Richard E. Peschel

Results of radical radiation therapy in clinical stage I, technically operable non-small cell lung cancer

From 1970 to 1983, 1,646 lung cancer patients were referred for treatment to the Hunter Radiation Therapy Center, Yale-New Haven Hospital. Forty-three patients had clinical Stage I non-small cell lung cancer felt to be surgically resectable but were treated with radical radiation therapy either for medical reasons (37 patients) or because the patient refused surgery (six patients). This group of clinical Stage I lung cancer patients is understaged by modern criteria since the majority of patients did not have thoracic CT scans and staging was based on fairly limited clinical and radiographic studies. The histological diagnosis was squamous cell carcinoma in 53% of the Stage I patients, adenocarcinoma in 25%, and other non-small cell histologies in 22%. All patients were treated with megavoltage irradiation and the mediastinum was treated in 88% of the patients. Eleven patients were treated with a continuous course (CC) and 32 patients received split course (SC) therapy based on physician preference. The CC consisted of a median fraction size of 200 cGy to a total median dose of 5900 cGy in 6-7 weeks. The SC used a median fraction site of 275 cGy to a total median dose of 5400 cGy over a 6-week period with a 2-week rest in the middle of treatment. The actuarial survival rate of the 43 clinical Stage I patients was 36% at 3 years and 21% at 5 years. Intrathoracic failures occurred in 39% of the patients. Despite the fact that the CC group was similar to the SC group in terms of age, histology, and tumor extent, the CC patients had a lower thoracic failure rate (2/11) versus 15/32), a longer median survival (51.6 months versus 27 months), and a better actuarial 5-year survival rate (45% versus 12%) when compared to the SC patients. Using Cox regression analysis to compare survival curves, the CC group had a significantly better survival compared to the SC group (p = .04).

Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer

Patients diagnosed with early prostate cancer after 2000 can expect better outcomes from treatment than patients who were diagnosed in the 1980s and early 1990s. These improved outcomes are the result of stage migration, new technologies such as three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated external-beam radiotherapy (IMRT), better implant techniques, and optimum use of hormone therapy. We review the outcomes for radical prostatectomy, permanent seed implant, 3DCRT, and IMRT. For patients with clinical stage T1c or T2 disease and a Gleason score of less than 8, 5-year biochemical disease-free survival is remarkably similar for all the above treatments. Furthermore, complication rates are acceptable for all these modalities. For patients with bulky T2-3 disease or a Gleason score of 8-10, hormone therapy plus 3DCRT or IMRT is an excellent treatment choice. Studies of radical prostatectomy show the most reliable long-term results, and the studies of external-beam radiotherapy have used the best scientific methods to assess efficacy. On the basis of current data, we recommend specific treatment options.

Dosimetric effects of needle divergence in prostate seed implant using 125I and 103Pd radioactive seeds.

In prostate seed implants, radioactive seeds are implanted into the prostate through a guiding needle with the help of a template and real-time imaging. The ideal locations of the guiding needles and the relative positions of the seeds in each needle are determined before the implantation under the assumption that the needles inserted at different locations will remain parallel. In actual implantation, the direction of the needle is subject variation. In this work, we studied how the dosimetry quality of an implant may be affected when the guiding needles deviate from its planned orientations. Needle divergence of varying degree was simulated on spherical models and actual patient implants. It was found that needle divergence degraded the dosimetric quality of an implant: The minimum target dose, the target dose coverage and therefore the tumor biological effective dose were quantitatively decreased as compared to the reference implant. The magnitude of degradation increased almost linearly with respect to the magnitude of needle divergence. For iodine-125 implants, the average reduction in minimum target dose was about 10% and 20% for needle divergence of standard deviation of 5(0) and 10(0), respectively. The dose coverage in the target was reduced by about 1% and 3% for needle divergence of standard deviation of 5(0) and 10(0), respectively. Implants designed with palladium-103 showed additional 5% reduction in minimum target dose while the effect on dose coverage was about the same as compared to the iodine-125 implants. The degree of dosimetry degradation was shown to be dependent on the size of target volume, the seed spacing used, the use of seeding margin, and on the actual configuration of needle orientations in a given implant. One needs to minimize the physical causes of needle divergence in order to minimize its impact on planned dosimetry. The study suggests that the displacement between a needle image and its planned grid point at the base of prostate should be kept less than 5 mm in order to minimize the reduction in D(min)(<5%) and the increase in cell-survival (< a factor of 10) from the planned dosimetry.

