Medicine Section - Charged-Particle (Proton or Helium Ion) Radiation Therapy

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Charged-particle beams consisting of protons or helium ions are a type of particulate radiation therapy that contrast with conventional electromagnetic (i.e., photon) radiation therapy due to the unique properties of minimal scatter as the particulate beams pass through the tissue, and deposition of the ionizing energy at a precise depth (i.e., the Bragg Peak). Thus radiation exposure to surrounding normal tissues is minimized. The theoretical advantages of protons and other charged-particle beams may improve outcomes  when the following conditions apply:

• Conventional treatment modalities do not provide adequate local tumor control,
• Evidence shows  that local tumor response depends on the dose of radiation delivered, and
• Delivery of an adequate radiation dose to the tumor is limited by the proximity of vital radiosensitive tissues or structures

The use of proton or helium ion radiation therapy has been investigated in two general categories of tumors/abnormalities:

• Tumors located next to vital structures, such as intracranial lesions, or lesions along the axial skeleton such that complete surgical excision or adequate doses of conventional radiation therapy are impossible. These tumors/lesions include uveal melanomas, chordomas, and chondrosarcomas at the base of the skull and along the axial skeleton.
• Tumors that are associated with a high rate of local recurrence despite maximal doses of conventional radiation therapy. The most common tumor in this group is locally advanced prostate cancer (i.e., Stages C or D1 [without distant metastases], also classified as T3 or T4 and tumors with Gleason scores of 8 to 10). These patients are generally not candidates for surgical resection, and the 5- and 10- year local recurrence rate associated with conventional radiation are estimated at 24% - 28% and 39% - 42%, respectively.

Note: The use of proton or helium radiation in conjunction with stereotactic guidance is addressed in a separate policy on Stereotactic Radiosurgery, Surgery, Policy No. 16.

Policy/Criteria

Charged-particle irradiation with proton or helium ion beams may be considered medically necessary in the following clinical situations:

1. Primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension, and with tumors up to 24 mm in largest diameter and 14 mm in height.
2. Postoperative therapy (with or without conventional high-energy x-rays) in patients who have undergone biopsy or partial resection of the chordoma or low-grade (I or II) chondrosarcoma of the basisphenoid region (skull-base chordoma or chondrosarcoma) or cervical spine. Patients eligible for this treatment have residual localized tumor without evidence of metastasis.
3. Primary therapy of clinically localized prostate cancer.

Charged-particle irradiation with proton beams is considered investigational for all other indications.

Scientific Background

Uveal Melanoma, Chordoma, and Chondrosarcoma

Prostate Cancer

The evaluation of treatment options for clinically localized prostate cancer is problematic because there is not convincing evidence that any treatment is more effective than watchful waiting in improving clinically meaningful patient outcomes. Even assuming that an intervention can improve outcomes compared to watchful waiting, the variable and often indolent natural history of clinically localized prostate cancer would require randomized trials with follow-up of ten to fifteen years to determine if proton beam therapy is associated with equivalent or superior long-term outcomes compared to external beam radiation therapy. These data are not currently available and will not be available from direct comparable studies in the foreseeable future. The lack of these trials prohibits strict scientific conclusions regarding the comparative efficacy of proton beam therapy and conformal external beam radiation therapy. However, the published data do document significant similarity in outcomes of charged-particle beam radiation therapy compared to conventional conformal external beam radiation therapy in the treatment of clinically localized prostate cancer.

In 1995, Shipley and colleagues reported results of a randomized clinical trial comparing outcomes of conventional radiation therapy with versus without an additional radiation “boost” of proton beam therapy. (5) Patients treated in the control arm received a total of 67.2 Gy, while those in the “high-dose” arm received a total of 75.6 Gy. This study, initiated in 1982, was designed to determine if this dose escalation of 12.5% would increase the 5- and 8-year rates of local control, disease-specific survival, overall survival, or total tumor-free survival with acceptable side effects. Surprisingly, there was no statistically significant difference in any of the outcomes measured. On subgroup analysis, patients with poorly differentiated cancer achieved a statistically significant improvement in the rate of local control, but not in other outcomes such as overall survival or disease-specific survival. Patients in the high-dose arm experienced a significantly increased rate of complications, most notably rectal bleeding.

