Int. J. Radiation Oncology Biol. Phys., Vol. 57, No. 3, pp. 654 ­ 664, 2003
Copyright © 2003 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/03/$­see front matter
doi:10.1016/S0360-3016(03)00625-4
CLINICAL INVESTIGATION
Prostate
EFFICACY OF IRRADIATION AND EXTERNAL HYPERTHERMIA IN
LOCALLY ADVANCED, HORMONE-REFRACTORY OR RADIATION
RECURRENT PROSTATE CANCER: A PRELIMINARY REPORT
JOHN A. KALAPURAKAL, M.D., MARGARET PIERCE, R.N., ALAN CHEN, M.D., AND
VYTHIALINGAM SATHIASEELAN, PH.D.
Division of Radiation Oncology, Northwestern University, Robert H. Lurie Cancer Center, Chicago, IL
Purpose: To present a preliminary report on the feasibility, efficacy, and toxicity of irradiation (RT) and
hyperthermia (HT) in patients with locally advanced, hormone-refractory prostate cancer (LAHRPC) who may
or may not have received prior RT.
Methods and Materials: Between 1997 and 2002, 13 consecutive patients with LAHRPC or RT-recurrent prostate
cancer were treated with RT and HT on a Phase I­II protocol. Eight patients had RT-recurrent LAHRPC
(Group A) and 5 had LAHRPC without prior RT (Group B). All patients had large and clinically symptomatic
tumors. The median RT dose was 39.6 Gy and 66.6 Gy in Groups A and B, respectively. External deep HT was
delivered using a BSD-2000 Sigma-60 applicator. The median number of HT treatments was 8 in group A and
10 in group B.
Results: The median follow-up was 14 and 13 months for Groups A and B, respectively. All patients achieved a
complete or partial response (CR/PR) and complete palliation of symptoms. Eleven patients had follow-up CT
scans that demonstrated a CR in six and a PR in five. Two patients, who died of metastasis, did not have CT scans
and had a PR on digital rectal examination. Two patients demonstrated a biochemical CR. The median duration
of the CR/PR among Group A patients was 12 months after therapy. Three patients in Group A developed tumor
recurrence at 9, 17, and 27 months after repeat RT to doses of 39.6, 36, and 50 Gy, respectively. At last follow-up,
no Group B patient developed local recurrence. Grade 1-2 rectal bleeding was noted in 3 patients. RT and HT
were generally well tolerated by all patients who had not previously undergone RT. Of the 8 patients who had,
6 (75%) tolerated retreatment well with minimal or no complications. Two patients in the repeat RT group had
severe complications. One patient with lymphoma and factor XI deficiency developed Grade 4 hemorrhagic
cystitis. Another previously irradiated patient developed a rectovesical fistula 4 months after retreatment, after
disappearance of a large, invasive, and necrotic tumor.
Conclusion: This preliminary report demonstrates the feasibility and efficacy of RT and HT in patients with
LAHRPC, who may or may not have received prior RT. Presently, such patients who have undergone previous
RT have no effective treatment options. RT and HT were generally well tolerated by patients who were not
previously undergone RT. Of those who had been, most (6 of 8) tolerated retreatment well with minimal or no
complications. The high-risk factors for treatment- and tumor regression-related side effects include the presence
of large necrotic tumors, previous RT with a large dose/fraction, and the presence of bleeding disorders. Despite
the size of these large tumors, RT and HT resulted in significant tumor shrinkage, rapid serum prostate-specific
antigen decline, durable treatment responses, and durable palliation of symptoms. Additional clinical studies are
warranted.
© 2003 Elsevier Inc.
Prostate cancer, Radiotherapy, Hyperthermia, Hormone refractory, Local recurrence, Palliation, Retreatment.
INTRODUCTION
(4) in these patients remains to be defined. The effects of
antiandrogen therapy are temporary, and most patients de-
Patients who experience biochemical relapse after primary
velop hormone-refractory disease (5). Patients who develop
irradiation (RT) can have a high survival rate (1). The role
locally advanced and hormone-refractory prostate cancer
of salvage surgery (2), cryosurgery (3), and brachytherapy
(LAHRPC), with or without prior RT, may have significant
Reprint requests to: John A. Kalapurakal, M.D., Division of
Acknowledgments--We acknowledge the support and cooperation
Radiation Oncology, Northwestern Memorial Hospital, 251 E.
of the Departments of Urology and Oncology at Northwestern
Huron St., LC-178, Chicago, IL 60611. Tel: (312) 926-3761; Fax:
University. We thank Thomas Prost and Nick Vlamakis from the
(312) 926-6374; E-mail: j-kalapurakal@northwestern.edu
Media Services Department of Northwestern Memorial Hospital
Presented in part at the annual meetings of the North American
for preparation of the figures.
