Considerations in Beam Delivery
Today, most heavy-charged-particle-beam treatment facilities utilize a beam scattering system and passive beam-shaping devices (for example an aperture to shape the perimeter of the particle beam and a tissue compensator to shape the distal edge or Bragg peak region in order to contour it to the distal edge of the target). These devices are carefully designed so that they avoid unnecessarily over-radiating pulmonary tissue while allowing for factors such as altered stopping power in aerated tissue and physiologic motion. Scanning-beam technology is under development at several treatment centers; most authorities believe this will provide enhanced target coverage and normal tissue protection not currently achievable with the passive beam-shaping methods that are commonly used today. However, the application of this technology for treating intra-thoracic targets presents a significant challenge due to physiologic internal motion and potentially unreliable radiologic path lengths. Until we have a thorough understanding and reliable control of these variables, it is likely that scattered beams will continue to be utilized for lung cancer treatment.
No standardized treatment techniques or beam arrangements exist for using heavy-charged-particle beams in patients with lung cancer. The most extensive experience in this area comes from Loma Linda University Medical Center, where proton beams have been utilized since the mid 1990s. For patients with solitary pulmonary nodules, the beam arrangements employed have been relatively simple, typically consisting of lateral, posterior, and posterior oblique beams. Frequently the lateral beam is preferred, as it typically provides the lowest volume of normal lung tissue exposure. This is in distinct contrast to photon beams, which will continue through the mediastinum into the contralateral lung. Lateral proton beams, however, are very useful for lung cancer treatment, as the Bragg peak allows the beams to stop distal to the tumor, frequently at the mediastinal pleural surface, thus completely sparing the mediastinum and contralateral lung. Multiple treatment beams per day have been utilized; hypofractionated treatment courses have been common. Treatment techniques in patients with locally advanced lung cancer can be significantly more challenging when mediastinal lymph nodes are targeted, other sensitive normal-tissue structures come into play, such as heart, esophagus, and spinal cord. In a recent clinical trial at Loma Linda University Medical Cancer, these patients are being treated with protons and chemotherapy. Typically, the patients are treated using anterior beams (which stop short of the spinal cord), along with lateral and posterior oblique beams. When beams are designed to limit the dose to the esophagus or spinal cord, it is generally preferred that the edge of the aperture be used to protect these structures. If a beam is designed to stop short of a critical normal tissue region, great care is taken to account for physiologic motion and the presence of inconsistent tissue densities within the chest.
Protons have been the most commonly used particle beam for treatment of patients with lung tumors. At Loma Linda, patients with clinical stage I non-small cell lung cancer who are either medically inoperable or refuse a recommended surgical intervention, have taken part in a clinical trial that involves the use of proton particle beams. The latest report includes 68 patients treated with either 51 CGE or 60 CGE in ten fractions over a two-week course. The area targeted for treatment includes the gross tumor volume as well as a PTV that includes additional margin for respiratory motion. Typically, two to four beams are utilized for treatment, with at least two fields being treated each day. Various beam weightings have been utilized, generally with preference given to lateral beams to minimize lung exposure (Fig. 3). The therapy has been exceptionally well tolerated, with a low incidence of grade-one pneumonitis and no reported grade three toxicities.
Disease-specific survival at three years was 73%. Patients with T1 tumors have achieved local control in 87% of cases; those with tumors larger than three cm (T2) have had local failures up to 50% at three years, which has led to a third dose escalation: the current regimen delivers 70 CGE in ten equally divided fractions over two weeks. Although no survival or local control data are yet available at this dose level, after treating nearly forty patients at this escalated total dose there does not appear to be any difference in tolerance. Additionally, no decline in post-treatment pulmonary function (FEV1 or PO2) has been observed.
In Japan, Nihei reported on 37 patients with stage I non-small-cell lung cancer treated with proton beam therapy. Most patients received between 80 and 88 Gy equivalent, utilizing fraction sizes ranging from 3.5 to 4.9 Gy. The reported two-year local-regional relapse-free survival rate for T1 tumors was 79%; for T2 tumors the rate was 60%. They identified six cases of grade 2 and 3 pulmonary toxicity, with the majority of these seen in patients with larger tumors. Shioyama and colleagues have reported on 28 patients with stage I non-small-cell lung cancer treated with proton beams to a median dose of 76 Gy at 3 Gy per fraction. Patients with T1 tumors had a 70% overall survival at five years, while patients with T2 tumors had a significantly lower survival (approximately 16%). Pulmonary toxicity was reported as minimal.