In 2000 Schulte and colleagues published 39 month outcomes in 911 patients with limited stage clinically localized prostate cancer treated at Loma Linda University Medical Center. (6) Patients were treated with either protons alone or proton boost following standard external beam radiation therapy. Proton therapy was delivered at a dose of 74 to 75 Gy. Response to treatment was assessed both clinically and biochemically (PSA levels), with a patient being scored as a biochemical failure if he experienced three consecutive PSA elevations above a nadir (American College of Radiology consensus conference definition of biochemical failure).  Patients were also assessed for any acute and/or late treatment-related morbidity, which was scored according to the Radiation Therapy Oncology Group (RTOG) morbidity scoring system. Five-year actuarial clinical and biochemical disease-free survival for the entire group of patients is 89% and 79% respectively. The patients were subsequently stratified into early (T1-T2 and PSA less than 15) and locally advanced (T1-T2 and PSA greater than 15 or T2-T4 with PSA less than 50) groups. A statistically significant difference in biochemical disease-free survival was seen between the two groups (89% versus 68%, p= less than 0.001). The biochemical disease-free survival rates in clinically localized prostate cancer patients treated with proton beam therapy, when compared to historical controls who received radical prostatectomy, external beam radiation therapy, or brachytherapy, indicate comparable outcomes. In this series, treatment related morbidity was low with no grade III or IV gastrointestinal or genitourinary toxicity. The incidence of grade II gastrointestinal toxicity was 3.5%. Time to symptom onset was two to 58 months (median, 26 months). Rectal bleeding was described as “self-limiting and resolved within a few months”. The most common treatment side effect of proton therapy is gastrointestinal bleeding. The estimated 5-year outcomes of no biochemical evidence of disease were 82%. Actual long-term outcomes and survival are not included in the published report.

The majority of reports published since the 1996 TEC Assessment documented the experience of the Loma Linda University Medical Center. In 2004, investigators at Loma Linda reported their experience with 1,255 patients with prostate cancer who underwent 3D-CRTproton beam radiation therapy. (7) Outcomes were measured in terms of toxicity and biochemical control, as evidenced by PSA levels. The overall biochemical disease-free survival rate was 73% and was 90% in patients with initial PSA less than or equal to 4.0. The long-term survival outcomes were comparable with those reported for other modalities intended for cure.

From the published literature, it appears that dose escalation is an accepted concept in treating organ-confined prostate cancer. (8) Proton beam therapy, using 3-D conformal radiation planning (3-D CRT) or intensity modulated radiation planning (IMRT), is one technique used to provide dose escalation to a more well-defined target volume. However, dose escalation is more commonly offered with conventional external beam radiation therapy using 3-D CRT or IMRT. The morbidity related to radiation therapy of the prostate is focused on the adjacent bladder and rectal tissues; therefore, dose escalation is only possible if these tissues are spared. Even if IMRT or 3-D CRT permits improved delineation of the target volume, if the dose is not accurately delivered, perhaps due to movement artifact, the complications of dose escalation can be serious, as the bladder and rectal tissues are now exposed to even higher doses. The accuracy of dose delivery applies to both conventional and proton beam therapy. (9)

In summary, the available published evidence from a single institution's large experience, (6, 10, 11) seems to indicate that proton beam therapy for the treatment of clinically localized prostate cancer appears to have biochemical disease-free survival rates at least as good as standard therapies of prostate cancer and with equivalent or potentially less treatment related morbidity thus making it appealing to patients. Therefore, given the baseline uncertainty regarding long-term outcomes associated with any or no treatment of clinically localized prostate cancer, decisions regarding any treatment option for prostate cancer are frequently reframed as an issue of patient preference, even while acknowledging the decision must be made based on incomplete data. Given the evolving acceptance of proton beam therapy as a standard of care and biochemical control as an accepted outcome measure of prostate cancer treatments, the policy is changed to consider standard dose proton beam therapy as a medically appropriate treatment option for men with clinically localized prostate cancer.

