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The RADPLAT treatment is an investigational therapy for advanced head and neck
squamous cell
carcinoma. This therapy is currently being studied at the Department of
Otolaryngology-Head & Neck
Surgery at the University of Tennessee Health Science Center as part of a
multi-center study. The
RADPLAT concept was pioneered by Dr. K.Thomas Robbins, formerly our department
chairman. The UT research effort is currently under the direction of Dr.
Sandeep Samant.
Interested healthcare providers, families, or patients are encouraged to
contact:
Sandeep Samant, MD, FACS- Assistant Professor
Department of Otolaryngology-Head and Neck Surgery
University of Tennessee Medical School
956 Court Avenue B226
Memphis, TN 38163
(901) 448-5886
The following is reprinted from Practical Reviews in Otolaryngology-Head & Neck
Surgery,Volume 6 -
Number 8, February 1999.
In an effort to improve outcomes for patients with advanced head and neck
cancer, recent clinical trials
have focused on combined-method nonsurgical therapy. The RADPLAT (radiation +
platinum)
technique, which uses supradose intra-arterial cisplatin and concomitant
radiation therapy, has shown
promising results in phase II single-institutional studies. This article reviews
this work with respect to the
concept of, rationale for, therapeutic effect of, and outcome of RADPLAT. The
data support further
investigations of this approach, particularly with regard to organ preservation
and function and the
restoration of quality of life. Further confirmation of the benefits of RADPLAT
will be seen upon
completion of a National Cancer Institute-sponsored study involving 10 academic
medical centers.
The acronym RADPLAT (radiation plus platinum) refers to a chemoradiation
protocol that has been
developed for the treatment of patients with advanced head and neck cancer. The
program uses a novel
technique to infuse cisplatin directly into the tumor bed while minimizing the
systemic effects of the drug.
Microcatheters are placed angiographically to permit superselective rapid
infusions of cisplatin, while
sodium thiosulfate, a neutralizing agent for cisplatin, is simultaneously
infused systemically. This
technique makes it feasible to increase the dose intensity of cisplatin to an
amount at least five times
greater than that permitted in standard chemotherapy protocols. This enables the
delivery of an enormous
amount of drug over a relatively short time.
The theoretical advantage of the high-dose-intensity chemotherapy regimen used
in the RADPLAT
technique is related to the phenomenon of acquired drug resistance. Head and
neck tumors have a high
rate of response to combination chemotherapy, particularly cisplatin-based
chemotherapy, when it is used
in the neoadjuvant setting. Despite the initial sensitivity of the tumor,
however, a survival advantage for
patients treated in this manner has yet to be shown. One explanation for this
treatment failure is the drug
resistance that is known to develop rapidly after exposure to chemotherapeutic
agents.
Clinical trials using concomitant chemotherapy and radiation have provided some
evidence to show that
this approach is better than the use of radiation alone for patients with
unresectable disease. This was
certainly the finding by Brizel et al in their recently published article in the
New England Journal of
Medicine entitled Hyperfractionated Irradiation With or Without Concurrent
Chemotherapy for Locally
Advanced Head and Neck Cancer. Of the 116 patients who underwent randomization
in this study, the
overall survival rate at 3 years was 55% in the combined therapy group and was
only 34% in the
hyperfractionated group. Most strikingly was the rate of local regional control
of disease at 3 years, which
was 70% in the combined treatment group compared with 44% in the
hyperfractionated group. The
authors concluded that combined treatment for advanced head and neck cancer is
more efficacious and
not more toxic than hyperfractionated radiation alone.
Intra-arterial chemotherapy has an advantage over standard IV chemotherapy
because the concentration
of the drug delivered directly to the tumor bed can be greater than that
delivered to other organs.
Depending on the amount of drug taken up by the tumor during this first pass, it
may be possible to infuse
a cytotoxic agent through this route in a concentration greater than that which
would be tolerated IV. It is
important to remember that the entire benefit of intra-arterial delivery must be
achieved during this first
pass. After the drug leaves its target and enters the systemic circulation, it
behaves as if it had been
injected IV.
The results of the intra-arterial trials have varied. but several studies,
particularly those using
cisplatin-based regimens, indicate that a high response rate can be achieved.
Others argue that the best
results of intra-arterial chemotherapy do not surpass the best response rates
seen with IV chemotherapy
and that the intra-arterial approach has no real advantage, especially when
there is a given increase in risk
for local toxicity. Most of the technical complications that have occurred,
however, have been related to
catheter placement and include thrombosis, dislodgment, and hemorrhage. Newer
and safer angiographic
techniques now permit highly selective placements of microcatheters into small
arteries under direct vision
achieved with fluoroscopy. These advances in interventional vascular radiology
make it possible to
selectively and repeatedly infuse chemotherapeutic agents into head and neck
tumors with minimal side
effects.
Targeted chemoradiation, which we refer to here as the RADPLAT technique,
involves infusing cisplatin
over 3 to 5 minutes through a microcatheter placed intra-arterially. Angiographic techniques are used to
selectively encompass only the dominant blood supply of the targeted tumor. The
intra-arterial infusion of
cisplatin is started, and sodium thiosulfate (9 g/m over 30 minutes, followed
by 12 g/m2 over 2 hours) is
simultaneously administered IV. This allows the tumor bed to receive the full
dose of cisplatin before
receiving a neutralizing agent and allows the systemic organs to receive the
neutralizing agent before
receiving the cisplatin.
