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I. J. Radiation Oncology ??Biology 0 Physics

1006

Table 1. Patient characteristics: TNM stage and tumor grade

September 1991, Volume 21, Number 4 Table 2. Acute and late bowel toxicity as assessed by mucosal endoscopic findings

Ml

MO

Dose* T2 T3 T4

NO

Nl

NO

Nl

Totals

2 12 16

1 8

1 6

1 2

2 15 32 49

Gl (well differentiated) = 5; G2 (moderately differentiated) = 18; G3 (poorly differentiated) = 24; G4 (anaplastic) = 2.

Forty-nine patients were entered into the study. The average age was 70 years, range 45-78. The TNM stage and tumour grade are shown in Table 1. Eighteen patients (37%) had received prior or concurrent hormone therapy; three (6%) were recurrent post-prostatectomy. No patient has been lost to follow-up. The mean follow-up was 24 months (range 10-87, median 18 months). Forty-eight patients have been followed for a minimum of 12 months. Data for late effects and tumor response have been restricted to these patients; data for early toxicity include all forty-nine patients. Prior to treatment the patients were evaluated with a full history and physical examination, baseline laboratory studies, chest X ray, and other radiology as appropriate. Assessment of bowel mucosal reaction was by endoscopic photography. Acute and late mucosal changes were graded l-4 (see footnote to Table 2), and were compared with reactions in patients who had been treated radically with cobalt irradiation. Acute (3 months) radiation morbidity was assessed by the RTOG/EORTC scoring system (RTOG Head Office, unpublished). Mild and moderate toxicity has been defined as a score of 1 and 2, respectively, severe toxicity as 3 or 4. Following treatment patients were periodically fully assessed. Routine follow-up biopsies were not performed, but clinically suspicious recurrences were confirmed by needle biopsy. A local response was defined as at least a 50% reduction in prostatic dimensions by digital examination, and local control as maintenance of such a response. Planning and treatment techniques

A Styrofoam body shell lined with polyurethane is individually constructed with the patient lying in the right lateral decubitus position. A planning CT scan is performed, in some cases with a contrast containing Foley catheter in the bladder and rectum, and an anal marker. CT pictures are reconstructed using a 3dimensional planning computer. The target volume is identified as tumor volume (as defined by clinical examination and radiographic data) plus a margin of up to 1 cm laterally, anteriorly, and inferiorly. Posteriorly and superiorly the margin is less, so as to minimize irradiation of the rectosigmoid and small bowel. The target volume is viewed in each dimension, and occasion-

30112 33115 34.5115 37.5115

Acute

Late

1.67 1.64 2.09 2.43

1.43 1.83 1.44 2.2

Note: The scoring system is as follows: (1) acute-normal, late-no reaction; (2) acute-edema, late-mild telangiectasia; (3) acute-contact fragility/vascular congestion, late-severe telangiectasia; (4) acute-ulceration, late-ulceration/stenosis. Figures given are the mean score, as defined below. The dose/response for late toxicity is statistically significant (p = 0.05, 2-tailed test for trends in proportion) but not for acute @ = 0.63). *Gy, no of fractions.

ally further beam shaping is performed to minimize the dose to surrounding structures. The 90% isodose line defines the treatment volume and conforms to the target volume as closely as possible. The treatment planning considerations have been described (12) (Fig. 1). Because the pion beam is fixed, the treatment volume is irradiated by moving the patient on a computerized treatment couch in a raster fashion, that is, by the sequential irradiation of consecutive points in a series of transverse lines to cover the lateral dimensions of the tumor. A range shift sequence is needed to cover the depth of the target volume for each point irradiated. Uniformity of dose across the treatment volume is achieved by appropriate spot weightings, which are calculated and controlled by computer. Daily verification films are taken, and the accuracy of the immobilization system has been shown to be good, with a mean daily displacement of less than 2.5 mm (26) which is corrected following verification giving an overall reproducibility of 1 mm. Patients were generally treated with a parallel anterior/posterior spot scan array in the early part of the study, and an anterior array alone more recently. The target absorbed dose (T.A.D.) is prescribed at the 100% isodose. The physical beam profile compensates for the RBE variation across the volume, so as to produce a biologically “flat” profile (29). The dose distribution is uniform ( ? 5%) across the target volume. The dose rate is approximately 30 cGy,,/minute. RBE estimations

Between 1982-1984, 12 patients with prostatic cancer and 21 with other pelvic malignancies (bladder and rectal cancer) took part in an RBE estimation study, previously reported (6). The acute effects of pions were assessed from a numerical scoring system (modified RTOG) together with a clinical narrative, physical and radiological examinations, endoscopic photography, and other findings to provide a general index of the severity of the radiation effect. Cobalt radiotherapy was used as the standard for comparison, allowing the acute and late RBE to be calculated. Results

Pions

for prostate 0 T. Ptctoas et al.

1007

Table 3. Dose escalation and approximate 6oCoequivalents

Dose(Gya)*

No. of pts.