Hyperthermia Society, Reno, NV, 2002; European Society of
Received Dec 18, 2002, and in revised form Apr 23, 2003.
Hyperthermia and Oncology, Bergen, Norway, 2002; and Ameri-
Accepted for publication May 8, 2003.
can Radium Society, Las Croabas, PR, 2002.
654
Efficacy of RT and HT in LAHRPC J. A. KALAPURAKAL et al.
655
impairment of their quality of life because of tumor invasion
Radiotherapy
into adjacent pelvic organs (6). Presently, such patients who
RT was delivered using 10 ­18-MV X-rays with CT-
have received prior RT have no effective treatment options.
based three-dimensional treatment planning techniques and
This report is an update of an earlier report (7) on the
alpha-cradle cast immobilization. In all patients, the plan-
feasibility, efficacy, and toxicity of RT and hyperthermia
ning target volume included the gross tumor volume with a
(HT) in patients with LAHRPC who may or may not have
margin of 1­2 cm. RT was delivered at 1.8 Gy/fraction. The
undergone prior RT.
prescription isodose line ranged from 95% to 100%. The
median total RT dose was 39.6 Gy (range 29.8 ­50) in
Group A and 66.6 Gy (range 59.4 ­70.2) in Group B. The
METHODS AND MATERIALS
presence of large tumors with invasion into the rectum and
bladder precluded the safe delivery of higher doses to Group
Between 1997 and 2002, 13 consecutive patients with
B patients.
LAHRPC or RT-recurrent prostate cancer were treated with
RT and HT on a Food and Drug Administration and insti-
Hyperthermia
tutional review board­approved Phase I­II protocol spon-
External deep HT was delivered using a BSD-2000 Sig-
sored by the BSD Medical Corporation (Salt Lake City,
ma-60 applicator (BSD Medical, Salt Lake City, UT). A
UT). Of the 13 patients, 8 had RT-recurrent LAHRPC
Sigma-60 annular phased-array radiofrequency device op-
(Group A) and 5 had LAHRPC without prior RT (Group B).
erating in the frequency range of 92­72 MHz was used.
At the initial consultation, a detailed history and physical
Both phase and amplitude steering were used to maximize
examination, including a digital rectal examination (DRE),
temperatures in the prostate and minimize patient discom-
was performed, and blood was drawn for serum prostate-
fort. Patients were monitored continuously during each
specific antigen (PSA) measurement, complete blood count,
treatment for changes in vital signs and for symptoms of
and liver and kidney function tests. A pretreatment CT scan
heat intolerance such as pain. Power was increased in a
of the abdomen and pelvis and bone scan were also ob-
stepwise fashion until the patient could no longer tolerate
tained. Endoscopy (sigmoidoscopy or cystoscopy) was per-
further increases in power. A treatment session lasted for 60
formed in most patients to document tumor invasion into
min from the time temperature monitoring was started. A
adjacent organs. A biopsy was obtained to confirm the
description of this HT delivery system and details about
presence of recurrent prostate cancer. The TNM staging
thermometry have been previously published (7, 9).
system was used to describe the tumor stage (8).
HT was delivered twice weekly, at least 72 h apart, for a
maximum of 10 treatments. HT was administered approxi-
mately 1 h after RT. Previous reports have demonstrated the
Informed consent
adequacy of endoluminal thermometry (10) and the com-
All patients were presented with the available therapeutic
plications associated with interstitial thermometry (11) in
options, including no further treatment, symptomatic man-
patients with deep-seated pelvic tumors. In this study, in-
agement (narcotic analgesics,
-blockers, blood transfu-
terstitial thermometry was not performed, because these
sions, etc.), palliative surgical urinary and/or bowel diver-
patients were already symptomatic from advanced tumors.
sion, other Phase I­II chemotherapy protocols, RT alone, or
Furthermore, the main objective of our study was to maxi-
treatment with RT and HT. All patients provided informed
mize patient tolerance and thus maintain the HT treatment
consent before enrollment in the study.
