Hypofractionated Radiation Therapy for Localized ...

10.1.2

Hypofractionated Radiation Therapy for Localized Prostate Cancer

N I CH O L AS G. Z AO RSK Y RO B ERT B. D EN

J J OV E RV I E W Dose-escalated conventionally fractionated external beam radiation therapy (EBRT; a single 1.8–2.0 Gy fraction, delivered in approximately 15 minutes per day, 5 days per week, for 8–9 weeks, to a total dose of 76–80 Gy) is an established treatment modality for men in all disease risk groups. Emerging evidence from experimental and clinical studies from the year 2001 suggested that the α/β ratio for prostate cancer may be as low as 1.5 Gy, which has prompted investigators around the world to explore moderately hypofractionated radiation therapy (HFRT; 2.1– 3.5 Gy/fraction, for approximately 15 minutes per day, 5 days per week, for about 4 weeks, to a total dose of ~52–72 Gy). This chapter reviews the impetus and the current clinical evidence supporting moderate hypofractionated EBRT for prostate cancer. Although HFRT has many theoretical advantages, there is no clear evidence from prospective, randomized, controlled trials showing that hypofractionated schedules have improved outcomes or lower toxicity than conventionally fractionated regimens.

J J BAC KG RO U N D TO D OS E - ES C A L ATE D CO N V E NTI O N A LLY FR AC TI O N ATE D R A D I ATI O N TH E R A PY Prostate cancer is the second most prevalent solid tumor diagnosed in men of the United States and Western Europe (1). Given the widespread utilization of prostatespecific antigen (PSA) testing, most contemporary prostate cancer patients present with localized disease (clinical stage T1–T2). For these patients, EBRT is a popular treatment option. In the mid-1990s, the most commonly used method to deliver EBRT was a four-field technique (i.e., two beams aimed in the anteroposterior axis and

two in the left–right lateral axis). At the time, there was no consistent agreement on the optimal dose of fractionation regimen used for treatment (2). Nondose-escalated conventionally fractionated radiation therapy (non-DECFRT; a single 1 .8–2.0 Gy fraction lasting 15 minutes per day, 5 days per week) schedules were typically administered over 6 to 7 weeks with doses of 60 to 70 Gy (3). By the turn of the century, DE-CFRT (a single 1.8–2.0 Gy fraction, delivered in approximately 15 minutes per day, 5 days per week, for 8–9 weeks, to a total dose of 76–80 Gy) gained popularity as it was shown in multiple randomized controlled trials (RCTs) to improve rates of tumor control and decrease cancer- specific mortality (4–8). The rationale behind the efficacy of DE-CFRT was that it provided a homogenous dose distribution to the prostate and surrounding tissues (e.g., pelvic lymph nodes), which potentially harbor micrometastases.

J J R ATI O N A LE BE H I N D H Y P O FR AC TI O N ATE D R A D I ATI O N TH E R A PY HFRT (2.1–3.5 Gy/fraction, for about 15 minutes per day, 5 days per week, for about 4 weeks) is theoretically advantageous compared to DE-CFRT for three reasons. First, radiobiological models in 2001 suggested that the use of higher doses per fraction would improve killing of prostate cancer cells and minimize toxicity to the surrounding tissues. Second, the patient would benefit from a shorter overall treatment time (8 weeks of DE-CFRT vs. 4 weeks of HFRT). Third, HFRT is theorized to be more cost efficient. Radiobiology CFRT is theorized to kill prostate cancer cells though the “3 Rs” of radiation therapy (RT): (1) reoxygenation (allowing more cells to become oxic, which makes RT more effective); (2) redistribution (allowing for tumor cells to cycle into more radiosensitive phases of the cell cycle); and (3) repair (allowing normal cells to repair sublethal 17 9