Studies are underway at Loma Linda that utilize proton beam radiotherapy in conjunction with chemotherapy for the treatment of locally advanced lung cancers. Neo-adjuvant and concurrent chemotherapy is administered with proton therapy, which is given as a concomitant boost. The dose to the sub-clinically involved mediastinum is 46 CGE in two CGE fractions with a GTV, BID boost of 30 CGE during the last three weeks of treatment. Despite the much larger target volumes in such cases, significant sparing of normal tissues still is achieved (Figs 4 and 5). In the most recent evaluation of ongoing results in 19 patients, no Grade 3 or 4 esophageal toxicities were observed; Grade 3 leukopenia was seen in two patients, and Grade 3 thrombocytopenia occurred in one individual.
Two phase II clinical trials are currently underway thattest the use of proton radiotherapy in combination with concurrent chemotherapy for locally advanced (Stage III), inoperable non-small-cell lung cancer. Studies at the University of Florida (ClinicalTrials.gov identifier: NCT00881712) and the University of Texas M.D. Anderson Cancer Center (ClinicalTrials.gov identifier: NCT00495170) are currently evaluating proton radiation in combination with Paclitaxel(Drug information on paclitaxel) and Carboplatin(Drug information on carboplatin). These safety/efficacy studies are similar, yet differ in some details. In the Florida study, the primary outcome measure is to determine whether there is a reduction in acute toxicity from combined concomitant chemotherapy and radiotherapy, compared to previous cooperative group trials. In this trial, disease control, median overall survival, and five-year survival are identified as secondary outcome measures. In the M.D. Anderson study, median survival time is the primary outcome measure, with local control, progression-free survival, disease-specific survival, and disease free survival as secondary outcomes. The M.D. Anderson study also seeks to determine whether grade 3 and higher toxicities are reduced; whether pre- and post-treatment PET/CT are useful in predicting clinical outcome; and whether a biomarker can be used for predicting treatment response and toxicities. Patients in the Florida study receive 80 CGE at two CGE per fraction to PET-positive deposits of gross primary disease and PET-positive deposits of gross nodal disease measuring more than 15 mm; 60 CGE at two CGE per fraction to PET-positive deposits of gross nodal disease measuring less than 15 mm; and 40 CGE in two CGE per fraction to full nodal stations containing foci of PET-positive gross disease, or anatomically adjacent to nodal stations containing PET-positive gross disease.
Strong evidence exists showing that dose escalation can provide improved local tumor control in non-small-cell lung cancer, and that it can be delivered safely when the radiation delivered to healthy pulmonary tissue is minimized with conformal delivery via proton beams. To date, clinical results have demonstrated that lung cancer treatment is feasible and that severe treatment-related toxicity has been minimal in both early and locally advanced cases, thus allowing for further dose escalation if clinically indicated.
Historically, new technology that was proven to improve dose delivery to the intended target and/or decrease dose to surrounding healthy tissues has made its way into common clinical practice; it would make sense that the use of proton beams in treatment would follow this path. Some would contend that randomized, controlled Phase III trials that compare proton therapy to photons are needed to first establish “evidence” that proton therapy is indicated for treating non-small-cell lung cancer. However, the only testable therapeutic variable in such trials would be the volume of normal tissue irradiated; both conformal IMRT and proton therapy encompass the targeted region similarly, but proton beams yield a significantly smaller volume integral dose to normal tissues. Some have questioned the wisdom of designing such trials, positing that data supporting the benefits to normal tissue dose reduction already exists. In any case, there appears to be enough evidence to warrant the continued exploration of proton therapy, which most likely has not yet reached its full potential in the treatment of cancers of the lung.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgements: The author would like to thank William Preston for his assistance with manuscript preparation. This work was supported by the James M Slater chair for proton therapy research.