for at least 1 h. The data obtained from the rectal temper-
ature probes (endoluminal temperatures) thus provided an
Patient and tumor characteristics
indirect measure of the temperatures achieved within the
The clinical characteristics, treatment, and follow-up data
prostate gland (11). The rectal temperature probe was
are presented in Table 1. The mean patient age was 76 years
placed in a single plastic catheter that was inserted to a
(range 54 ­ 82). Tumor size was measured from the pretreat-
distance of 7­ 8 cm from the anal verge. The temperature
ment CT scans. The tumor size was expressed as the height
probes used included a luxtron optical multisensor probe in
by width by AP dimension. Tumor size measurement in-
9 patients and a Bowman temperature probe in 4. Thermom-
cluded the prostate and seminal vesicle and tumor extension
etry data are given in Table 2 (12). The median number of
into adjacent organs. All patients had large tumors, with a
HT treatments was 8 (range 5­10) in Group A and 10 (range
median dimension of 7.5 cm
6.5 cm
6.5 cm (range 6.5
2­10) in Group B.
7.5
6 to 12
13
14). The clinical symptoms at
presentation included pelvic pain (13 of 13), hematuria (9 of
Prior therapy
13), urinary retention (5 of 13), rectal pain/obstruction (4 of
The details of prior therapy, including surgery, RT, hor-
13), rectal bleeding (2 of 13), and lymphedema (1 of 13).
monal therapy, chemotherapy, and palliative surgery are
The tumor demonstrated evidence of invasion into the uri-
outlined in Table 1. All patients had hormone-refractory
nary bladder in 8 patients, rectal invasion or obstruction in
prostate cancer after several years of hormonal therapy with
6, and pelvic bone/soft tissue invasion in 5 patients. Distant
multiple antiandrogens, including leuprolide acetate, bica-
metastasis was present in 8 patients.
lutamide, megestrol acetate, and estrogens. Orchiectomy
656
Table 1. Clinical characteristics, treatment, and follow-up of patients in Groups A and B
Age at
Presenting signs and symptoms;
Pt.
diagnosis
Gleason
serum PSA (ng/mL); Tumor
Group
No.
(y)
score
Prior therapy
size (cm)
RT
HT(n)/completion date
Results (time after RT/HT)
Toxicity
A
1
79
3
3
RT (70 Gy, 1988), TAS
LE, hematuria, pelvic pain; 60;
30.6 Gy, prostate; 38 Gy, LN;
HT
CR on DRE and CP (3 mo); CT scan (9 mo) continued
None
I.
7
6
6
(5)/May 1998
CR; DOD
J.
2
80
3
3
RT (70 Gy, 1984),
Bleeding PR and rectal
36 Gy
HT (7)/October 1998
CP end of RT/HT; CR on DRE (3 mo); CT scan (12 mo)
None; patient alive at
Radiation
orchiectomy,
obstruction, pelvic pain,
continued CR; endoscopy (13 mo) CR (Fig. 3B); LR in
last follow-up (4 y)
bicalutamide,
hematuria; 30; 7.5
6
6
rectum (17 mo)
megesterol acetate,
(Fig 1)
TURP
3
Oncology
3
54
4
3
Prostatectomy 1984, RT
Pelvic pain; 9.1; 6.5
7.5
6
50 Gy
HT (8)/December 1998
CP end of RT/HT for 3 y; PSA
0.1 ng/mL at 3 mo until
Grade 1 rectal
(60 Gy, 1985),
20 mo; CT scan--tumor soft-tissue CR, bone PR until
bleeding; patient
cystectomy (1990)
27 mo, then LR
alive at last follow-
for recurrence, TAS
up (4 y)

4
78
3
4
RP, RT (60 Gy, 1994),
Pelvic pain, hematuria,
45 Gy
HT (9)/April 2000
CP 2 mo after RT/HT; tumor PR on CT scan (2 mo);
None
TAS, SPC (February
retention; 8
7
6.5
DOD
Biology
2000)
5
76
3
3
TAS, RT hemipelvis
Pelvic pain scale: 5/5,
29.8 Gy
HT (8)/November 2000
CP end of RT/HT, CR on DRE, CT scan--soft-tissue CR,
Urethral stricture (6
(30 Gy/10, June
hematuria; 11
11
8.5
bone PR 3 mo; CP (16 mo)
mo); NHL-related

1998), chemotherapy
factor XI
Physics
for NHL; RT
deficiency; 8 mo
hemipelvis 12 Gy/4
later, Grade 4
f, September 2000
cystitis, Grade 2
rectal bleeding (14
mo)
6
80
5
5
RT (65 Gy, 1990),
Rectal pain, hematuria; 35; 6.5
39.6 Gy
HT (10)/October 2000
CP end of RT/HT until death; CR on DRE and endoscopy
Grade 1 rectal
Volume
TAS, megesterol
7
6
(5 mo); LR in bladder (9 mo); DOD (14 mo)
bleeding (8 mo)
acetate
7
73
2
3
RT (65 Gy, September
Pelvic pain, hematuria, urinary
41.4 Gy
HT (10)/October 2001
Decrease in pelvic pain; CT scan CR (4 mo); metastasis in
Rectal ulcer (2 mo);
1997), TAS, CT,
retention, rectal pain and
pelvic and abdominal LN
urinary fistula with
57,
radiolabeled-antibody
obstruction; 83; 8
7
9;
tumor CR (4 mo)
Number
therapy
tumor necrosis present (Fig.
