The University of Texas MD Anderson cancer center’s recommended proton therapy indications

Accelerated partial breast irradiation

• ■

  The safety and efficacy of proton partial breast irradiation (PBI) is established for early-stage breast cancer. Proton PBI provides a more homogeneous dose distribution and reduction in exposure to the normal breast, heart, and lung compared with photon and brachytherapy PBI techniques and has been associated with excellent local control and reduced toxicity. [CR] We are investigating a 10-fraction hypofractionated proton regimen, which may be more cost-effective and also improve the therapeutic ratio.

• ■

  Inclusion criteria

  • i.

    The patient must have stage 0, I, or II breast cancer. If stage II, the tumor size must be 3 cm or less.

  • ii.

    On histological examination, the tumor must be ductal carcinoma in situ (DCIS) or invasive adenocarcinoma of the breast.

  • iii.

    Surgical treatment of the breast must have been lumpectomy. The margins of the resected specimen must be histologically free of tumor (DCIS and invasive). Reexcision of surgical margins is permitted.

  • iv.

    Gross disease must be unifocal with pathologic (invasive and/or DCIS) tumor size 3 cm or less. (Patients with microscopic multifocality are eligible as long as total pathologic tumor size is ≤3 cm.)

  • v.

    The target lumpectomy cavity must be clearly delineated, and the target lumpectomy cavity/whole breast reference volume must be less than or equal to 30% based on the postoperative/preenrollment computed tomography (CT) scan.

• ■

  Exclusion criteria:

  • i.

    Men are not eligible.

  • ii.

    T2 (>3 cm), T3, stage III, or stage IV breast cancer.

  • iii.

    More than three histologically positive axillary nodes.

  • iv.

    Axillary nodes with definite evidence of microscopic or macroscopic extracapsular extension.

  • v.

    Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes at time of enrollment unless there is histologic confirmation that these nodes are negative for tumor.

  • vi.

    Suspicious microcalcifications or densities (in the ipsilateral or contralateral breast as documented on mammogram or breast ultrasound) unless biopsied and found to be benign.

  • vii.

    Nonepithelial breast malignancies such as sarcoma or lymphoma.

  • viii.

    Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters.

  • ix.

    Paget disease of the nipple.

  • x.

    Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible.)

  • xi.

    Clear delineation of the extent of the target lumpectomy cavity not possible.

  • xii.

    Treatment plan that includes regional nodal irradiation.

  • xiii.

    Prior radiation to the index breast.

  • xiv.

    Documented diagnosis of collagen vascular disease, specifically dermatomyositis with a creatine phosphokinase level above normal or with an active skin rash, systemic lupus erythematosus, or scleroderma.

  • xv.

    Pregnancy or lactation at enrollment.

  • xvi.

    Women of reproductive potential must agree to use an effective nonhormonal method of contraception during therapy.

Left or right-sided early or locoregionally advanced breast cancer requiring breast or chest wall plus regional nodal irradiation (i.e., lymph node-positive disease, advanced T stage, and/or medial tumor location)

• ■

  Adjuvant radiotherapy improves survival in breast cancer patients, suggesting that persistence of locoregional tumor is associated with an increased risk of developing metastases and death. Results of modern randomized controlled clinical trials highlight the importance of regional nodal irradiation in reducing distant events in this population. [CR] ^, [CR] Targeting of the regional lymphatics results in lung and heart doses associated with increased major cardiac events, cardiac deaths, lung cancer, and lung cancer deaths in a patient population where advances in systemic therapy and other multidisciplinary care has resulted in decreasing breast cancer-specific mortality. Proton radiotherapy improves coverage of the regional lymphatics while substantially reducing mean lung and mean heart doses (MHDs) to levels significantly correlated with reduced cardiac events, lung cancer, and symptomatic pneumonitis. [CR] We are currently enrolling patients in the national RADCOMP trial (NCT02603341) that is randomizing patients who receive regional nodal irradiation between proton and photon radiation.

• ■

  Inclusion criteria

  • i.

    Age 18 years or older.

  • ii.

    Histologic confirmation of breast cancer resected by lumpectomy or mastectomy with or without immediate reconstruction and whole breast/chest wall and regional nodal irradiation planned with or without a boost to the lumpectomy cavity/chest wall.

  • iii.

    The axilla must be staged by sentinel node biopsy alone, sentinel node biopsy followed by axillary node dissection, or axillary lymph node dissection alone.

  • iv.

    pStage T1-T4N0-N3M0 or ypStage T0-4N0-N3M0.

