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Correspondence
be reduced by collaboration with other surgical colleagues. Many
gynecologic oncologists partner with urologists for complex continent
urinary conduits after pelvic exenteration and with plastic surgeons
for a myocutaneous flap after radical pelvic surgery, for example, and
we believe that patients with ovarian cancer should also be offered the
potential benefit of subspecialty surgical consultation if it will improve
their overall survival. The complexity of preplanning surgical consultations for advanced ovarian cancer debulking surgery should not be
any different than for these other surgical collaborations.
It is incumbent on the gynecologic oncologist to ensure that pressures to minimize operating room and intensive care unit usage do not
compromise the surgical outcome for our patients. To suggest, as
Robinson1 does, that removing the spleen and/or the peritoneal lining
of the diaphragm would make a cytoreductive surgery “massive” and
will put a patient at significant risk for “never fully” recovering or
being “able to receive chemotherapy” is in fact unrealistic and misleading. The published data, as well as our own experiences, do not
support this bias. Although we strive to give every patient the best
chance to receive optimal debulking, we recognize that the elderly or
frail patients with multiple comorbidities and extensive ovarian carcinomatosis may not tolerate a prolonged, extensive operation, and we
agree that these patients are best treated with neoadjuvant chemotherapy (NACT). This brings us to Robinson’s second point.
Although American Board of Obstetrics and Gynecology gynecologic oncology board certification requires a certain amount of
requisite knowledge, training, and experience, there is a huge range
and variability in the scope of training in fellowships and an even wider
gap in the continued, postfellowship development of surgical skills,
especially with respect to ovarian cancer debulking. We live in an
outcomes-based society, and the best reported outcomes are with
primary debulking surgery (PDS) in appropriately selected patients,
with numerous reported overall survivals of 50 months or more with
PDS3 compared with 30 to 34 months with NACT, as reported in the
European Organisation for Research and Treatment of Cancer
(EORTC) trial4 and in the study by Tiersten et al5 that was referenced
by Robinson.1 Giving our patients the best opportunity for the longest
survival is our obligation. The extent of the surgery should not be
limited by our ego, surgical training, skills, or experience. We have
found that disease previously deemed unresectable becomes safely
resectable with appropriate support, education, and training.6
If an individual surgeon’s results are similar to those reported in
the PDS arm of the EORTC trial (40% optimal and 18% complete
gross resection rate), then the choice between PDS and NACT likely
will not impact progression-free and overall survival. But we believe
that our patients deserve better whenever possible. Although we agree
that NACT is the proper path for selected patients with advanced ovarian
cancer, the danger of the EORTC trial report is that this approach will be
broadly applied to all patients with advanced ovarian cancer, denying
otherwise excellent surgical candidates the well-established benefits of
appropriately aggressive surgical cytoreduction and its concomitant
improvements in overall survival. We believe that no patient with
ovarian cancer should have NACT initiated until she has been evaluated by a gynecologic oncologist who is trained, prepared, committed,
and able to perform optimal cytoreduction. Our patients trust us to
offer them their best chance at survival. They deserve nothing less.
