with doses below 9000 rad and 10/44 (22.7%) with larger doses. Statistically significant differences were observed among the Stage IIB (P = 0.02) and III patients (P = 0.005) respectively. The lateral parametrial dose also showed some correlation with tumor control, although the differences were not statistically significant. The survival in patients with Stage IIB and III was 10% higher in the patients treated with higher parametrial doses. However, the differences are not statistically significant. These results strongly suggest that higher doses of irradiation must be delivered to patients with Stage IIB and III, but improvement in tumor control must be weighed against an increasing number of complications. Factors other than the total doses of irradiation, such as the characteristics of the tumor and the quality of the intracavitary insertion influence the therapeutic results in irradiation of carcinoma of the uterine cervix. Other therapeutic approaches must be designed to improve the effect of irradiation in the tumor without further injury to the normal tissues. Hypoxic cell sensitizers, hyperthermia and high LET particles are under investigation.

IRRADIATION OF CARCINOMA OF THE PROSTATE LOCALIZED TO THE PELVIS: ANALYSIS OF TUMOR RESPONSE AND PROGNOSIS

Abstract A group of 195 patients with histologically proven adenocarcinoma of the prostate limited to pelvis were treated with definitive irradiation between 1967 and December 1976. In 42 patients with Stage B adenocarcinoma, the tumor free actuarial five year survival was 80%; for 141 with Stage C it was 56%; there were no long term survivors in 12 patients with Stage D1 (extensive tumor limited to the pelvis, without distant metastasis). The pelvic failure rate was 7% in Stage B, 17% in Stage C and 25% in Stage D1. Histological differentiation of the tumor had no significant impact in survival of patients with Stage B. However, in Stage C, patients with well or moderately differentiated tumor had a five year survival of 70% in contrast to 25% in those with poorly differentiated lesions. In this group of patients 60% of the failures resulted from distant metastasis. In Stage C, 38% of the patients who were treated with doses between 5500 and 6000 rad developed pelvic failures, as opposed to 20% of those treated with a mean dose of 6500 rad and 12% in patients receiving 7000 rad or greater dose. The addition of hormonal therapy, usually castration and diethylstilbestral (DES) (5 mg daily), did not significantly affect the prognosis of patients with Stage B or C. Major complications of therapy occurred in 11% of the patients. The most common problem was urinary incontinence which was observed in 13.3% of 60 patients who had a transurethral resection (TUR) as opposed to 4.4% in 135 patients on whom this procedure was not performed. Less severe complications were noted in 18% of the patients and treated with conservative management. Leg edema developed in three of 14 patients on whom a staging laparotomy was performed (21.4%) in contrast to only three of 181 patients without such a procedure (1.6%). At the present time external irradiation is a viable alternative to radical prostatectomy in the treatment of Stage B and the modality of choice in patients with Stage C adenocarcinoma of prostate. It is important to identify prognostic factors that may optimize the effectiveness of irradiation in the management of this tumor. In order to improve the prognosis of carcinoma of the prostate, effective systemic therapy will be necessary to control micrometastasis in patients with poorly differentiated lesions.

Analysis of pelvic tumor control and impact on survival in carcinoma of the uterine cervix treated with radiation therapy alone.

A total of 1054 patients with histologically confirmed invasive carcinoma of the uterine cervix were treated with radiation therapy alone between 1959 and 1982. All patients are available for a minimum of 3 years follow-up. Radiation therapy consisted of external irradiation to the whole pelvis (1000-2000 cGy) and parametria (for a total of 4000-6000 cGy) combined with two intracavitary radioactive source insertions (6000-7500 cGy to point A). Patients with Stage IIB, III, and IVA have been consistently treated with somewhat higher doses of external irradiation and intracavitary insertions. A small group of 54 patients with Stage IIB or IIIB had pelvic lymphadenectomy following the irradiation (1960-1964). There was a strong correlation between the tumor regression within 30 days from completion of radiotherapy and the incidence of pelvic recurrences or distant metastases for each of the anatomical stages. The 10-year survival rate for Stage IB was 76%, Stage IIA 60%, Stage IIB 45%, and Stage III 25%. Many of the deaths were due to intercurrent disease. Thus, the 10-year tumor-free survival was 80% for Stage IB, 60% for Stages IIA and IIB and 35% for Stage III. In Stage IB total doses of 6000 cGy or higher to point A resulted in 94% pelvic tumor control. In Stage IIA, the pelvic tumor control was 87% with doses of 6000 cGy to point A or higher. However, in Stage IIB the pelvic tumor control was 58% with doses below 6000 cGy, 78% with 6001-7500 cGy and 82% with higher doses. In Stage IIIB the pelvic tumor control was 42% with doses below 6000 cGy, 57% with 6001-7500 cGy and 68% with higher doses. Tumor control in the pelvis was correlated with the following 5 year survivals: Stage IB-95% (353 patients); Stage IIA-84% (116 patients); Stage IIB-84% (308 patients); Stage IIIB-74% (245 patients). The 5-year survival for patients that recurred in the pelvis was 30% for Stage IB, about 15% for Stages IIA-B and only 5% in Stage III. Patients with tumor control in the pelvis had a significantly lower incidence of distant metastases than patients who initially failed in the pelvis (9.3% vs. 58.6% in Stage IB, 21.6% vs 52.6% in Stage IIA, 19.8% vs 16.7% in Stage IIB, and 31.2% vs 50% in Stage III). In Stage IIB the figures were 19.8% and 16.7% because the initial pelvic recurrence was frequently concurrent with distant metastases.(ABSTRACT TRUNCATED AT 400 WORDS)

