II clinical trial

Copyright

0360.3016191 $3 00 + .I0 0 1991 Pergamon Press plc

??Phase I/II Clinical Trials NEON

ION RADIOTHERAPY: DAVID

RESULTS

E. LINSTADT, AND

M.D.,‘%*

THEODORE

OF THE PHASE JOSEPH

L. PHILLIPS,

R. CASTRO,

I/II CLINICAL

TRIAL

M.D.1,2.3

M.D.‘,233

‘Department of Radiation Oncology, University of California, San Francisco; *Research Medicine Division, University of California Lawrence Berkeley Laboratory: and 3Northern California Cancer Center Neon ion radiotherapy possesses biologic and physical advantages over megavoltage X rays. Biologically, the neon beam reduces the oxygen enhancement ratio and increases relative biological effectiveness. Cells irradiated by neon ions show less variation in cell-cycle related radiosensitivity and decreased repair of radiation injury. The physical behavior of heavy charged particles allows precise delivery of high radiation doses to tumors while minimizing irradiation of normal tissues. In 1979 a Phase I-II clinical trial was started at Lawrence Berkeley Laboratory using neon ions to irradiate patients for whom conventional treatment modalities were ineffective. By the end of 1988 a total of 239 patients had received a minimum neon physical dose of 1000 cCy (median follow-up for survivors 32 months). Compared with historical results, the 5-year actuarial disease-specific survival (DSSs) and local control (LC,) rates suggest that neon treatment improves outcome for several types of tumors: a) advanced or recurrent macroscopic salivary gland carcinomas (DS& 59%; LCs 61%); b) paranasal sinus tumors (DSSS 69%; LCs 69% for macroscopic disease); c) advanced soft tissue sarcomas (DSSs 56%, LCs 56% for macroscopic disease); d) macroscopic sarcomas of bone (DSSs 45%; LCs 59%); e) locally advanced prostate carcinomas (DSSs 90%; LCs 75%); and f) biliary tract carcinomas (DSSs 28%; LCs 44%). Treatment of malignant gliomas, pancreatic, gastric, esophageal, lung, and advanced or recurrent head and neck cancer has been less successful; results for these tumors appear no better than those achieved with conventional x-ray therapy. These findings suggest that Phase III trials using the neon beam should be implemented for selected malignancies. Neon, Carcinoma, Sarcoma, Heavy ions, Heavy charged particles, High-LET, Radiotherapy, Chordoma, Bile duct, Paranasal sinus, Prostate, Salivary gland, Soft tissue sarcoma, Bone sarcoma. INTRODUCTION

ure can be attributed to a tumor’s low intrinsic radioresponsiveness coupled with dose limitations imposed by the tolerance of adjacent normal tissues. Neon ion irradiation offers potential advantages with respect to both of these problems. First, the neon beam has high linear energy transfer (high-LET) characteristics, producing biological behavior similar to neutron beams. Compared to X rays, there is: a) reduction in the oxygen enhancement ratio (OER) with proportionately greater killing of hypoxic cells, b) less variation in cell-cycle related radiosensitivity, and c) less capability for repair of radiation injury (5, 24). These qualities result in increased relative biological effectiveness (RBE) compared to low-LET megavoltage photon beams. Secondly, the physical characteristics of particle beams (including sharp distal and lateral beam

edges, and a defined, limited depth of penetration) provide dose distributions which are superior to X rays (24). This latter feature allows precise delivery of high radiation doses to tumor while avoiding irradiation of adjacent normal tissues. Because of these qualities, neon has been proposed as a potentially superior treatment alternative to megavoltage x-ray beams. In 1979 the Radiotherapy Section of the University of California Lawrence Berkeley Laboratory (LBL), the UCSF Department of Radiation Oncology, and the Northern California Cancer Center (NCCC) began a multi-site Phase I-II clinical trial investigating the role of neon ion irradiation. The purpose of the trial was to develop techniques for therapy planning and delivery, evaluate the acute and late toxicity of neon irradiation, and then systematically study the tumor response of a variety of malignancies. In general, patients were selected for treatment when their tumors could not be expected to respond favorably to conventional forms of therapy. The intent of this retrospective review is to report the local

Reprint requests to: David E. Linstadt, M.D.. Radiation Therapy Dept., Bldg. 55- I2 1, Lawrence Berkeley Laboratory, Berkeley, CA 94720.