2).
8
78
5
4
RT (66.6 Gy, June
Pelvic pain, hematuria, urinary
43.2 Gy
HT (10)/May 2002
Decrease in pelvic pain; CT scan 4 mo; after RHT--CR;
None
1992), TAS, CT, RT
retention, rectal bleeding,
sigmoidoscopy 5 mo after RHT--CR, with skip lesion
3,
(18 Gy), TURP
2
pain and obstruction; 319; 7
above previous tumor site
2003
6
9
B
1
82
4
4
Estrogens, TAS (1994)
Pelvic pain, urinary obstruction,
59.4 Gy
HT (2)/January 1998
CP; tumor PR on DRE; no CT scans done; DOD (6 mo)
None
hematuria; 2.7; 8
8
8
2
71
4
5
TAS (1992)
Rectal obstruction, pain; 318; 7
66.6 Gy
HT (10)/October 2000
Tumor CR on DRE (4 mo); CT scan­tumor PR (12 mo);
None
6
7
PSA
0.1 ng/mL (2 mo) until last follow-up (24 mo);
CP (Figs. 3, 4)
3
66
3
3
Prostatectomy,
Urinary obstruction, pelvic pain;
70.2 Gy
HT (10), bicalutamide/April
DRE, ultrasound scan, CR (6 wk); CT scan­tumor soft-
Grade I rectal bleeding
orchiectomy (1994)
13.8; 6.5
7
9
2000
tissue CR, bone sclerosis (4 mo); CP
4
69
3
3
Orchiectomy 1993,
Pelvic pain, ureteral obstruction;
64.8 Gy
HT (10)/September 2001
CT scan PR (4 mo); significant PSA response from 672 to
None
bicalutamide
672; 12
13
14
56 ng/mL at 14 mo after RT/HT; CP
5
76
TAS (1998)
Hematuria, pelvic pain; 11
13
66.6 Gy
HT (10)/January 2002
CP at end of RT/HT; PR on DRE (3 mo); DOD
None
12
Abbreviations: PSA
prostate-specific antigen; RT/HT
radiotherapy plus hyperthermia; TAS
total androgen suppression; LE
lymphedema; LN
lymph nodes; CR
complete
response; DRE
digital rectal examination; CP
complete palliation (of symptoms); DOD
died of disease; TURP
transurethral resection of prostate; PR
partial response; LR
local recurrence; NHL
non-Hodgkin's lymphoma.
Efficacy of RT and HT in LAHRPC J. A. KALAPURAKAL et al.
657
Table 2. Summary of temperature data measured in rectal lumen
died of progressive distant metastasis: 4 in Group A and 2
in Group B.
