11.5 Heavy Particles in Lung Cancer

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11.5 Heavy Particles in Lung Cancer

David A. Bush

David A. Bush, MD

Associate Professor, Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, California, USA

11.5.1 Introduction

Lung cancer remains a major medical problem worldwide, with a clear need for more effective treatments. Unfortunately, the inadequacies in lung cancer treatment are well seen by reviewing the history of lung cancer treatment with radiation therapy. In patients with unresectable lung cancer, radiation therapy is the main modality used to attempt to eradicate gross disease from within the thorax.

Early work in lung cancer used chest radiography to evaluate local tumor control and led to a conclu- sion that local disease control was reasonably good while systemic failure was responsible for excessive mortality. With advances in imaging techniques and use of more aggressive follow-up evaluations, it is clear that local tumor control is not as good as initially thought. Local failure rates following radical thoracic radiotherapy have been reported to be as high as 60–80%. Clearly, if radiation therapy is go- ing to play a signiﬁ cant role in improving cure rates in lung cancer patients, local disease eradication within the chest will need to be substantially increased. Virtually all local relapses following radiation therapy can be traced back to either poor tar- geting of the primary tumor site and/or delivery of an inadequate dose of radiation treatment. It would

seem reasonable that simply increasing the dose delivered would confer an increased incidence of tumor control; however, serious treatment-related side effects such as pneumonitis and esophagitis would likely also increase. Thus, there appears to be a need to deliver accurate, high-dose radiation treatment without excessive doses given to sensitive normal tissues for patients with lung cancer.

Before discussing the role of heavy particles in treating lung cancer, it is important to understand some deﬁ nitions and basic physical and biological differences of this treatment compared with X-ray (photon) treatment. As the name implies, particles have size and mass; hence, they are subject to the laws of momentum, in contrast to electromagnetic radiation (photons). Particles may be charged (protons and heavy ions) or uncharged (neutrons), which has a profound effect on how they deposit energy (dose) in tissues. The term “heavy” implies that these particles are heavier than electrons; however, there is a large variation in the size (i.e., atomic weight) of particles used for therapy, which dictates the biological effect of these beams. Particle beams differ from photon beams in two important ways: dose distribution and biological effectiveness.

11.5.2

Dose Distribution

It is ﬁ rst important to understand how photons deposit their energy in human tissues. As a photon beam enters tissues of the body, the deposited dose quickly builds up and reaches a maximum only a few centimeters below the skin’s surface. From there, the dose declines exponentially as it traverses through the body until the beam exits. Most lung tumors lie deep within the body, generally within a range of 5–20 cm from the skin’s surface. Thus, when a photon beam reaches the depth within the body where the tumor lies, it generally is delivering approximately 60–80% of the maximum dose administered. Once

CONTENTS

11.5.1 Introduction 473 11.5.2 Dose Distribution 473 11.5.3 Biological Effects 474 11.5.4 Clinical Results 475 11.5.5 Summary 479 References 479

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the photon beam traverses the tumor’s full thickness, it continues to deliver radiation treatment to tissues distal to the targeted region until the beam exits the body.

Charged particles deposit their energy in tissues with a distinctly different distribution when compared with X-rays. Charged particles have a ﬁ nite range in tissue and deposit most of their energy just before stopping. This is known as the Bragg peak effect. For a collimated proton beam of a given energy, the dose delivered upon entering the body proximal to the intended target is approximately 50–60% of the maximum dose delivered. By varying the beam energy, the high dose or Bragg peak region can be made to cover the full thickness of the intended target region, thus delivering the maximal dose of each beam to the intended target instead of just the below the skin, as X-rays do. Once a charged particle beam has reached the distal edge of the targeted region, the beam stops, and no further dose is delivered to distal tissues. Thus, when charged particle beams are compared with X-ray beams, it can be easily shown that a higher proportion of the dose is delivered to the intended target while minimizing the dose delivered outside the targeted region, reducing normal tissue exposure. While avoiding a larger portion of normal tissue, charged particle beams may safely deliver higher doses to targets within the thorax than is possible with conventional X-ray beams. A graphic representation of the dose delivered per depth in tissue for photons and charged particles (i.e., protons) is shown in Fig. 11.5.1.

