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To: radoncjc@net.bio.net
Subject: November 1999 Internet Radiation Oncology Journal Club (IROJC)
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Date: Mon, 08 Nov 1999 07:10:40 -0500
From: Brian Goldsmith <bgoldsmith@iname.com>

November 1999 Internet Radiation Oncology Journal Club (IROJC)

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Posting of references for review and discussion
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The 54th collection of references suggested for attention and
discussion by the IROJC's Board of Editors:

Sarah Donaldson, M.D.
Editor, Pediatric Radiation Oncology

Robert Foote, M.D.
Editor, Head and Neck / Skin Radiation Oncology

Abram Recht, M.D.
Editor, Breast Radiation Oncology

Rich Hoppe, M.D.
Editor, Reticuloendothelial System Radiation Oncology

Dan Petereit, M.D.
Editor, Gynecological Radiation Oncology

Andrew Turrisi, M.D.
Editor, Lung and Mediastinum Radiation Oncology

Joel Tepper, M.D.
Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology

Mack Roach, M.D.
Editor, Genitourinary Radiation Oncology

Glenn Bauman, M.D. Ph.D.
Editor, Central Nervous System Radiation Oncology

Rod Withers, M.D., D.Sc.
Editor, Radiobiology

James Hayman, M.D.
Editor, Health Services Research

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HEALTH SERVICES RESEARCH, A NEW IROJC CATEGORY!

Starting with this issue, a new content category has been added entitled

"Health Services Research", edited by James Hayman.  Each month, an
article will be cited and reviewed dealing with such diverse topics as
quality of life (including studies dealing with palliative care), cost
and cost-effectiveness, variations in utilization and practice patterns,

patient preference and satisfaction with treatment and outcome, practice

guidelines, technology assessment, availability and access to medical
care, workforce issues and quality assurance.

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You're encouraged to critically review this set of references and
respond by posting your comments to the IROJC readership at
radoncjc@net.bio.net. Comments should be in compliance with IROJC
commentary rules (see below).

In the month that follows this posting of references, submitted
comments will be delivered to the e-mail boxes of the IROJC readership,
with the goal of stimulating a professional discussion of these
references and their subjects.

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ARCHIVED IROJC POSTINGS and commentary are available on the World Wide
Web!

Look for them on http://www.bio.net/
Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then
go to "RADIATION-ONCOLOGY/Prototype". Or directly access the
RADIATION-ONCOLOGY folder at
http://www.bio.net/hypermail/RADIATION-ONCOLOGY/

There's also a freeWAIS search tool at the website, for searching
archived postings for keywords or phrases!

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Commentary Rules:

(1) Please cite the subject category in the header of your e-mail
message, e.g., Subject: CNS 11/99.

(2) Address the readership at large - not the Editor who suggested the
reference. The Editor is under no obligation to respond to questions
posed by the IROJC readership.

(3) The Editor's selection is not necessarily an endorsement of the
authors' conclusions. In fact, articles may be selected for criticism.

(4) Comments posted to the Internet are public. Professional wording is
prudent.

(5) Comment only on journal articles that you have read recently, and
please keep comments specific.

(6) In order to minimize confusion, limit comments to the current
month's list of references.

(7) Please sign all comments and questions to the IROJC. By identifying
yourself, you promote a more collegial and friendly environment!

(8) Address to the Moderator (briandeb@bellatlantic.net) private
questions and comments which are not intended for IROJC posting
and public reading.

******************
Peds: Donaldson 11/99

AU: Green DM; Hyland A; Chung CS; Zevon MA; Hall BC
TI: Cancer and cardiac mortality among 15-year survivors of cancer
diagnosed during childhood or adolescence.
SO: J Clin Oncol 1999 Oct;17(10):3207-3215
URL: http://www.jco.org/cgi/content/full/17/10/3207
PDF: http://www.jco.org/cgi/reprint/17/10/3207

Abstract:
PURPOSE: To evaluate the impact of cardiac disease and second malignant
neoplasms on late mortality rate and to identify risk factors for late
mortality among 15-year survivors of cancer diagnosed during childhood
or adolescence.
PATIENTS AND METHODS: Gender-specific all-cause and cause-specific
(cardiac disease, cancer) standardized mortality
ratios were calculated. Kaplan-Meier survival estimates and Cox
regression analyses were performed to determine the relationship
of several demographic and treatment variables to survival.
RESULTS: Patients who survived for 15 years after diagnosis had excess
subsequent all-cause, cancer (second malignant neoplasms only), and
cardiac mortality rates. No decrease in the late mortality rate by
treatment era (1960 to 1970, 1971 to 1984) was identified. Risk factors
for males included disease recurrence during the first 15 years after
diagnosis, treatment with doxorubicin, and the diagnosis of Hodgkin's
disease. Those for females included treatment with radiation therapy,
treatment with an alkylating agent, and disease recurrence during the
first 15 years after diagnosis. Cox regression analysis demonstrated
that only an initial duration of remission of less than 15 years (P less

than  .01) and treatment with doxorubicin (P equals .08) were
significantly associated with shorter survival time for males. No
variable was significantly associated with shorter survival time for
females in Cox regression analysis.
CONCLUSION: Fifteen-year survivors of childhood cancer have excess
mortality. More effective treatments must be developed to reduce this
excess risk. Fifteen-year relapse-free survivors did not have excess
mortality. This group will require continued observation to determine
whether excess mortality will become apparent as more events occur.

Editor's comments:
This article is important in emphasizing the risk factors for excess
mortality among children who are cancer survivors of at least 15
years. While Radiation Oncologists are well aware of the problems
related to prior radiation, this article points out that the most
frequent cause of death in the cohort studied was the original cancer.
The second most common was second malignant neoplasm. Four of the 5
children who developed a second malignant tumor had received prior
radiotherapy, but none of the tumors were clearly radiation related. One

was a meningioma in a patient with ALL who presumably had CNS
radiotherapy for cranial prophylaxis, and one irradiated Hodgkin's
Disease survivor, who was a smoker, developed lung cancer. The third
most comon cause of death was cardiac disease, with important risk
factors being anthracycline chemotherapy as well as mediastinal
radiotherapy. In summary there was no excess  mortality risk among the
15 yr. relapse-free survivors.  Ways to limit the excess mortality risk
include decreasing exposure to environmental carcinogens, and modifying
treatment, which in many respects has already been done with current
therapy. Thus hopefully we can look forward to  a further decrease in
the risk of treatment-associated complications in the future.