Mean treat vol. (cc)

25/10/l 1 30/12/19 33115121 34.5115120 36115123 37.5/15/19

1 8 17 12 1 10

800 550 585 400 600 375

Vo equiv*t

Vo equiv*$

52126136 63131143 66133146 70135149 74137152 80140156

5 l/25/35 61/30/42 6213l/43 67133146 72136150 76138153

*Doses quoted are Gylno. of fractions/mean duration of course (days). tcalculated using an RBE of 1.5 and the Ellis nominal standard dose (NSD) equation where D (NSD).‘P.“.Nez4. Walculated using an RBE of 1.5 and o/B ratio of 3 for late isoeffect.

group of five patients with small volume tumors were given a high dose early in the study. The prescribed dose also varied with the treatment volume (as defined by the 90% isodose). A cut-off of 500 cc was used, doses above that volume being approximately 5% lower. RESULTS Tolerance and toxicity

Fig. 1. Three-dimensional CT plans. In the upper (transverse) scan, the prostate and seminal vesicles are outlined on consecutive 5 mm slices, with the treatment volume outlined as a box. The middle scan shows the same information in the saggital plane. It is noted that the posterior and superior margins are only a few mm. In the lower scan (coronal) the 90%, 75%, and 50% isodoses and spot scan array configuration are marked. The isodose pattern follows the outlined prostate (not shown for clarity)

Toxicity analysis was the main aim of this study. Acute and late bowel toxicity, as assessed by mucosal endoscopic findings, is summarized in Table 2. A dose response effect is observed for the late bowel mucosal reaction @ = 0.05) but not for the acute. There was no significant correlation between dose and RTOG side effect intensity. Overall, the incidence of mild/moderate acute effects is 84% and of severe acute effects 6%. The incidence of mild/moderate late effects is 15% and of severe late effects 4%. Seven of the nine late effects occurred within 15 months of treatment, and all within 2 years. Figure 2 shows the actuarial late complication rate. There was no significant correlation between treatment volume and toxicity, nor between integral

rather than the superimposedbox. 1.0

gave an RBE estimation

of 1.52( k 0.02). Long term follow-up of survivors (minimum follow-up now 6 years) has shown that no separate RBE exists for late effects damage.

t

Dose escalation study

The first patient was deliberately given a palliative (safe) dose without adverse reaction. The dose was then rapidly escalated to 30 Gy, in 12 fractions; the first seven patients received this dose in 1982-1983. The dose was further escalated (Table 3) and toxicity was assessed at each dose level before a decision was made to proceed to the next level. However, it was realized that late side effects could take time to develop, and for this reason a

0.2 0

..___._.____......... ______

// _._... M,f#j

. ...‘---- _I ‘_ f ___I’ Ir;--;---T;--;-T 4

8

12

18

20

// 24

-

// -

severe

28

32

60

14

14 Number at risk

lime (months) 48 45

41

36

33

25

22

Fig. 2. Actuarial late complication rates. 7/48 (15%) had mild toxicity (RTOG scale l-2) and 2148 (4%) had severe toxicity (RTGG scale 3-4).

1008

I. J. Radiation Oncology 0 Biology 0 Physics

September 1991, Volume 21, Number 4

Table 4. Details of patients suffering severe complications Dose*/vol

Comments

1. 37.505 390 cc

Developed urinary retention at the end of treatment; pretreatment cystoscopy had shown borderline ureteric obstruction. Also had a proven urinary tract infection. Acute RTOG score 4 (bladder obstruction) Developed urinary retention at the end of treatment; had pre RT obstructive symptoms. TURP performed 1 month following RT; acute RTGG score 4 (bladder obstruction) Admitted to hospital 1 week after finishing radiotherapy with spurious diarrhea; plain abdominal X ray showed distended bowel loops; given IV fluids; rapid and uncomplicated recovery; acute RTOG score 3 Developed progressive pelvic tumor with rectal and bladder involvement, leading to a recta-vesical fistula; at surgery extensive tumor was present; late RTGG score 4 (fistula - tumour related) Perforated small bowel successfully resected 2 years following RT; had received 36 Gy/12 with Cobalt RT to posterior pelvis and sacrum 6 years earlier; no apparent overlap of RT fields; not sure which course of RT responsible; late RTOG score 4 (bowel perforation); protocol violation.

2. 30112 610 cc 3. 30112 600 cc

4. 33115 690 cc

5. 37.5115 550 cc

*Gy,.jno. of fractions.