Supported in part by NC1 grants CA I9 138, CA 2 1874, and DOE contract number DE AC03 76SF00098. Accepted for publication 12 October 1990.

Although megavoltage irradiation is an effective treatment modality for a wide variety of human cancers, in certain clinical settings results remain poor. Often treatment fail-

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control and survival rates of patients who underwent neon irradiation. identifying which tumors responded most favorably to the neon beam.

METHODS

AND

MATERIALS

Medical records were reviewed of all patients treated at LBL between 1979 and the end of 1988. Two hundred thirty-nine patients received neon beam physical radiation doses 2 1000 cGy. These patients make up the population used for this analysis. (Table 1) The treatment technique has been previously described in detail (7. 8, 12, 13). Because of the limited availability of the neon ion beam, most patients received mixed beam treatments combining neon. photon, and helium beams to bring their total tumor doses up to appropriate levels. The neon RBE for acute radiation reactions relative to megavoltagc X rays has been measured both in \~ivoand in vitro at 2.0-3.5, depending on fraction size, type of tissue irradiated. beam energy. size of the extended Bragg peak. and biological endpoint chosen (5, 14, 15, 32, 33, 42. 43, 48, 53). To express particle radiation doses in terms comparable to megavoltage X rays, the beam’s acute RBE value was used to calculate the “equivalent radiation dose” (expressed in cGyE) using the formula: neon physical

cGy X RBE = equivalent

cGyE,,,,,.

The corresponding acute-reacting tissue RBE for the helium beam is 1.2-1.4 (15, 32. 42, 43). and by definition the megavoltage x-ray RBE is 1.00. The total radiation dose (in cGyE) for the mixed beams was calculated as follows: CGY

Emm + cGYE,,,,,,,, + cGY~,> = total equivalent

This “total equivalent responds to the dose

Table 1. Distribution

_

radiation dose” (in cGyE) corof conventionally fractionated

of natients

Tumor

Melanoma Biliary tract Stomach Paranasal sinus Prostate Oral cavity/oropharynx/nasopharynx Esophagus Malignant glioma Salivary gland Lung Bone/soft tissue Pancreas Other Total

dose (cGyE)

in studv bv tumor tvne

April IO0

I.

Volume

20. Number

4

megavoltage X rays that would produce the same acute biologic effect as the mixed beams (27, 35). This cGyE dose is by no means exact because of differing mixes of LET values within the extended Bragg Peak and differences in RBE between different tissue types. However. despite its limitations. the “cGyE” value is useful to facilitate comparison with standard x-ray treatment results. Treatment sites included the brain, head and neck, salnasopharynx, paranasal sinuses, lung, ivary glands, esophagus. stomach, pancreas. bile ducts. prostate, and paraspinal/truncal locations. Specific histologic types of interest included salivary gland tumors, melanoma, malignant gliomas. and soft tissue and bone sarcomas. Chemotherapy was administered to many of the patients at some time during their illness. However, it was not used uniformly in large numbers of patients with the exception of a subgroup of pancreatic cancer patients who underwent aggressive combined modality treatment. Consequently, the impact of chemotherapy upon treatment outcome could not be studied in detail. Patients were analyzed with respect to disease-specihc survival (DSS) and local control (LC) of tumor. For the survival analysis, deaths due to disease or treatment complications were scored as events. Deaths due to unrelated illness were censored at the time they occurred. Local control was determined by serial clinical and radiographic exams and dehned as no evidence of residual tumor. Autopsy data were available for only a minority of patients. For the local control analysis, tumor persistence or local failure following irradiation were scored as events. Patients dying from distant metastatic disease. complications, or intercurrent illness with local control were censored from analysis at the time of death. No patients were lost to follow-up. Survival and time to local failure were calculated from the date irradiation began. Actuarial local control and disease-specific survival rates were calculated using the method of Berkson and Gage (2). Univariate dose-response analysis was performed for both total radiation dose (cGyE) and neon physical dose (cGy) using the chi-squared test with the Yate’s correction. Statistical significance was assigned to p values < .05.