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PART II • Treatment for Low-Risk, Localized Disease

damage). As the total RT dose delivered increases, the number of surviving cancer cells decreases. However, the advantages of dose escalation are countered by the damage to surrounding normal tissues. An α/β ratio estimates the effects of radiation on tissues. The α/β ratio is generally believed to be >10 Gy for early-responding tissue (e.g., skin, mucosa, and most tumors) and 3 to 5 Gy for late-responding tissue (e.g., connective tissues, muscles), where genitourinary (GU) and gastrointestinal (GI) toxicity occur. The α/β ratio is used in the calculation of the biologically equivalent dose (BED): BED = (nd[1 + d/(α/β)]) where n is the number of radiation fractions and d is the fraction size. Hypothesis-generating reports in 2001 suggested that prostate cancer cells had a relatively low α/β ratio of ~1.5 Gy, implying that the cells were more sensitive to large fraction doses (9). In addition, calculation models with an α/β ratio of 1.5 Gy showed that a prolonged course of RT (i.e., from CFRT) was disadvantageous. First, dose escalation is necessary to offset accelerated cancer cell repopulation (10). Second, given the lower α/β ratio for prostate cancer than late-responding tissues, there would be potential for therapeutic gain and minimized toxicity to surrounding tissues with larger fraction sizes (11, 12).

Notably, not all trials assumed that the argument of a low α/β ratio for prostate cancer in their m ethodology. The “initial” (i.e., pre-2001) HFRT versus CFRT trials (13–15) had no assumptions about the α/β ratio and used non-DE-CFRT. Although there has been controversy in calculating the accurate α/β ratio for prostate cancer (16), investigators of HFRT trials after 2001 (i.e., “modern” trials) (17–22) tried to maintain a high BED (at an α/β ratio of 1.5) to kill prostate cancer cells while minimizing the BED (at α/β ratios of 3–10) for toxicity. The BED curves for α/β ratios of 1.5 to 10 Gy for CFRT (to a total dose of 66 and 78 Gy), initial HFRT trials, and m odern HFRT trials included in this chapter are juxtaposed in Figure 10.1.2.1. Patient Perspective The 8 weeks of DE-CFRT is inconvenient to men who live far from RT centers or are unable to travel, and it is the most frequently patient-cited disadvantage of DE-CFRT and a major cause of patient nonadherence (23). Considering the travel time and automobile expenses, the shorter course of HFRT may save each man an average of $1,900 in out-of-pocket expenses (24). Thus, a man would appreciate the HFRT schedule compared to DE-CFRT.

Biologically equivalent dose (BED) versus α/β ratios for initial and modern trials of hypofractionated radiation therapy (HFRT) compared to conventionally fractionated radiation therapy (CFRT). A plot of BED curves for HFRT studies included in this chapter (red lines); compared to CFRT, at 2.0 Gy/fraction, to a total dose of 66 in 33 fractions (nondose escalated, dotted black lines), or 78 Gy in 39 fractions (dose escalated, dotted black lines).

F I G U R E 10 .1. 2 .1

C H A P T E R 10.1. 2 • Hypofractionated Radiation Therapy for Localized Prostate Cancer

Cost Effectiveness Resource allocation could be improved with HFRT. According to calculations models, wage costs outweigh the cost of machines due to the labor-intensive nature of RT planning and delivery (25–28). Moreover, although treatment planning complexity increases with novel technologies, the planning is only done at the start of EBRT, while cost builds with the delivery of each fraction (29). For example, it is estimated that staffing RT facilities accounts for 50% of their cost (30). Thus, changing to HFRT from DE-CFRT may decrease the number of work hours and overall cost of treating each patient.