  • v.

    Indications for regional nodal irradiation per treating physician (lymph node–positive disease, T3 to T4, medial tumor location).

  • vi.

    Breast implants and expanders allowed.

• ■

  Exclusion criteria

  • i.

    Medical contraindication to receipt of radiotherapy.

  • ii.

    Severe, active comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

  • iii.

    Active systemic lupus or scleroderma.

  • iv.

    Pregnancy or women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception.

Ares C, Khan S, Macartain AM, et al. Postoperative proton radiotherapy for localized and locoregional breast cancer: potential for clinically relevant improvements? Int J Radiat Oncol Biol Phys. 2010;76:685-697.

Bradley JA, Dagan R, Ho MW, et al. Initial report of a prospective dosimetric and clinical feasibility trial demonstrates the potential of protons to increase the therapeutic ratio in breast cancer compared with photons. Int J Radiol Oncol Biol Phys. 2016;95(1): 411-421.

Bush DA, Do S, Lum S, et al. Partial breast radiation therapy with proton beam: 5-year results with cosmetic outcomes. Int J Radiat Oncol Biol Phys. 2014;90(3):501-505.

Bush DA, Slater JD, Garberoglio C, Do S, Lum S, Slater JM. Partial breast irradiation delivered with proton beam: results of a phase II trial. Clin Breast Cancer. 2011;11(4): 241-245.

Chang JH, Lee NK, Kim JY, et al. Phase II trial of proton beam accelerated partial breast irradiation in breast cancer. Radiother Oncol. 2013;108(2):209-214.

Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087-2106.

Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-565.

Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998.

Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804): 1707-1716.

Depauw N, Batin E, Daartz J, et al. A novel approach to postmastectomy radiation therapy using scanned proton beams. Int J Radiat Oncol Biol Phys. 2015;91(2): 427-434.

Doyen J, Falk AT, Floquet V, et al. Proton beams in cancer treatments: clinical outcomes and dosimetric comparisons with photon therapy. Cancer Treat Rev. 2016;43: 104-112.

EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.

Galland-Girodet S, Pashtan I, MacDonald SM, et al. Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional conformal accelerated partial-breast irradiation: a phase 1 trial. Int J Radiat Oncol Biol Phys. 2014; 90(3):493-500.

Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013; 14(11):1086-1094.

Johansson J, Isacsson U, Lindman H, Montelius A, Glimelius B. Node-positive left-sided breast cancer patients after breast-conserving surgery: potential outcomes of radiotherapy modalities and techniques. Radiother Oncol. 2002;65(2):89-98.

Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet . 1999;353(9165):1641-1648.

MacDonald SM, Patel SA, Hickey S, et al. Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial. Int J Radiat Oncol Biol Phys . 2013;86(3):484-490.

MacDonald SM, Jimenez R, Paetzold P, et al. Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery. Radiat Oncol . 2013;8:71.

Mast ME, Vredeveld EJ, Credoe HM, et al. Whole breast proton irradiation for maximal reduction of heart dose in breast cancer patients. Breast Cancer Res Treat . 2014;148(1):33-39.

McGee LA, Iftekaruddin Z, Chang JHC, et al. Postmastectomy chest wall reirradiation with proton therapy for breast cancer. Int J Radiat Oncol Biol Phys . 2017;99(2):E34-E35.

Moon SH, Shin KH, Kim TH, et al. Dosimetric comparison of four different external beam partial breast irradiation techniques: three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, helical tomotherapy, and proton beam therapy. Radiother Oncol . 2009;90(1):66-73.

Plastaras JP, Berman AT, Freedman GM. Special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer. Semin Oncol . 2014;41(6):807-819.

Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol . 2013;31(32):4038-4045.

Ovalle V, Strom EA, Shaitelman S, et al. Proton partial breast irradiation: detailed description of acute clinico-radiologic effects. Cancers (Basel) . 2018;10(4).

Ovalle V, Strom EA, Godby J, et al. Proton partial-breast irradiation for early-stage cancer: is it really so costly? Int J Radiat Oncol Biol Phys . 2016;95(1):49-51.

Patel SA, Tan T, Chin Y, et al. Assessment of cardiac function following proton radiation in a cohort of post mastectomy patients with locally advanced breast cancer. Int J Radiat Oncol Biol Phys . 2015;93(3 Suppl):e52.

Poortsman PM, Collette S, Kirkove C, et al. Internal mammary and mediastinal supraclavicular irradiation in breast cancer. N Engl J Med . 2015;373(4):317-327.