Dennis S. Chi
Memorial Sloan-Kettering Cancer Center, New York, NY
Robert E. Bristow
University of California, Irvine Medical Center, Orange, CA
Deborah K. Armstrong
Johns Hopkins Kimmel Cancer Center, Baltimore, MD
Beth Y. Karlan
Cedars-Sinai Medical Center, Los Angeles, CA
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Robinson WR: Neoadjuvant chemotherapy is rarely the easy way out. J Clin
Oncol 30:1563, 2012
2. Chi DS, Bristow RE, Armstrong DK, et al: Is the easier way ever the better
way? J Clin Oncol 29:4073-4075, 2011
3. Chi DS, Musa F, Dao F, et al: An analysis of patients with bulky advanced stage
ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery
(PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs
neoadjuvant chemotherapy (NACT). Gynecol Oncol 124:10-14, 2012
4. Vergote I, Tropé CG, Amant F, et al: Neoadjuvant chemotherapy or primary
surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943-953, 2010
5. Tiersten AD, Liu PY, Smith HO, et al: Phase II evaluation of neoadjuvant
chemotherapy and debulking followed by intraperitoneal chemotherapy in women
with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer:
Southwest Oncology Group Study S0009. Gynecol Oncol 112:444-449, 2009
6. Chi DS, Eisenhauer EL, Zivanovic O, et al: Improved progression-free and
overall survival in advanced ovarian cancer as a result of a change in surgical
paradigm. Gynecol Oncol 114:26-31, 2009
DOI: 10.1200/JCO.2011.41.1744; published online ahead of print at
www.jco.org on March 12, 2012
■ ■ ■
Role of Radiation Therapy in the
Management of Locally Advanced
Pancreatic Cancer
TO
THE
EDITOR: The article by Loehrer et al1 provides us with
additional, albeit not definitive, evidence to support the use of radiation
therapy in all patients with locally advanced pancreatic cancer (LAPC)
who could have been eligible for this study. We agree with the editorial by
Philip et al2 that this study is weakened by the small number of patients
1564
© 2012 by American Society of Clinical Oncology
and the failure to reach its planned accrual target. However, whether the
result of this study is weakened further by the lack of demonstrable difference between both arms in progression-free survival is a point of debate.
The authors have indicated that the difference in progression-free survival
can be explained by the difficulty in distinguishing post-therapy inflammatory changes from residual disease. In addition, the accurate visualization of pancreatic malignancies requires a strict adherence to a complex
computed tomography scan protocol and the availability of a skilled
radiologist who is particularly interested in this disease. These requirements may not have been met by some of the participating centers.
JOURNAL OF CLINICAL ONCOLOGY
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2012 of
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It is Philip’s opinion that “the small benefit of radiation therapy in an average patient with LAPC indicates that only a subgroup
of patients benefit from radiation therapy while there will be
those who will not only derive no benefit but be harmed by its
toxicities.”2(p4067) With the lack of supporting evidence, we do not
agree with this statement.
Pancreatic cancer is one of the most lethal cancers because of our
failure to adequately control not only the distant spread of the disease
but also the local persistence and/or progression. In a recent landmark
study by Iacobuzio-Donahue et al,3 reporting on the autopsy findings
of patients with early and late pancreatic cancer, 16 (89%) of 18 patients
who were diagnosed with early pancreatic cancer that was resected were
found to have a component of local persistence/progression at the time of
autopsy. Only four of 18 patients died of metastatic disease without
evidence of local persistence.3 Similar findings were also reported in
other studies.4,5 In addition, all patients diagnosed with LAPC who
were treated without surgery were found to have persistent/progressive local disease at autopsy. Of note, 28% of those patients died with
only local disease without evidence of distant spread. We cannot
conceive how we can improve the overall survival rate in this disease by
improving only distant control.
The importance of local control is further clarified by noting that
the only modality that is proven to significantly affect the complete
eradication of the disease is surgical resection with negative margins
(R0 resection). Even when a microscopic amount of local disease is left
behind (ie, R1 resection), the overall survival rate decreases substantially. We realize, however, that radiation therapy with conventional
doses of 45 to 50 Gy is not successful in achieving adequate locoregional control. Prospective studies that use chemoradiotherapy in a
neoadjuvant approach report a low pathologic complete response rate
of about only 5%.6-9 There is a clear need to find techniques that
facilitate higher dose delivery to the tumor with acceptable morbidity.
The target volume for radiation therapy has changed recently as
many investigators have abandoned older techniques that aimed at the
prophylactic treatment of several lymph node regions; therefore, large
areas of normal tissues are encompassed in the radiotherapy fields.
Modern techniques now include only gross disease with small margins. The use of intensity-modulated radiotherapy techniques also
avoids exposing large volumes of normal tissue to intermediate dose
levels. These changes became feasible only with recent technological
advances and have resulted in decreasing radiation-associated morbidity. For example, Crane et al10 report a low grade 3 toxicity rate
associated with radiotherapy when modern techniques are used.
