Chimeric rabies SADB19-VSVg-pseudotyped lentiviral vectors mediate long-range retrograde transduction from the mouse spinal cord.

Lentiviral vectors have proved an effective method to deliver transgenes into the brain; however, they are often hampered by a lack of spread from the site of injection. Modifying the viral envelope with a portion of a rabies envelope glycoprotein can enhance spread in the brain by using long-range axon projections to facilitate retrograde transport. In this study, we generated two chimeric envelopes containing the extra-virion and transmembrane domain of rabies SADB19 or CVS-N2c with the intra-virion domain of vesicular stomatitis virus. Viral particles were packaged containing a green fluorescent protein reporter construct under the control of the phosphoglycerokinase promoter. Both vectors produced high-titer particles with successful integration of the glycoproteins into the particle envelope and significant transduction of neurons in vitro. Injection of the SADB19 chimeric viral vector into the lumbar spinal cord of adult mice mediated a strong preference for gene transfer to local neurons and axonal terminals, with retrograde transport to neurons in the brainstem, hypothalamus and cerebral cortex. Development of this vector provides a useful means to reliably target select populations of neurons by retrograde targeting.

Changes in GABAergic neuron distribution in situ and in neuron cultures in ovine (OCL6) Batten disease.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited human and animal diseases characterized by progressive brain atrophy. A form in sheep is syntenic to the human CLN6 disease. Cell type specific neurodegeneration in these sheep was indicated by the distribution of GABAergic interneurons in coronal sections of normal and CLN6 affected sheep brains. A reduction of parvalbumin immunoreactive neurons in NCL cerebral cortex was the most striking feature. This was most pronounced in parietal cortex where very few positive cells remained. Calretinin immunoreactive somata in infragranular layers of the neocortex were also reduced while the number of calbindin positive cells was similar in affected and normal brains. There were fewer GAD immunoreactive neurons in the deeper layers of all NCL cortical areas examined. The parietal lobe was relatively more affected than frontal or temporal lobes while the cerebellum and the basal ganglia showed no signs of selective neuron loss. Since horizontally extending basket cells are mainly labelled by parvalbumin, the loss of these interneurons in the neocortex may render pyramidal neurons more excitable and compromise their co-ordinated output. In vitro, cultures of control and affected neurons from 60 to 70-day-old fetal brain hemispheres were examined for the presence of GABAergic and glutamatergic neurons. Different neurons developed distinct immunoreactivity to glutamate or GABA but the overall distribution was similar in normal and affected cultures. This culture system may provide a useful model to compare GABAergic cell function of normal and NCL affected neurons.

Splicing variants in sheep CLN3, the gene underlying juvenile neuronal ceroid lipofuscinosis.

Mutations in different genes underlie different forms of the neuronal ceroid lipofuscinoses (NCLs, Batten disease). Subunit c of mitochondrial ATP synthase specifically accumulates in most of them, including the juvenile CLN3 form and a sheep form orthologous to CLN6. Products of these genes are likely to be components of a complex or pathway for subunit c turnover, and their expression may be cross-regulated. Different bands, some with different subcellular distributions, were detected by antisera against different regions of CLN3 on Western blots of sheep tissues. Affected liver blots were the same as controls but a specific 50-kDa band was at higher concentration in affected brain homogenates than in controls. Others have also reported bands reacting differently to different CLN3 antibodies. When the 3' end of sheep CLN3 cDNA was amplified by RT-PCR, four mRNA splicing variants were found. Different CLN3 splicing variants at the 5' end of the human cDNA have been reported. These mRNA splicing variants may account the variation of epitope distribution and the different subcellular locations of the CLN3 gene product(s). The predicted size of the unmodified CLN3 protein is 48 kDa. Significantly higher molecular weight bands may correspond to oligomers of a CLN3 isoform or to a CLN3 isoform tightly bound to another protein.

Non-metastatic Ewing's sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy.

Eighty-five patients (37 female, 48 male; median age 14 years) with non-metastatic Ewing's sarcoma received definitive treatment at the University of Texas M.D. Anderson Cancer Center between 1969 and 1988. Multidisciplinary therapy was administered as follows: combination chemotherapy (CC) and local radiotherapy (XRT): 65 patients; CC, XRT and surgery, 19 patients; and XRT and surgery, 1 patient. This permitted a 10-20 year follow-up for 75% of our patients. The overall survival at 5 and 10-20 years was 46.1%, and 37.2%, respectively. At 5 years, 80.5% of live patients had control of local disease. The influence of sex, age, ethnicity, primary site, size, lactic dehydrogenase (LDH) level, presence or absence of systemic symptoms, and XRT dose (<60 Gy and

Brain metastases as the only manifestation of an undetected primary tumor.