Parameter
Group A
Group B
Patients (n)
8
5
Symptom palliation
Treatments (n)
67
42
Despite the large and clinically symptomatic tumors, all
Temperature (°C)
patients achieved complete palliation of symptoms either by
Average
41.1 (41.4­40.7)
41.4 (41.9­41.0)
the end of treatment (10 of 13) or within 3 months after
Maximum
41.6 (42.3­40.8)
42.3 (42.9­41.7)
therapy (3 of 13). The palliation of symptoms was durable
Minutes
40.0°C (n)
35.8 (49.5­13.1)
42.6 (54.1­26.5)
Minutes
41.0°C (n)
14.6 (25.6­1.8)
31.4 (46.6­17.1)
in most patients, lasting until the last follow-up visit or
Minutes
42.0°C (n)
3.4 (7.9­0.0)
6.2 (25.0­0.0)
death. In 2 Group A patients in whom the tumor relapsed,
CEM @ 42.5°C (n)
68.1 (119.0­4.0)
103.0 (262.0­14.0)
symptoms of rectal obstruction and pelvic pain reappeared
CEM @ 43.0°C (n)
35.8 (75.0­2.0)
53.4 (135.0­7.0)
at 17 months and 36 months, respectively, after RT and HT.
Abbreviation: CEM
cumulative equivalent minutes.
Numbers in parentheses are the range.
Tumor and biochemical response
All patients achieved a CR or PR after RT and HT (Table
1). Eleven patients underwent CT during follow-up. Two
had been performed in 2 patients. In 1 patient (Table 1,
patients who died of metastasis did not undergo CT and had
Group B, Patient 2) who underwent orchiectomy, Casodex
a PR by DRE 2­3 months after therapy.
was added before RT and HT. In all other patients, no new
A tumor CR was demonstrated by CT in 6 patients (5 in
hormonal therapy agent was added during or after RT and
Group A and 1 in Group B). A tumor CR was demonstrated
HT. The advanced stage of these hormone-refractory tu-
by CT and endoscopy in 4 Group A patients (Figs. 1 and 2).
mors was evident by the presence of distant metastasis at
A tumor PR was demonstrated by CT in 5 patients. Of them,
presentation in 5 (63%) of 8 Group A patients and 2 (40%)
2 had a CR of the soft-tissue component of the tumor in the
of 5 Group B patients. Furthermore, distant metastasis ap-
pelvis and a PR of the bony component that continued to
peared in 2 additional patients in Group A and 1 patient in
show bone remodeling after therapy. The other 2 patients
Group B.
had significant tumor shrinkage (Fig. 4). Two patients dem-
onstrated a biochemical CR, achieving undetectable serum
PSA levels 2 and 3 months after treatment (Group A, Patient
Follow-up
3 and Group B, Patient 2). One (Group A, Patient 3) had a
All patients were followed at 6 weeks after therapy ini-
biochemical relapse 20 months after retreatment; the other
tially and then every 2­ 4 months after therapy. At each
continued to maintain biochemical remission 24 months
follow-up visit, a detailed clinical examination, including
after therapy (Fig. 3).
history, physical examination, DRE, and serum PSA esti-
At last follow-up, the median duration of CR/PR among
mation, was performed. CT or ultrasound scans of the pelvis
Group A patients was 12 months (range 4 ­27) after therapy.
were obtained every 3­ 6 months, if the patient's condition
Of these, 3 died at 4, 6, and 19 months after retreatment,
permitted. In patients with tumor invasion into the rectum or
without local recurrence. Three patients developed tumor
bladder, every attempt was made to obtain posttherapy
recurrence at 9 months (urinary bladder), 17 months (rec-
endoscopy to document tumor response, if the patient's
tum), and 27 months (pelvis) after 39.6, 36, and 50 Gy,
condition permitted. Among patients without distant metas-
respectively. Of the 5 Group B patients, none had local
tasis, the serum PSA half-life after RT and HT was calcu-
recurrence, and the median duration of CR/PR was 15
lated using a previously published formula (13). The Re-
months (range 4 ­32). Two patients died at 6 months of
sponse Evaluation Criteria in Solid Tumor (RECIST) were
widespread metastasis.
used to define tumor response. A complete response (CR)
Six patients without distant metastasis demonstrated a
was defined as the complete disappearance of the target
rapid decline in serum PSA after treatment (Fig. 3). The
lesions. A partial response (PR) was defined as at least a
PSA half-life in these patients was calculated from plots of
30% decrease in the sum of the longest diameter of the
the form log PSA
log A
Bt, where A is the initial PSA
target lesion (14). Late radiation toxicity was scored using
level, B is the rate of PSA decline, and t is time in days. The
the Radiation Therapy Oncology Group (RTOG)/European
median half-life was 31.4 days (range 6.8 ­59.2) (13).