Iodine-125 implants versus external beam therapy for stages A2, B, and C prostate cancer

From 1974 to 1984, 307 patients with local prostate cancer (Stage A2, B, or C) were referred to the Hunter Radiation Therapy Center, Yale-New Haven Hospital for definitive radiation therapy. One hundred forty-one patients underwent an interstitial Iodine-125 implant (IMP) and 166 patients received external beam irradiation (EB). For IMP patients with Stage A2, B, and C tumors, the actuarial 5-year disease-free survival (NED) rates were 88%, 84%, and 38% and the 9-year NED survival rates were 88%, 62%, and 30%, respectively. For EB patients with Stage A2, B, and C tumors, the 5-year NED survival rates were 88%, 77%, and 43% and the 9-year NED survival rates were 74%, 63%, and 37%, respectively. The NED survival rates by histologic grade were equivalent for the IMP and EB patients. The absolute local control rate (LCR) was 77% for all of the IMP patients but if one excludes patients who were inadequately treated, the LCR was 82%. LCR in the EB patients was 86%. The LCR for Stage A2, B, and C patients treated with EB was 100%, 94%, and 82%, respectively. The LCR for Stage A2, B, and C patients treated with an adequate IMP was 100%, 83%, and 71%, respectively. The complication rate was 8.5% in the IMP patients (with 0% severe complications) and 14% in the EB patients (with 3% severe complications). Our results indicate that a carefully selected group of IMP patients (Stage A2, B) will have an equivalent NED survival rate and an excellent LCR compared to EB patients but with fewer and less severe side effects.

Effective Treatment of Stage I Uterine Papillary Serous Carcinoma with High Dose-Rate Vaginal Apex Radiation (192Ir) and Chemotherapy

PURPOSE Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.

The rapid onset of cutaneous angiosarcoma after radiotherapy for breast carcinoma

Malignant neoplasms known to develop following external beam radiation include squamous cell carcinoma, osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma, mixed mullerian tumors, malignant schwannoma, myelogenous leukemia and angiosarcoma. Latency periods of many years characterize the onset of these tumors following the exposure. Cutaneous angiosarcoma following radiotherapy for breast carcinoma has been rarely documented, occurring up to 13 years postirradiation. Two cases of this entity are reported occurring 37 months postradiotherapy at the site of mastectomy performed for mammary duct carcinoma.

Whole Pelvic Radiotherapy Versus Prostate Only Radiotherapy in the Management of Locally Advanced or Aggressive Prostate Adenocarcinoma

PURPOSE To determine whether whole pelvic radiotherapy (WPRT) or prostate-only radiotherapy (PORT) yields improved biochemical disease-free survival (BDFS) in patients with advanced or aggressive prostate adenocarcinoma. METHODS AND MATERIALS Between 2000 and 2007, a consecutive sample of 277 patients with prostate adenocarcinoma and at least a 15% likelihood of lymph node involvement who had undergone WPRT (n = 68) or PORT (n = 209) at two referral centers was analyzed. The median radiation dose in both arms was 75.6 Gy. The outcome measure was BDFS, as determined using the prostate-specific antigen nadir + 2 ng/mL definition of failure. BDFS was calculated using the Kaplan-Meier method and compared with the log-rank test. A multivariate analysis was performed to assess for confounding. Treatment-related toxicity was assessed using the National Cancer Institutes Common Terminology Criteria for Adverse Events guidelines. The median follow-up was 30 months. RESULTS WPRT patients had more advanced and aggressive disease at baseline (p < .001). The 4-year BDFS rate was 69.4% in the PORT cohort and 86.3% in the WPRT cohort (p = .02). Within the entire cohort, after adjustment for confounding variables, the pretreatment prostate-specific antigen (p < .001), Gleason score (p < .001), use of hormonal therapy (p = .002), and use of WPRT (vs. PORT, p = .006) predicted for BDFS. Patients undergoing WPRT had increased acute gastrointestinal toxicity (p = .048), but no significant difference in acute genitourinary toxicity was seen (p = .09). No difference in late toxicity was found. CONCLUSION WPRT may yield improved BDFS in patients with advanced or aggressive prostate adenocarcinoma, but results in a greater incidence of acute toxicity.