No.

RESU L’I‘S 6 8 9

12 12 I3 I4 I6 I8 20 31 64 I6 239

Sixteen patients with malignant gliomas underwent irradiation. Nine had glioblastomas (GBM) and seven had anaplastic astrocytomas (AA). Follow-up times ranged from 3 to 77 months. Total radiation doses ranged from 4800 cGyE to 6900 cGyE (median 4933 cGyE), and neon physical doses ranged from 1375 to 2496 cGy (median dose 1856 cGy). Local control was obtained in only one patient (GBM histology) who died 3 I months after treatment. At the time of this analysis only one patient was alive, and she had developed local recurrence 25 months after treatment for an AA. Two patients (both with GBM)

Neon ion radiotherapy

developed radiation brain necrosis which proved fatal. One received 2240 cGy of neon (total dose of 5440 cGyE, RBE 2.43). The other patient died from combined local failure and brain necrosis after receiving 167 1 cGy of neon (4800 cGyE, RBE 2.98). Both of these patients were irradiated solely with the neon beam. Although the acute skin reaction experienced by these patients was consistent with the RBE value used to calculate the equivalent dose (cGyE), it appeared that the RBE for late CNS effects was substantially higher (4.0-4.5). Head and neck cancer Thirteen patients underwent irradiation of locally advanced (T4) or recurrent squamous cell carcinomas ofthe oral cavity, oropharynx, and nasopharynx. Twelve patients were treated with macroscopic disease: one had microscopic residual following salvage surgery for recurrence. Total radiation doses ranged from 3000-8040 cGyE (median 6000 cGyE): neon doses ranged from 1000-2084 cGy (median 1209 cGy). The 3-year DSS rate was 19%. Local control was achieved in only one patient who died of intercurrent illness 4 months after treatment. Paranasal .rinus tumors Twelve patients were treated for primary tumors arising within the paranasal sinuses. Gross residual tumor was present in 10 patients at the time irradiation was begun; microscopic disease remained in the other two. Median follow-up for surviving patients was 38 months (range 5.9-85.5). A total of four patients died of disease: two from locally recurrent tumor. and two from distant metastases with local control. The 5-year actuarial DSS rate for all patients was 69%. Both patients treated with microscopic disease remain free of disease. Three patients treated with gross disease failed locally at 1 1, 37, and 76 months after treatment. The 5-year actuarial LC rate for patients irradiated with macroscopic tumor was 69% (Fig. 1). Salivary? gland tumor.7 Eighteen patients were treated for locally advanced major and minor salivary gland tumors. Histology in-

MACROSCOPIC

PARANASAL

SINUS

TUMORS

763

0 D. E. LINSTADT CI (11.

eluded five mucoepidermoid carcinomas, four adenocarcinemas, and nine adenoidcystic carcinomas. Follow-up times for survivors ranged from 5 to 88 months (median 38 months). All patients had macroscopic tumor at the start of irradiation. Seven patients died as a result of disease: two from distant metastases with local control, one from distant metastases and local failure, and four as a result of local failure alone. The 5-year DSS rate was 59%. Six patients experienced local failure at times ranging from 10 to 76 months after the start of treatment. The 5-year actuarial LC rate was 6 1% (Fig. 2). Lung cancer Twenty patients with unresectable lung cancer underwent neon beam irradiation with curative intent. Gross tumor was present in all patients when irradiated. Three patients had clinical Stage II disease (AJCC 1988 staging system), 11 had Stage III-A, and 6 had III-B. Eight were squamous cell carcinomas, eight were adenocarcinomas, three were large cell/undifferentiated carcinomas, and one was adenoid cystic carcinoma. Total radiation doses ranged from 4800 to 7400 cGyE (median 6300 cGyE). Neon doses ranged from 1108-2895 cGy (median 2245 cGy). Only one patient survived: he presented with a Stage III-B (T4NlMO) adenocarcinoma, and remains free of disease 5 1 months after treatment. The 5-year actuarial DSS rate was 5%, with a median survival of 8 months. Local control was achieved in six patients: the 5-year actuarial LC rate was 12%. Univariate statistical analysis suggested that higher neon doses significantly improved local control (p < .05). The 5-year actuarial LC rate was 34% for patients receiving >2200 cGy of neon (local control in 6 of 1 1 patients), whereas no patient receiving 12200 cGy achieved local control. In contrast, there was no significant relationship between total radiation dose and local control (p > .50).

