Chemoradiation for locally advanced squamous cell carcinoma of the head and neck for organ preservation and palliation.

OBJECTIVES: To measure the efficacy and toxic effects of our chemoradiotherapy regimen by means of response and survival in patients with advanced squamous cell carcinoma of the head and neck (HNSCC) for organ preservation in resectable disease or palliation in unresectable disease. DESIGN: All patients underwent evaluation by the multidisciplinary head and neck cancer team, with pathological diagnosis and staging. All patients underwent assessment for response to therapy using results of physical examination and radiologic imaging. Patients were followed up at 3-month intervals for a planned period of 5 years. SETTING: Academic center. PATIENTS: Thirty-eight previously untreated patients with newly diagnosed HNSCC were treated from June 1, 1996, through December 31, 1998, of whom 20 had resectable and 18 had unresectable tumors. INTERVENTION: Patients received intravenous cisplatin, 100 mg/m(2) for 1 hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000 mg/m(2) on days 1 through 4 and 29 through 32; and radiation therapy, 150 rad twice daily for 12 days. The patients were given a 7- to 10-day break, and radiation therapy was restarted on day 29 for 12 additional days (total dose, 7200 rad). MAIN OUTCOME MEASURES: Complete, partial, and total response rates; disease-free survival; overall survival; and toxic effects. RESULTS: Toxic effects of treatment were moderately severe, including grades III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%). In the 18 patients in the unresectable group, complete response in the 17 primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and 9 (60%), respectively; in the 20 patients undergoing organ preservation, complete response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases. Complete response for all 38 patients was achieved in 31 (82%). In the unresectable group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up from 29 to 45 months. In the organ preservation group, 75% of patients are alive without disease, and 8 have been followed up for 36 to 48 months. Of the 5 patients who have died, only 2 died of disease, with recurrences at 13.0 and 16.5 months. CONCLUSIONS: Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily external beam radiation is highly effective in achieving durable complete responses in patients with resectable HNSCC undergoing organ preservation and patients with unresectable HNSCC undergoing palliation. Toxic effects of this regimen were moderate to severe.

High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

Improving treatment planning accuracy through multimodality imaging.

PURPOSE: In clinical practice, physicians are constantly comparing multiple images taken at various times during the patient's treatment course. One goal of such a comparison is to accurately define the gross tumor volume (GTV). The introduction of three-dimensional treatment planning has greatly enhanced the ability to define the GTV, but there are times when the GTV is not visible on the treatment-planning computed tomography (CT) scan. We have modified our treatment-planning software to allow for interactive display of multiple, registered images that enhance the physician's ability to accurately determine the GTV. METHODS AND MATERIALS: Images are registered using interactive tools developed at the University of North Carolina at Chapel Hill (UNC). Automated methods are also available. Images registered with the treatment-planning CT scan are digitized from film. After a physician has approved the registration, the registered images are made available to the treatment-planning software. Structures and volumes of interest are contoured on all images. In the beam's eye view, wire loop representations of these structures can be visualized from all image types simultaneously. Each registered image can be seamlessly viewed during the treatment-planning process, and all contours from all image types can be seen on any registered image. A beam may, therefore, be designed based on any contour. RESULTS: Nineteen patients have been planned and treated using multimodality imaging from November 1993 through August 1994. All registered images were digitized from film, and many were from outside institutions. Brain has been the most common site (12), but the techniques of registration and image display have also been used for the thorax (4), abdomen (2), and extremity (1). The registered image has been an magnetic resonance (MR) scan in 15 cases and a diagnostic CT scan in 5 cases. In one case, sequential MRs, one before treatment and another after 30 Gy, were used to plan patient's initial fields and boost, respectively. Case illustrations are shown. CONCLUSIONS: We have successfully integrated multimodality imaging into our treatment-planning system, and its routine use is increasing. Multimodality imaging holds out the promise of improving treatment planning accuracy and, thus, takes maximum advantage of three dimensional treatment planning systems.