Sequelae of lateral ovarian transposition in unirradiated cervical cancer patients

The sequelae of lateral ovarian transposition (LOT) in cervical cancer patients has been examined only in the light of the effect of pelvic radiation therapy on ovarian preservation. Preservation of ovarian function has not been examined in the absence of radiation therapy, and symptomatic ovarian cyst formation in transposed ovaries with the need for subsequent surgery has not been addressed in either radiated or unirradiated cervical cancer patients. We studied 84 premenopausal FIGO stage IA or IB cervical cancer patients treated by primary radical hysterectomy between the years 1978 and 1988. None of these patients received adjuvant radiation therapy. Fifty-nine of eight-four patients had radical hysterectomy (RH) without LOT. These patients were compared to 25 of 84 patients who had LOT in addition to RH. The incidence of symptomatic ovarian cysts, the majority requiring operative intervention, was 24% in the ovarian transposition patients as compared to 7.4% in those who had RH alone. This threefold increase in symptomatic benign ovarian cyst formation in the translocated ovary was significant (P = .048). On the other hand, LOT in these RH patients does not appear to increase the incidence of early menopause (P greater than 0.05). On follow-up of those patients who did not incur additional surgery or radiation, 4.3% became menopausal, as compared to 4.1% of those patients undergoing RH alone, with the mean ages of the two groups being comparable.

Ependymomas of the spinal cord

Many patients with spinal cord ependymomas (SCE) undoubtedly benefit from post-operative radiation therapy; however, because of the wide variability in the total doses given, the optimal post-operative dose for SCE remains unclear. Several recent papers recommend total doses of 4000 rad to 5000 rad in 4 1/2 to 6 weeks. Unfortunately, only a small number of patients reported in the literature have been consistently treated to these high dose recommendations. Nine consecutive adult patients with SCE have been treated in a consistent way at Yale-New Haven Hospital with total doses of approximately 4500 rad to 5000 rad at 180 rad to 200 rad per day. The acute and chronic morbidity from such treatment has been minimal and no patient has had a local recurrence at 8 months to 8 years following treatment.

PSA based review of adjuvant and salvage radiation therapy vs. observation in postoperative prostate cancer patients

Because of the uncertainties regarding the efficacy of postoperative radiation therapy for early prostate cancer, treatment strategies following radical prostatectomy include: (1) observation alone in high‐risk patients, (2) adjuvant radiation therapy (PSA undetectable) in high‐risk patients, or (3) salvage radiation therapy for biochemical and clinical recurrence. Fifty‐two patients treated with postoperative radiation therapy in either an adjuvant setting (13) or for salvage (39) were retrospectively reviewed. The actuarial biochemical disease‐free survival (bNED) rates following radiation therapy were calculated using the life‐table method. Univariate and multi variate analyses were used to define the clinical factors that predict biochemical failure following postoperative radiation therapy. In addition, the bNED survival rate for 36 high‐risk surgery patients who were simply observed following prostatectomy was determined. The 3‐year bNED survival rate for the adjuvant radiation group was 85% compared with 27% for salvage radiation and 43% for the observation group. These results are statistically significant. Factors that predict biochemical failure following postoperative radiation therapy include preoperative PSA level, pre‐radiation therapy PSA level, and seminal vesicle involvement. At our institutions, adjuvant radiation therapy was a superior strategy compared with either observation alone or salvage radiation therapy for high‐risk postoperative prostate cancer patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 29–36 (2000).