A. Awan

Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities: Clinical and radiobiological results

PURPOSE The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. METHODS AND MATERIALS Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation 7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and > or = 10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy); however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. RESULTS Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of > or = 5 cm (p = 0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with > or = 10 cm margins (100%) (p = 0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving > or = 60 Gy (p = 0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4% vs. those receiving 64-66 Gy (87.0%) (p = 0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses > or = 63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p < 0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. CONCLUSIONS Our data confirm the importance of maintaining an initial field margin of at least 5 cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins > or = 10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.

Acute toxicity during external-beam radiotherapy for localized prostate cancer: Comparison of different techniques

PURPOSE The chronic and acute toxicities associated with conventional radiotherapy of localized prostate cancer are well documented. However, the degree and incidence of toxicities with conformal techniques are not known. Studying side effects associated with modern radiotherapeutic techniques is more important now since there has been a general trend to use computerized tomography-based techniques in recent years; beams eye view-based conformal techniques are also becoming more commonplace. It is possible that the local disease control can be improved with the delivery of higher doses than currently used. Conformation of the treatment volume to the target volume may facilitate such dose-escalation. However, prior to such dose-escalation, it is important to know the toxicities associated with such techniques with conventional doses. METHODS AND MATERIALS We have compared week-by-week acute toxicities associated with conventional (Group A, 16 patients), computerized tomography-based, manual (Group B, 57 patients) and beams eye view-based (Group C, 43 patients) techniques during 7 weeks of radiotherapy. Group B and C patients were treated contemporaneously (1988-1990). RESULTS Acute side effects gradually increased from week 1 through weeks 4-5 and generally declined or plateaued after that. The incidence of acute toxicities was significantly less with the beams eye view/based technique than with the other two methods. For instance, the percentages of Grade 2 acute genitourinary toxicities for Groups A, B, and C were as follows: Week 1-0, 0, 0; Week 2-6, 0, 0; Week 3-6, 9, 2; Week 4-12, 14, 9; Week 5-35, 14, 9; Week 6-31, 16, 7; Week 7-33, 8, 8, respectively. The p values associated with differences in acute genitourinary toxicities for Weeks 1-7 using chi-square test were 0.072, 0.627, 0.389, 0.538, 0.123, 0.06, and 0.012; the p values for acute gastrointestinal toxicities were 0.512, 0.09, 0.031, 0.031, 0.003, < 0.0001, and 0.004, respectively. Pairwise comparison (Wilcoxon rank-sum test) showed statistically significant lower acute toxicity in Group C than Group B (e.g., p values, Weeks 1-7 for gastrointestinal toxicity: 0.633, 0.056, 0.010, 0.014, < 0.0001, < 0.0001, and < 0.0001, respectively) in the latter part of the treatment course. No correlation was found between the extent of toxicity and the patient age or the overall treatment time. Also, no correlation was found between the degree of toxicity and the radiation dose and fraction size, within the narrow ranges used (65-70 Gy and 180-200 cGy, respectively). A trend suggesting increased severity of toxicity with increase in the volume of treatment was seen. CONCLUSION The findings in this retrospective study need to be confirmed by other prospective studies.

Radiobiological characterization of head and neck and sarcoma cells derived from patients prior to radiotherapy

The radiobiological parameters of 33 tumor cell lines were studied in biopsy samples obtained from patients prior to radiotherapy. Epithelial tumor cells derived from head and neck cancer patients were more radioresistant than tumor cell lines derived from patients with sarcoma regardless of method of analysis. The presence of radioresistant tumor cell lines was associated with local failure in some patients. However, the presence of radiosensitive tumor cells did not necessarily predict local control. Our data suggest radiocurability is complex and inherent radiobiological parameters of tumor cells may be only one factor in radiotherapy outcome.

Changing face and different countenances of prostate cancer: Racial and geographic differences in prostate-specific antigen (PSA), stage, and grade trends in the PSA era

The purpose of this investigation was to examine changes in pretreatment prostate‐specific antigen (PSA), stage, and grade over the past decade as a function of race and geographic region. A multiinstitutional database representing 6,790 patients (1,417 African‐American, 5,373 white) diagnosed with nonmetastatic prostate cancer between 1988 and 1997 was constructed. PSA, stage, and grade data were tabulated by calendar year and region, and time trend analyses based on race and region were performed. There was an overall decline of PSA of 0.8%/year, which was significant (P = 0.0001), with a faster rate of decline in African‐Americans (1.9%/year) than for whites (0.6%/year). The odds ratio (OR) for a stage shift was 1.09, which was significant (P < 0.0001), and this shift was greater in whites. The OR for an overall grade shift was 1.15, which was significant (P < 0.0001). Although grade and PSA trends were similar for the different regions, there were significant regional differences in stage trends. The implications are that the face of prostate cancer has changed over the past decade; i.e., the distributions of stage, grade, and PSA (the most important prognosticators) have changed. In addition, the countenances of that face are different for whites and African‐Americans. For African‐Americans, this is good news: the stage, grade, and PSA distributions are more favorable now than before. For whites, the trends are more complex and more dependent on region. These findings should be used for future clinical and health‐policy decisions in the screening and treatment of prostate cancer.