An updated search of the literature based on the MEDLINE database through January 2008 returned one new clinical study of proton beam boost therapy for the treatment of prostate cancer. Zietman and colleagues randomized 392 patients with localized prostate cancer (stage T1b through T2b, serum PSA less than 15 ng/mL, and no evidence of metastasis) to two different radiation doses delivered by conformal techniques. (12) All patients received conformal photon therapy to a dose of 50.4 Gy. The difference between groups was in the boost dose delivered by proton beam therapy. The boost dose was either 19.8 Gy or 28.8 Gy. All patients received radiation therapy without adjuvant or concurrent hormonal therapy. The clinical target volume for all patients included the prostate and seminal vesicles with a margin of 10 mm for potential microscopic infiltration. The five-year freedom from biochemical failure was 61.4% for patients in the conventional-dose group and 80.4% for patients in the high-dose group. The actuarial estimate of local control at five years was 47.6%for conventional dose and 67.2% for high dose (p less than 0.001). At the time of publication there was no difference in the overall survival rates between the two groups (97% vs. 96%, p=.80) Grade 2 acute rectal morbidity was higher in the high dose group (57% compared to 41%; p=0.004) as well as late gastrointestinal morbidity (17% compared to 8%; p=.005). As noted in an accompanying editorial, it is likely that high radiation doses delivered to men with localized prostate cancer is associated with improved biochemical control of the disease. (13) However, whether PSA control with high dose proton beam therapy translates into clinically meaningful end-points such as longer survival is not known. The editorial goes on to state:

“As such, this study has not answered the important question of whether patients should accept the modest but real incremental risk of higher radiation doses for the uncertain ultimate benefit derived. Several other questions also remain unanswered: (1) Would higher radiation doses beyond 79 Gy provide even greater benefit? (2) What is the optimal radiation method of dose escalation? and (3) Given that the addition of androgen suppression to radiotherapy has recently been shown to improve survival in some patients, is dose escalation even the best way to improve radiotherapeutic outcomes in this disease?”

Additional Indications

Available scientific evidence on the use of proton beam for other indications is limited. The published results of four studies in patients with non-CNS tumors document preliminary outcomes of phase I/II clinical trials of proton beam therapy for a number of cancers including bladder cancer, uterine cancer, hepatocellular carcinoma, sinonasal undifferentiated carcinoma, medulloblastoma, axial skeletal tumors, and lung cancer. Information from more cases, results of more long-term observations, and comparison to standard treatments is needed. (14-21) In most studies proton beam therapy is used in combination with other therapies. This, plus lack of a comparison group makes it difficult to isolate the independent contribution proton beam therapy has made. Additionally, larger studies that evaluate a potential decrease in morbidity associated with the use of proton beam therapy compared with traditional photon beam therapy would be helpful.

Three published studies of proton therapy for age-related macular degeneration (ARMD) and two articles setting forth a theoretical basis for using protons were identified.(22-24) One of the studies is a randomized placebo-controlled clinical trial of 37 patients.(22)  Proton irradiation was associated with a trend toward stabilization of visual acuity, but this association did not reach statistical significance. No correlations were found within the fluorescein angiography data, including greatest linear dimension of choroidal neovascular membranes total size, area of active leakage, area of associated subretinal hemorrhage, and intensity. The remaining two studies are phase I/II trials looking at the feasibility of proton therapy, toxicities, and dose escalation to identify the maximum tolerated dose for control of exudative ARMD.(23,24) Future studies are needed with more complex design and larger sample size to determine whether radiation can play either a primary or adjunctive role in treating these lesions.

