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Date: Tue, 1 Apr 97 07:22:13 HST
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From: bjg@mhpcc.edu (Brian Goldsmith)
Subject: April 1997 Internet Radiation Oncology Journal Club (IROJC)

April 1997 Internet Radiation Oncology Journal Club (IROJC)

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Posting of references for review and discussion
-------------------------------------------------------

The 23nd collection of references suggested for attention and discussion by
the IROJC's Board of Editors:

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

Bill Mendenhall, 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

Perry Grigsby, M.D.
Editor, Gynecological Radiation Oncology

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

Joel Tepper, M.D.
Editor, Gastrointestinal Radiation Oncology

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

David Larson, M.D. Ph.D.
Editor, Central Nervous System Radiation Oncology

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

Jim Purdy, Ph.D.
Editor, Radiation Oncology Physics and Dosimetry

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You are 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 the professional ground rules listed
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!

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to search archived postings for keywords or phrases!

------------------------------------------------------------

Commentary Ground Rules:

Please,

(1) Cite the subject category in the header of your e-mail message, e.g.
Subject: Head and Neck 4/97.

(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) Recognize that the Editor's selection is not necessarily an endorsement
of the authors' conclusions.  In fact, articles may be selected for
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(4) Be aware that your comments, once 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
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IROJC reference will not be posted.

(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 (hawaiirt@aol.com) private questions and
comments which are not intended for IROJC posting and public reading.


******************
Peds: Donaldson 4/97

AU: Heyn R, Newton WA, Raney RB, Hamoudi A, Bagwell C, Vietti
T, Wharam M, Gehan E, Maurer HM.
TI: Preservation of the bladder in patients with rhabdomyosarcoma.
SO: J Clin Oncol 1997; 15:69-75.

Abstract:
PURPOSE: To review the pathologic findings from children with gross
residual rhabdomyosarcoma (RMS) of the bladder and compare the treatment
outcome of those who underwent cystectomy with those who did not.
PATIENTS AND METHODS: Primary and follow-up records and pathology specimens
for 28 patients with gross residual disease entered onto the Intergroup
Rhabdomyosarcoma Study (IRS) III were reviewed. These patients were
assigned to receive 20 weeks of multiagent induction chemotherapy and 4
weeks of radiotherapy. Future therapy decisions were based on clinical and
histologic evaluation at 20 weeks.
RESULTS: All patients had a clinical and histologic response. Thirteen
patients underwent cystectomy at intervals that ranged from 1.5 to 38
months after the start of therapy. All but one patient are alive and well
without recurrence. Reasons for cystectomy included presumed evidence of
tumor growth from imaging studies, findings at cystoscopy, or histologic
interpretation of biopsies. In 12 of 14 specimens from 15 patients who
retained their bladder, no tumor cells were seen at first or second
evaluation. In cystectomy specimens, tumor cellularity was markedly reduced
and all tumor cells were in
varying degrees of cellular maturation. Review of primary tumor specimens
showed a greater degree of cellular maturation in patients with retained
bladders than in those who underwent cystectomy.
CONCLUSION: Bladder RMS is responsive to chemotherapy and radiotherapy.
Twelve of 26 patients showed complete loss of tumor cells after induction
therapy. Cystectomy specimens showed diminished tumor cells with varying
degrees of cellular maturation. It is hypothesized that these tumors may
have shown further maturation and ultimate loss of matured cells with
continuing therapy.

Editor's comments:
This paper reports an important observation from the Intergroup
Rhabdomyosarcoma Study Group regarding children with intravesical
rhabdomyosarcoma. The combination of chemotherapy and radiotherapy is
highly successful in eradicating tumor, and allowing
preservation of the bladder.  Following this combined modality therapy,
imaging studies are not particularly useful in determining response to
therapy. Cystoscopy with biopsy is most conclusive, but has demonstrated
progressive myogenic maturation in many cases so studied. Thus pathologic
interpretation of biopsy specimens becomes very important as the presence
of mature cells is not an indication for cystectomy.  Clinicians are
advised to take a careful watch and wait approach when the tissue from a
bladder biopsy shows maturation of cells. Today very few children will
require bladder removal for cure.

******************
Head/Neck/Skin: Mendenhall 4/97

AU: Nordsmark M, Overgaard M, Overgaard J.
TI: Pretreatment oxygenation predicts radiation response in advanced
squamous cell carcinoma of the head and neck.
SO: Radiother Oncol 1996; 41:31-39.