Organization for Research and Treatment of Cancer late
radiation morbidity scoring scheme.
Acute and late toxicity
One patient with lymphedema of the genitalia and ex-
tremities developed moist desquamation of the groin after
RESULTS
HT and RT to the prostate and inguinal lymph nodes. All
The tumor response and treatment-related toxicity are
other patients tolerated the treatment well. No patient de-
described in Table 1 and Figs. 1­ 4. The median follow-up
veloped hyperthermia-induced skin burns. The delayed tox-
for Group A patients was 14 months (range 4 ­ 48) and was
icity from RT and HT included RTOG Grade 1 rectal
15 months (range 6 ­32) for Group B patients. Six patients
bleeding in 2 patients and RTOG Grade 3 rectal bleeding in

658
I. J. Radiation Oncology Biology Physics
Volume 57, Number 3, 2003
Fig. 1. Sigmoidoscopy demonstrating CR of RT and hormone-refractory prostate cancer invading rectum (Group A,
Patient 2, Table 1). (a) Pretreatment image demonstrating 5
5-cm tumor invading rectum. (b) Tumor CR in rectum
13 months after 36 Gy and HT.
1 patient. RT and HT were generally well tolerated by all
multiagent chemotherapy. After retreatment with RT and HT,
patients who had not previously undergone RT. Among
he developed a non-Hodgkin's lymphoma­related bleeding
those who had, most (6 of 8, 75%) tolerated retreatment
diathesis secondary to factor XI deficiency. Eight months after
well with minimal or no complications. Two patients in the
retreatment, he developed Grade 4 hemorrhagic cystitis that
repeat RT group had severe complications.
was related to repeat RT, chemotherapy, and coagulopathy. He
One (Group A, Patient 5) developed urinary stricture after
underwent a suprapubic catheter placement and required sev-
retreatment that required dilation. He also had progressive
eral hospital admissions for multiple blood transfusions. Four-
low-grade non-Hodgkin's lymphoma for which he received
teen months after retreatment, he developed Grade 2 rectal

Efficacy of RT and HT in LAHRPC J. A. KALAPURAKAL et al.
659
Fig. 2. Tumor response after RT (41.4 Gy) and HT in Patient 7 (Group A, Table 1). (a, b) Pretreatment CT scans
demonstrating 8
7
9-cm tumor (arrows) with necrosis (N) obstructing rectum (RE). (c, d) CR of tumor 4 months
after RT and HT. Necrotic tumor has disappeared, leaving a fistula in its place (arrow).
bleeding. His symptoms were controlled after transfusions
occasions before retreatment. Despite his previous treatment,
with fresh frozen plasma. This patient had received high-dose/
he had intractable pelvic pain owing to recurrent prostate
fraction (3 Gy) palliative RT (30 Gy and 12 Gy) on two earlier
tumor in the pelvic soft tissues and bone, necessitating consid-

660
I. J. Radiation Oncology Biology Physics
Volume 57, Number 3, 2003
Fig. 2. (Cont'd)
eration of additional RT. His local symptoms were controlled
with a large necrotic tumor invading the bladder and rectum
until he died 19 months later of metastatic prostate cancer and
developed a tumor-related rectal ulcer 2 months after ther-
lymphoma.
apy. A Gastrografin enema revealed multiple short fistulous
One previously irradiated patient (Group A, Patient 7)
tracts extending from the rectum into the prostatic neo-
Efficacy of RT and HT in LAHRPC J. A. KALAPURAKAL et al.
661
Fig. 3. Serum PSA response during and after RT and HT in Patient 2 (Group B, Table 1). Pretreatment PSA was 318
ng/mL. PSA at conclusion of 66.2 Gy and 10 HT treatments was 1.2 ng/mL. Tumor response illustrated in Fig. 4. Serum
PSA half-life was 6.8 days.
plasm. He underwent diversion colostomy. Before retreat-
these patients (18). This is largely because they have either
ment, his tumor was large and had invaded and obliterated
been irradiated previously, as in Group A, or have high serum
the rectal lumen, and he was unable to have daily bowel
PSA levels that indicate distant metastasis, as in Group B. The
movements. On DRE, the tumor was very soft and fluctuant
prevalent view that such patients do not require local therapy
owing to tumor necrosis. He continued to self-administer
such as RT needs to be reexamined. In this report, the extent of
daily enemas even after retreatment against medical advice.
disease in the Group B patients demonstrated that they could
This practice most likely resulted in the rectal ulceration
live long enough to develop progressive pelvic disease and
secondary to perforation of the fluctuant and necrotic tumor.
debilitating symptoms. Furthermore, the serum PSA response
Four months after RT and HT, he developed a rectovesical
in a few patients (Fig. 3 and Table 1, Group B, Patient 4)
fistula after tumor regression and a CR. He then underwent
would contest the hypothesis that high serum PSA levels is
urinary diversion (Fig. 2).
equated with occult/manifest distant metastasis in all patients.