******************
Head/Neck/Skin: Foote 11/99

AU: Narayan K; Crane CH; Kleid S; Hughes PG; Peters LJ
TI: Planned neck dissection as an adjunct to the management of patients
with advanced neck disease treated with definitive radiotherapy: for
some or for all?
SO: Head Neck 1999 Oct;21(7):606-13

Abstract:
BACKGROUND: Management of patients with head and neck carcinoma and
advanced nodal disease is controversial. The purpose of this analysis
was to evaluate the efficacy and toxicity of definitive radiotherapy
followed by planned neck dissection in patients with bulky neck disease.

MATERIALS AND METHODS: The records of 52 patients who were treated
between 1989 and 1995 at the Peter MacCallum Cancer Institute with a
planned neck dissection after radical radiotherapy were reviewed. All
had advanced neck disease with one or more nodes greater than or equal
to 3 cm in maximum diameter, 94% being staged N2-3. The most common
primary site was the oropharynx (56%). Sixty percent of patients had
either T2 or T3 primaries and all were AJCC stage IV. Treatment
consisted of high- dose radiotherapy to the primary and involved neck
sites using various fractionation protocols followed by radical or
modified radical neck dissection after confirmation of a complete
response at the primary site. The median follow-up for living patients
was 58 months (range 32- 97).
RESULTS: There were nine regional failures, of which three were outside
the dissected neck, yielding a 5-year actuarial overall neck control
rate of 83% and an in-field control rate of 88%. In-field control rates
by neck stage were N1 3/3; N2 31/35; N3 11/13 and NX 1/1. There was only
one in-field failure among 28 patients who had pathologically negative
neck specimens compared with five in 24 patients with morphologic
evidence of residual disease. Of the 24 patients with pathologically
positive necks, 5 were long-term survivors and were probably cured by
their surgery. Another 4 died of intercurrent disease without documented

recurrence of their head and neck cancer. Ten patients recurred at their

primary sites (5-year actuarial control 79%) and 8 developed distant
metastases (5-year actuarial rate 20%). A total of 21 patients failed at

one or more sites and none was salvaged. Five-year actuarial
disease-free survival was 57% and overall survival 38%. Nine patients
(17%) sustained significant complications following neck dissection.
CONCLUSIONS: In patients with advanced neck disease who are treated
primarily with radical radiotherapy, planned neck dissection provides
excellent regional control and appears to cure a subset of patients.
However, routine neck dissection adds significant morbidity to treatment

and should ideally be avoided in those patients in whom surgery is
either unnecessary (no residual tumor) or futile (unsalvageable disease
recurrence outside the dissected neck). Based on our analysis and other
recently reported series, we now recommend observing patients who have a

complete response to high-dose radiotherapy (+/- chemotherapy). The
ability of PET imaging to detect residual viable tumor in the head and
neck or at distant sites is under investigation. Copyright 1999 John
Wiley & Sons, Inc. Head Neck 21: 606-613, 1999.

******************
GYN: Petereit 11/99

AU: Mohan DS; Samuels MA; Selim MA; Shalodi AD; Ellis RJ; Samuels JR;
Yun HJ.
TI: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I
endometrial adenocarcinoma.
SO: Gynecol Oncol 1998 Aug;70(2):165-71.

Abstract:
OBJECTIVE: The treatment of patients with stage I endometrial
adenocarcinoma is often shorter and less expensive if total abdominal
hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), and
therapeutic lymphadenectomy are used rather than TAH, BSO, pelvic lymph
node sampling, and pelvic external beam radiation. We studied whether
the survival and morbidity of patients treated with therapeutic
lymphadenectomy are equal to or better than with these alternative
treatments.
METHODS: We reviewed the medical records of patients with stage I
endometrial adenocarcinoma who were enrolled in the MetroHealth Medical
Center tumor registry between 1970 and 1993 after undergoing full pelvic
lymph node dissection, in addition to total abdominal hysterectomy,
bilateral salpingo-oophorectomy, and vaginal brachytherapy. The mean
number of resected nodes was 33 (median, 31; interquartile range, 19).
Patients were followed for 1. 6-20 years (median, 8 years; interquartile
range, 5.8 years). Morbidity and survival rates were compared to
published series using similar treatment strategies and to those from
studies using pelvic external beam radiation and pelvic lymph node
sampling rather than lymphadenectomy.
RESULTS: Of 192 patients with pathologic stage I (FIGO 1988) endometrial
adenocarcinoma, 178 patients had full pelvic lymph node dissection; 159
patients were evaluable. The 15-year overall survival was 98%; 10- and
15- year disease-free survivals were 96 and 94%, respectively. Overall
morbidity was 18% (29/159), and moderate-to- severe morbidity was 13%
(21/159). Recurrences were seen in 4.4% (7/159) of patients. Grade and
myometrial invasion were not significant predictors of disease-free
survival after full pelvic lymph node dissection (grade, P equals 0.42;
stage, P equals 0.67). The results compare favorably with those of
similar studies and with studies of pelvic external beam radiation.
CONCLUSIONS: Primary surgical management with total abdominal
hysterectomy, bilateral salpingo-oophorectomy, therapeutic pelvic
lymphadenectomy, and vaginal brachytherapy is a viable and possibly
preferable option for patients with stage I endometrial adenocarcinoma.
Copyright 1998 Academic Press.