Abstract::
BACKGROUND AND PURPOSE: Hypoxic tumor cells are known to be relatively
radioresistant.  The aim of the study was to correlate oxygenation status
and radiation response in advanced squamous cell carcinomas of head and
neck.
METHODS AND PATIENTS: Pretreatment oxygenation status was measured in 34
lymph nodes and one primary tumor neck using oxygen electrodes.  The
primary oxygenation endpoint was the fraction of pO2 values less than 2.5
mmHg.  Patients received standardized, conventional, external radiotherapy
66-68 Gy in 33-34 fractions.
RESULTS:  Sixteen patients had loco-regional failure.  Among these 16
patients the median of the fraction of pO2 values less than 2.5 mmHg was
22% (range 0-95%) as compared to 6% (range 0-51%) among patients with
loco-regional control.  When separating all 35 patients by the median of
the fraction of pO2 values less than 2.5 mmHg and comparing the 2 years
actuarial tumor control probability using Kaplan-Meier estimates, the most
hypoxic subgroup had significantly lower loco-regional tumor control
(P=0.013, Logrank test).  By univariate regression analysis the fraction of
pO2 values less than 2.5 mmHg was found to be significant as continuous
variable (P=0.010).  Finally, by Cox multiple regression analysis the
fraction of pO2 values less than 2.5 mmHg was found to be the strongest
independent variable in predicting radiation response when using tumor
control in the site of pO2 assessment as treatment endpoint (P=0.018).
CONCLUSION:  These results suggest that pretreatment tumor oxygenation is
predictive of radiation response, when using the fraction of pO2 values
less than 2.5 mmHg as endpoint.

******************
GYN: Grigsby 4/97

AU: Russell AH; Shingleton HM; Jones WB; Fremgen A; Winchester DP; Clive R;
Chmiel JS.
TI: Diagnostic assessments in patients with invasive cancer of the cervix:
a national patterns of care study of the American College of Surgeons.
SO: Gynecol Oncol 1996; 63(2):159-65.

Abstract:
Using a standard collection form designed by a multidisciplinary committee of
specialists, cancer registrars at 703 hospitals submitted anonymous data on
11,721 patients with cervical cancer diagnosed during 2 study years, 1984 and
1990. Information concerning the initial use of diagnostic assessments was
analyzed with respect to the potential influences of clinical stage,
patient age,
race/ethnicity, insurance status, and modalities of therapy employed. Estimates
of the yield of diagnostic information for each test were correlated with
clinical
stage and patient age. Judged by the number of procedures performed, the
intensity of pretreatment assessment declined between 1984 and 1990.
Substantially increased use of the newer body imaging modalities
(computerized axial tomography and magnetic resonance imaging) with high
probabilities of revealing abnormalities attributed to cancer, balanced major
declines in utilization of procedures historically important in staging and
assessment (cystoscopy, proctoscopy, barium enema, excretory urography
(intravenous pyelogram), bone scintography, and lymphangiography).
Race/ethnicity and insurance status had no discernible independent impact on
the intensity of diagnostic evaluation. Patients with more advanced clinical
stages underwent more extensive testing, as did patients treated initially with
radiation compared to surgery. Periodic review of assessment strategies would
seem prudent to avoid widening discrepancies between sanctioned staging
formalisms with endorsed and authorized appraisals and actual clinical practice.

******************
GI: Tepper 4/97

AU: Schild SE, Gunderson LL, Haddock MG, Wong WW, Nelson H.
TI: The treatment of locally advanced colon cancer.
SO: Int J Radiat Oncol Biol Phys 1997; 37(1):51-58.