Neutrons are also considered heavy particles;

however, they differ from other particles in that they possess no charge. This lack of charge has a signiﬁ - cant effect in the way neutrons deposit their dose in tissues. In fact, dose distributions for collimated neutron beams are very similar to those of low-energy X-ray beams (Raju 1980). Thus, neutrons do not possess the normal tissue-sparing properties described above for charged particle beams.

11.5.3

Biological Eﬀ ects

Throughout the history of radiation therapy, the vast majority of clinical outcomes have been generated through the use of X-rays or photons. This information was gathered clinically over many years of radiotherapy practice. Through this trial-and-error process, normal tissue tolerance levels have been es-

tablished for vital organs such as the spinal cord and bowel. This information is vital to the safe application of radiotherapy to patients with various malignan- cies. These guidelines, however, cannot be applied to all radiation types. Photons are known to be a sparsely ionizing type of radiation treatment. Some heavy particles, though, are known as densely ionizing radiation. This means that many more ionizations will occur per path length for a heavy particle as compared with an X-ray; therefore, certain heavy particle radiation beams can produce different biological re- sponses even if the physical dose is the same.

This has led to the concept known as relative biological equivalents (RBE). The RBE for a particular type of radiation is a factor that is determined ex- perimentally or clinically and that, when multiplied by the physical dose, results in an equivalent biological effect when compared to the same dose given with photons from a cobalt-60 source (Hall 2000).

For example, if a type of radiation was found to have an RBE of 2 for spinal cord injury, a dose of 25 Gy of that type of radiation would be expected to cause the same injury to the spinal cord as would 50 Gy of cobalt-60 photons.

RBE, however, has proven to be a difﬁ cult param- eter to measure. Even for a given radiation type, a number of factors can alter the RBE, such as radiation dose, the number of fractions, and dose rate, as well as the tissue and endpoint being studied. Thus, there may not be a single RBE value that is appropriate for a radiation type in all situations. Densely ionizing heavy particle beams that have clinically signiﬁ cant associated RBEs are neutrons and heavy charged ions such as carbon and iron. These radiation types may have considerable uncertainties as to the appropriate dose to administer for tumor eradication, as well as

Fig. 11.5.1 Percent dose deposited per depth in tissue for pho- ton and charged particle beams

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for normal tissue complications. Hence, a need exists to collect a large body of clinical data to determine the safe and effective radiation doses when admin- istering these types of radiations. Protons, however, have a linear energy transfer (LET) and RBE that differ little from that of cobalt-60 X-rays. Thus, it is easier to extrapolate safe and effective dose levels from the long history of X-ray therapy to help guide treatment plans when proton beams are used.

11.5.4

Clinical Results Neutron Therapy

Non-small cell lung cancer (NSCLC) frequently pres- ents with large volume disease within the chest. Large tumors generally have areas of hypoxia that are relatively radioresistant. Because the biological effect of neutron therapy is less dependent on oxygenation than is X-ray therapy, neutrons were thought to be valuable in treating patients with large lung tumors.

In the 1970s, Eichorn (1982) began using neutron therapy in patients with lung cancer. He treated patients with various combinations of photon and neutron therapy and used autopsy information to assess the results in terms of local tumor eradication. He found that complete pathologic tumor response with photon treatment was 33%, compared with 48–51%

in patients receiving various proportions of neutron therapy. This was felt to be a strongly positive result and led to a number of prospective trials.

Based on these early encouraging results, the Radiation Therapy Oncology Group initiated the ﬁ rst of two randomized trials evaluating neutron therapy in lung cancer (Laramore et al. 1986). The ﬁ rst trial began in 1979 and enrolled 113 patients with unresectable NSCLC. Subjects were randomized to three treatment arms. The control arm received 60 Gy in 30 fractions over 6–7 weeks with conventional X-ray therapy. There were two experimental arms, with one receiving neutron radiation alone to a total dose of 18 neutron Gy in 12–24 fractions over 6–7 weeks.

The second arm received “mixed beam” irradiation in which patients received two neutron treatments and three photon treatments per week. The study was designed so that the biological effective dose was es- sentially equivalent in all three treatment arms. The overall local control and long-term survival rates showed no differences in the three treatments, but a higher number of life-threatening and fatal side ef-

fects were noted in patients treated with increasing neutron dosages. These toxicities mainly consisted of pulmonary complications, subcutaneous ﬁ brosis, and myelitis. The severe toxicity rate was 5% in the photon arm, 14% in the mixed-beam arm, and 31%

in the neutron-alone arm. Five complications were fatal, occurring only in the neutron-treated patients and related to pulmonary complications and myelitis. Reasons given for this increased complication rate include low-energy neutron generators, poor beam shaping and port veriﬁ cation techniques, and inadequate understanding of the RBE values used in dose calculations.