BACKGROUND: The prognosis of patients with brain metastasis as the only manifestation of an undetected primary tumor generally is considered to be poor. Therefore, most treatment is palliative. The authors reviewed the clinical outcomes and treatment results of patients presenting with brain metastasis from an undetected primary tumor at The University of Texas M. D. Anderson Cancer Center. METHODS: Between 1977-1996, 220 patients were referred to the study department for the treatment of brain metastasis from an undetected primary tumor. The patients' records were reviewed to identify those for whom brain metastasis was the only manifestation of the primary tumor. The majority of patients were excluded from the current analysis because extracranial metastasis also were present. Thirty-nine patients qualified for this retrospective review. The level of neurosurgical excision varied, but all patients received radiotherapy. Tumor control in the brain and survival were analyzed by various tumor-related and treatment-related factors. RESULTS: In 31 patients, the brain metastasis were adenocarcinomas, whereas the remaining patients had tumors of various other histologies. In 12 patients, the primary tumor eventually was found, most commonly in the lung. The median survival time for all patients was 13.4 months. Overall survival rates (OS) at 1, 3, and 5 years were 56%, 19%, and 15%, respectively. Intracranial disease control was 72% at 5 years. Patients who received gross total resection (GTR) and radiotherapy had significantly better OS than patients who received radiotherapy alone. The OS of patients whose primary tumor was identified was similar to that of patients in whom the primary tumor remained occult. CONCLUSIONS: Brain metastasis as the only manifestation of an unknown primary tumor is a distinct clinical entity. The prognosis for patients with this presentation is better than that of patients with brain metastasis in general. Although the majority of patients die of extracranial disease, a few will achieve long term survival. Treatment to the brain is effective in controlling local disease; aggressive treatment with GTR and radiotherapy is recommended.

Radiation therapy of pelvic recurrence after radical hysterectomy for cervical carcinoma.

OBJECTIVES: To evaluate the efficacy of radiation therapy and potential prognostic factors in patients treated for pelvic recurrence of cervical carcinoma after radical hysterectomy. MATERIALS: The records of 50 patients treated between 1964 and 1994 for an isolated pelvic recurrence of cervical carcinoma a median of 10.5 months after initial radical hysterectomy were retrospectively reviewed. Patients were categorized according to the extent of disease on clinical examination as group 1, mucosal involvement only (5); group 2, paravaginal extension (11); group 3, central recurrence with pelvic wall extension (13); and group 4, recurrences limited to the pelvic sidewall (21). Seven patients with group 3 or 4 disease who had a poor performance status were treated with palliative intent using hypofractionated radiotherapy. The remaining 43 patients were treated with curative intent, 33 with radiotherapy only and 10 with a combination of cisplatin-based chemotherapy and radiotherapy. Survival rates were calculated from the date of initial recurrence. Median follow-up of surviving patients was 109 months. RESULTS: The overall 5-year survival rate was 33% for all 50 patients (median survival, 18 months), 39% for the 43 patients treated with curative intent, and 25% for patients with isolated sidewall recurrences treated with curative intent. The survival rate was 69% for patients with group 1 and 2 disease and 18% for those treated with curative intent for group 3 disease (P = 0.07). The survival rate was better for patients with recurrent squamous carcinomas (51%) than for those with adenocarcinomas (14%) (P = 0. 05). Three group 4 patients who survived more than 5 years were treated with external-beam radiation alone. Eight-one percent of patients who had a second recurrence had evidence of disease progression. Three patients experienced late treatment complications. CONCLUSIONS: Patients who experience an isolated recurrence of cervical cancer after initial radical hysterectomy have an excellent prognosis if disease does not involve the pelvic wall. Occasional long-term survivors of recurrent disease involving the pelvic wall justify an aggressive treatment approach.

Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix.