Fourteen patients with esophageal carcinoma underwent definitive irradiation. Thirteen patients were irradiated with gross tumor; one had microscopic residual following resection. Squamous histology was present in

MACROSCOPIC

0

SALIVARY

GLAND

TUMORS

20 t

ow’ 0

a

12

000’ 24

TIME

36

48

50

72

86

0

(MONTHS)

Fig. 1. Actuarial local control post-irradiation macroscopic paranasal sinus tumors.

c 12

24

TIME

for patients

with

35

48

60

72

84

(MONTHS)

Fig. 2. Actuarial local control for patients with macroscopic ivary gland tumors.

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Neon ion radiotherapy

0

MACROSCOPIC

radiation proctitis which eventually required colostomy (total dose 7900 cGyE: X-ray dose 5040 cGy, neon dose 1200 cGy, RBE 2.38). Sofi tissue surcomus Twelve patients with soft tissue sarcomas were treated. Histologic types included two chondrosarcomas, three neurofibrosarcomas, three malignant fibrous histiocytomas, one synovial sarcoma, one rhabdomyosarcoma, and two undifferentiated sarcomas. Two patients were irradiated palliatively for symptomatic macroscopic distant metastases. Microscopic disease was present in two patients at the time of irradiation. and gross tumor remained in the other 10. Follow-up times for survivors ranged from 3-5 1 months (median 44 months). Four patients had tumors located in sites that had been previously irradiated; consequently, their neon dose was substantially limited. Total radiation doses varied from 3740-8000 cGyE (median 6000 cGyE). Neon doses ranged from 1000-2458 cGy (median 1400 cGy). Six patients died: one from distant metastases, one from locally recurrent tumor, and four from combined distant metastases with local failure. The 5-year actuarial DSS rate for patients without distant metastases at the time oftreatment was 56%. Local control was achieved in both patients treated for microscopic residual tumor (sites and doses included retroperitoneum. 8000 cGyE: and thigh, 6960 cCyE). Five patients with macroscopic tumors had not been previously irradiated. They were treated with total doses ranging between 60007850 cGyE. Three remain free of disease; the 5-year actuarial LC rate was 56%. One patient developed a colonic stricture which required partial colectomy following 8000 cGyE to a retroperitoneal MFH: he remains free of disease 45 months after treatment. There were no other significant complications.

Nineteen patients underwent irradiation for primary bone sarcomas: two had known distant metastases at the time of irradiation. Macroscopic tumor was present in all but one patient. Seven patients were irradiated for chordoma, five had osteogenic sarcomas, five had chondrosarcomas, and two had undifferentiated sarcomas. (Two of the osteogenic sarcomas arose in the paranasal sinuses and were included in the paranasal sinus site analysis as well.) Total radiation doses ranged between 5000-7650 cGyE (median 6960 cGyE). Neon doses ranged from 1050-2595 cGy (median 1680 cGy). The 5-year actuarial DSS rate was 45% for patients for presenting without distant metastases. The 5-year actuarial LC rate for patients with macroscopic disease was 59% (Fig. 3). (Local control of macroscopic osteogenic sarcoma was achieved in 3 of 4 patients.) One previously irradiated patient died due to radiation brain necrosis following neon heavy-ion treatment to a radiation-induced undifferentiated sarcoma

765

D. E. LINSTADI ef L/I BONE

SARCOMA

0 40

t 0.20

t

t

Fig. 3. Actuarial local control post-irradiation macroscopic sarcomas of bone.

for patients

with

arising in the skull, This patient had received 5040 cGy and 3 courses of I- 13 1 for a follicular carcinoma of the thyroid 9 years before developing her sarcoma in the treatment field. She was treated at LBL with an additional 6500 cGyE (1920 CGY Helium, RBE 1.25: 1165 cGy neon, RBE 3.5 1). Again, although the acute skin reaction was consistent with the RBE’s employed. the late CNS reaction RBE was probably underestimated.