Editor's comments:
Surgical evaluation of the pelvic and para-aortic lymph nodes continues
to be a controversial subject within the gynecologic oncology
community.  Some advocate that a complete lymphadenectomy is justified
for nearly  all stages of endometrial cancer and that it is therapeutic
–- even in the absence of nodal metastases.  Two letters to the editor
recently appeared in Gynecologic Oncology which took issue with the
claims made by a surgical study from Mohan et al.[1-3]

With complete surgical staging, Mohan et al. suggested a therapeutic
benefit, lower complication and similar cure rates than “comparable
series” of incomplete surgical staging and pelvic radiotherapy, and
implied essentially no role for pelvic radiotherapy in the sub-group of
stage I patients studied.[3] Only surgical stage I patients were
evaluated.  All patients had a total abdominal hysterectomy, bilateral
salpingo-oophorectomy, pelvic lymph node sampling, and peritoneal
cytologic sampling.  A median of 33 lymph nodes were retrieved.  One
hundred ninety-two patients were identified in which 33 patients were
excluded:  14 because of incomplete staging and 19 because of incomplete
follow-up.  The majority of patients had low risk prognostic factors:
94% had either histologic grades 1 or 2 and 83% had either stage IA or
IB disease.  All patients had adjuvant radiation with either low dose-
rate or high dose- rate vaginal brachytherapy.  Seven percent of
patients received pelvic radiotherapy to 45 Gy because of extension to
the uterine serosa or clear cell histology.  The 15 year overall
survival and disease-free survivals were 98% and 96%, respectively.
Despite these excellent cure rates, significant morbidity was observed
in 13% of patients (non-actuarial reporting).

The authors implied that “skeletonizing the external iliac vessels”
improves outcome by removing occult tumor emboli that are not documented
pathologically.  This mechanism of improving outcome has also been
suggested by Kilgore et al.[4]  Did the 7% of patients who received
pelvic radiotherapy have  outer 1/3 myometrial invasion and/or high
grade tumors?  Is it possible that the addition of pelvic radiotherapy
resulted in similar outcomes for the high-risk patients and the low-risk
patients.  This conversion of high-to low-risk patients with pelvic
radiotherapy has been verified by others.[5] The authors erroneously
compare their results to Kucera et al., and claim to achieve superior
results because of complete surgical staging.  The report by Kucera et
al. is a prospective study that tailored radiation to the extent of
uterine disease.[5]  The majority of patients that received pelvic
radiotherapy had stage IC disease, while the remaining patients received
vaginal cuff brachytherapy.  They were able to demonstrate that
high-risk stage I patients treated with adjuvant pelvic radiotherapy can
have similar outcomes to those of low-risk patients.  The low-risk
population had 5 year overall survival rates ranging from 91-100% with
much lower complication rates than reported by Mohan et al.

The primary issue is whether grade 1 or 2, stage IA/IB patients even
need an assessment of the pelvic lymph nodes -- they certainly do not
need pelvic radiotherapy.  Patients with stage IA or IB (less than 1/3
myometrial invasion), and histologic grade 1 or 2 only have less than 3%
incidence of pelvic lymph node metastases as reported from the sentinel
GOG study.[6] In the current study, 83% of patients had either stage IA
or IB disease.  The 13% significant morbidity rate seems unnecessary for
these patients.  Why are the authors advocating such an aggressive
surgical approach (median number of nodes removed 33), when other
surgeons have reported that limited surgical assessment will provide the
same information with lower morbidity rates?

My conclusion from the Mohan report is that excellent survival rates
were observed because the majority of patients had early stage disease
and were appropriately treated with adjuvant vaginal cuff
brachytherapy.  Complete surgical staging only contributed to high
morbidity rates that could have been avoided through limited surgical
staging, or no pathologic assessment of the lymph nodes at all.  This
study does not support the emerging practice that surgical staging
eliminates the need for pelvic radiotherapy for high-risk stage I
endometrial patients.

REFERENCES
1. Petereit DG, Greven KM.  Surgical staging in endometrial cancer:  is
excellent survival due to thorough surgical staging or patient
selection? Gynecologic Oncology   1999;73:467-468.
2. Parikh S, Ravi A, Sundararaman S, et al.  Re:  Long-term outcomes of
therapeutic pelvic lymphadenectomy for stage I endometrial
adenocarcinoma. Gynecologic Oncology   1999;73:464-465.
3. Mohan DS, Samuels MA, Selim MA, et al.  Long-term outcomes of
therapeutic pelvic lymphadenectomy for stage I endometrial
adenocarcinoma. Gynecologic Oncology   1998;70:165-171.
4. Kilgore LC, Partridge EE, Alvarez RD, et al.  Adenocarcinoma of the
endometrium: survival comparisons of patients with and without pelvic
node sampling. Gynecologic Oncology   1995;56:29-33.
5. Kucera H, Vavra N, Weghaupt K.  Benefit of external irradiation in
pathologic Stage I endometrial carcinoma: a prospective clinical trial
of 605 patients who received postoperative vaginal irradiation and
additional pelvic irradiation in the presence of unfavorable prognostic
factors. Gynecologic Oncology   1990;38:99–104.
6. Creasman W, Morrow C, Bundy B, et al.  Surgical pathologic spread
patterns of endometrial cancer.  A Gynecologic Oncology Group Study.
Cancer   1987;60:2035–2041.