Surgeon specialty is associated with outcome in rectal cancer treatment.

AbstractPURPOSE: The aim of this study was to determine the effect of surgeon specialty on disease-free survival and local control in patients with adenocarcinoma of the rectum. Patients underwent curative treatment with neoadjuvant external beam radiotherapy and proctectomy by colorectal surgeons and noncolorectal surgeons. METHODS: The records of 384 consecutive patients treated by colorectal surgeons (n = 251) and noncolorectal surgeons (n = 133) from 1977 to 1995 were reviewed independently by physicians in the Division of Radiation Oncology. Local recurrence was defined as pelvic recurrence occurring in the presence or absence of distant metastatic disease. RESULTS: The study population comprised 213 males, mean age 64 (range, 19–97) years. Preoperative radiotherapy was delivered as 4,500 cGy in 25 fractions six to eight weeks before surgery (n = 293) or 2,000 cGy in 5 fractions immediately before surgery (n = 91). Concurrent preoperative chemotherapy was given to 14 patients, postoperative chemotherapy to 55. Overall actuarial disease-free survival and local control rates were 74 and 90 percent, respectively, at five years. Actuarial disease-free survival and local control rates at five years were 77 and 93 percent for colorectal surgeons vs. 68 and 84 percent for noncolorectal surgeons (P ≤ 0.005 for both, Tarone-Ware). Multivariate analysis revealed that pathologic stage and background of the surgeon were the only independent predictors of disease-free survival (both P ≤ 0.006, Cox proportional hazards) and that pathologic stage, background of the surgeon, and proximal location of the tumor were independent predictors of local control (all P ≤ 0.02, Cox proportional hazards). Radiation dose and use of chemotherapy were not significant factors. Sphincter preservation was more common by colorectal surgeons (131/251, 52 percent) than noncolorectal surgeons (40/133, 30 percent; P = 0.00004, Fisher’s exact test, two-tailed). CONCLUSION: Good outcome for patients with adenocarcinoma of the rectum who undergo neoadjuvant external beam radiotherapy and proctectomy is associated with subspecialty training in colon and rectal surgery.

Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associated with outcome.

BACKGROUND AND PURPOSE In recent years, treatment with combined chemotherapy and radiation has become the standard of care for epidermoid carcinoma of the anus. However, optimal radiotherapy techniques and doses are not well established. MATERIALS AND METHODS During the period 1975-1997, 106 patients with epidermoid carcinoma of the anal canal underwent radiation therapy. Treatment policies evolved from radiation therapy alone or with surgery, to combined chemotherapy and radiation followed by surgery, to combined chemotherapy and radiation. RESULTS Overall 74% of patients were NED (no evidence of disease) at last follow-up. The most important clinical correlate with ultimate freedom from disease (includes the contribution of salvage surgery) was extent of disease. The 5-year ultimate freedom from disease was 87+/-5% for T1/T2N0, 78+/-10% for T3N0 (15% salvaged by surgery), and 43+/-10% for either T4N0 or any N+ lesions (P<0.001, Tarone-Ware). There was no difference between planned vs. expectant surgery (5-year ultimate NED: 67+/-11% planned surgery vs. 73+/-5% expectant surgery). The most important correlate with late toxicity was a history of major pelvic surgery (surgical vs. non-surgical group: P=0.013, Fishers exact test, two-tailed summation). Thirty-three additional malignancies have been seen in 26 patients. The most common additional malignancies were gynecologic (nine cases), head and neck (six cases), and lung cancer (five cases). CONCLUSIONS For T1/T2N0 disease, moderate doses of radiation combined with chemotherapy provided adequate treatment. T4N0 and N+ lesions are the most appropriate candidates for investigational protocols evaluating dose intensification. T3N0 tumors may also be appropriate for investigation; however, dose intensification may ultimately prove counterproductive if the cure rate is not improved and salvage surgery is rendered more difficult. The volume of irradiated small bowel should be minimized for patients who have a past history of major pelvic surgery or who (because of locally advanced tumors) may need salvage surgery in the future. Because of the occurrence of additional malignancy, patients with anal cancer should receive general oncologic screening in long-term follow-up.

Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate

The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.

Medically inoperable stage I adenocarcinoma of the endometrium treated with radiotherapy alone.

Definitive therapy for Stage I adenocarcinoma of the endometrium consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pre- and/or post-operative radiotherapy (RT) is employed in selected patients with poor prognostic factors such as poorly differentiated tumors or deep myometrial invasion by tumor. The results are reported of RT alone in 69 patients with Stage I adenocarcinoma of the endometrium who presented with severe, acute, and chronic medical illnesses which prevented surgical management of their disease. Sixty-three patients (91.3%) were obese or hypertensive. Twenty-seven patients (39.1%) had diabetes mellitus, 16 (23.2%) had congestive heart failure, and the remaining patients had such conditions as stroke (17.4%), coronary artery disease (15.9%), and recent myocardial infarction (13.0%). The median age for this group of patients was 72.0 years compared to 60.0 years for a concurrent group of 304 patients with Stage I adenocarcinoma of the endometrium treated at our institution with combined surgery and RT. RT consisted of intracavitary insertions alone (11 patients), intracavitary plus low dose external beam therapy (9 patients), and intracavitary therapy plus high dose external beam therapy (49 patients, definitive RT). Younger patients and those with poorly differentiated disease were treated more aggressively. The 5- and 10-year overall survival for all patients was 76.8 and 33.3%, respectively. The 5- and 10-year disease-free survival was 88.1 and 82.4%, respectively. The 5-year overall and disease-free survival for the group of 49 patients treated with definitive RT was 85.4% and 88.7% with 15/49 (30.6%) having poorly differentiated tumors. For the definitive therapy group, the 5- and 10-year disease-free survival was 94.3, 92.3, and 78.0% for grades I, II, and III, respectively. Analysis of patterns of failure showed that none of the patients failed in the pelvis alone. Two out of 11 (18.2%) receiving intracavitary therapy alone and 3/49 (6.1%) receiving definitive RT failed in the pelvis with simultaneous distant metastasis (DM). Three patients in the definitive RT group failed with DM only. Severe complications occurred in 8 patients (16%), all of whom received definitive RT.

Treatment of rectal adenocarcinoma with endocavitary and external beam radiotherapy: results for 199 patients with localized tumors.

PURPOSE Endocavitary radiation (RT) provides a conservative alternative to proctectomy. Although most suitable for small, mobile lesions, patients with less favorable tumors are often referred if they are poor surgical candidates. Knowing the extent to which radiation can control such tumors can be an important factor in making clinical decisions. METHODS AND MATERIALS One hundred ninety-nine patients, who received endocavitary RT with or without external beam RT (EBRT) during 1981 through 1995, were followed for disease status for a median of 70 months, including deaths from intercurrent causes. In the early years of the study, 21 patients were treated with endocavitary RT alone, the remainder of the patients received pelvic EBRT (usually 45 Gy in 25 fractions) 5-7 weeks before endocavitary RT. RESULTS Overall, 141 patients (71%) had local control with RT alone. Salvage surgery rendered an additional 20 patients disease free, for an ultimate local control rate of 81%. On multivariate analysis for local control (excluding surgical salvage), the most significant factors were mobility to palpation, use of EBRT, and whether pretreatment debulking of all macroscopic disease had been done (generally a piecemeal, nontransmural procedure). Of 77 cases staged by transrectal ultrasonography, the local control rate with RT alone was 100% for uT1 lesions, 85% (90% with no evidence of disease after salvage) for freely mobile uT2 lesions, and 56% (67% with no evidence of disease after salvage) for uT3 lesions and uT2 lesions that were not freely mobile. CONCLUSIONS Patients with small mobile tumors that are either uT1 or have only a scar after debulking achieve excellent local control with endocavitary RT. About 15% of mobile uT2 tumors fail RT; therefore, careful follow-up is critical. Small uT3 tumors are appropriate for this treatment only if substantial contraindications to proctectomy are present.

Transitional cell carcinoma of the kidney 25-year experience.

Seventy patients with transitional cell carcinoma of the kidney operated upon at Barnes Hospital during the last 25 years are reviewed. The relationship of the pathologic stage, grade, findings on excretory urography and survival is studied. The stage and survival rates were predicted fairly accurately on the basis of the excretory urogram alone. Survival of patients was determined occasionally by the status of the associated bladder tumors more than by the renal cancer. Because of tumor multiplicity we recommend total nephroureterectomy as the treatment of choice. The role of radiation therapy is considered.