Mclunoma Six patients were treated for malignant melanoma located in a variety of sites including paranasal sinus, esophagus, lymph nodes, and skin. Gross tumor was present at the time irradiation began in all cases. Total radiation doses ranged from 4800-8000 cGyE (median 6000 cGyE). Neon dose ranged from 1253-3420 cGy (median 1530). Local control was obtained in two patients. One had a cutaneous lesion which was controlled when the patient died from distant metastases 13 months after irradiation (5400 cGyE; 1530 cGy neon). The other originated in the paranasal sinuses and was controlled when the patient died from distant disease 8 months after treatment (7500 cGyE: 1520 cGy neon).

Sixteen patients underwent neon beam irradiation for a variety of neoplasms. Many were irradiated with distant metastases during the Phase I portion of the trial when information regarding the beam’s clinical RBE was being obtained. Based on acute skin reaction and tumor response, the results from these neon patients confirmed the clinical applicability of acute RBE values in the 2.03.0 range. Later in the study, other tumors were treated including such histologies as thyroid carcinoma, colon carcinoma, renal cell carcinoma, plasmacytoma, and bladder cancer. For these types of tumors, the number of patients treated were too small for critical analysis.

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I. J. Radiation

Oncology 0 Biology 0 Physics

DISCUSSION This multi-site trial has established the clinical feasibility of neon ion irradiation in the treatment of a wide variety of human malignancies. Although a total of 239 patients were included in this analysis, the number of patients in each tumor subgroup was consistent with the trial’s overall Phase I-II design. Neon doses were gradually escalated and toxicity limits were reached. Complications, although sometimes fatal, were relatively infrequent and well within accepted limits for advanced, refractory tumors treated with curative intent. The beam’s clinical acute-reaction RBE appeared consistent with experimental in vitro and in vivo measurements in the range of 2.03.5 (average 2.5). The clinical RBE for late effects may be higher, particularly for the CNS. A more detailed analysis of late complications is beyond the scope of this paper, but will be addressed in the future. In vivo human studies have suggested that slowly growing tumors respond most favorably to high-LET radiation (1, 30). Repair of potentially lethal damage (PLDR) by non-cycling or slowly-cycling tumor cells has been proposed as a cause of x-ray treatment failure for relatively radioresistant tumors (5 1, 54). PLDR is substantially reduced with high-LET forms of radiation (6. 24) and this factor could explain why high-LET irradiation appears to be most effective for slowly growing tumors. Alternatively, Eichhorn has postulated that decreased variation in cellcycle related radiosensitivity may be important, postulating that for both tumors and normal tissues, the smaller the proportion of proliferating cells. the greater the RBE of high-LET radiation ( 16). Together, differences in repair and cell-cycle specific radiosensitivity provide an attractive theoretical framework suggesting which tumors are most likely to respond high-LET radiation. In the future. individualized predictive assays may prove useful to delineate growth parameters or inherent radiosensitivity suited to high-LET therapy. Based on DSS and LC rates. neon treatment of malignant gliomas. melanoma, advanced or recurrent head and neck squamous cell carcinomas, non-small cell lung, esophageal, gastric, and pancreatic malignancies was not better than conventional therapy. These findings are generally in accord with the high-LET neutron experience reported from other centers (3, 4). Malignant gliomas treated with neutron boosts have failed to show a survival advantage over patients treated with X rays alone, although local control appears better with neutrons (20,2 I, 28). Neon beams potentially offer an improvement; they possess the high-LET advantage with substantially better dose-distribution characteristics. Further investigation of neon’s role in the treatment of GBM is now underway with the opening of a Phase II study (NCCC protocol 6-G-87). Mixed results have been obtained with neutron therapy of advanced head and neck cancers. Overall, there appears