******************
GI / Soft Tissue Sarcoma: Tepper 11/99
No Reference Selected

******************
CNS: Bauman 11/99

AU: Muacevic A; Kreth FW; Horstmann GA; Schmid-Elsaesser R; Wowra B;
Steiger HJ; Reulen HJ.
TI: Surgery and radiotherapy compared with gamma knife radiosurgery in
the treatment of solitary cerebral metastases of small diameter.
SO: J Neurosurg 1999 Jul;91(1):35-43

Abstract
OBJECT: The aim of this retrospective study was to compare treatment
results of surgery plus whole-brain radiation therapy (WBRT) with gamma
knife radiosurgery alone as the primary treatment for solitary cerebral
metastases suitable for radiosurgical treatment.
METHODS: Patients who had a single circumscribed tumor that was 3.5 cm
or smaller in diameter were included. Treatment results were compared
between microsurgery plus WBRT (52 patients, median tumor dose 50 Gy)
and radiosurgery alone (56 patients, median prescribed tumor dose 22
Gy). In case of local/distant tumor recurrence in the radiosurgery
group, additional radiosurgical treatment was administered in patients
with stable systemic disease. Survival time was analyzed using the
Kaplan-Meier method, and prognostic factors were obtained from the Cox
model. The patient groups did not differ in terms of age, gender,
pretreatment Karnofsky Performance Scale (KPS) score, duration of
symptoms, tumor location, histological findings, status of the primary
tumor, time to metastasis, and cause of death.  Patients who suffered
from larger lesions underwent surgery (p less than 0.01). The 1-year
survival rate (median survival) was 53% (68 weeks) in the surgical group

and 43% (35 weeks) in the radiosurgical group (p equals 0.19). The
1-year local tumor control rates after surgery and radiosurgery were 75%

and 83%, respectively (p equals 0.49), and the 1-year neurological death

rates in these groups were 37% and 39% (p equals 0.8). Shorter overall
survival time in the radiosurgery group was related to higher systemic
death rates. A pretreatment KPS score of less than 70 was a predictor of

unfavorable survival. Perioperative morbidity and mortality rates were
7.7% and 1.6% in the resection group, and 8.9% and 1.2% in the
radiosurgery group, respectively. Four patients presented with transient

radiogenic complications after radiosurgery.
CONCLUSIONS: Radiosurgery alone can result in local tumor control rates
as good as those for surgery plus WBRT in selected patients.
Radiosurgery should not be routinely combined with radiotherapy.

Editor's comments:
The comparison of radiosurgery and surgical resection for patients with
solitary metastasis is problematic due to the absence of completed
randomized trials.  Several organizations have tried to mount randomized

trials to answer this question but large patient numbers (at least
250-300) to no avail.  The MDACC is currently running a randomized trial

of surgery versus radiosurgery without immediate whole brain
radiotherapy (deferred till time of relapse).

This non-randomized, retrospective study compares groups of patients
treated with radiosurgery or surgery according to "institutional
preference".  52/228 surgically treated patients were selected as
contemporary controls for the radiosurgery patients according to the
criteria: stable systemic disease, tumor size less than 3.5 cm, solitary

on MRI and not needing decompression because of symptoms of increased
intracranial pressure.  Patients treated with surgery also received
whole brain radiation, however radiosurgery treated patients did not
receive whole brain radiotherapy (but could have repeat gamma knife).

Local control between the two modalities was quite good.   Distant
cranial control with radiosurgery was worse (probably because omission
of the WBXRT but ultimately the number of patients dying of progressive
intracranial disease was similar.  These results agree with Patchell's
trial where ommission of WBXRT led to more intracranial recurrences but
ultimately no survival difference (when surgery was used as the primary
treatment for the solitary metastasis)

Of interest, an overall survival difference of about 10% at 1 year and a

doubling of median survival for surgery over radiosurgery was noted.
Neither result was significant statistically, but the study had
inadequate power to detect this difference.

So what can you conclude?  Surgery and radiosurgery probably have
similar local control benefits.  Whole brain radiotherapy added to
either modality probably increases intracranial control but probably
doesn't impact on survival.  Even for solitary lesions, radiosurgery is
still suitable for a minority of patients (about 25% in this series).
Local treatment with omission of whole brain radiotherapy may still be
successful as long as careful MRI monitoring is performed along with
salvage local therapy for new intracranial lesions as necessary.

Lets hope the MDACC is successful in completing their randomized
comparison. Until that time, the choice between surgery and radiosurgery

will continue to be determined by Level III evidence and provider bias.
In particular prospective comparisons using validated quality of life
endpoints between the two modalities are urgently needed.

******************
Breast: Recht 11/99

AU: Fisher B; Bryant J; Wolmark N; Mamounas E; Brown A; Fisher ER;
Wickerham DL; Begovic M; DeCillis A; Robidoux A; Margolese RG; Cruz AB
Jr; Hoehn JL; Lees AW; Dimitrov NV; Bear HD.
TI: Effect of preoperative chemotherapy on the outcome of women with
operable breast cancer.
SO: J Clin Oncol 1998 Aug;16(8):2672-85
URL: http://www.jco.org/cgi/content/abstract/16/8/2672

Abstract:
PURPOSE: To determine, in women with primary operable breast cancer, if
preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC)
therapy yields a better outcome than postoperative AC therapy, if a
relationship exists between outcome and tumor response to preoperative
chemotherapy, and if such therapy results in the performance of more
lumpectomies.
PATIENTS AND METHODS: Women (1,523) enrolled onto National
Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly
assigned to preoperative or postoperative AC therapy. Clinical tumor
response to preoperative therapy was graded as complete (cCR), partial
(cPR), or no response (cNR). Tumors with a cCR were further categorized
as either pathologic complete response (pCR) or invasive cells (pINV).
Disease-free survival (DFS), distant disease-free survival (DDFS), and
survival were estimated through 5 years and compared between treatment
groups. In the preoperative arm, proportional-hazards models were used
to investigate the relationship between outcome and tumor response.
RESULTS: There was no significant difference in DFS, DDFS, or survival
(P equals .99, .70, and .83, respectively) among patients in either
group.  More patients treated preoperatively than postoperatively
underwent lumpectomy and radiation therapy (67.8% v 59.8%,
respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after

lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P
equals .23). Outcome was better in women whose tumors showed a pCR than
in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates,
85.7%, 76.9%, 68.1%, and 63.9%, respectively; P less than .0001), even
when baseline prognostic variables were controlled. When prognostic
models were compared for each treatment group, the preoperative model,
which included breast tumor response as a variable, discriminated
outcome among patients to about the same degree as the postoperative
model.
CONCLUSION: Preoperative chemotherapy is as effective as postoperative
chemotherapy, permits more lumpectomies, is appropriate for the
treatment of certain patients with stages I and II disease, and can be
used to study breast cancer biology. Tumor response to preoperative
chemotherapy correlates with outcome and could be a surrogate for
evaluating the effect of chemotherapy on micrometastases; however,
knowledge of such a response provided little prognostic information
beyond that which resulted from postoperative therapy.