J J I N ITI A L TR I A L S COM PA R I N G C FRT A N D H FRT From 1986 to 1993, nonrandomized studies from around the world reported similar outcomes between HFRT and non-DE-CFRT schedules (31–34). Two “initial” HFRT phase III prospective studies (shown in Table 10.1.2.1) were published in 2005 (13) and 2006 (14, 15). Lukka et al. (13) reported that freedom from biochemical failure (FFBF) and acute toxicity were worse in the HFRT arm, and late toxicities were equal. Yeoh et al. (14, 15) similarly compared HFRT to CFRT. Thirty-six of 108 patients developed BF in the HFRT arm, compared to 49 of 109 patients in the CFRT arm. Multivariate analyses revealed that the CFRT schedule was the only statistically significant variable for increased BF and worse GU symptoms at 4 years. Lukka et al. (13) and Yeoh et al. (14, 15) reached opposite conclusions about HFRT compared to CFRT. These conclusions are likely due to a few factors. First, the trials were designed to compare widely used non-DE-CFRT regimens in their respective countries with no specific assumptions about the α/β ratio before the trial. To highlight this difference, the total dose of the CFRT arms were 66 (13) and 64 Gy (14, 15) [at an α/β ratio of 1.5, the BEDs are 154 (13) and 144 (14, 15)], which is lower than more contemporary conventional doses of 78 to 80 Gy (Figure 10.1.2.1) (4–6). Second, the arms were not designed to be isoeffective. Third, the study by Lukka et al. (13) reported that the percent of positive biopsies at 2 years was equal between the arms, which is in contradiction to the FFBF rates, possibly suggesting that local control was equivalent, but that patients in the HFRT arm had failed distantly. In addition, the study by Lukka et al. (13) used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition (35) (i.e., three consecutive PSA rises) and other definitions of BF; in contrast, the study by Yeoh et al. (14, 15) used the ASTRO (35) and Phoenix (i.e., nadir + 2 ng/mL) (36, 37) definitions. Yeoh et al. (14, 15) found a significant difference between their FFBF rates with the

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use of the Phoenix definition, but not with the ASTRO definition. The relationship between ASTRO-defined BF and overall survival (OS) or prostate cancer–specific survival (PCSS) has not been clearly demonstrated (38, 39). The Phoenix definition has since been shown to be a better predictor of distant metastasis, OS, and PCSS (36, 37). Thus, although these initial studies provide valuable insight in comparing HFRT and CFRT, they do not conclusively show that one schedule has improved outcomes or toxicities compared to the other schedule, likely because their methods were so different from modern trials.

J J MO D E R N TR I A L S COM PA R I N G C FRT A N D H FRT Prospective phase III superiority studies (17–22) (also on Table 10.1.2.1) have been published based on the assumption that the α/β ratio for prostate cancer is 1.5 Gy. The hypotheses of the trials were designed to show one of two endpoints: (1) if the HFRT course had a higher BED than the CFRT arm, then HFRT FFBF rates should be improved while having equal toxicity; or (2) if the BED of the HFRT course were isoeffective to a CFRT course, then FFBF rates should be equivalent, and there should be reduced toxicity in the HFRT arm. The modern trials failed to reach either endpoint. Pollack et al. (20, 21) predicted equivalent acute toxicities between the HFRT (BED at α/β of 3 = 133) and the CFRT (BED at α/β of 3 = 127) with improved tumor control in the HFRT arm. In their 2011 update (21), they reported that 5-year rates and FFBF were not significantly different (both 86%). Radiation therapy oncology group (RTOG) grade ≥2 GU toxicities were statistically higher in the HFRT arm (18.3% vs. 8.3%, P = .028). Moreover, men on the HFRT schedule had a significantly higher rate of GI toxicity during weeks 2 through 4. Pollack et al. attributed the higher incidence of toxicities to the shorter course of the HFRT schedule, the inclusion of lymph nodes in the high-risk patients, the use of a modified RTOG toxicity scale, and the mean biological doses to the prostate (including the urethra) being >80 Gy. Unexpectedly, their initial assumption of isoeffectiveness of the trial design appears to be incorrect. Arcangeli et al. (17–19) hypothesized that the delivery of an isoeffective dose to prostate tumors using HFRT would reduce the incidence of late complications, have a sparing effect on early responding tissues, and produce equal FFBF rates compared to CFRT. The BED difference between the two arms (at an α/β ratio of 1.5) was only 3, yet a statistically significant difference in 5-year FFBFs was noted: 85% versus 79%, respectively. In addition, there was no reported difference in late toxicity at 5 years between the two schedules. To put this

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Kuban et al. (22)

Pollack et al. (20, 21)

Arcangeli et al. (17–19)

Yeoh et al. (14, 15)

Lukka et al. (13)

Reference

102

102

151

Mostly L, I

56

60

72

75.6

70.2

76

I, H

80

55

64

52.5

152

35

90

64

62

H

NR

L, I, H

66

Total dose (Gy)