None of the other 12 Group A or B patients developed a
The first priority of patients with locally advanced cancer
treatment-related fistula of the bowel or bladder or devel-
is to achieve a cure and survive the cancer. Concerns of
oped urinary or bowel incontinence at last follow-up.
therapy-related toxicity, although important, are secondary
in their view. When considering treatment options, it is
important for treating physicians to understand these prior-
DISCUSSION
ities of patients. A study addressing these issues was con-
Hormone-refractory prostate cancer is difficult to manage
ducted among Stage II-IV head-and-neck cancer patients,
and presents a major therapeutic challenge to all physicians
most of whom were functioning reasonably well before
(15). The availability of serum PSA determination has resulted
therapy. Most patients ranked being cured (75%) as their top
in the early detection of hormone-refractory cancer. Thus, the
priority. The other top priorities were living as long as
demographics of patients with hormone-refractory disease are
possible (56%) and having no pain (35%). Items that related
changing, with patients younger and healthier with few comor-
to the toxicity of treatment such as being able to swallow
bid illnesses (15, 16). The role for early intervention with
food, keep their natural voice, being able to chew, keeping
chemotherapy is increasing in an effort to prevent tumor pro-
normal taste were ranked high by 19%, 18%, 8%, and 4% of
gression and dissemination. However, in patients who can
patients, respectively (19). In another report, the attitudes of
tolerate chemotherapy, the response rates have been low and
cancer patients, doctors, nurses, and the general public to
nondurable, and a survival benefit has yet to be proved (15,
chemotherapy were compared. When asked whether they
17). Patients with chemotherapy- and hormone-refractory tu-
would accept intensive chemotherapy that would prolong
mors exhibit a slow but relentless pattern of progression, ulti-
life by 3 months or achieve a relief of symptoms in 1%,
mately resulting in death. This pattern of disease progression
approximately 40% of patients answered in the affirmative
was evident in all patients included in this report. They had
compared with 0% of radiotherapists and 10% of controls.
large tumors and debilitating symptoms owing to pelvic tumor
This suggests that patients with cancer find it difficult to
progression. Few reports are available on the role of RT in
accept circumstances in which no treatment options are

662
I. J. Radiation Oncology Biology Physics
Volume 57, Number 3, 2003
Fig. 4. Tumor response after RT (66.6 Gy) and HT in Patient 2 (Group B, Table 1). (a) Pretreatment CT scan
demonstrating large (7
6
7 cm) tumor (arrows) obstructing rectum (R). UB
urinary bladder. (b) CT scan 12
months after treatment revealing tumor shrunk to residual (2
2
1.5-cm) cystic mass in seminal vesicle. See Fig.
3 for serum PSA response.
available. Moreover, they were willing to undergo treatment
quality of life (20). In this report, patients with advanced
that had a minute chance of a possible benefit and to accept
and recurrent prostate cancer sought quality-of-life im-
a high degree of toxicity to maximize life expectancy and
provement from debilitating symptoms after treatment with
Efficacy of RT and HT in LAHRPC J. A. KALAPURAKAL et al.