Editor's comments:
The recent publication of 5-year results from the NSABP B-18 trial
answers some, but not all, of the questions which I posed in an earlier
editorial (Recht, J Clin Oncol 1997;15:2479-82) when their initial
report of response rates in this trial appeared (Fisher et al, J Clin
Oncol 1997;15:2483-93). One of the issues that this article does settle
is whether the increased risk of local failure in patients treated with
breast-conserving therapy (BCT) following preoperative chemotherapy
reported in their earlier abstract (Fisher et al, Proc Am Soc Clin Oncol

1997;16:127a) was in individuals in whom the surgeon initially proposed
to perform lumpectomy (who I called "conventional" candidates for BCT)
or in those patients who were originally thought to require a mastectomy

who were downstaged sufficiently to go on to BCT (the "unconventional"
candidates). The risk of ipsilateral breast tumor recurrence (IBTR) was
nearly the same in the former group (30/435, or 6.9%) as in patients who

underwent lumpectomy prior to chemotherapy (26/450, or 5.8%); but the
risk in the latter group was substantially greater (10/69, or 14.5%).
Nonetheless, these data do not answer another question I posed before:
namely, whether patients who are unconventional candidates for BCT might
have better long-term results if they were treated with mastectomy,
rather than BCT. It would have been very helpful for the distant
disease-free and overall survival rates to be presented separately (for
each arm) for those
patients for whom lumpectomy was initially proposed and for those for
whom mastectomy was initially proposed. In particular, the critical
aspect of such a comparison will be to see if the results in these
subgroups were the same in the preoperative and postoperative arms. If
they are different, the results would have substantial clinical
implications for patient treatment and future study design.

Another question arises with regards the authors' speculations regarding

the potential value of tamoxifen in patients younger than 50 years old
in reducing IBTR following preoperative chemotherapy. In patients age 50

or older, the risk of IBTR was similar in patients in whom lumpectomy
was initially planned on the postoperative treatment arm (3.3%) and the
postoperative treatment arm (1.8%), but the risk of IBTR was still much
greater in the patients downstaged to lumpectomy in the preoperative arm

(11%), despite the routine use of tamoxifen. Therefore, it seems likely
that tamoxifen would decrease the risk of IBTR in the younger-age group
regardless of treatment approach, but it would probably not entirely
eliminate the problem of an increased risk of IBTR in the patients
initially intended to have mastectomy. This problem may also be
magnified because more of the patients in the younger group are likely
to have tumors negative for the estrogen receptor protein (ERP),
compared to the older group. Thus, it would have been helpful to have
data on the risk of IBTR in these subgroups according to ERP status.

Finally, in their discussion the authors mentioned the rate if IBTR in
patients in the preoperative arm who had a pathologic complete response.

However, they did not present data on the rates in patients with other
degrees of response. This would again be clinically useful information,
especially if presented separately for those patients in whom mastectomy

or lumpectomy was initially intended.

******************
RES: Hoppe 11/99

AU: Jerusalem G; Beguin Y; Fassotte MF; Najjar F; Paulus P; Rigo P;
Fillet G.
TI: Whole-body positron emission tomography using 18F-fluorodeoxyglucose
for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's
lymphoma has higher diagnostic and prognostic value than classical
computed tomography scan imaging.
SO: Blood 1999 Jul 15;94(2):429-33
URL: http://www.bloodjournal.org/cgi/content/abstract/94/2/429
PDF: http://www.bloodjournal.org/cgi/reprint/94/2/429

Abstract:
A residual mass after treatment of lymphoma is a clinical challenge,
because it may represent vital tumor as well as tissue fibrosis.
Metabolic imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission
tomography (PET) offers the advantage of functional tissue
characterization that is largely independent of morphologic criteria. We

compared 18F-FDG PET to computed tomography (CT) in the posttreatment
evaluation of 54 patients with Hodgkin's disease (HD) or
intermediate/high-grade non-Hodgkin's lymphoma (NHL). Residual masses on
CT were observed in 13 of 19 patients with HD and 11 of 35 patients with
NHL. Five of 24 patients with residual masses on CT versus 1 of 30
patients without residual masses presented a positive 18F-FDG PET study.

Relapse occurred in all 6 patients (100%) with a positive 18F-FDG PET, 5

of 19 patients (26%) with residual masses on CT but negative 18F-FDG
PET, and 3 of 29 patients (10%) with negative CT scan and 18F-FDG PET
studies (P less than or equal to .0001). We observed a higher relapse
and death rate in patients with residual masses at CT compared with
patients without residual masses at CT (progression-free survival at 1
year: 62 +/- 10 v 88 +/- 7%, P equals. 0045; overall survival at 1 year:

77 +/- 5 v 95 +/- 5%, P equals .0038). A positive 18F-FDG PET study was
even more consistently associated with poorer survival: compared with
patients with a negative 18F-FDG PET study, the 1-year progression-free
survival was 0% versus 86% +/- 5% (P less than .0001) and the 1-year
overall survival was 50% +/- 20% versus 92% +/- 4% (P less than .0001).
The detection of vital tumor by 18F-FDG PET after the end of treatment
has a higher predictive value for relapse than classical CT scan imaging

(positive predictive value: 100% v 42%). This could help identify
patients requiring intensification immediately after completion of
chemotherapy. However, 18F-FDG PET mainly predicts for early progression
but cannot exclude the presence of minimal residual disease, possibly
leading to a later relapse.

Editor's comments:
This paper nicely complements the January 1999 IROJC-RES selection that
discusses the role of PET for initial staging.  In this paper, PET is
shown to be a valuable restaging tool, with relapse closely correlated
with PET positivity after treatment.  There isn't any mention of what
the therapy was - if it was chemotherapy alone, then there would be good

argument to irradiate the PET positive sites. Also, note that even PET
is not perfect, 8/48 patients with a negative PET relapsed.