These new innovations have also enabled dose escalation studies to be
carried out with early improved results.11
Although we agree that radiation therapy as it is delivered now
with current doses of 45 to 50 Gy is unlikely to result in good local
control in patients with LAPC, we feel that it is unwise to ignore the
serious problem of local control and focus only on controlling distant
metastases. We would like to paraphrase the opinion of IacobuzioDonahue et al3 that the common belief that all patients with pancreatic
cancer die as a result of widespread metastatic disease is unfounded.
We believe that improving local control is necessary for the vast majority of patients with early and locally advanced pancreatic cancer.
We hope that continuous innovations of radiation therapy techniques
and dose delivery will cause such improvement.
Amr Aref and Richard Berri
Van Elslander Cancer Center, Grosse Pointe Woods, MI
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Loehrer PJ Sr, Feng Y, Cardenes H, et al: Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An
Eastern Cooperative Oncology Group trial. J Clin Oncol 29:4105-4112, 2011
2. Philip PA: Locally advanced pancreatic cancer: Where should we go from
here? J Clin Oncol 29:4066-4068, 2011
3. Iacobuzio-Donahue CA, Fu B, Yachida S, et al: DPC4 gene status of the
primary carcinoma correlates with patterns of failure in patients with pancreatic
cancer. J Clin Oncol 27:1806-1813, 2009
4. Tepper J, Nardi G, Sutt H: Carcinoma of the pancreas: Review of MGH
experience from 1963 to 1973—Analysis of surgical failure and implications for
radiation therapy. Cancer 37:1519-1524, 1976
5. Gudjonsson B: Cancer of the pancreas: 50 years of surgery. Cancer
60:2284-2303, 1987
6. Stokes JB, Nolan NJ, Stelow EB, et al: Preoperative capecitabine and
concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol
18:619-627, 2011
7. White RR, Xie HB, Gottfried MR, et al: Significance of histological response
to preoperative chemoradiotherapy for pancreatic cancer. Ann Surg Oncol 12:
214-221, 2005
8. Le Scodan R, Mornex F, Partensky C, et al: Histopathological response to
preoperative chemoradiation for resectable pancreatic adenocarcinoma: The
French phase II FFCD 9704-SFRO trial. Am J Clin Oncol 31:545-552, 2008
9. Talamonti MS, Small W Jr, Mulcahy MF, et al: A multi-institutional phase II trial
of preoperative full-dose gemcitabine and concurrent radiation for patients with
potentially resectable pancreatic carcinoma. Ann Surg Oncol 13:150-158, 2006
10. Crane CH, Varadhachary GR, Yordy JS, et al: Phase II trial of cetuximab,
gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for
locally advanced (T4) pancreatic adenocarcinoma: Correlation of Smad4(Dpc4)
immunostaining with pattern of disease progression. J Clin Oncol 29:3037-3043,
2011
11. Ben-Josef E, Griffith K, Francis IR, et al: Phase I radiation dose-escalation
trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate
gemcitabine (FDR-G) for unresectable pancreatic cancer. J Clin Oncol 27:226s,
2009 (suppl; abstr 4602)
DOI: 10.1200/JCO.2011.40.8674; published online ahead of print at
www.jco.org on March 12, 2012
■ ■ ■
Radiotherapy Improves Survival in
Unresectable Pancreatic Cancer: Small
Trial but Big (and Credible) Results
TO THE EDITOR: Excited as we are about the results of the
Eastern Cooperative Oncology Group E4201 trial demonstratwww.jco.org
ing that radiation with gemcitabine is superior to gemcitabine
alone for patients with locally advanced pancreatic cancer,1 we
read the accompanying editorial by Philip2 with mixed feelings.
Although we fully support Philip’s thoughts regarding the way
forward, we strongly disagree with the general sentiment of the
editorial that the study is tantalizing but not convincing and
that the results should not impact the standard of care.
© 2012 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Providence Hospital: Helen L. DeRoy Medical Library on
Copyright © 2012 American
Society
Clinical
Oncology. All rights reserved.
August 20,
2012 of
from
12.231.156.71
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