PURPOSE: To determine the time course and incidence of late complications from radiation therapy in patients treated with radiation for FIGO Stage IB carcinoma of the uterine cervix, and to evaluate patient and tumor factors associated with an increased probability of treatment complications. METHODS AND MATERIALS: The medical records of 1784 patients with FIGO Stage IB cervical carcinoma who were treated with initial radiation therapy between 1960 and 1989 were retrospectively reviewed. Follow-up was obtained from clinic visits and correspondence with patients and their physicians. Treatment complications were graded retrospectively. Complication rates were calculated actuarially; patients who died of disease or intercurrent illness without experiencing a major complication were censored at the time of death. There were 1241, 924, 548, and 274 patients followed for more than 5, 10, 15, and 20 years, respectively. RESULTS: Of patients treated for Stage IB cervical carcinoma, 7.7% and 9.3% had experienced major (> or = Grade 3) complications at 3 and 5 years, respectively. After 5 years, there was a small but continuous risk of approximately 0.34% per year, resulting in an overall actuarial risk of having had major complications of 14.4% at 20 years. The risk of developing major urinary tract complications was approximately 0.7% per year for the first 3 years of follow-up, decreasing to about 0.25% per year for at least 25 years. In contrast, the risk of developing rectal complications was about 1% per year during the first 2 years, with a subsequent sharp decline to about 0.06% per year between Years 2 and 25. The risk of fistula formation was approximately doubled in the 234 patients who underwent adjuvant extrafascial hysterectomy (5.3 vs. 2.6% at 20 years; p = 0.04) and in the 111 patients who had pretreatment laparotomy (5.2 vs. 2.9%; p = 0.007). The risk of developing small bowel obstruction was increased in patients who underwent pretreatment laparotomy (14.5 vs. 3.7% at 10 years; p < 0.0001) and in patients who weighed < 120 pounds (8.2 vs. 3.6%; p = 0.004), but was not increased in patients who underwent adjuvant hysterectomy. A significantly greater risk of gastrointestinal complications was observed in black and non-Hispanic white patients than in Hispanic women (p = 0.01), even though there was no difference in the rate of developing urinary tract complications (p = 1.0). There was no correlation between the actuarial risk of developing major complications and the patients' age at the time of treatment, but the cumulative risk was greater for patients who were treated at a young age because these patients were more likely to survive to be exposed to a very long period of risk. CONCLUSIONS: Using techniques described by Fletcher and Delclos, the risk of major complications from aggressive irradiation for Stage IB carcinoma of the cervix is low and does not warrant compromises in the intensity of treatment that might decrease the high cure rates achieved in such patients. The long time course of some late complications also suggests that continued surveillance of survivors, by physicians experienced in the diagnosis and management of the sequelae of the curative radiation treatment of cervical cancer, is important.

Interdigitating versus concurrent chemotherapy and radiotherapy for limited small cell lung cancer.

PURPOSE: Sequencing and timing of chemotherapy and radiotherapy for limited small-cell lung cancer (LSCLC) was studied in two consecutive trials. METHODS AND MATERIALS: In the interdigitating (IDG) trial, three cycles of COPE (cyclophosphamide 750 mg/M2 i.v. Day 1, vincristine 2 mg i.v. Day 8, cisplatin [DDP] 20 mg/M2 Days 1-3, etoposide 100 mg/M2 i.v. Days 1-3), were followed by thoracic radiation therapy (1.5 Gy bid 5-6 h apart, repeated twice at 3-week intervals) to give 45 Gy in 9 weeks; COPE was given during the intervals and for two more cycles. Operable patients had thoracotomy followed by IDG. Prophylactic cranial irradiation (PCI), 2.0 Gy x 15 fractions with a total dose of 30 Gy in 3 weeks, was given to the complete responders (CR) after completion of chemotherapy. In the concurrent (CON) trial, patients received DDP 60 mg/M2 i.v. Day 1, and etoposide 120 mg/M2 i.v. Days 1-3 for four cycles, every 3 weeks, and concurrent thoracic radiation therapy to 45 Gy with either 1.8 Gy daily, for 5 weeks or 1.5 Gy bid for 3 weeks. Prophylactic cranial irradiation (PCI) was given to the complete responders, 2.5 Gy daily for 2 weeks (25 Gy) (approximately 3 months after the initiation of treatment). RESULTS: The IDG group had 28 evaluable patients with median follow-up of 17.5 months. The CON group had 33 evaluable patients with median follow-up of 21 months. Overall survival rates for IDG patients were 79% at 1 year, 39% at 2 years, 30% at 3 years, and 27% at 4 years compared to 93%, 70%, 51%, and 46%, respectively, for the patients treated with CON (p = 0.01). Loco-regional recurrence (44%) and distant metastasis (48%) was more frequent as the first site of failure in the IDG group compared to the CON group (30% and 30%, respectively). Brain metastases constituted 30% of first metastases with IDG compared to none with CON. Esophagitis was significantly greater with CON. Hematologic and pulmonary toxicity were similar with IDG and CON. One death due to infection was seen in each treatment group. CONCLUSION: Concurrent chemoradiotherapy appears to be more effective than IDG. Earlier administration of PCI with concurrent chemotherapy and thoracic irradiation may reduce the risk of brain metastasis.