Abstract:
PURPOSE: The results of therapy for 103 patients with locally advanced
colon cancer who received radiotherapy were analyzed to determine the
outcome and tolerance of therapy. METHODS AND MATERIALS: Between 1974 and
1994, 103 patients received radiotherapy and maximal resection of locally
advanced colon cancers. Following resection, 50 patients had no residual
disease, 18 patients had microscopic residual disease, and 35 patients had
gross residual disease. External beam radiotherapy was initiated 1 to 4
months following resection except in two patients who received preoperative
radiotherapy. Treatment was delivered to the tumor bed and adjacent lymph
nodes using 4 to 18 MV X-rays with doses ranging from 16.2 to 60 Gy.
Intraoperative electron radiotherapy (IOERT) was also administered to 11 of
the patients with doses ranging from 10 to 20 Gy. Chemotherapy was
administered to 77 patients. Follow-up in survivors ranged from 0.5 to 17
years (median: 5.8 years).
RESULTS: The 5-year actuarial local failure rate was 10% for patients with
no residual disease, 54% for patients with microscopic residual disease,
and 79% for patients with gross residual disease (p < 0.0001). For patients
with residual disease, local failure occurred in 11% of patients receiving
IOERT compared with 82% of patients receiving only external beam therapy (p
= 0.02). The 5-year actuarial survival rate was 66% for patients with no
residual disease, 47% for patients with microscopic residual disease, and
23% for patients with gross residual disease (p = 0.0009). The 5-year
survival rate in patients with residual disease was 76% for patients
receiving IOERT and 26% for patients receiving external beam therapy alone
(p = 0.04).
CONCLUSIONS: Patients with locally advanced colon cancer who have had a
complete resection have a high probability of local control after external
beam irradiation with/without 5 fluorouracil (5FU)-based systemic therapy.
The toxicity of therapy can be minimized with attention to treatment
technique and dose. Local control and survival rates in patients with
residual disease who received IOERT appear to be significantly greater than
for those patients who received external beam radiotherapy therapy alone.

Editor's Comments:
Although this article doesn't really answer any questions, it does again
raise the issue of radiation therapy for locally advanced colon cancer.
Unfortunately, although this issue has been around for quite a few years,
the benefit of radiation therapy and its indications, are not any closer to
resolution than they were 12-15 years ago.  The high failure rate after
resection of tumors invading adjacent structures has been demonstrated and
was emphasized in the present article where many patients failed locally
despite the use of radiation therapy.  One mistake in the paper (although
not the fault of the authors since the information is new) is the comment
that data from the Intergroup randomized trial of adjuvant radiation
therapy will answer the question of the value of postoperative radiation
therapy in colon cancer.  Unfortunately, that study was closed because of
poor accrual and the number of patients will not be sufficient to have a
substantial power of demonstrating a beneficial result.

The other caution in reading this paper is the purported beneficial result
from IORT.  Although I think it likely that higher radiation doses will
improve local control and survival, the patient numbers are so small in the
IORT group (11),and the imbalances regarding chemotherapy and the time
period in which the patients were treated are such that the comparative
survival curves are probably not of much meaning and the local control
curves may not be much better.  The authors state that "some degree of
caution is warranted in the interpretation of the results...". That is an
understatement.  Nonetheless, the information from this paper that good
local control and survival can be obtained for locally advanced colon
cancer with the use of radiation therapy and chemotherapy, and that higher
doses are likely to improve local control, are important concepts for
patient management.

******************
CNS: Larson 4/97

AU: Gregor A, Cull A, Traynor E, Stewart M, Lander F, Love S.
TI: Neuropsychometric evaluation of long-term survivors of adult brain
tumours: relationship with tumour and treatment parameters.
SO: Radiother Oncol 1996; 41:55-59.

Abstract:
BACKGROUND: Cognitive deficits are the hallmark of dose limiting late
radiation morbidity in the CNS. Little is known about the neuropsychometric
morbidity of treatment in adults with primary brain tumours. We set out to
evaluate systematically the neuropsychometric function of all long-term
survivors in order to document the frequency and severity of impairment and
study its relationship with tumour and treatment related parameters.
MATERIALS AND METHODS: 30 patients surviving in clinical and radiological
remission for >4 years following irradiation were recalled for clinical
examination, CT/MRI scan and neuropsychometric testing. The 14 males, 16
females, (mean age 42.5 years), represented all but one long term survivors
treated with radiotherapy in the Department of Clinical Oncology between
1971 and 1990. Twenty-five patients had a histological diagnosis of glioma.
Patients treated before 1987 (n=16) received whole brain irradiation (WBI);
focused irradiation (FI) has been used since (n=14).
RESULTS: The two groups were similar in age, initial tumour type and
surgical treatment, but the WBI group showed more evidence of
neuropsychometric impairment than the FI group with significantly lower
group median scores in tests of visuospatial organisation (WAIS Block
Design, P=0.01), visual memory (Rey Complex figure, P=0.003) and complex
information processing (Trails A, P=0.003; Trails B, P=0.002). Pre-morbid
IQ estimated from sociodemographic variables, was comparable in the 2
groups which were not significantly different in their emotional state as
assessed by the HADS. On univariate analysis radiation volume (P=0.05) and
time from treatment (P=0.02) were the main factors associated with
neuropsychometric deficit. Multivariate analysis by logistic regression
confirmed WBI as the only independent predictor of neuropsychometric
impairment (WBI vs. FI, odds ratio=7.1, 95% C.I. 1.2-42.3, P=0.03).
CONCLUSIONS: Neuropsychometric deficits are common and can be related to
time from treatment and radiation technique. Neuropsychometric testing can
be a useful tool in the evaluation of different treatment strategies.