Prophylactic cranial irradiation in adenocarcinoma of the lung a possible role

Seventy‐eight patients with modified Stage II or Stage IIIM0 adenocarcinoma of the lung were evaluated retrospectively with regard to the impact of prophylactic cranial irradiation (PCI) (30 Gy in 15 fractions) in preventing central nervous system (CNS) metastases. Twenty patients received PCI and 58 did not. There were no significant differences between these groups with respect to age, sex, stage, or median survival (17.4 months with PCI versus 16.9 months without PCI; P = 0.6). One (5%) of 20 patients receiving PCI developed CNS metastases, compared with 14 (24%) of 58 patients not receiving PCI (P = 0.06). The time from diagnosis to development of CNS metastases and survival after CNS involvement was 51 weeks and 14 weeks, respectively, for the patient who received PCI; and a median time of 50 weeks and 26 weeks, respectively, for the patients not receiving PCI. In nine (64%) of the 14 non‐PCI patients the CNS was the first and only site of relapse. A Cox regression analysis demonstrated that nodal involvement was significantly associated with an increased risk of CNS metastases. These data suggest that PCI may decrease the incidence of CNS metastases, and that it may be beneficial in the management of patients with NI or N2 disease.

Beams eye view-based photon radiotherapy I

Geographic miss, dosimetric miss (underdosing), and proximity of the tumor to sensitive normal tissues are some of the causes of inadequate radiation dose delivery; this is one of many causes of failure after radiotherapy. In the past decade, computerized tomography (CT)-based treatment planning has helped to overcome some of these problems. Beams eye view (BEV)-based radiotherapy planning is an improvement over CT-based treatment planning that may further increase the therapeutic ratio. Since January 1988, we have treated 198 patients with BEV-based photon radiotherapy. About 40% of our patients treated with radical radiotherapy undergo BEV-based treatment, and about 70% of patients who undergo planning CT in the treatment position receive BEV-based radiotherapy. Our findings are as follows: (a) routine use of BEV-based RT (BEVRT) is possible in a busy radiation oncology department; (b) BEVRT improves geometric coverage of tumors; (c) BEVRT is extremely useful in the design of oblique portals; (d) time commitments for various members of the RT treatment-planning team are reasonable; (e) BEVRT helps individualize RT technique; (f) preliminary data suggest decreased acute toxicity with the use of BEVRT for prostate cancer patients. Whether these advantages will help to improve the outcome (i.e., improve local control and survival) and/or decrease the long-term toxicity is not yet known.

In vitro radiobiological parameters of human sarcoma cell lines

In vitro radiobiologic survival parameters have been determined for 7 human osteosarcoma, 5 human soft tissue and bone sarcomas, and 4 Ewings sarcoma cell lines. The mean D0 values were 99.5 +/- 11.6 cGy, 90.5 +/- 7.7 cGy and 95.8 +/- 7.9 cGy for osteosarcomas, soft tissue and bone sarcomas and Ewings sarcomas, respectively. These in vitro survival data do not predict the clinical radiation resistance generally attributed to osteosarcomas and soft tissue and bone sarcomas, and do not differ substantially from the results obtained with the clinically radioresponsive Ewings sarcomas.

Methotrexate, vinblastine, doxorubicin and cisplatin followed by radiotherapy or surgery for muscle invasive bladder cancer : the university of Chicago experience

A total of 29 patients with muscle invasive bladder cancer, clinical stage T2N0 (12), T3aN0 (9), T3bN0 (5), T3N2 (2) or T4N2 (1), underwent 2 to 4 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy followed by either radiotherapy (15), radical cystectomy (11) or no local therapy (3). The overall response rate to M-VAC chemotherapy was 69%, with 31% clinical complete responses and 38% clinical partial responses. A functioning bladder was maintained in 55% of the responding patients, although bladder wall calcifications were observed in 4 of 15 irradiated patients. Overall survival was 71% and disease-free survival was 55% at a median followup of 57 months. For the 12 stage T2N0 cancer patients overall survival was 100% at a median followup of 52 months. For the stages T3a and T3bN0 cancer patients overall survival was 63%, while all 3 node positive patients died. Neoadjuvant chemotherapy with a modified M-VAC regimen is well tolerated and may result in bladder preservation.

Curative radiotherapy following chemotherapy for invasive bladder carcinoma (a preliminary report)

Twenty-five patients with invasive transitional cell carcinoma of the bladder (Stage T2, T3, T4) received combined modality therapy using four cycles of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) chemotherapy followed by surgery or radiation therapy (RT). Sixteen patients had complete (N = 8) or partial (N = 8) response to MVAC. Curative RT was delivered to 11 responders with T2 or T3 disease and to 2 patients with T4 disease. All 11 with T2 and T3 disease are currently alive, 7 with normal bladder function. The two with T4 disease are dead of disease. Three patients required salvage cystectomy for local recurrence and one patient had cystectomy for bladder stones. Follow-up ranged from 11 to 50 months with a median of 31 months. No late chemo-radiotherapy treatment-related complications to the intestines or in bladder function (other than one bladder stone formation) occurred. These preliminary results are encouraging and warrant further evaluation of this innovative approach in treating invasive carcinoma of the bladder. T2 and T3 patients with a complete or partial response to MVAC may be excellent candidates for a bladder-sparing treatment.