Ureteral stricture as a late complication of radiotherapy for stage IB carcinoma of the uterine cervix.

BACKGROUND: Ureteral stricture is a rare late complication of curative radiotherapy for carcinoma of the cervix. A retrospective study was performed to determine the incidence and latency of radiation-induced ureteral stricture, to investigate possible contributing factors, and to compare the time course and presenting characteristics of ureteral compromise caused by late radiation injury or tumor recurrence. METHODS: The records of 1784 patients with FIGO stage IB carcinoma of the cervix treated with radiotherapy at The University of Texas M. D. Anderson Cancer Center between 1960 and 1989 were reviewed. The characteristics of patients who developed ureteral stricture as a first manifestation of recurrent disease or without evidence of pelvic recurrence were compared. The risk of ureteral compromise was calculated actuarially. RESULTS: There were 29 patients with severe radiation-induced ureteral stricture. The overall incidences of severe ureteral stenosis were 1.0, 1.2, 2.2, and 2.5% at 5, 10, 15, and 20 years, respectively, reflecting a continuous actuarial risk increase of approximately 0.15% per year. Four patients died of complications from bilateral ureteral stricture. Patients who were treated with centrally blocked external fields or who received more than two transvaginal radiation treatments were at increased risk for developing ureteral stenosis. The risk was similar for patients treated with radiation alone or followed by extrafascial hysterectomy. CONCLUSIONS: During the first 5 years after treatment, tumor recurrence is the most common cause of ureteral stricture in patients treated with radiotherapy for carcinoma of the cervix. However, radiation injury to the ureter, although rare, may not become apparent for many years, necessitating continued vigilance throughout the lives of these patients.

Comparison of charges related to radiotherapy for soft-tissue sarcomas treated by preoperative external-beam irradiation versus interstitial implantation.

BACKGROUND: We compared treatment-related charges associated with external beam irradiation and interstitial implantation for soft-tissue sarcoma of the extremity. METHODS: Charges related to radiotherapy in 35 patients with soft-tissue sarcoma of the extremity were reviewed. Preoperative external beam irradiation (EB) delivering 50 Gy in 25 fractions with 6 MV photons was administered to 12 of the patients evaluated. The remaining 23 patients were treated with interstitial implantation (IR) as the only radiotherapeutic intervention. The anatomic distribution of the sarcomas treated by IR included 14 lower-extremity (LE) and nine upper-extremity (UE) lesions. The average length of iridium wire used for IR was 78 cm. Because LE lesions tend to be larger, the average length equaled 109.5 cm as compared with the 47 cm for UE implants. RESULTS: The radiotherapeutic approach represented the only difference in treatment-related charges because the operative procedure of wide local excision was performed in each group. No difference in perioperative complications was observed between the two treatment approaches. Charges were stratified according to hospital-based and professional services. Radiotherapy-based hospital charges for the administration of EB averaged $6,515 compared with $4,050 for IR (p < 0.0001). Professional services also were significantly different, totaling $4,390 for EB and $3,240 for IR (p < 0.0001). The total of these charges for radiotherapy procedures and professional fees equaled $10,905 for EB compared with $7,290 for IR (p < 0.0001). Incorporating the necessary operating-room time for implant placement ($750) and five additional hospital days ($1,800), the costs associated with IR totaled $9,840; using chi-square analysis, the cost for IR remained significantly (p < 0.0001) less expensive than the $10,905 associated with EB. Because a large component of the radiotherapy cost for IR is related to the length of iridium 192 wire required, charges were stratified according to the location of the tumor. The total charge for IR of the UE equaled $9,345 compared with $10,335 for LE implants. Chi-square comparison for both UE and LE implants continued to show significant differences (p < 0.0001) when related to EB therapy. CONCLUSION: Cost-analysis comparison of brachytherapy versus external beam irradiation found lower charges for patients undergoing adjuvant irradiation with brachytherapy for soft-tissue sarcoma. To optimize the cost-benefit ratio, prospective studies are necessary to define the application of these radiotherapeutic approaches based on clinical criteria.

The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix.