Presley CJ, Soulos PR, Herrin J, et al. Patterns of use and short-term complications of breast brachytherapy in the national Medicare population from 2008–2009. J Clin Oncol . 2012;30(35):4302-4307.

Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med . 1997;337(14):956-962.

Shah C, Badiyan S, Berry S, et al. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol . 2014;112(1):9-16.

Stick LB, Yu Jen, Maraldo MV, et al. Joint estimation of cardiac toxicity and recurrence risks after comprehensive nodal photon versus proton therapy for breast cancer. Int J Radiat Oncol Biol Phys . 2017;97(4):754-761.

Strom EA, Amos R, Shaitelman SF, et al. Proton partial breast irradiation in the supine position: treatment description and reproducibility of a multibeam technique. Pract Radiat Oncol . 2015;5(4):e283-e290.

Strom EA, Ovalle V. Initial clinical experience using protons for accelerated partial-breast irradiation: longer-term results. Int J Radiat Oncol Biol Phys . 2014;90(3): 506-508 .

Taylor CW, Wang Z, Macaulay E, et al. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys . 2015;93(4):845-853.

Verma V, Shah C, Mehta M. Clinical outcomes and toxicity of proton radiotherapy for breast cancer. Clin Breast Cancer . 2016;16(3):145-154.

Verma V, Iftekaruddin Z, Badar N, et al. Proton beam radiotherapy as part of comprehensive nodal irradiation for locally advanced breast cancer. Radiother Oncol . 2017; 123(2):294-298.

Wang X, Zhang X, Li X, et al. Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? Br J Radiol . 2013;86(1029):20130176.

Wang X, Amos RA, Zhang X, et al. External-beam accelerated partial breast irradiation using multiple proton beam configurations. Int J Radiat Oncol Biol Phys . 2011;80(5): 1464-1472.

Whelan TJ, Olivotto I, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Eng J Med . 2015;373(4):307-316.

Xu N, Ho MW, Li Z, Morris CG, Mendenhall NP. Can proton therapy improve the therapeutic ratio in breast cancer patients at risk for nodal disease? Am J Clin Oncol . 2014;37:568-574.

Adult craniospinal radiotherapy : primary central nervous system (CNS) tumors

• a.

  Decrease acute toxicity

  • i.

    Reduce weight loss, hydration issues, nausea, vomiting [CR]

  • ii.

    Minimize treatment breaks that affect disease control [CR]

  • iii.

    Improve chemotherapy tolerance

• b.

  Reduce late toxicities

• c.

  Improve quality of life and symptom burden

Adult low-grade glioma and anaplastic oligodendroglioma in whom long-term survival is expected [CR] ^, [CR]

• a.

  Decrease neuroendocrine and auditory toxicity

• b.

  Decrease neurocognitive deficits [CR]

• c.

  Improve quality of life and symptom burden

Selected meningiomas and Sellar tumors: large tumors, young patients, other comorbidities (neurofibromatosis, Li-Fraumeni, etc.)

• a.

  Evidence of better survival in aggressive meningioma with higher dose possible with proton radiation therapy [CR]

• b.

  Long-term survival expectation

• c.

  Decrease neuroendocrine, auditory toxicity

• d.

  Decrease neurocognitive deficits

• e.

  Improve quality of life and symptom burden

Recurrent, previously irradiated tumors in the brain, thorax, or abdomen: proton therapy will decrease the risk of overlap in normal organs during treatment planning for recurrent disease.

Intensity-modulated proton therapy is indicated for intracranial brain tumors and tumors near the skull base, such as chordoma [CR]

Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015 121(10):1712-1719.

Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol. 2009;8(9):810-818.

Brown AP, Barney CL, Grosshans DR, et al. Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma. Int J Radiat Oncol Biol Phys. 2013;86(2):277-284.

Farnia B, Allen PK, Brown PD, et al. Clinical outcomes and patterns of failure in pineoblastoma: a 30-year, single-institution retrospective review. World Neurosurg. 2014; 82(6):1232-1241.

Barney CL, Brown AP, Grosshans DR, et al. Technique, outcomes, and acute toxicities in adults treated with proton beam craniospinal irradiation. Neuro Oncol. 2014;16(2):303-309.

Arvold ND, Lessell S, Bussiere M, et al. Visual outcome and tumor control after conformal radiotherapy for patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys. 2009;75(4):1166-1172.

Hug EB, Devries A, Thornton AF, et al. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol. 2000;48(2):151-160.