The tetrad and hexad: maximum beam separation as a starting point for noncoplanar 3D treatment planning: prostate cancer as a test case.

PURPOSE: In contrast to computer optimized three-dimensional (3D) treatment planning, we have used maximally separated, noncoplanar beams as the starting point for 3D treatment planning of prostate cancer to maximize the rate of dose fall off from the target volume and minimize dose to surrounding tissues. MATERIALS AND METHODS: A planar four-field plan, a planar six-field plan, a tetrad plan, and a hexad plan are analyzed using a 3D treatment planning system which is capable of displaying real-time 3D dose distributions within volume reconstructed data sets (VISTAnet--an extension of the virtual simulator). The tetrad plan is based on the methane molecule and the hexad plan has a minimum separation of 58 degrees on beam entrance. All fields are conformal. The irradiated volume equals the clinical target volume plus a 1 cm margin. Competing plans are compared using cumulative dose-volume histograms and normal tissue complication probabilities. RESULTS: The crossover point, the isodose surface that conforms more to the beams than the target, is introduced and described. The hexad and tetrad plans result in tighter dose distributions when compared to the planar plans with the same number of beams. The tetrad plan treats a volume less than or equal to the planar six-field plan at isodose surfaces above 18% except between 37% and 44% where the tetrad volume is slightly larger. As expected from integral dose considerations, the amount of normal tissue receiving some radiation increases, but the amount receiving clinically significant amounts of radiation decreases as the number of beams increase. The plan involving the largest number of noncoplanar beams results in the tightest isodose distribution. Analysis of rectal and bladder cumulative dose volume histograms does not reveal a clearly superior plan based on normal tissue complication probabilities. CONCLUSIONS: Using basic principles of solid geometry, maximally separated beams without significant overlap on exit or entrance can be designed which minimize clinically significant dose to surrounding tissues and tighten the isodose distribution around the target volume. The emphasis of this treatment plan optimization is geometric in contrast to methods using computer optimization or artificial intelligence.

Simultaneous chemoradiation in the treatment of advanced head and neck cancer.

Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were randomly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil (5-fluorouracil). There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers. In the group of patients with unresectable cancers, however, there was a statistically significant advantage to the addition of chemotherapy, both in terms of disease-free survival and date to progression.

A comparison of postoperative techniques for carcinomas of the larynx and hypopharynx using 3-D dose distributions.

If a head and neck cancer originates low in the neck with a primary site below the shoulders, a technical challenge to the radiation oncologist exists in that the entire neck needs treatment while avoiding overlap of multiple fields on the spinal cord. No standard solution to this problem exists. We have developed a 3-D treatment planning tool that can be used to develop and compare 3-D treatment plans and dose distributions. Using this tool, we have studied the following techniques for the postoperative treatment of carcinomas of the larynx and hypopharynx, tumors that often embody the problems discussed above: (a) the mini-mantle technique used at the Massachussetts General Hospital, (b) a 3-field technique used at the University of Florida at Gainesville (UF 3-field), (c) a 3-field technique used at our institution and at many others (standard 3-field), and (d) the kicked out lateral technique used at our institution and at others. The 3-D dose distributions from these plans are compared. With 100% delivered just anterior to the vertebral body at mid-neck, the mini-mantle technique results in large 120% hot spots laterally and anteriorly in the neck. Near the mastoid tips, however, the dose falls to 100%. The upper neck nodes may be underdosed since this is 20% cooler than the lateral-anterior neck dose (where a large 120% hot spot exists). The spinal cord is adequately blocked. The two 3-field techniques result in small hot spots at the junction of the lateral and anterior fields. Because different methods are used to prevent overlap at the spinal cord, these hot spots occur anteriorly in the standard 3-field technique and laterally in the UF 3-field technique. The spinal cord block results in untreated neck tissue which can be supplemented with electrons in the standard 3-field technique, but is left untreated in the UF 3-field technique. Both techniques result in a generous length of spinal cord which does not receive full dose. The kicked out lateral technique treats the entire neck and reconstructed pharynx without matching fields at midneck. The upper mid mediastinum is underdosed 10-20% despite being within the posterior inferior portion of the beam. This could be minimized by using a tissue compensator. Unless there is significant subglottic extension or significant risk of disease in the upper mediastinum, we favor treating these malignancies with the kicked out lateral technique, which avoids the problem of junctioning lateral and anterior fields and provides a fairly homogeneous dose distribution.