PURPOSE: To define the influence of tumor size and morphology on rates of central tumor control (CTC), pelvic tumor control (PTC), and disease-specific survival (DSS) in patients treated with radiotherapy for squamous cell carcinoma of the intact uterine cervix. METHODS AND MATERIALS: Records of 1526 patients treated with radiotherapy for FIGO Stage IB squamous cell carcinoma of the intact uterine cervix between 1960 and 1989 were retrospectively reviewed. The maximum tumor or cervical diameter was determined from clinical descriptions for 1494 patients. Tumors were divided into nine size categories. Tumors > or = 4 cm were further classified according to the dominant morphology (i.e., exophytic or endocervical). Median follow-up was 12.2 years. Five-year CTC, PTC, and DSS rates were calculated actuarially. RESULTS: CTC, PTC, and DSS rates correlated strongly with tumor diameter (p < 0.0001). Overall, CTC, PTC, and DSS rates for patients with tumors < 5 cm were 99%, 97%, and 88%, respectively. For patients with tumors 5-7.9 cm these rates were 93%, 84%, and 69%, respectively. There were no significant differences in the rates of PTC, CTC, or DSS between subgroups of patients with lesions 5-7.9 cm in diameter. The rates of CTC (97%) and DSS (76%) for patients with 5-7.9 cm exophytic tumors were significantly better than those for patients with endocervical tumors of the same size (91% and 66%, respectively); there was no difference in the PTC rate. CONCLUSION: Although the CTC rates were excellent for all patients with tumors < 8 cm in diameter, these rates for tumors < 5 cm (99%) and for exophytic tumors 5-7.9 cm (97%) make it difficult to justify the use of adjuvant hysterectomy. Although patients with tumors of 5-7.9 cm had consistently poorer PTC and DSS rates than did patients with smaller tumors, the control rates achieved with aggressive radiotherapy were still excellent. The strong correlation between tumor size and outcome suggests that tumor diameter should be assessed when tumors are clinically evaluated and staged and when treatment results are reported for patients with FIGO Stage IB carcinoma of the uterine cervix.

The relationship between brachytherapy dose and outcome in patients with bulky endocervical tumors treated with radiation alone.

PURPOSE: To evaluate the relationship between brachytherapy dose and outcome in patients treated with external radiotherapy (40 Gy to the whole pelvis) and intracavitary radium therapy for bulky endocervical tumors. METHODS AND MATERIALS: Between 1962 and 1985, 98 patients with Stage IB-IIB bulky endocervical carcinomas (> or = 6 cm in diameter) treated with radiotherapy alone received 40 Gy to the whole pelvis followed by 2 or more intracavitary treatments. Twenty-five patients received < 6000 mg-hr of intracavitary treatment and 73 received > or = 6000 mg-hr (an average dose to point A of approximately 49 Gy). Brachytherapy exposures ranged from 4800-7885 mg-hrs. RESULTS: Patients who received < 6000 mg-hr tended to have unfavorable (narrow) vaginal anatomy (p < 0.01) and to be treated in the later years of the study (p < 0.01). The high-dose group included a somewhat greater proportion of patients with positive lymphangiograms or poor responses to initial external beam treatment. Despite having somewhat more favorable tumors, patients who received less than 6000 mg-hr had a higher rate of pelvic disease recurrence at 5 years (33%) than those who received higher doses (16%) (p = 0.03). Actuarial survival rates at 5 years were 44% and 60% for the low- and high-dose groups, respectively (p = 0.14). Among those who received more than 6000 mg-hr, there was no significant relationship between brachytherapy dose and pelvic disease control. Calculated actuarially, the rate of major (> or = grade 3) complications at 5 years was 23% in the low-dose group and 10% in the high-dose group (p = 0.1). CONCLUSIONS: The relatively high incidence of pelvic disease recurrence and complications in patients who receive less than 6000 mg-hr reflects the narrow therapeutic window for complication-free pelvic disease control in patients with bulky central disease and unfavorable normal tissue anatomy. The results also demonstrate a high pelvic control rate and acceptable morbidity in patients with favorable anatomy treated with high-dose radiotherapy alone.

Treatment of endometrial carcinoma with radiation therapy alone.