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to be no significant local control advantage to neutrons over X rays, despite a slightly higher neutron complication rate (52). A randomized RTOG trial between neutron and photon irradiation showed a statistically significant improvement in complete response rate for neutrons. although survival rates were not significantly different (22). A larger RTOG trial comparing mixed photon and neutron beams against photons alone showed no difference in control of the primary tumor or overall survival, although neutrons did produce a significant improvement in the complete response rate of metastatic neck nodes (23). The results from the current neon series were not encouraging, as no patient attained long-term local control. However, these were advanced tumors irradiated at a time when treatment techniques were still developing and with gradually escalating doses. In the future, improved conformal therapy techniques and predictive assays to select for slowly growing tumors may establish a role for high-LET treatment of these tumors. Neutron beams have not improved results in the treatment of non-small cell lung cancer (47). A randomized 3-arm RTOG trial compared neutron irradiation alone versus mixed neutrons and photons and photons alone. There were no significant differences in terms of local control or survival between the three arms. although complication rates and treatment-related mortality were higher in the patients receiving neutrons (29). The current neon trial did produce one long-term survivor, giving a 5-year actuarial DSS rate of 5%. A univariate dose-response analysis suggested that higher neon doses were associated with significantly improved local control. Although the number of patients in this series is small, the neon results do not appear to be any better than those reported using conventional X rays ( 17, 37, 40, 4 1). Treatment of most gastrointestinal malignancies has shown little improvement with high-LET forms of radiation. The RTOG randomized clinical trial showed no advantage for neutrons or mixed neutron/photon beams when compared to conventional photon irradiation in the treatment of unresectable pancreatic cancer (49). A similar prospective trial comparing lower-LET helium ions with X rays noted similar findings (34). Consistent with the superior dose-distribution of particles. neon beams appeared to improve acute radiation tolerance, but no survival advantage was apparent for pancreatic, gastric, or esophageal cancers. In the future, conformal therapy using a scanned heavy-ion beam may provide sufficient improvement in the therapeutic ratio to be useful in the treatment of these GI malignancies. The neon beam results did appear to offer potentially improved survival and local control for patients with paranasal sinus tumors. macroscopic salivary gland tumors, bile duct carcinomas, macroscopic soft tissue and bone sarcomas, and advanced prostate carcinomas (Table 2). The neon beam patients with paranasal sinus tumors showed an actuarial 5-year DSS rate of 69%, and a 5-year

Neon ion radiotherapy

Table 2. Treatment outcome comparing neon beam, neutron, and conventional X-ray therapy for selected types of tumors Neon beam Tumor

and endpoint

Macroscopic (long-term Macroscopic (long-term (long-term Macroscopic (long-term Macroscopic (long-term

studied

salivary gland Ca local control) paranasal sinus Ca survival) local control) soft tissue sarcomas local control) sarcoma of hone local control)

Neutrons

X rays

(T)

(%I)

(RI)

61

60-70

25-36

69 69

30+ 50-86

32-40

56

50-54

30-50

59

49-55

21-33

N/A

See text for references.

LC rate of 69% for patients irradiated with macroscopic disease. These results seem better than those achieved historically with conventional x-ray treatment; photon irradiation alone has been reported to yield a 40% cure rate at 5 years for ethmoid sinus tumors, with corresponding survival rates in the 32-35%1 range for maxillary sinus tumors (36, 38). Based on the encouraging results with high-LET forms of radiation (9. 18) it appears that a Phase III study should be implemented comparing the neon beam with X rays in the treatment of advanced paranasal sinus tumors. Locally advanced or recurrent salivary gland tumors also appear to respond favorably to high-LET radiation. Patients with macroscopic tumors who are treated with conventional X rays alone achieve local control approximately 25% of the time (10, 26). The UCSF photon experience noted 36% local control for inoperable tumors (19). On the other hand, patients treated with neutrons at multiple centers report local control rates on the order of 60-70% ( 10, 26, 46) and based on these results it has been suggested that fast neutrons are the treatment of choice for these tumors (26). The current neon results are similar to those reported for neutrons: the 5-year DSS rate was 59% with a 5-year LC rate of 6 1Yo, and suggest that either neutrons or neon ions are indicated for unresectable or macroscopically residual salivary gland tumors. Bile duct tumors typically grow slowly with a low incidence of distant metastases. Death is usually due to locally progressive disease. Overall 5-year survival rates following surgery are reported in the 8% range. although survival for resected tumors involving the ampulla of Vater or distal common bile ducts have been reported as high as 28% (50). Unresectable bile duct tumors have occasionally responded to external beam irradiation followed by temporary Ir- 192 implantation (25). Although the current study consists of a small number of patients, all had unfavorable tumors. and the results were encouraging with a 28% 5-year survival rate and 44% local control rate. These results suggest that further studies with neon ions should be undertaken for bile duct carcinoma following actuarial