******************
Lung/Mediastinum: Turrisi 11/99

AU: Stuschke M, Eberhardt W, Pottgen C, Stamatis G, Wilke H, Stuben G,
Stoblen F, Wilhelm HH, Menker H, Teschler H, Muller RD, Budach V, Seeber
S, Sack H.
TI: Prophylactic cranial irradiation in locally advanced non–small-cell
lung cancer after multimodality treatment: long-term follow-up and
investigations of late neuropsychologic effects.
SO: J Clin Oncol 1999 Sep; 17(9):2700-2709
URL: http://www.jco.org/cgi/content/full/17/9/2700
PDF: http://www.jco.org/cgi/reprint/17/9/2700

Abstract:
PURPOSE: Relapse pattern and late toxicities in long-term survivors were

analyzed after the introduction of prophylactic cranial irradiation
(PCI) into a phase II trial on trimodality treatment of locally advanced

(LAD) non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB
NSCLC were treated with induction chemotherapy, preoperative
radiochemotherapy, and surgery. PCI was routinely offered during the
second period of study accrual. Patients were given a total radiation
dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1
day after the last chemotherapy cycle.
RESULTS: Introduction of PCI reduced the rate of brain metastases as
first site of relapse from 30% to 8% at 4 years (P equals .005) and that

of overall brain relapse from 54% to 13% (P less than .0001). The effect

of PCI was also observed in the good-prognosis subgroup of 47 patients
who had a partial response or complete response to induction
chemotherapy, with a reduction of brain relapse as first failure from
23% to 0% at 4 years (P equals .01). Neuropsychologic testing revealed
impairments in attention and visual memory in long-term survivors who
received PCI as well as in those who did not receive PCI. T2-weighted
magnetic resonance imaging revealed white matter abnormalities of higher

grades in patients who received PCI than in those who did not.
CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC
to a clinically significant extent, comparable to that in
limited-disease small-cell lung cancer. Late toxicity to normal brain
was acceptable. This study supports the use of PCI within intense
protocols for LAD-NSCLC, particularly in patients with favorable
prognostic factors.

Editor's comments:
The dust up about small cell prophylactic cranial irradiation has been
rationally settled in the meta-analysis discussed a few weeks back. The
issue of absolute risk-reduction remains the focus of concern for some.
My response to this concern is that the worst way to lose higher
cognitive function is from a metastasis.  With the relative risk of
reduction so obvious, the potential problem of late cognitive effects
seems wrongly placed as a major issue - - now with a survival benefit
shown, it seems that the dust should settle.  Let's wait and see.

This months paper has an issue that has been lurking in the wings for a
decade.  When I first heard that PCI was proposed for NSCLC, I was a
doubter -- we had too few that survived and too few active chemotherapy
combinations.  Then there were the results of SWOG 8300 from the early
80's that suggested a survival detriment to PCI.  The case closed for a
while, but the issue didn't go away.

The neoadjuvant chemotherapies and radiochemotherapies improved, some
went on to surgery, and with amazing consistency, trials were reporting
isolated brain metastases.  It was only a matter of time before someone
reported an attempt to reduce their frequency.  The Stuschke paper
provides that data very nicely.

The risk of relapse without PCI seems in the ball park - 20-30%. The
reduction to about 10 % also seems right.  Kathy Albain reported similar

observations from SWOG 8805 - initially the PCI was mandated, then it
was forbidden: 25% relapse rate without PCI and 11% with.

The Essen trial used 30 Gy in 15 fractions.  Is this the right dose?
Interestingly, the PCI seemed to be given before the surgery.  Not all
ultimately get curative surgery, but even on theoretic grounds, I wonder

if this is the best time.  The primary tumor and residual nodes, if any,

harbor the resistant cells.  Should the PCI strategy be used while they
continue to remain in place, presumably with an ability to metastasize?
These investigators have provided us with some data to think about.
Only a prospective trial will answer the question.  Are we ready for
that?

There is a French trial asking a dose question in PCI.  Should we think
about mounting a yes/no trial of PCI in NSCLC?  I think so.

******************
GU: Roach 11/99
No Reference Selected

******************
Radiobiology: Withers 11/99

AU: Brada M, Burchell L, Ashley S, Traish D.
TI: The incidence of cerebrovascular accidents in patients with
pituitary adenoma.
SO: Int J Radiat Oncol Biol Phys 1999 Oct 1;45(3):693-8.

Abstract:
BACKGROUND AND PURPOSE: Patients with pituitary adenomas are effectively
treated with a combination of surgery, radiotherapy, and medical
therapy. Nevertheless, long-term studies suggest increased mortality
that is independent of tumor control, with cerebrovascular accidents
(CVA) as the major contributing cause. The purpose of this study was to
define the frequency of CVAs in a cohort of patients with pituitary
adenoma and identify potential predisposing factors.
PATIENTS AND METHODS: A cohort of 331 United Kingdom (UK) residents with
pituitary adenoma treated at the Royal Marsden Hospital (RMH) between
1962 and 1986 was studied. The frequency of CVA was assessed from RMH
and referring hospital records and clinicians, by postal questionnaire
of referring hospitals and general practitioners, and by examination of
all death certificates. The data were analyzed by actuarial methods, and
risk factors were assessed by multivariate analysis. The data were
compared to the incidence of CVA in the general population using a
published UK population cohort.
RESULTS: Sixty-four of 331 patients developed CVA after primary
treatment of pituitary adenoma. The actuarial incidence of CVA was 4%
(95% CI: 2-7%) at 5 years, 11% (95% CI: 8-14%) at 10 years, and 21% (95%
CI: 16-28%) at 20 years measured from the date of radiotherapy. The
relative risk of CVA compared to the general population in the UK was
4.1. Age was an independent predictive factor for CVA. However, the
relative risk in comparison to the general population was independent of

age. The relative risk of developing CVA was higher in women compared to

men, in patients undergoing debulking surgery compared to less radical
procedures, and in patients diagnosed and treated in the 1980s compared
to previous decades. The dose of radiotherapy was an additional
independent prognostic factor on multivariate analysis. CONCLUSION:
Patients with pituitary adenoma treated with surgery and radiotherapy
have a significantly increased risk of CVA compared to the general
population. The factors which may contribute to the increased risk
include the presence of pituitary adenoma and consequent endocrine
disturbances and the treatment, particularly the extent of surgery and
the dose of radiotherapy. When assessing the value of treatment
strategies, it is therefore important to include not only intermediate
endpoints of tumor and hormonal control, but also late toxicity,
including the incidence of CVA and overall survival as the
primary endpoint. The potential predisposing factors for CVA need
further elucidation to develop treatment strategies with lower risk and
consequently, reduced mortality.