663
RT and HT. This goal was met in most patients, except
tolerance of the different organs and late toxicity after
among those with complications such as Grade 4 cystitis
retreatment is not fully known. It depends on a number of
and tumor response-related urinary fistula. Even among
factors, including organ type, previous radiation dose,
these patients, a significant and durable tumor response
dose per fraction, interval between RT sessions, and use
occurred after therapy. It is important to note that these
of chemotherapy and/or surgery (29). In a report from
patients had no known alternative treatments that would
Thomas Jefferson University, among patients with RT-
provide any meaningful tumor response or palliation.
recurrent rectal cancer, good palliation of symptoms oc-
The synergistic role of HT and RT has been demonstrated
curred after low doses of repeat RT and chemotherapy.
in randomized clinical trials in locally advanced primary
The Grade 3 and 4 late toxicity rate was 23% and 10%,
breast cancer (21), malignant melanoma (22) and pelvic
respectively. Small bowel obstruction, chronic cystitis,
tumors (23). The Dutch Deep Hyperthermia Group in a
and fistula formation was observed in 17%, 6%, and 8%,
randomized study demonstrated a significantly superior tu-
respectively (27). In the present report, with similar re-
mor response with deep HT (using the BSD 2000 system)
peat RT doses as in the Jefferson experience, most pa-
and RT in 358 patients with locally advanced bladder,
tients (6 of 8, 75%) tolerated retreatment well with no or
uterine cervix, and rectal cancer. The CR rate for RT com-
minimal complications (2 patients developed Grade 1­2
pared with RT plus HT was 39% and 55% (p
0.001),
rectal bleeding). One patient with a lymphoma-related
respectively. In patients with cervical cancer, the 3-year
factor XI deficiency that developed after retreatment had
survival rate was 27% in the RT group and 51% in the RT
Grade 4 hemorrhagic cystitis. Another previously irradi-
plus HT group (p
0.009). The incidence of acute or late
ated patient developed a tumor regression-related recto-
radiation toxic effects did not increase with the addition of
vesical fistula 4 months after retreatment. The patients at
HT. Interstitial thermometry was used in that study, but no
higher risk of retreatment or tumor regression-related
thermometry details were provided (23). In a report from
complications are those with necrotic tumors that destroy
Stanford University, 4 patients with locally recurrent pros-
tissue planes (Fig. 2), previous RT at a higher dose/
tate cancer after initial treatment with 192Ir brachytherapy
fraction, or bleeding disorders. The measures taken to
were retreated with deep HT and RT (60 Gy, in two 30-Gy
minimize retreatment complications included the use of
split courses). None of the patients experienced severe rectal
low-to-moderate doses of RT for retreatment, a lower
or bladder reactions. Three of four achieved a clinical CR at
dose/fraction (1.8 Gy), patient immobilization, and three-
7­24 months after treatment. The authors concluded that
dimensional CT treatment planning.
repeat RT and HT had the potential to control local disease
with minimal complications (24). In the present study, RT
CONCLUSION
and HT proved successful, with tumor responses (CR plus
PR) of 100%, with most being CRs lasting from 9 months
This preliminary report demonstrated the feasibility and
to 3 years, among assessable patients. Furthermore, the
efficacy of RT and HT in patients with LAHRPC and RT-
impact on quality of life has been significant, with durable
recurrent prostate cancer. At present, such patients, especially
palliation of disabling symptoms.
those who have previously been irradiated, have no effective
Repeat RT is increasingly being used in the manage-
treatment options other than chemotherapy or symptomatic
ment of recurrent tumors at various sites, including the
management. RT and HT were generally well tolerated in
head and neck (25), brain (26), and rectum (27). The
patients who had not been previously irradiated. Among those
local control rates with repeat RT range from 40% to 75%
who had previously undergone RT, most (6 of 8) tolerated
(25­27). Because the repeat RT doses are generally
retreatment well with minimal or no complications. The pa-
lower, RT is usually administered in combination with
tients at greater risk of retreatment or tumor regression-related
radiosensitizing agents such as chemotherapy (25, 27) or
complications were those with necrotic tumors that destroyed
HT (28). Whenever repeat RT is used, the risk of acute
tissue planes, previous RT at a higher dose/fraction, or bleed-
and late toxicity, including permanent organ damage
ing disorders. Despite the large and symptomatic tumors, RT
resulting in tissue necrosis, fistula formation, or life-
and HT resulted in significant tumor shrinkage, rapid serum
threatening vascular injury, is increased (25­27). In the
PSA decline, durable treatment responses (CRs and PRs), and
RTOG 96-10 study which treated recurrent head-and-
durable palliation of disabling symptoms. Additional clinical
neck tumors with RT and concurrent chemotherapy, he-
studies are warranted to define the role of this therapy better in
matologic Grade 5 toxicity occurred in 7% and 2 patients
the evolving care of patients with hormone-refractory and
died secondary to tumor hemorrhage (25). The radiation
RT-recurrent prostate cancer.
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