******************
Physics/Dosimetry: Purdy 3/97
No Reference Selected.

******************
Breast: Recht 4/97

AU: Mullen EE, Duetsch M, Bloomer WD.
TI: Salvage radiotherapy for local failures of lumpectomy and breast
irradiation.
SO: Radiother Oncol 1997; 42:25-29.

Abstract:
BACKGROUND AND PURPOSE:  In-breast tumor recurrence (IBTR) following
lumpectomy and breast irradiation is usually managed by mastectomy.  For
women who refused mastectomy at the time of a IBTR, a repeat course of
radiotherapy following repeat
lumpectomy was offered.
MATERIALS AND METHODS:  Sixteen women with an IBTR following lumpectomy,
axillary node dissection and breast irradiation were treated with repeat
lumpectomy and radiotherapy to the operative area.  Fifteen patients
received 5000 cGy / 25 fractions.  One patient discontinued radiotherapy
for non-medical reasons after having received only 3200 cGy / 16 fractions.
The interval from completion of the initial course of radiotherapy to
documentation of IBTR varied from 10-130 months (median 31 months).
RESULTS:  Four patients (20%) have had further local failure.  Ten of
sixteen patients (62.5%) are alive and free of disease at 42-119 months
from completion of the repeat course of radiotherapy.  Of these latter
patients, one had another in-breast tumor recurrence treated by excision
alone and another had an in-breast tumor recurrence in the contra lateral
breast post-lumpectomy and irradiation.  Four patients died with distant
metastasis, one is currently alive with contralateral breast cancer and
distant metastasis, and one is alive with an extensive recurrence in the
re-irradiated breast.  Two of the patients with distant metastasis had
abnormal bone scans at the time they received the repeat course of
radiotherapy.  There have been no severe late sequelae from the repeat
course of radiotherapy.
CONCLUSIONS:  For selected patients, a repeat course of radiotherapy for an
IBTR following lumpectomy and radiotherapy is well tolerated and may
provide long-term local control.

Editor's Comments:
This is one of the very few reports on the use of further radiotherapy in
an attempt to preserve the breast after the failure of initial breast-
conserving management. As such, it is an important addition to the
literature. (The authors have previously reported these patients in part
in abstract form.) However, the heterogeneous nature of the population
makes interpretation of the "take-home message" somewhat difficult. It
should be noted that all except one local failure of initial treatment was
near the lumpectomy site. None of the patients had received a boost
previously (only 50 Gy to the breast). Hence, the risk of complications
might be higher in patients treated to higher doses initially. Also, only
9 of the patients have a minimum potential follow-up of five years. Of
these, one presented with metastatic disease as well as local failure. Two
of the eight remaining patients had a local failure within 5 years of
retreatment, and another at 62 months after retreatment. Hence, the long-
term re-recurrence rate appears substantial. Thus, my preference remains
that patients with operable local failures following initial treatment
with conservative surgery and radiotherapy should undergo mastectomy, but
for the (fairly rare) patient who refuses mastectomy this may be a
fallback option.

******************
RES: Hoppe 4/97

AU: Rueda A, Alba E, Ribelles N, Sevilla I, Ruiz I, Miramon J.
TI: Six cycles of ABVD in the treatment of stage I and II Hodgkin's
lymphoma: a pilot study.
SO: J Clin Oncol 1997; 15(3):1118-1122.