Editor's comments:
This paper draws on a large long term experience and provides very
valuable information. It is the third paper within a year to show
evidence of a long-term increase in vascular accidents associated with
arterial damage from relatively low doses of radiation therapy (mostly
less than 50 Gy in fractions of 2 Gy or less): the other two papers
related to coronary artery disease after treatment of Hodgkins Disease
in Rotterdam and at Stanford. This evidence has emerged because the
patients were relatively young and the treatment yielded high rates of
long term survival, both of which make possible actuarial analyses at 20

to 30 years. Although this late effect is a price worth paying, it is
dose-dependent, and it is worthwhile exploring options to reduce the
(biological) dose to the vessels if possible. The authors indicate that
these very late effects should be more widely appreciated in counseling
and follow up of patients at risk. The vascular damage in question,
which occurs in sizeable arteries and not smaller arteries and
arterioles, is a late effect of irradiation in its own right. Although
secondary injury develops in the organs the vessels supply, those
secondary effects are not directly radiation-induced. The earlier
developing, but nevertheless, "late" effects of irradiation (e.g.
myelitis, fibrosis, etc) are not, in my view, the result of
radiation-induced vascular damage, but rather are changes which develop
independently as a result of injury to glial cells, fibroblasts, etc.
and become manifest in parallel with slowly-developing vascular damage.
The authors speculate on the possible role of pituitary injury but the
etiology of late developing arterial damage is, at present, unknown. It
certainly appears to be an independent effect which does not develop
secondary to damage to the tissues the arteries supply!

******************
Health Services Research: Hayman 11/99

AU: Steenland E, Leer J, van Houwelingen H, Post WJ, van den Hout WB,
Kievit J, de Haes H, Martijn H, Oei B, Vonk E, van der Steen-Banasik E,
Wiggenraad RGJ, Hoogenhout J, Warlam-Rodenhuis C, van Tienhoven G,
Wanders R, Pomp J, van Reijn M, van Mierlo T, Rutten E.
TI: The effect of a single fraction compared to multiple fractions on
painful bone metastases: a global analysis of the Dutch Bone Metastasis
Study.
SO: Radiother Oncol 1999; 52:101-109

Abstract:
PURPOSE: To answer the question whether a single fraction of
radiotherapy that is considered more convenient to the patient is as
effective as a dose of multiple fractions for palliation of painful bone

metastases.
PATIENTS: 1171 patients were randomised to receive either 8Gy×1 (n
equals 585) or 4Gy×6 (n equals 586). The primary tumour was in the
breast in 39% of the patients, in the prostate in 23%, in the lung in
25% and in other locations in 13%. Bone metastases were located in the
spine (30%), pelvis (36%), femur (10%), ribs (8%), humerus (6%) and
other sites (10%).
METHOD: Questionnaires were mailed to collect information on pain,
analgesics consumption, quality of life and side effects during
treatment. The main endpoint was pain measured on a pain scale from 0
(no pain at all) to 10 (worst imaginable pain). Costs per treatment
schedule were estimated.
RESULTS: On average, patients participated in the study for 4 months.
Median survival was 7 months. Response was defined as a decrease of at
least two points as compared to the initial pain score. The difference
in response between the two treatment groups proved not significant and
stayed well within the margin of 10%. Overall, 71% experienced a
response at some time during the first year. An analysis of repeated
measures confirmed that the two treatment schedules were equivalent in
terms of palliation. With regard to pain medication, quality of life and

side effects no differences between the two treatment groups were found.

The total number of retreatments was 188 (16%). This number was 147
(25%) in the 8Gy×1 irradiation group and 41 (7%) in the 4Gy×6 group. It
was shown that the level of pain was an important reason to retreat.
There were also indications that doctors were more willing to retreat
patients in the single fraction group because time to retreatment was
substantially shorter in this group and the preceding pain score was
lower. Unexpectedly, more pathological fractures were observed in the
single fraction group, but the absolute percentage was low. In a
cost-analysis, the costs of the 4Gy×6 and the 8Gy×1 treatment schedules
were calculated at 2305 and 1734Euro respectively. Including the costs
of retreatment reduced this 25% cost difference to only 8%. The saving
of radiotherapy capacity, however, was considered the major economic
advantage of the single dose schedule.
CONCLUSION: The global analysis of the Dutch study indicates the
equality of a single fraction as compared to a 6 fraction treatment in
patients with painful bone metastases provided that 4 times more
retreatments are accepted in the single dose group. This equality is
also shown in long term survivors. A more detailed analysis of the study

is in progress. © 1999 Elsevier Science Ireland Ltd. All rights
reserved.