83

85

108

109

466

470

n

Median FU (mo)

30

42

26

38

20

40

20

32

20

33

2.40

1.80

2.7

2

3.1

2

2.75

2

2.63

2

187

166

197

177

190

187

156

149

144

154

Total Gy/ Fractions Fraction 1.5

130

121

133

127

126

133

105

107

98

110

3

BED (Gy), at α/β =

89

89

89

91

81

96

70

77

66

79

10

5-y ASTRO: 96% (NS) 5-y Phoenix: 97% (NS)

5-y ASTRO: 92% (NS) 5-y Phoenix: 94% (NS)

5-y Phoenix: 86% (NS)

5-y Phoenix: 86% (NS)

5-y Phoenix: 85% (P = .04)

5-y Phoenix: 79% (P = .04)

7.5-y Phoenix: 53% (P < .05) 7.5-y ASTRO: 44% (NS)

7.5-y Phoenix: 34% (P < .05) 7.5-y ASTRO: 44% (NS)

5-y ASTRO: 53%

5-y ASTRO: 60%

FFBF

18.3

8.3

11

16

NR

NR

1.3

1.3

GU

5-y clinical failure: 19 0% (NS)

5-y clinical failure: 19 0% (NS)

5-y LRF/DM: 1.3% (NS)

5-y LRF/DM: 1.0% (NS)

5-y DM: 10% (NS) 5-y LF: 7% (NS)

5-y DM: 14% (NS) 5-y LF: 11% (NS)

7.5-y OS: 69% (NS)

7.5-y OS: 71% (NS)

5-y OS: 87% (NS) 2-y positive biopsy rate: 51% (NS)

5-y OS: 85% (NS) 2-y positive biopsy rate: 53% (NS)

Other Outcomes

14

6

6.8

5

14

17

NR

NR

1.9

1.9

GI

RTOG Late Toxicity Grade ≥2 (%)

Source: Adapted from Ref. (61). Zaorsky NG, Ohri N, Showalter TN, et al. Systematic review of hypofractionated radiation therapy for prostate cancer. Cancer Treat Rev. 2013;39:728–736.

Abbreviations: ASTRO, American Society of Therapeutic Radiology and Oncology; BED, biologically equivalent dose; CFRT, conventionally fractionated radiotherapy; DM, distant metastasis; L, low risk; LRF, local-regional failure; FFBF, freedom from biochemical failure; FU, follow-up; GI, gastrointestinal; GU, genitourinary; H, high risk; HFRT, hypofractionated radiotherapy; I, intermediate risk; NS, not significant; NR, not reported; OS, overall survival.

Modern

Initial

Era

Risk Groups

JJ Table 10.1.2.1 Multi-arm phase III studies comparing CFRT and HFRT


in perspective, the dose escalation RCTs (4–8), which showed significant improvements of BF, had BED differences of approximately 20. Arcangeli et al. did not provide a clear reason for this observation, but noted that patients at high risk (in particular, those with Gleason >7 and PSA > 20 ng/mL) were those who had improved BF rates following HFRT. Finally, there was no reported difference in late toxicity at 5 years between the two schedules. A few factors may have contributed to the lack of difference in observed toxicity rates. The study by Arcangeli et al. included high-risk patients, which may have affected planning target volumes (prostate alone vs. prostate and seminal vesicles) and treatment setup. In addition, there is a possibility of different mechanisms of radiation damage or repair for late rectal and bladder effects with HFRT in the presence of concomitant androgen deprivation therapy. Finally, they used different toxicity grading methods. The third modern RCT to compare HFRT to CFRT was performed by Kuban et al. (22). The authors hypothesized that the arms would have equivalent acute toxicities and that there would be improved outcomes in the HFRT arm. They randomized 102 men to receive CFRT (BED at α/β of 1.5 = 166) to a dose of 75.6 Gy in 42 fractions and 102 men to receive HFRT (BED at α/β of 1.5 = 187) to a dose of 72 Gy in 30 fractions. The 5-year Phoenix FFBF rates were 92% and 96% (not significant), respectively,

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and no patient had a clinical failure. GI and GU toxicity rates were similar between the two groups. Thus, they did not prove their hypothesis. Dose escalation studies (4–8) have helped to determine the standard of care in determining the optimal CFRT schedule. To compare the outcomes and toxicities in the HFRT studies, the rates of FFBF (Figure 10.1.2.2), GU toxicity (Figure 10.1.2.3), and GI toxicity (Figure 10.1.2.4) of phase III HFRT RCTs are benchmarked dose escalations studies of CFRT.