Virtual simulation: initial clinical results.

We have developed a graphics-based three-dimensional treatment design system that permits the physician to easily understand which anatomy will be treated for any arbitrary beam orientation. Our implementation of this system differs from others in that the software (the Virtual Simulator) simulates the full functionality of a (physical) radiation therapy simulator allowing it to be easily used by physicians. The details of the of our initial clinical experience with virtual simulation are presented in this paper. Virtual simulation was attempted in 71 patients and completed in 65. In 41/71 patients (58%), the beam orientations chosen differed significantly from those traditionally used in our department. Although virtual simulation lead to traditional radiation portals in the remaining patients, in 23/71 (32%) secondary blocking was designed which was different from that which would have been conventionally employed. Thus, overall, virtual simulation lead to treatment changes in 64/71 (90%) of the patients in whom it was attempted. In 78% of evaluable patients the treatment designed with virtual simulation could be implemented on the physical simulator with a precision of +/- 5 mm (+/- 3 mm for brain and head and neck). Thus virtual simulation allowed both accurate planning and execution of treatment plans that would be difficult to achieve with conventional methods.

Ewing's sarcoma: surgical resection as a prognostic factor.

A retrospective review of 46 cases of Ewing's (43) and extraosseous Ewing's (3) sarcoma was performed to examine for prognostic factors. Follow-up ranged from 27 to 135 months with a mean of 77.6 months, 86% greater than 36 months. Nine (20%) patients presented with distant metastases, 98% received multiagent chemotherapy, and 98% received radiation therapy. Overall actuarial survival and local control at 5 years were .52 +/- .08 and .78 +/- .07, respectively. The freedom from relapse or treatment related mortality at 5 years was .46 +/- .08. In 12 (26%) patients, surgical resection of the involved bone or soft tissue was part of the initial treatment plan. Ninety-two percent (11/12) of these patients also received radiation therapy. In addition to surgical resection, tumor size (less than 500 cc vs. greater than or equal to 500 cc), primary site (central vs. other), and stage were also analyzed for prognostic significance, and where appropriate, were included in Cox multivariate analyses. Considering all patients, the 5-year actuarial survival was .92 +/- .08 vs. .37 +/- .09 for patients receiving and not receiving surgical resection, respectively (p = .001 by logrank, p = .02 by Cox). To make the groups more comparable, 8 patients with local failure and 5 patients with non-evaluable primary sites were excluded. After these exclusions, the presence or absence of surgical resection had decreased significance: .92 +/- .08 vs. .59 +/- .11, respectively; p = .01 by logrank, p = .07 by Cox. Only primary site remained statistically significant: .86 +/- .08 for noncentral sites vs. .38 +/- .16 for central sites, p less than .0002 by logrank, p = .0004 by Cox. Surgical resection when added to local irradiation has prognostic significance in this retrospective review. The reason for this is not clear, but may be related to a decrease in local failure after resection.

Carcinoma of the female urethra: a review of results with radiation therapy.

Low stage female urethral carcinoma is curable by radiation therapy alone and is amenable to brachytherapy techniques whereby high doses of irradiation can be delivered safely. A 60 to 80 per cent 5-year survival rate with preservation of bladder function and control can be expected with good radiotherapeutic techniques. Except for stage Tis or early stage T1 lesions of the anterior urethra that can be treated with limited surgical excision, irradiation should be considered as an alternative to more extensive surgery for low stage bulky lesions. While there has been some success with radiation therapy alone for advanced disease, the cure rate probably can be improved with a combined approach using surgery, radiation therapy and possibly chemotherapy.