Speirs CK, Simpson JR, Robinson CG, et al. Impact of 1p/19q codeletion and histology on outcomes of anaplastic gliomas treated with radiation therapy and temozolomide. Int J Radiat Oncol Biol Phys. 2015;91(2):268-276.

Brown AP, Barney CL, Grosshans DR, et al. Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma. Int J Radiat Oncol Biol Phys. 2013;86(2):277-284.

Kabolizadeh P, Chen YL, Liebsch N, et al. Updated outcome and analysis of tumor response in mobile spine and sacral chordoma treated with definitive high-dose photon/proton radiation therapy. Int J Radiat Oncol Biol Phys. 2017;97(2):254-262.

Weber DC, Ares C, Villa S, et al. Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: a phase-II parallel non-randomized and observation study (EORTC 22042-26042). Radiother Oncol. 2018;128(2):260-265.

Cairncross G, Wang M, Jenkins R, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3): 337-343.

Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374:1344-1355.

Moeller BJ, Chintagumpapa M, Philip JJ, et al. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat Oncol. 2011;6:58.

Stage I–III esophageal cancer

• ■

  Proton therapy had clinical benefit in terms of postoperative morbidity and hospitalization in a multinational study comparing protons and intensity-modulated photon therapy for esophageal cancer after accounting for patient, tumor, and treatment factors. [CR]

  • i.

    Postoperative overall complications reduced by 40%.

  • ii.

    Postoperative pulmonary complications reduced by 47%.

  • iii.

    Postoperative cardiac complications reduced by 48%.

  • iv.

    Postoperative wound complications reduced by 75%.

  • v.

    Postoperative length of hospitalization reduced from a mean of 12.4 days (photons) to 9.2 days (proton).

  • vi.

    Postoperative 90-day mortality: 4.3% (photon) versus 0.9% (proton).

• ■

  The relative benefits of proton therapy compared with the best intensity-modulated radiation therapy (IMRT) plans are based on the following systematic evaluation of a 55-patient cohort study [CR] :

  • i.

    Mean lung dose reduced by at least 30%.

  • ii.

    Lung volume of 5 Gy reduced by 45%, volume of 10 Gy reduced by 30%, and volume of 20 Gy reduced by 20% to 5%.

  • iii.

    Mean heart dose reduced by at least 35%.

  • iv.

    Mean liver dose reduced by 70% (for mid to distal esophageal tumors).

  • v.

    Maximum spinal cord hot spot dose reduced by 20%.

• ■

  Proton therapy significantly spares heart and cardiac substructures in a large cohort of esophageal cancer [CR]

  • i.

    Compared with IMRT, proton beam therapy (PBT) resulted in significantly lower mean heart dose (MHD) and heart V5, V10, V20, V30, and V40, along with lower radiation exposure to the four chambers and four coronary arteries.

  • ii.

    Compared with passively scattered proton therapy (PSPT), intensity-modulated proton therapy (IMPT) resulted in significantly lower heart V20, V30, and V40 but not MHD or heart V5 or V10. IMPT also resulted in significantly lower radiation doses to the left atrium, right atrium, left main coronary artery, and left circumflex artery, but not the left ventricle, right ventricle, left anterior descending artery, or right coronary artery. Factors associated with lower MHD included PBT ( P < .001).

• ■

  Definitive chemoradiation using proton beam therapy versus IMRT for esophageal cancer improves survival outcomes [CR]

  • i.

    Compared with IMRT, PBT had significantly better overall survival (OS; P = .011), progression-free survival (PFS; P = .001), distant metastasis-free survival (DMFS; P = .031), as well as marginally better locoregional failure-free survival (LRFFS; P = .075).

  • ii.

    No significant differences in rates of treatment-related toxicities were observed between groups.

  • iii.

    On multivariate analysis, IMRT had worse OS (hazard ratio [HR]: 1.454; P = .01), PFS (HR: 1.562; P = .001), and LRFFS (HR: 1.461; P = .041) than PBT. Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6% vs. 25.0%; P = .038) and PFS rates (33.5% vs. 13.2%; P = .005) in the PBT group for patients with stage III disease.

• ■

  Inclusion criteria

  • i.

    All resectable or unresectable esophageal cancer patients with nonmetastatic esophageal cancers.

  • ii.

    Adenocarcinoma or squamous cell carcinoma.

  • iii.

    Eligible to receive definitive or preoperative chemoradiation.

  • iv.

    Involves any part of the proximal thoracic to distal esophagus, the gastroesophageal junction, and the cardia of the stomach.

IMPT is indicated for esophageal cancer.