J J LI M ITATI O N S A N D FU TU R E D I R EC TI O N Intertrial Comparisons There are a number of important caveats to consider when interpreting results of trials that compare HFRT to CFRT. First, the methods of the initial studies differed greatly from the modern studies. Second, all three modern studies were designed as superiority studies; thus, it would be incorrect to infer that the absence of a difference in any study implies equivalence between the arms. Moreover, although dose escalation studies indicated that DE-CFRT was associated with improved FFBF when compared to non-DE-CFRT, all studies of HFRT are inconsistent in their results. Finally, when compared to dose escalation studies, the follow-up of the HFRT studies is not yet as

F I G U R E 10 .1. 2 . 2 Freedom from biochemical failure (FFBF) versus follow-up time of conventionally fractionated radiation therapy (CFRT) versus

hypofractionated radiation therapy (HFRT) randomized controlled trials (RCTs) benchmarked to high-dose radiation therapy (RT) arm of escalation RCTs for prostate cancer. The y-axis shows the FFBF, and the x-axis shows the median follow-up time in years. Individual arms of phase III RCTs comparing CFRT (green circles) and HFRT (red circles) are shown on the plot with first author and year of publication. As a benchmark for these studies, the higher dose arms of dose escalation studies (blue squares) are shown on the plot with first author and year of publication. The individual RT schedule of an arm is shown near each data point: total dose, number of fractions, and Gy/fraction.

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F I G U R E 10 .1. 2 . 3 Radiation therapy oncology group (RTOG) grade ≥2 genitourinary (GU) toxicity versus follow-up time of conventionally frac-

tionated radiation therapy (CFRT) versus hypofractionated radiation therapy (HFRT) randomized controlled trials (RCTs) benchmarked to high-dose radiation therapy (RT) arm of escalation RCTs for prostate cancer. The y-axis shows incidence of late RTOG grade ≥2 toxicity (%), and the x-axis shows the follow-up time in years. Individual arms of phase III RCTs comparing CFRT and HFRT are shown on the plot with first author and year of publication. As a benchmark for these studies, the higher dose arms of dose escalation RCTs are shown on the plot with first author and year of publication. Green circles refer to the GU toxicity rates of CFRT arms. Red circles refer to the GU toxicity rates of HFRT arms. Blue squares refer to the GU toxicity rates of the higher dose arm of dose escalation studies. The individual RT schedule of an arm is shown near each data point: total dose, number of fractions, and Gy/fraction. Source: Adapted from Ref. (61). Zaorsky NG, Ohri N, Showalter TN, et al. Systematic review of hypofractionated radiation therapy for prostate cancer. Cancer Treat Rev. 2013;39:728–736.

long, and the significance of the results may change. In addition, a number of factors preclude comparing the results of HFRT trials to the expected outcomes and toxicities of DE-CFRT regimens used today. Efficacy With respect to efficacy, HFRT trials had differing planning target margins, treatment techniques, and fractionations schedules, which may all affect outcomes (40). The specific endpoints evaluated in these studies vary. For example, as Yeoh et al. (14, 15) reported, FFBF rates may be significant with the Phoenix definition, but not with the ASTRO definition. In addition, the study by Yeoh et al. did not report on differing FFBFs among risk groups, and their inclusion criteria were based on the American Joint Committee on Cancer (AJCC). The National Comprehensive Cancer Network (NCCN) model is a superior prognosticator of FFBF to the AJCC and remains the preferred method for risk-based clinical management of prostate cancer with radiotherapy (41); thus, the reported rates of FFBF may have changed if they had used NCCN criteria. Although Arcangeli et al. (17–19) noted improved FFBF among high-risk patients, no HFRT study has looked