In the mid-1980s, modern neutron treatment facilities became available in the United States. These facilities were equipped with hospital-based cyclo- trons that could produce high-energy neutron beams with isocentric beam delivery systems. Prospective trials were developed to determine the optimal neutron dose for lung cancer, and it was determined that 20 Gy in 12 fractions over 4 weeks would be used in a subsequent randomized trial. In 1986, the Neutron Therapy Collaborative Working Group 85–24 was initiated. A total of 200 patients were enrolled and were randomized to receive deﬁ nitive thoracic irradiation with either photons or neutrons (Koh et al. 1983).

Patients receiving photon treatment completed 66 Gy in 33 fractions over 7 weeks. Patients randomized to receive neutron therapy received a total of 20.4 neutron Gy in 12 fractions over 4 weeks, with spinal cord being limited to 10 neutron Gy. All patients were required to undergo treatment simulation, CT- based treatment planning, and port ﬁ lm veriﬁ cation.

Statistical analysis revealed no observed difference in overall survival, with a median survival in neutron- treated patients of 9.7 months. A subset analysis was performed, which revealed that patients with squa- mous carcinoma had improved 2-year survival of 16% vs. 3% in the photon arm (p=0.02). Treatment toxicities were described as similar in both treatment groups; however, three treatment-related deaths occurred in the neutron arm.

In 1987, Livingston et al. (1987) reported on a prospective trial combining chemotherapy and neutron therapy in patients with advanced lung cancer.

Seventy-three patients were enrolled in this trial and received induction chemotherapy with vinblastine, mitomycin C, and cisplatin. Patients then received neutron therapy to areas of gross disease within the chest of 17–22 neutron Gy in 12 fractions over 4 weeks. During neutron therapy, patients also received elective brain radiation of 36 Gy. Following neutron therapy, chemotherapy was again given to

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complete a total of four cycles. Survival at 2 years of all patients treated in this trial was approximately 12%. Twelve (16%) patients died of treatment-related causes. It was believed that at least some of the deaths were in part due to the use of physics-based neutron generators with limited treatment delivery systems.

In light of these clinical results, it is difﬁ cult to fore- see a signiﬁ cant role for neutron therapy in the future NSCLC treatment. Because of the poor dose distribution characteristics of neutron beams combined with an increased RBE, treatment-related toxicities seem to be increased compared with the current literature reports on conformal photon therapy. Many neutron facilities are no longer clinically active, and little clinical research is currently being conducted on the use of neutron therapy in lung cancer.

Proton Beam Therapy

Proton therapy differs from neutron therapy in two important ways. First, the RBE of proton beams is quite similar to that of photon beams, so knowl- edge of normal tissue tolerance is more accurately known. Proton beams also have a favorable dose distribution proﬁ le because of the Bragg peak effect of charged particle beams. Proton therapy has been in clinical use since the late 1950s at the Harvard Cyclotron Laboratory and at the Lawrence Livermore Laboratory in Berkeley, California. Although initial work in proton therapy established a clinical role for this treatment in patients with tumors in the eye and the base of the skull, little work was done in lung cancer.

In 1991, the fi rst hospital-based proton treatment center became operational at Loma Linda University Medical Center (LLUMC), with a goal of applying this form of treatment to tumors in other parts of the body (Slater 1992). It was believed that patients with localized NSCLC could benefi t from the normal tissue-sparing effects of proton beam therapy by al- lowing the safe application of signifi cant dose escalation. The potential gain with dose escalation with proton beams is well described in a publication by Fowler (2003), who predicted signifi cant gains in local tumor control by using this modality.

The ﬁ rst clinical trial in patients with NSCLC initiated at LLUMC targeted patients with stage I, medically inoperable lung cancer. Eligible patients were staged with a contrast-enhanced CT scan, with the addition of PET scanning when it became available.