Abstract:
PURPOSE: Chemotherapy is the standard treatment in advanced Hodgkin's
lymphoma and a therapeutic alternative for early stages. Although
polychemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine
(ABVD) is equivalent or
superior to mechloretamine, vincristine, procarbazine, and prednisone
(MOPP) in advanced disease, no series have been published using ABVD
without associated radiotherapy in early stages. We report the results
obtained with the administration of six cycles of ABVD alone in clinical
stage I and II disease.
PATIENTS AND METHODS: From January 1990 to October 1994, 23 patients with
stage I or II Hodgkin's lymphoma were treated with six cycles of ABVD; six
patients who met the criteria for mediastinal bulky disease also received
radiotherapy to the mediastinum.
RESULTS: After six cycles, 20 complete responses (CRs) and three partial
responses (PRs), which became CRs after radiotherapy, were obtained.
Toxicity was moderate and manageable. With a median follow-up duration of
37 months (range, 12 to 75), three patients have relapsed and one has died.
Overall and progression-free survival rates at 42 months are 95% and 84%,
respectively.
CONCLUSION: Six cycles of ABVD are effective and safe in the treatment of
stage I and II Hodgkin's lymphoma, at least in the short term, but
long-term observation data are not yet available.

Editor's Comments:
It is somewhat surprising that the JCO published a study like this with so
few patients and such brief median follow-up, but it is one that rad oncs
will have to become familiar with because it will be quoted in tumor boards
by medical oncologists.  The title is somewhat misleading. The implication
is that 6 cycles of ABVD chemotherapy was the only treatment in this pilot
study.  In fact, 6/23 patients had mediasatinal irradiation.  In total,
only 17 patients were treated with ABVD alone, the median follow up was 37
months, and 2 of the ABVD patients relapsed (both in previously involved
sites).  The authors imply an advantage to ABVD over XRT because of the
challenge in executing a proper XRT plan - this is disputed by PCS data
that shows that effective technology for treating HD with XRT has been
transferred to the community at large.

It is not so surprising that ABVD x 6 works pretty well in early stage HD.
After all, ABVD x 6-8 works very well in advanced disease.  However, the
fact that it works as well as XRT and the fact that salvage of failures was
possible with extended field RT does not make it the treatment of choice.
6 cycles of ABVD is likely much more than is needed for most patients,
especially if one adds low dose involved field treatment.  The Milan group
has studied this in a much more logical manner.  They administered ABVD x 4
then randomized IF vs. EF (36 Gy).  There was no difference in the 2 XRT
arms and the results in both arms were excellent (reported in abstract
only).  This is a much more logical (and somewhat more brief) course of
treatment than ABVD x 6.  Many other groups are testing combined modality
programs with chemotherapy of only 1-2 months duration.

******************
Lung/Mediastinum:  Turrisi 4/97

AU: Choi NC, Carey RW, Daly W, Mathisen D, Wain J, Wright C, Lynch T,
Grossbard M, Grillo H.
TI: Potential impact on survival of improved tumor downstaging and
resection rate by preoperative twice radiation and concurrent chemotherapy
in Stage IIIA non-small cell lung
cancer.
SO: J Clin Oncol 1997; 15(2):712-722.

Abstract:
PURPOSE: The main objectives of this study were (a) to ascertain the
feasibility and toxicity of preoperative twice-daily radiation therapy and
concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA
(N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor
response, resection rate, pathologic tumor downstaging, and survival.
METHODS: Eligibility included biopsy-proven N2 lesion (stage IIIA) by
mediastinoscopy, Karnofsky performance score 70, and weight loss less than
5% in the 3 months before diagnosis. The treatment program consisted of two
courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42
Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day;
surgery on day 57; and one more course of postoperative chemotherapy and 12
to 18 Gy of concurrent twice-daily radiation.
RESULTS: Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15
women, age 38 to 77 years) were enrolled onto this prospective study. Forty
of 42 patients tolerated the intended dose (42 Gy) of preoperative
radiation and 37 of 39 resected patients received prescribed postoperative
radiation. The intended dose of chemotherapy was given in 100%, 70%, and
60% of patients for the first, second, and third courses of chemotherapy.
Marked dysphagia that required intravenous hydration was noted in 14% of
patients (six of 42). Myelotoxicities included grade 3 granulocytopenia in
23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile
neutropenia that required hospital admission was noted in 9% of 113
chemotherapy courses. Surgical resection was performed in 93% of patients.
Treatment-related mortality was noted in 7% of patients. The overall
survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2, 3,
and 5 years, respectively, with a median follow-up time of 48 months.
Pathologic examination of the surgical specimen showed a downward shift in
tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (N0)
in 24% (10 of 42), and to stage 0 (T0N0) in 9.5%, for a total of 67%. The
degree of tumor downstaging was also translated into a survival benefit:
5-year survival rates from the time of surgery were 79%, 42%, and 18% for
postoperative tumor stages 0 and I, II, and III, respectively (P = .04).
CONCLUSION: Concurrent chemoradiotherapy using twice-daily radiation is an
effective induction regimen that resulted in 67% tumor downstaging, and an
encouraging 37% 5-year survival rate. The degree of tumor downstaging may
be a useful intermediate end point for survival benefit in stage IIIA (N2)
NSCLC.