PURPOSE: To review the results of treatment with radiotherapy alone in 152 patients with adenocarcinoma of the endometrium who had medical or surgical contraindications to hysterectomy. METHODS AND MATERIALS: We reviewed the records of all patients who were treated with radiotherapy alone for uterine carcinoma at The University of Texas M. D. Anderson Cancer Center between 1960 and 1986. One hundred fifty-two cases were analyzed. Most patients had multiple medical problems. One hundred sixteen patients were treated with intracavitary radiotherapy alone. A combination of external beam and intracavitary radiotherapy was used for 10 patients with Stage I disease who had unusually large cavities, 10 patients with Stage II disease, and 13 of 15 patients with Stage III or IV disease. Histologic material was reviewed in 91 cases. RESULTS: Ten years after treatment, these patients were twice as likely to have died of intercurrent illness as of uterine cancer. The 5-year disease-specific survival rate of patients with Stage I disease was 87%. The disease-specific survival of patients with Stage II disease was 88%, which was not significantly different from that of Stage I patients. Stage III and IV patients had a significantly poorer disease-specific survival rate of 49% at 5 years. Intrauterine recurrence occurred in 14% of the patients with Stage I or II disease. Salvage treatment was attempted in 5 of the 10 patients who had isolated intrauterine recurrences of Stage I disease and was successful in all cases. Extrauterine pelvic recurrence developed in only 3% of Stage I and II patients. Of 82 Stage I and II carcinomas that were available for pathologic review, 17 (21%) were clear-cell or papillary serous variants. The disease-specific survival rate of patients with Stage I or II papillary serous carcinomas was 43%, significantly poorer than that of patients with endometrioid carcinomas. Seven patients experienced acute anesthesia-related complications; none were fatal. Five patients had serious late complications of radiation therapy. CONCLUSION: Radical radiotherapy achieved acceptable DSS and local control rates in patients with medically or surgically inoperable uterine carcinoma. However for patients with localized disease, such treatment is justified only when the operative risk exceeds the 10-15% uterine recurrence rate expected with radiation alone.

Intracranial ependymoma in children: analysis of prognostic factors.

Between 1955 and 1986, 25 children (aged 2 weeks to 15 years) were treated for intracranial ependymoma at M.D. Anderson Cancer Center. Nine patients had supratentorial primaries (5 high-grade, 4 low-grade), and 16 had infratentorial primaries (9 high-grade, 7 low-grade). Five patients had gross complete resection and 20 had incomplete resection. Seven patients received craniospinal irradiation (25-36 Gy to the neuro-axis, 45-55 Gy to tumor bed), 12 received local field irradiation (29-60 Gy, median 50 Gy). Five infants had adjuvant chemotherapy without radiotherapy, and 6 children had post-radiotherapy adjuvant chemotherapy, and 12 patients had salvage chemotherapy with various agents and number of courses. Eight patients are alive, disease-free and without relapse from 1 year to 12 1/2 years from diagnosis (median 42 months). The primary failure pattern was local recurrence. The data suggest that 1) the long-term cure rate of children with ependymoma is suboptimal; 2) histologic grade may be of prognostic importance for supratentorial tumors; 3) prognosis appears worse for girls and infants under 3 years of age; 4) in well-staged patients routine spinal irradiation could be omitted; 5) the role of adjuvant chemotherapy is unclear.

Bulky endocervical carcinoma: a 23-year experience.

Between 1962 and 1985, 371 patients had initial treatment for bulky endocervical carcinomas of the uterine cervix at The University of Texas M.D. Anderson Cancer Center. All patients had concentric expansion of the cervix by tumors that measured at least 6 cm in greatest transverse diameter. Of the 361 patients treated with curative intent, 211 (57%) had FIGO Stage I disease that was believed to be confined to the uterus, 59 (16%) had FIGO Stage IIA disease, and 101 patients (27%) had FIGO Stage IIB disease. Median follow-up time of surviving patients was 130 months. Actuarial survival rates of 361 patients treated with curative intent were 54% and 48% at 5 and 10 years, respectively. The actuarial pelvic disease control rate was 76% at 10 years. Patients whose tumors were less than 8 cm in maximum diameter (279 patients) had a better survival rate than those with tumors greater than or equal to 8 cm in diameter (92 patients) (p less than 0.01). Of the 282 patients who underwent lymphangiography, survival rate was significantly better for those with negative studies than it was for the 113 patients (40%) with positive or suspicious studies (p less than 0.01). There was no correlation between FIGO stage and survival rate (p = 0.64) or pelvic control rate (p = 0.59). Of patients treated with curative intent, treatment was by radiation alone (RT) in 244 (68%) or by radiation followed by hysterectomy (RT+S) in 117 (32%). Although there has been an overall shift in policy away from the use of adjuvant hysterectomy during the past decade, many patient selection factors also influenced the choice of treatment during the study years, resulting in a significantly higher proportion of patients with adverse prognostic features in the RT group. Patients chosen for treatment with RT alone had a greater likelihood of having tumors greater than or equal to 8 cm (p = 0.03), FIGO stage IIB (p less than 0.01), positive lymphangiogram (p = 0.02), and persistent palpable parametrial disease after external radiotherapy (p less than 0.01). Patients treated with RT alone also had a lower overall survival rate at 10 years than patients treated with RT+S (45% vs 64%, p less than 0.01). Although multivariate analysis suggested that treatment had an independent influence upon survival rate, it was difficult to draw firm conclusions about the value of adjuvant surgery because of the numerous biases in patient selection, some of which may have been difficult to quantify.(ABSTRACT TRUNCATED AT 400 WORDS)

Thymoma: treatment and prognosis.