An updated search of the literature through January 2008 returned one new published study of proton beam therapy in breast cancer and one study of proton beam therapy for stage I non-small-cell lung cancer. (25-27)  Kozak and colleagues addressed the technical feasibility of proton three dimensional conformal, external beam partial breast irradiation (3D-CPBI) in 20 patients with fully excised node-negative, early stage breast cancer. (25) In a second publication of apparently the same group of 20 women, an analysis of cosmetic outcomes and tumor recurrence at 12 months is reported. (26) The authors propose that 3D-CPBI using protons instead of standard photon therapy offers dose improved homogeneity to the tumor bed while sparing normal breast tissue from a radiation dose.  In light of the lack of a randomized comparison group, short follow-up, small number of patients, and favorable prognoses of the enrolled patients, conclusions concerning the equivalence of 3D-CPBI to whole breast radiation therapy cannot be made. Hata and colleagues reported results of a feasibility study of 21 patients with stage I non-small-cell lung cancer (NSCLC) who underwent hypo fractionated high-dose proton beam therapy.(27) The two-year overall survival and cause-specific survival rates were 74% and 86% respectively. Lack of randomization and small sample size prevent conclusions concerning the effectiveness of hypo fractionated high-dose proton beam therapy for the treatment of NSCLC. Data from additional studies, more long-term observations, and comparison to standard treatments are still needed.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.10
2. TEC Assessment: Charged Particle (Proton or Helium Ion) Irradiation for Uveal Melanoma and for Chordoma or Chondrosarcoma of the Skull Base or Cervical Spine, 1996; BlueCross and BlueShield Association Technology Evaluation Center, Vol. 11, Tab. 1
3. Suit H, Urie M. Proton beams in radiation therapy. J Nat Cancer Inst 1992;84:155-63
4. Damato B, Kacperek A, Chopra M et al. Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience. Int J Radiat Oncol Biol Phys 2005; 62(5):1405-11.
5. Shipley WU, Verhey LJ, Munzenrider JE. Advance prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal photons compared with conventional dose irradiation using protons alone. Int J Radiation Oncol Biol Phys 1995;32:3-12
6. Schulte RW, Slater JD, Rossi CJ, Slater JM. Value and perspectives of proton radiation therapy for limited stage prostate cancer. Strahlentherpie und Onkologie 2000;176: 3-8
7. Slater JD, Rossi CJ, Yonemoto LT et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys 2004; 59(2):348-52.
8. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncologica 2004; 43(4):316-81.
9. Kuban D, Pollack A, Huang E et al. Hazards of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57(5):1260-8.
10. Hanks GE. A question filled future for dose escalation in prostate cancer. Int J Radiation Oncol Biol Phys 1995;32:265-66
11. Cox JD. Dose escalation by proton irradiation for adenocarcinoma of the prostate. Int J Radiation Oncol Biol Phys 1995;32:265-66
12. Zietman AL, DeSilvio ML, Slater JD et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate. A randomized controlled trial. JAMA 2005;294:1233-1239
13. DeWeese TL, Song DY. Radiation dose escalation as treatment for clinically localized prostate cancer. JAMA 2005;294:1233-1239
14. Miyanaga N, Akaza H, Okumura T et al. A bladder preservation regimen using intra-arterial chemotherapy and radiotherapy for invasive bladder cancer: a prospective study. Int J Urology 2000;7(2):41-8
15. Bush D, Hillebrand DJ, Slater J et al. High-dose proton beam radiotherapy of hepatocellular carcinoma: Preliminary results of a phase II trial. Gastroenterology 2004;127:S189-S193
16. Bonnet RB, Bush D, Cheek GA, Slater JD, et al. Effects of proton and combined proton/photon beam radiation on pulmonary function in patients with resectable inoperable non-small cell lung cancer. Chest 2001;120(6):1803-10
17. Kagel K, Koichi T, Okumura T et al. Long-term results of proton beam therapy for carcinoma of the uterine cervix. Int J Rad Oncol Biol Phys 2003;55(5):1265-71
18. Huang D, Xia P, Akazawa P, et al. Comparison of treatment plans using intensity-modulated radiotherapy and three-dimensional conformal radiotherapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2003; 56(1): 158-68.
19. Yuh GE, Loredo LN, Yonemoto LT et al. Reducing toxicity from craniospinal irradiation: using proton beams to treat medulloblastoma in young children. Cancer J 2004;10(6):386-90
20. St Clair WH, Adams JA, Bues M Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma.  J Radiat Oncol Biol Phys 2004;58(3):727-34
21. Hug EB, Fitzek MM, Liebsch NJ et al. Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimensional treatment planning. Int J Radiat Oncol Biol Phys 1995;31(3):467-76
22. Ciulla TA, Danis RP, Klein SB. Proton therapy for exudative age-related macular degeneration: a randomized, sham-controlled clinical trial. Am J Ophthalmol  2002;134(6):905-6
23. Flaxel CJ, Friedrichsen EJ, Smith JO et al.  Proton beam irradiation of subfoveal choroidal neovascularisation in age-related macular degeneration. Eye  2000;14 ( Pt 2):155-64
24. Adams JA, Paiva KL, Munzenrider JE et al.  Proton beam therapy for age-related macular degeneration: development of a standard plan.  Med Dosim  1999;24(4):233-8
25. Taghian AG, Kozak KR, Katz A et al. Accelerated partial breast irradiation using proton beams: initial dosimetric experience. Int J Rad Oncol Biol Phys 2006;65(5):1404-10
26. Kozak KR, Smith BL, Adams J et al. Accelerated partial breast irradiation using proton beams: initial clinical experience. Int J Rad Oncol Biol Phys 2006;66(3):691-8
27. Hata M, Tokuuye K, Kagel K et al. Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int J Radiat Oncol Biol Phys. 2007;68(3):786-93.

Cross References

Stereotactic Radiosurgery and Stereotactic Radiotherapy, Regence Medical Policy Manual, Surgery, Policy No. 16

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