Editor's Comments:
This is a pilot conducted at the MGH using time-honored chemotherapy --
cisplatin (100 mg/m2), velban and adding 5 FU, a known radiation sensitizer.

Perhaps the most nettlesome issue is what to do about stage IIIA lung
cancer:  who gets surgery (alone or combined), who gets chemotherapy, and who
gets radiotherapy to the chest as part of pre-operative management.  This
paper reviews some of the important papers on the subject, and supplies its
statistics, which do compare favorably to the larger group studies.  One must
keep in mind that single institutional experiences with good results tend to
be published, especially when they are from major centers.

I was surprised to find no reference to the two chemotherapy followed by
surgery papers from Rosell (NEJM 330:153-158, 1994) and Roth (JNCI 86:673-680,
1994) demonstrating when using even older chemotherapeutics, these result in
improved survival over surgery alone.  However, some have noted that right
pneumonectomies were disproportionally represented in the surgery alone arm of
the Barcelona study, and that this factor accounts for survival differences
even more than the chemotherapy.  Whether one needs to add radiotherapy when
one uses surgery is a very open question.  But the more fundamental question
is whether surgery adds to survival when chemo-radiotherapy is used.

This issue is the subject of an intergroup trial (INT 0139) sponsored by
the RTOG, and joined by all of the major groups.  The interest in the use of
radiotherapy and surgery for local control in Stage IIIA NSCLC faces the
thoracic community.  Selected studies have picked patients for surgery, but
the selection bias for those that can undergo surgery prevents comparison to
non-surgical treatments.  This study isolates the variable of surgery in N2-
proven stage IIIA disease.  All patients get cisplatin, etoposide and 45 Gy in
5 weeks, and one group gets more radiotherapy to the dose of 61 Gy.  Two
cycles of chemotherapy are concurrent; two follow the definitive local
treatment.  The study has 163 patients entered as of February 28 --- almost
50% of accrual.  The slowness of accrual is the source of worry -- the reasons
are legion,  some well intentioned, others perhaps very biased, and some
either ignorant or mean-spirited.  The surgeons must want to do this study for
it to meet completion of its accrual goals.  The data monitoring committee has
not stopped the study because of obvious survival or failure differences.

We hope to  use treatment that is effective and curative, but we also
must discern how much toxicity we cause with therapy.  The MGH approach uses
classically large treatment volumes covering bony landmarks of the thorax,
mid-supraclavicular line and well into the left atrium (7 cm below the
carina).  Added to the large volume was an attempt to intensify the treatment
with BID 1.5 Gy fractions.  There should be no surprise then that esophagitis
rates and intensity were brisk, and the total dose was cut from 45 Gy to 42 Gy
(with restricted volumes, very similar chemotherapy, and 45 Gy in BID 3 weeks,
we treated esophagus cancer at Ann Arbor with remarkably less esophagitis, but
we used tumor plus 2 cm radial margin and 5 cm above and below).  The issue is
not what is the correct method, but more one of toxicity.  The MGH volume,
dose, chemotherapy schemes causes remarkable esophagitis.

The patients had excellent results in terms of resection and survival.
We do not have a catalog of how many required right pneumonectomies or how
these patients balanced against other series in the subtleties of prognostic
factors, tumor sizes, number of lymph nodes, etc.  One wonders how much the
volume opted for has led to the good results, and how much has been the source
of the toxicity.

Last one must raise the issue of the value of post-operative therapy with
a surgery and surgical recovery induced gap.  Albain and the SWOG group data
suggest that post-operative therapy, with chemotherapy and/or radiotherapy, led
to excess morbidity and no appreciable gain.  Clearly this issue is not
resolved, but the assumption that more chemotherapy is better needs to be
tested and not assumed -- there are cost issues as well as morbidity issues.

******************
GU: Roach 4/97
No Reference Selected.

******************
Radiobiology:  Withers 4/97
No Reference Selected.

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

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