at the effect of the optimal fractionation schedule among individual risk groups. Cancer- and patient-specific biomarkers including Ki-67 (42, 43); p53 (44); p21/waf1 (44); P120 (43); Bcl-2, Bax, and the Bcl2/Bax ratio (42, 44–46); and PCNA (43) affect rates of cellular growth and have been shown to predict cancer aggressiveness and recurrence. These biomarkers may contribute to variations in α/β ratios among individual prostate cancer cell lines. Future models will likely combine these markers with traditional pretreatment variables (e.g., PSA, Gleason) to create personalized fractionation schedules and predict outcomes (47). Toxicity Late effects from radiation can technically occur decades after therapy (48). Moreover, the RTOG toxicity score does not report on anorectal symptoms such as urgency of defecation and fecal incontinence (49). In addition, assessing quality of life has become an integral component of prostate cancer care. None of the HFRT trials used quality-of-life questionnaires nor did they asses how toxicities affect individual patient subpopulations (e.g., minority communities, men who have sex with men), who make up a large proportion of the prostate


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F I G U R E 10 .1. 2 . 4 Radiation therapy oncology group (RTOG) grade ≥2 gastrointestinal (GI) toxicity versus follow-up time of conventionally frac-

tionated radiation therapy (CFRT) versus hypofractionated radiation therapy (HFRT) randomized controlled trials (RCTs) benchmarked to high-dose radiation therapy (RT) arm of escalation RCTs for prostate cancer. The y-axis shows incidence of late RTOG grade ≥2 toxicity (%), and the x-axis shows the follow-up time in years. Individual arms of phase III RCTs comparing CFRT and HFRT are shown on the plot with first author and year of publication. As a benchmark for these studies, the higher dose arms of dose escalation RCTs are shown on the plot with first author and year of publication. Green circles refer to the GI toxicity rates of CFRT arms. Red circles refer to the GI toxicity rates of HFRT arms. Blue squares refer to the GI toxicity rates of the higher dose arm of dose escalation studies. The individual RT schedule of an arm is shown near each data point: total dose, number of fractions, and Gy/fraction. Source: Adapted from Ref. (61). Zaorsky NG, Ohri N, Showalter TN, et al. Systematic review of hypofractionated radiation therapy for prostate cancer. Cancer Treat Rev. 2013;39:728–736.

cancer patient demographic and often have specific quality-of-life concerns (50). Assessing Available Treatment Options Currently, there are multiple comparative treatment options used for localized disease, and their efficacies vary among risk groups (51). Novel modalities, including stereotactic body radiation therapy (SBRT; a single 3.5– 15.0 Gy fraction lasting 1 hour per day, 5 days per week, for about 2 weeks) and hadron therapy (specifically, protons), are gaining popularity as alternatives to DE-CFRT and HFRT schedules. Although neither SBRT (52) nor proton therapy (53) has proven to have improved outcomes of lower toxicities compared to other forms of EBRT, it will be necessary to consider them as possible treatment options alongside HFRT. Comparative effectiveness research will help to define the proper role of RT modalities for specific prostate cancer patients (54). Evolving Technology Technology has evolved since the publication of the earliest HFRT studies, and image-guided radiation therapy (IGRT) is now an integral component of SBRT (52, 55). To

put this in perspective, 72% of the patients in the study by Yeoh et al. (14, 15) were treated with two-dimensional radiation therapy; today, the patients could be treated with volumetric-modulated arc therapy and 4D radiofrequency tracking to increase normal organ sparing (56) and decrease intrafractional motion (57). Some retrospective studies show that IGRT improves outcomes with EBRT (58–60), and it is unknown how the use of novel technologies would impact HFRT.

JJ CO N C LUS I O NS DE-CFRT is an established treatment modality for almost all prostate cancer patients. Determining the optimal fractionation scheme has been one of the goals of radiation oncologists. HFRT is hypothesized to improve tumor control, patient quality of life, and cost. RCTs comparing HFRT and CFRT have been inconsistent in their results. The methods of initial HFRT studies do not compare to modern techniques of DE-CFRT. The modern HFRT studies have rejected their hypotheses of superiority of HFRT. As of 2013, HFRT regimens are still under investigation.

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