The region targeted for treatment included the gross tumor volume within the lung, with added margin for respiratory motion. No treatment was given to hilar

or mediastinal lymph nodes. Initially, the dose delivered was 51 CGE in 10 equally divided fractions. Once the safety proﬁ le of this treatment was established, the dose was increased to 60 CGE in 10 fractions. This fractionation schedule is approximately equivalent to 80 Gy given in standard fraction sizes.

A recent analysis of 68 patients treated in this trial has been performed. The median patient age was 72 years, with an average primary tumor size of 3.3 cm. Most patients were medically inoperable because of smoking-induced chronic obstructive pulmonary disease that was reﬂ ected by an average pretreatment FEV1 of 1.15 liters. There were no en- rollment restrictions based on tumor size, perfor- mance status, or pulmonary function. Median follow- up time was 30 months. Acute or subacute pulmonary toxicity was not observed in this group of patients.

No cases of symptomatic radiation pneumonitis occurred. Likewise, no esophageal or cardiac toxicity was identifi ed. All patients completed the prescribed treatment without diffi culty. The 3-year local control rate was found to be 74%, and the disease-specifi c survival was 72% (Fig. 11.5.2). The majority of deaths seen in this cohort were from intercurrent disease.

There was a signiﬁ cant improvement in local control for tumors <3 cm compared with tumors that were larger (87% vs. 49%), with a trend towards improved survival. Proton treatment and radiographic outcome for one patient in this trial are shown in Fig. 11.5.3 and Fig. 11.5.4.

Pulmonary toxicities were closely monitored in this trial. Initially, all patients underwent high-reso- lution CT scans to access radiographic lung injury. It was found that when local ﬁ eld proton beam therapy was used, considerably less lung injury was identi- ﬁ ed when compared with a similar group of patients treated with a combination of protons and X-ray ther-

Fig. 11.5.2 Disease-speciﬁ c survival of stage I lung cancer pa- tients treated with proton beam

0 6 12 18 24 30 36 42 48 54 60 Month

100 90 80 70 60 50 40 30 20 10 0

% Surviving

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Fig. 11.5.3 a, b Isodose plan for stage I lung cancer patient treated with proton beam. c Dose-volume histogram show- ing the percentage of total lung volume receiving a given dose

c

a b

a

d b

c

Fig. 11.5.4a–d CT images showing lung tumor before and after treatment. a, b Pretreatment. c, d Six months after proton therapy

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apy to a larger volume (Bush et al. 1999). This ﬁ nding underscores the close correlation between volume of lung irradiated and the degree of pulmonary injury observed. Pulmonary function both before and after treatment was also evaluated. An assessment of these results demonstrated no decrement in pulmonary function following treatment (Bonnet et al. 2001).

Based on the lack of observed morbidity or pulmonary toxicity, and increased in-ﬁ eld failure in patients with larger tumors, a dose escalation is planned.

After this initial work in early-stage lung cancer, a new study was initiated for patients with locally advanced NSCLC that also incorporated chemotherapy.

The concept in this trial, which continues to enroll patients, is to implement treatment modalities that have demonstrated improved outcomes in this group of patients. This trial incorporates treatment para- digms such as induction chemotherapy, concurrent chemoradiotherapy, and high dose radiation delivered in an accelerated fractionation schedule. Each of these concepts has been shown to improve outcomes in lung cancer patients in prior randomized trials.

Patients enrolled in this trial have stage II-IIIB NSCLC without evidence of systemic disease. Subjects receive two cycles of induction chemotherapy with Taxol and carboplatin. Proton beam therapy is administered to include the mediastinum and primary lung tumor. A proton beam boost is delivered to the region of gross disease as a second daily fraction in a twice-daily fashion. The total dose delivered to subclinical disease is 46 Gy in 23 fractions, whereas gross disease receives a total of 76 Gy in 38 fractions over 5 weeks.

Weekly chemotherapy with Taxol and carboplatin is given during proton treatment. Fifteen patients have completed this treatment with follow-up adequate to assess acute side effects. No severe hematologic complications or esophageal or pulmonary injuries have occurred.

Proton beam therapy is also available in Japan at the University of Tsukuba, and Shioyama et al. (2003) have reported their experience in treating lung cancer patients. The report describes 51 patients with NSCLC who were treated with proton beam therapy;

however, the majority (28) had clinical stage I disease.