Thirty-six patients with pathologically confirmed thymoma were treated at M.D. Anderson Cancer Center from 1962 to 1987. The tumors were staged based on invasion and intrathoracic dissemination. Twenty-one patients had total resection, five had subtotal resection, and 10 had biopsy alone. Twenty-two patients had definitive megavoltage radiation therapy with a median dose of 50 Gy. The 5-year, disease-free survival by stage was 74% for Stage I (n = 11), 71% for Stage II (n = 8), 50% for Stage III (n = 10), and 29% for Stage IVA (n = 7) (p less than 0.03). The 5-year, disease-free survival by extent of surgery was 74% for total resection, 60% for subtotal resection and 20% for biopsy only (p = 0.001). There were 15 patients with recurrences: two in Stage I, two in Stage II, five in Stage III, and six in Stage IVA. The median months to relapse, for those who failed treatment, were 46, 36, 2, and 13 for Stages I, II, III, and IVA respectively. Of the patients with recurrences four had a total resection, two subtotal resection, and nine biopsy only. Only one patient had distant metastases as the first site of relapse without intrathoracic relapse. For the eight patients who relapsed following radiation therapy, four were in the radiotherapy field. All four of the in-field failures were in patients who had a partial response. There were insufficient numbers of patients to determine a dose response to radiotherapy. For patients with invasive, incompletely resected disease, a multimodality approach may be necessary for long term, disease-free survival.

Comparison of surgery and radiation therapy for non-small cell carcinoma of the lung with mediastinal metastasis.

Interest in the potential role of induction chemotherapy for patients with marginally operable non-small cell carcinoma of the lung (NSCCL) led to a retrospective study of surgical resection and radiation therapy, alone or combined with each other and/or chemotherapy. All 169 patients seen at The University of Texas M. D. Anderson Cancer Center from 1980 through 1985 with evidence of NSCCL metastatic to ipsilateral mediastinal lymph nodes but without extrathoracic spread were evaluated (NSM0). All patients had histologic or cytologic confirmation of NSCCL and clinical or pathologic evidence of mediastinal involvement. Nine patients received CHM alone and were excluded. The male:female ratio was 3:1, and 50% were less than 60 years old. Squamous cell carcinoma was reported in 42%, adenocarcinoma in 45%, large-cell carcinoma in 9%, and unclassified carcinoma in 4%. Radiation therapy (RT) was selected for 81 patients (+ CHM in 56%), in 85% because of the extent of tumor involvement and in 15 for medical reasons. Of RT patients, 31% had a Karnofsky performance status (KPS) of less than or equal to 80, 30% had greater than 5% weight loss, and 9% had Stage IIIB disease. Surgical resection (SX) was used in 41 patients (+CHM in 41%), of whom 10% had KPS less than or equal to 80, 17% had greater than 5% weight loss, and 2% had Stage IIIB disease. SX + RT was the treatment for 38 patients (+ CHM in 36%), of whom 13% had KPS less than or equal to 80, 13% had greater than 5% weight loss, and 13% had Stage IIIB disease. The proportions of patients with KPS less than or equal to 80 and weight loss greater than 5% were significantly greater (p less than .01 and p less than .05, respectively) in the RT group than in the other treatment groups. Actuarial survival rates at 2 and 5 years were 24% and 9%, respectively, for RT, 32% and 17% for SX, and 46% and 25% for SX + RT. Overall survival rates for all 160 patients were 30% at 2 years and 14% at 5 years. Prognostic factors that were found to be important were KPS (p = .027) and weight loss (p = .001); age, sex, histology, and Stage IIIa versus IIIB disease were not significantly related to outcome. The results of treatment with SX + RT were significantly better than with RT alone (p = .03); the difference between RT alone and SX alone was not significant (p = .39).(ABSTRACT TRUNCATED AT 400 WORDS)

Maxillary sinus carcinomas: natural history and results of postoperative radiotherapy.