dose and toxicity. In all there were three severe early and two severe late effects. Details of these patients are summarized in Table 4. A frequently observed acute side effect, seen in 20%, was spurious diarrhea, resulting from constipation precipitated by (in some cases an otherwise inconsequential) radiation proctitis . Dietary adjustment following administration of aperient led to relief in all patients. No other unusual or unexpected side effect was observed. Skin and subcutaneous tissue toxicity was minimal due to the low entry doseRIlE, and at most comprised mild erythema and epilation. Urethral stricture unassociated with tumor recurrence was seen in only one patient. Unfortunately, potency was not always prospectively recorded, and was not assessable from chart review. A full analysis of side effects is given in Table 5. For small volume treatments (67.5 Gy. Smit et al. (31) reported a rapid rise in the incidence of radiation proctitis from 20% at doses 75 Gy. A confounding factor is the effect of treatment volume. Although the RTOG studies (22) did not find an increased complication rate with extended versus limited field radiotherapy, several authors have identified a volume effect. Sagerman et al. (25) found the incidence of acute morbidity (necessitating a break in treatment) in 11% of small volumes and 27% of extended volumes. They did not see a difference in the incidence of late effects. Mameghan et al. (18), in a comparison of three different techniques, show a significant increase in complications with progressively larger treatment volumes, but no independent dose effect. Preston et al. (23) report a significantly increased severe late (and possibly also severe acute) complication rate with larger volumes in a study where only localized prostatic volumes were used. Although there is some evidence to suggest that Stage C carcinoma requires a dose higher than 70 Gy (1 l), this may lead to a fall in the ther-

1010

I. J. Radiation Oncology 0 Biology 0 Physics

apeutic ratio with photon irradiation, especially if large volumes are treated because of a rising complication rate. Particle radiotherapy may achieve a therapeutic gain. A study of proton boost (24 Gy equivalent) following whole pelvic photon radiotherapy (50 Gy in 27 fractions) did not show a significant benefit in terms of tumor response or patient survival when compared with non-randomized controls (3). However, this high total dose (74 Gy) was delivered with the same complication rate as the conventional boost (where the total dose was 68 Gy). Neutron irradiation, which does not share the same dose distribution advantages of pions or protons, does have a higher LET, which may lead to an increased efficacy against hypoxic radioresistant tumors. A trial of mixed neutron/photon irradiation (13, 16) in Stage C and Dl prostate cancer has shown an improvement in local response and survival compared with randomized photon controls, apparently at no increased toxicity. The use of pions for prostate cancer has also been studied at the Los Alamos Meson Physics Facility (LAMPF) and at the PSI (Paul Scherrer Institute, previously Swiss Institute for Nuclear Research, SIN). At LAMPF (2, 27, 33), where 23 patients were treated, the severe late complication rate was 6/23 (26%) including 3 treatment-related deaths. The complication rate was dose related occurring mainly above doses of 44 Gy,. There was also a correlation with volume. Severe rectal injury occurred in 7.7% where the volume was cl000 cc and 33% > 1000 cc2. The average treatment volume of those suffering severe late complications was 1888 cc. At PSI details of the six prostate patients treated have not been reported, but the severe complication rate following treatment for bladder carcinoma has been 16/33 (48%) (28). Doses ranged from 33-40 Gy, in 20 fractions. A dose effect was observed for severe bowel and rectal complications, 13% c37.8 Gy,, 25% 37.8-38 Gy,, 63% >40 Gy,. In addition, the severe late bowel complication rate was markedly volume dependent, 22% ~500 cc rising to 90% >500 cc. It would appear therefore that at both PSI and LAMPF, high complication rates have been seen and appear related both to dose and volume. We have always tried to minimize the size of the treatment volume in order to be able to maximize the dose. In particular, we avoid full irradiation of the rectosigmoid, as the partial tolerance of this area appears much higher than the tolerance of the entire structure. In this study we have not observed a correlation between volume and toxicity, probably because of the above policy, and the fact that we

September 1991, Volume 21, Number 4 also make a dose reduction of 5% when the volume exceeds 500 cc. Our technique using a body shell and daily verification films allows a reproducibility of 1 mm, giving us the confidence to use narrow margins and thus smaller volumes. We have generally used a margin of up to 1 cm around the known disease with no attempt to treat the seminal vesicles routinely, unless they are considered to be involved by tumor. Posteriorly the margin is less, to minimize irradiation of the rectal mucosa. We do not usually treat volumes larger than 800 cc (which with a conventional 4-field photon “box” would correspond tofield sizes of approximately 12 X 12 X 9 cm). The complication rates in this study are comparable to those seen in most reported series. Acute minor/moderate toxicity is seen in 85% of patients following conventional photon radiotherapy (4, 23), and was seen in 84% in this study. Severe acute toxicity occurs in 5% (1) with photons and was 6% in this study. Chronic morbidity is of more concern. We have graded toxicity according to RTOG criteria, and have defined l-2 as mild/moderate and 34 as severe. This differs from the grading system used by others. In some reports severe toxicity has been defined as illness requiring hospital admission (lo), as requiring surgery (4), or as totally disabling symptoms (32). Some have not given their definition (14). The chronic severe complication rate in this study was 4%, which compares with reported rates of 3-12% (1, 4). We have shown that the clinical RBE for fractionated pion radiotherapy is 1.5. This figure is in very close agreement with that predicted on the basis of animal (29) and human data from this (5, 6) and other institutions (24). There does not appear to be an increase in RBE for late tissue damage, unlike the RBE for neutrons, which has been reported to rise from 2.5 to 3.1 when late effects are considered (34). We have safely escalated the dose of pion radiation to our estimate of tolerance levels, that is, 37.5 Gy, in 15 fractions (volume