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incomplete resection or when microscopic residual disease is suspected. Conservative surgery and x-ray therapy have proven effective in the management of many soft tissue sarcomas, particularly for extremity lesions where high radiation doses (60-70 Gy) may be delivered without risking injury treatment of unto critical viscera (I I). Unfortunately, resectable sarcomas (often located in the trunk or head and neck) has been less successful. Photon irradiation alone achieves local control only 30-50% of the time ( 11, 30). This class of tumors may be preferentially sensitive to high-LET irradiation: fast neutrons have improved local control to 50-54% (30, 39, 44). The results from the current trial support the role of high-LET irradiation in this setting; the 5-year actuarial local control rate for macroscopic soft tissue sarcoma using neon ions was 56%. Additionally, the superior dose-localization properties of heavy ions make this form of treatment attractive for patients with residual disease in retroperitoneal or truncal locations where adequate x-ray or neutron doses (60-70 GyE) often cannot be given safely. Sarcomas of bone have displayed a similar tendency toward improved local control with high-LET irradiation. Neutrons have achieved local control rates of 55% for macroscopic osteogenic sarcoma and 49% for macroscopic chondrosarcoma (30). These results appear superior to the photon experience, where local control rates of only 2 1YO(osteogenic sarcoma) and 33% (chondrosarcoma) have been reported (30). The neon beam outcome was similar to the neutron findings; the 5-year actuarial local control rate for non-osteogenic sarcomas was 54%. Also, in the current series, 3 of 4 macroscopic osteogenic sarcomas were controlled locally with total equivalent doses ranging from 6000-7 140 cGyE using RBE’s in the 2.5 range. It seems unlikely that such low equivalent doses would have controlled macroscopic disease unless the osteogenic sarcoma cells were selectively vulnerable to the high-LET radiation. Consequently, there is a strong suggestion that the clinical neon RBE for osteogenic sarcoma is substantially higher than 2.5-3.0. Additionally, the superior dose-distribution of neon ions makes this form of treatment attractive for sarcomas arising in the clivus and spine, where normal brainstem and spinal cord drastically limit the dose that can be safely delivered with either photons or neutrons. Based on these results, a randomized Phase II NCCC study (O-R-89) has been opened comparing neon with lower-LET helium ions in the treatment of macroscopic soft tissue and bone sarcomas. Finally, the small experience using neon ion in the treatment of locally advanced prostate cancer appears promising. The RTOG prospective study comparing photons with a mixed beam photon/neutron arm has suggested that disease-specific survival and freedom from local recurrence were significantly improved in the neutron-treated patients (3 1.45). The follow-up of the current study’s neon-treated patients is short, but the actuarial 5-

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year survival couraging for Currently the versus photon patients with

(90%) and local control rate (75%) are enpatients with such locally advanced tumors. NCCC is investigating the role of neon ion boosts in a phase III trial (4-P-85-1J) for Stage C and Dl disease. CONCLUSIONS

1. Neon ion radiotherapy has proven to be a clinically feasible curative treatment modality which appears to offer

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improved results over conventional therapy in selected human cancers.

megavoltage

x-ray

2. Tumors that appear to respond most favorably to neon beams include advanced paranasal sinus cancers, macroscopic salivary gland carcinomas, bile duct carcinomas, macroscopic soft tissue and bone sarcomas, and locally advanced prostate carcinomas. Treatment ofthese tumors with heavy ions should now be studied in phase III clinical trials.

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