A range of doses and fractionation schedules were used, but most patients received a hypofractionated treatment schedule with an average biological equivalent dose of approximately 80 Gy. The results were strikingly similar to those produced at Loma Linda.

The overall and cause-speciﬁ c survival rates were 60%

and 66%, respectively, for stage I patients. The overall local control rate was 57% at 5 years. Improved local tumor control and survival were noted for T1 tumors

vs. T2 lesions. Observed pulmonary side effects were reported to be minimal. Further study on using hypofractionated proton beam radiotherapy for early- stage lung cancer is being conducted at this institu- tion.

These results seem to indicate a role for proton beam radiotherapy in patients with early-stage lung cancer. Pulmonary complication rates are remarkably low, while local tumor control and disease-speciﬁ c survival rates seem improved over those reported with conventional radiotherapy techniques. Dose escalations are currently under further evaluation.

Clinical trials using proton therapy in conjunction with chemotherapy for locally advanced lung cancer are currently underway.

Heavy Ion Radiotherapy

Heavy ion beams have also been used to treat patients with lung cancer. These beams have dosimet- ric properties that are virtually identical to those of proton beams. They exhibit a Bragg peak effect wherein the maximal dose deposited is delivered just before the beam stops. Thus, highly conformal dose distributions can be delivered to localize targets within the lung, as with protons. The biological effectiveness of these beams, however, differs substantially from that of protons. The most frequently used heavy ion in clinical use is carbon. The RBE used in most settings for carbon ions is 3, similar to that in neutron therapy. This increased biological effect may be useful in increasing the chance of complete tumor eradication, but it may be harmful if the dose is deposited in normal tissue regions.

It would be expected that heavy charged particles may produce substantially less normal tissue dam- age compared with neutron therapy because of the improved physical dose deposition.

A facility capable of delivering high-energy carbon ion radiotherapy has been constructed in Chiba, Japan. Treatment for lung cancer began in 1994 and has been reported on by Miyamoto et al. (2003). As with proton therapy, the researchers elected to begin their studies with early-stage NSCLC patients who are medically inoperable or refused surgery. Their report summarizes outcomes of 81 patients with clinical stage I lung cancer treated with carbon ion therapy using doses ranging from 59.4 to 95.4 Gy equivalence in a dose escalation trial. They reported three cases of grade 3 radiation pneumonitis that resolved after therapy and was not felt to be a dose- limiting factor. Local tumor control was seen in 76%

of patients after 5 years. Improved tumor control was

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identifi ed in patients with smaller tumors as well as the use of higher doses. Cause-specifi c survival and overall survival at 5 years was 60% and 42%, respectively. A signifi cant correlation between tumor size and survival was found, similar to that reported with proton therapy.

Kadono et al. (2002) reported on the pulmonary function following heavy ion treatment in this group of patients. They detected the signiﬁ cant decrease in FEV1 and total lung capacity; however, this decrease was relatively small—6% and 4%, respectively. Other parameters such as DLCO and PAO₂ showed no sig- niﬁ cant changes. The authors concluded that no severe loss of pulmonary function occurred following this form of treatment.

Heavy ion radiotherapy with carbon ions appears to produce a good expectation of local tumor control and disease-speciﬁ c survival in patients with early- stage lung cancer. The rate of signiﬁ cant pulmonary toxicity appears low. As with proton beam therapy, this may represent an improvement compared with conventional photon therapy. To avoid severe normal tissue complications, as seen with other high RBE beams (neutrons), carbon ion radiation therapy should be used cautiously if it is applied to patients with locally advanced tumors that require mediastinal treatment.

11.5.5 Summary

A strong scientifi c rationale exists for using heavy particle beams in lung cancer patients. Neutron radiotherapy failed to show a signifi cant advantage compared with X-ray therapy, and normal tissue complications were considerable. A poor understanding of the biological effectiveness of these beams as well as poor quality of treatment delivery probably contributed to this outcome. Emerging evidence from two facilities using proton beam radiotherapy suggests that this type of treatment may provide a signifi cant advantage for patients in early-stage lung cancer. Proton therapy likely represents the most

“clinic-ready” particle for treatment because of the

superior dose distribution provided by charged particle beams, with a well-established biological effect after years of clinical use. Heavy charged particles such as carbon ions represent an exciting area of research that needs to be pursued; however, the increased biological effect of these beams needs to be carefully evaluated in the clinical setting.

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