AU: Bone Pain Trial Working Party
TI: 8 Gy single fraction radiotherapy for the treatment of metastatic
skeletal pain: randomised comparison with a multifraction schedule over
12 months of patient follow-up.
SO: Radiother Oncol 1999; 52:111-121

Abstract:
AIM: To compare a single fraction of 8 Gy with a course of multifraction

radiotherapy in terms of long-term benefits and short-term side effects
in patients with painful skeletal metastases.
METHODS: Seven hundred and sixty-five patients with painful skeletal
metastases requiring palliative radiotherapy were entered into a
prospective randomised clinical trial comparing 8 Gy single fraction
with a multifraction regimen (20 Gy/5 fractions or 30 Gy/10 fractions).
Patients recorded pain severity and analgesic requirements on
self-assessment questionnaires before treatment, at 2 weeks and at 1, 2,

3, 4, 5, 6, 8, 10 and 12 months after radiotherapy. Pain relief was the
primary endpoint of treatment benefit. Short-term side-effects were
compared in a subset of 133 consecutive patients who graded nausea,
vomiting and antiemetic usage prior to treatment and at daily intervals
from days 1 to 14.
RESULTS: Overall survival at 12 months was 44%, with no statistically
significant difference apparent between randomised groups. There were no

differences in the time to first improvement in pain, time to complete
pain relief or in time to first increase in pain at any time up to 12
months from randomisation, nor in the class of analgesic used.
Retreatment was twice as common after 8 Gy than after multifraction
radiotherapy, although retreatment for residual or recurrent pain did
not reflect a difference between randomised groups in the probability of

pain relief. The difference in the rate of retreatment is thought to
reflect a greater readiness to prescribe radiotherapy after a single
fraction, not a greater need. There were no significant differences in
the incidence of nausea, vomiting, spinal cord compression or
pathological fracture between the two groups.
CONCLUSIONS: A single fraction of 8 Gy is as safe and effective as a
multifraction regimen for the palliation of metastatic bone pain for at
least 12 months. The greater convenience and lower cost make 8 Gy single

fraction the treatment of choice for the majority of patients. © 1999
Elsevier Science Ireland Ltd. All rights reserved.

Editor's comments:
Both of these trials are large randomized trials (n equals 1171 in the
Dutch trial and n equals 765 in the British trial) in which patients
with painful bone metastases were randomized to either a single 8 Gy
fraction or 4 Gy x 6 in the Dutch trial or 3 Gy x 10 or 4 Gy x 5 in the
British trial (the vast majority of patients got the later).  In both
trials, patients were asked to complete pain and quality of life
questionnaires on a relatively frequent basis and an improvement in pain

at the treated site was the primary endpoint.  For the fractionation
schemes tested, in both trials, there was no statistically significant
difference in either the likelihood or degree of response, the time to
response or the durability of response.  While there was a greater
likelihood of re-treatment in both studies in those patients treated
with single fractions vs. multiple fractions (25% vs. 7% in the Dutch
trial and 23% vs. 10% in the British trial), it was not clear that the
patients who were retreated after a single fraction were necessarily in
more pain.  Instead, it appeared that radiation oncologists were just
more comfortable retreating patients previously treated with a single
fraction.  In both trials, more patients who received a single fraction
experienced pathologic fractures (24 vs. 10 in the Dutch trial and 7 vs.

2 in the British trial) but the absolute numbers are still relatively
low in both arms of each trial.  There was also no difference in the
incidence of cord compression in both arms of either trial.  In a
subgroup of patients in the British trial, there was no increase in the
incidence of acute toxicity in the single fraction arm.  Lastly the
Dutch trial also included a cost analysis and they reported that if one
accounts for the cost associated with re-treatment the direct medical
cost savings associated with the use of a single fraction was
approximately $200 per patient.  In both studies, the authors conclude
that a single fraction should be the treatment of choice for most
patients given its equivalent efficacy and greater convenience.

Taken together, these two large randomized trials add significant weight

to the growing body of evidence suggesting that shorter courses of
palliative radiation therapy are just as effect as longer courses.  The
investigators who were involved in organizing these studies are to be
commended for completing such large quality of life studies.  The effort

involved in collecting good quality quality of life data in patients
with metastatic disease is considerable.  In particular, the greater
than 95% compliance rate at every time point in the British trial is
phenomenal.  In my opinion, it is very difficult to argue with either
the results or the conclusions of these trials.  As reported by the PCS
in the mid-80s, I would not be surprised if 3 Gy x 10 is still the most
commonly used palliative fractionation scheme used in the US.  One could

argue that there would have been a difference if a more prolonged
fractionation scheme had been tested against the single 8 Gy fraction.
On the other hand, numerous smaller randomized studies have not
demonstrated an advantage to fractionation schemes that last longer than

a week and the only positive study was a post-hoc analysis of the old
RTOG randomized study.  The RTOG is currently enrolling patients in a
randomized study comparing a single 8 Gy fraction versus 3 Gy x 10,
which should address this very issue.  One could also argue that this
study is not generalizable to all patients with painful bone metastases
because the investigators chose not to offer participation to all
eligible patients or excluded many patients through the excessive use of

exclusion criteria.  However, the exclusion criteria in both trials do
not seem excessive and, at least in the Dutch trial, all patients with
painful bony metastases were registered and there did not appear to be
significant differences between those patients who were randomized (29%
of the total population) and those who were not.  In the British study
they estimated that only 10% of all eligible patients were randomized
but they also note that most patients treated at the largest accruing
center routinely treated non-protocol patients with a single 8 Gy
fraction, thereby implying that it was the better prognosis patients who

were enrolled in the trial.  While patients treated with a single
fraction may be more likely to be retreated and be at a slightly higher
risk of a pathologic fracture and while the cost savings might not be as

great as one might expect, there is now considerably less doubt that a
single fraction as effective and not more toxic than 5 or 6 days of
treatment and there is no doubt that it is more convenient for both
patients and their caregivers.  In reality, very little is known about
how radiation therapy decreases bony pain.  Even with 2 Gy x 20, we are
clearly not sterilizing metastatic deposits and so something else (e.g.,

cytokines, micro-environmental factors, etc.) must be primarily
responsible for the decrease in pain patients experience.  Accordingly,
there is no reason why such effects could not be induced by a lower dose

of radiation.  Old habits die hard and I am not sure that I am quite
ready to abandon my training-induced reaction to prescribe 3 Gy x 10.
In my heart, I believe that there are some patients who could benefit
from fractionation.  However, for most poor prognosis patients, I have
begun to use shorter courses of treatment based on the results of these
trials.

******************

Brian J. Goldsmith, M.D.
Moderator, IROJC