Between 1969 and 1985, 73 patients with maxillary sinus cancers underwent surgical excision and postoperative radiotherapy. The clinical stage distribution by the AJC system was 3T1, 16T2, 32T3, and 22T4. Six patients had palpable lymphadenopathy at diagnosis. Surgery for the primary tumor consisted of partial or radical maxillectomy, and if disease stage indicated it, ipsilateral orbital exenteration. This was followed by radiation treatment delivered through a wedge-pair or three-field technique. All but three patients received 50-60 Gy in 2 Gy fractions to an isodose line defining the target volume. Elective neck irradiation was not routinely given. Clinically involved nodes were treated with definitive radiotherapy (five patients) or combined treatment (one patient). Forty-five patients had no evidence of disease at the last follow-up. The 5-year relapse-free survival for the whole group was 51% The overall local control rate was 78%. Patients with larger tumors, particularly if they also had histological signs of nerve invasion, had a higher recurrence rate than others. The overall nodal recurrence rate without elective neck treatment was 38% for squamous and undifferentiated carcinoma, and only 5% for adenoid cystic carcinomas. Therefore, our current recommendation is to deliver elective nodal irradiation routinely to patients with squamous or undifferentiated carcinoma, except for those who have T1 lesions. Treatment complications were vision impairment, brain and bone necrosis, trismus, hearing loss, and pituitary insufficiency. The incidence of major side effects was determined by disease extent and treatment technique. Many technical refinements were introduced in order to limit the dose to normal tissues in an attempt to reduce the complication rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast.

Between 1955 and 1984, 376 patients with locoregionally advanced breast carcinoma were treated at The University of Texas M. D. Anderson Cancer Center with mastectomy and irradiation and without adjuvant chemotherapy. Patients with inflammatory carcinoma or synchronous bilateral primary tumors were excluded. There were 202 patients with Stage IIIA disease and 174 patients with Stage IIIB disease (AJC Staging--1983). In 124 patients the surgical management was confined to the breast only--total mastectomy (BR) and in 252 dissection of the axilla was performed--extended total, modified radical, or classic radical mastectomy (BR + AX). All patients had postoperative irradiation. The follow-up period ranged between 8 and 34 years. At 10 years, the actuarial disease-specific, relapse-free survival (DSRFS) rate for the entire group was 40%, and the actuarial locoregional control rate was 82%. For patients with Stage IIIA disease the DSRFS was 48% and locoregional control rate was 88%. For those with Stage IIIB disease, the figures were 30% and 74%, respectively. Most of the failures occurred within 5 years of the mastectomy and essentially all occurred within 10 years. When analyzed by type of surgery, both the locoregional control and DSRFS rates were improved by the axillary dissection, the difference being largely caused by fewer axillary node recurrences after dissection of both the breast and axilla than after removal of the breast alone. In the 252 patients in whom the axilla was assessed, the number of positive nodes was a powerful predictor of both locoregional control and survival. The DSRFS rates at 10 years for patients with 0, 1-3, and greater than or equal to 4 positive nodes were 63%, 48%, and 30%, respectively. The actuarial locoregional control rates at 10 years exceeded 95% for patients with 0-3 positive nodes and 75% for those with greater than or equal to 4 nodes. These results show that locoregionally advanced breast cancer is not a uniformly fatal disease when treated without chemotherapy and provide a baseline upon which to assess the value of adjuvant systemic therapy for this stage of disease.

Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter.

Between 1965 and 1985, 160 patients had initial treatment at the M. D. Anderson Cancer Center for Stage I adenocarcinoma of the uterine cervix less than or equal to 4 cm in diameter. Of these patients, 84 were treated with radiation therapy (RT) alone, 20 were treated with external and intracavitary radiation followed by total hysterectomy (R + S), and 56 were treated with radical hysterectomy (RH). Survival rate was strongly correlated with tumor volume (P = 0.0008), lymphangiogram findings (P = 0.01), and tumor grade (P = 0.0018). Patients with a normal-appearing cervix or a small visible or palpable tumor that did not expand the cervix more than 3 cm had survival and pelvic-control rates of more than 90% after treatment with RH or RT. However, after 5 years, 45% of patients treated with RH for tumors 3-4 cm in diameter had disease recurrence in the pelvis, compared with 11% of patients treated with either RT or R + S (P = 0.025). For patients treated with RH, recurrence was also strongly correlated with findings of lymph/vascular space invasion (P = 0.0004) and poorly differentiated tumor (P = 0.018). Major complication rates were comparable for the three treatment groups. The high rate of pelvic recurrence following treatment with radical hysterectomy alone for patients with tumors greater than 3 cm in diameter, particularly in the presence of lymph/vascular space invasion, poorly differentiated features, and/or positive nodes, should be considered in planning the primary management of patients with Stage I adenocarcinoma of the cervix.