Thiosulfate reacts covalently with cisplatin to produce a complex that is still
soluble but is totally devoid of
toxicity or antitumor activity. When this neutralization occurs in the plasma,
it effectively increases the
plasma "clearance" of cisplatin. Pharmacokinetic studies have demonstrated an
important additional
feature of thiosulfate: it is extensively concentrated in the urine. This
provides excellent protection against
cisplatin-induced nephrotoxicity.
Thus, the RADPLAT protocol involves admitting patients to the hospital and
hydrating them overnight.
The catheterization is performed by interventional radiologists while patients
are under local anesthesia in
the angiography suite. Transfemoral carotid arteriography is first performed to
assess the vascular
anatomy and any vessel pathology. The arteries that supply the region of primary
disease are then infused
with cisplatin. This is usually performed by placing a microcatheter, introduced
transaxially through a
tracker catheter, into the external carotid artery at the level of the orifice
of the dominant branching artery
leading to the tumor. Thus, cisplatin can be rapidly infused to selectively
encompass on initial exposure
only the territory of the targeted tumor. In selected patients who have bulky
disease that crosses the
midline, bilateral transfemoral catheterizations are performed to permit
simultaneous infusions of the
contralateral disease. In each patient, the goal is to infuse the component of
the disease that is considered
to be bulky or infiltrative and likely to fail to respond to radiation therapy
alone. Surgery and radiation are
used to treat the regional lymphatics, although in selected patients with
unresectable neck disease, it is
often possible to infuse the blood supply through the superior thyroid artery or
the thyrocervical trunk.
After the initial studies that used targeted cisplatin as a single treatment
method were completed,
investigations then focused on the use of concomitant therapy in which cisplatin
is administered
simultaneously with radiation therapy. Many interactions between radiation and
chemotherapeutic agents
could, in theory, make the concurrent use of these treatments more effective
than sequential use.
Thus, in the RADPLAT trial, when radiation therapy was administered
concomitantly with targeted
cisplatin chemotherapy, preliminary observations indicated an extremely high
complete pathologic
response rate, sustained disease control above the clavicles, and a relatively
low rate of severe toxicity.
Conventional external beam irradiation was used in daily fractions of 180 cGy to
280 cGy per fraction to
a total dose of 68.5 Gy to 74.0 Gy given over 7 to 8 weeks. All patients
received intra-arterial cisplatin
and IV sodium thiosulfate infusions concurrently on days 1, 8, 15, and 22 of the
radiation therapy.
Planned neck dissection was performed 2 months after treatment on patients whose
original nodal disease
was considered to be stage N2 or N3. Salvage surgery was performed on patients
in whom recurrent
disease developed that was considered resectable.
The most recent analysis of the RADPLAT data included 213 patients treated
between 1993 and 1997
who had a follow-up of 12 to 60 months. The distribution of the disease by
various sites included
oropharynx (n=89), hypopharynx (ii=44), larynx (n=44), oral cavity (n=22), nasal
pharynx (n=7), and
other head and neck sites (n=7). Approximately one third of the lesions were
massive and truly
anatomically unresectable, whereas two thirds were potentially resectable by
technical criteria, but
removal would have caused the loss of one or more organs necessary for speech
and swallowing. The
treatment group included 94 patient who had T4 disease and 102 patients who had
T3 disease. When
analyzed by the staging system, 29% had stage III disease, whereas 72% had stage
IV disease.
Of the 189 patients who were evaluable for response to treatment in the primary
site,171 (90.5%) had a
complete response, while 24 patients were unevaluable for response assessment
for various reasons. Of
the 130 patients evaluable for response to treatment in the regional lymph
nodes, 92 (70%) had a
complete response, and 37 (24%) had a partial response.
Grade III-IV chemotoxicity events included 18 hematologic, 15 gastrointestinal,
7 neurologic, 7
cardiovascular, and 2 otologic events. Thus, severe chemotoxicity was not a
dominant factor, and 170
patients were able to receive all four cycles of their chemotherapy infusions.
Twenty-two additional
patients received three cycles, whereas, only 21 patients received less than
this amount. Similarly, most
patients were able to receive the full dose of radiation therapy.
A total of 767 transfemoral superselective intra-arterial infusions were
performed among the total group of
patients. Only 10 patients had post-infusion CNS dysfunction. None of these
patients developed any
severe impairment as a consequence of these complications. This low rate of
technical complications
appears to justify the invasive approach, which can deliver huge concentrations
of cisplatin directly into
the tumor bed.
The projected Kaplan-Meier 5-year overall and disease-related survival rates
were 38% and 52%,
respectively. The rate of disease control above the clavicle for all patients
was 88%. Fifty-one patients
developed recurrent disease within the primary site (n=11), within the regional
lymph nodes (n=5), or at
distant sites (n=35).
A major goal of this treatment protocol was to identify a new strategy that
could offer improved survival
while avoiding major loss of organ function. The data given here strongly
suggest that patients are
remaining alive at a rate significantly higher than expected.
Death from persistent or recurrent disease within the primary site or the neck
is often associated with
catastrophic suffering related to marked alterations in important bodily
functions, severe pain, and
disfigurement. Very few patients in this study succumbed to persistent disease
after initial therapy, and
very few developed recurrent disease in the local and regional sites. Most
patients who died of disease did
so because of recurrent tumors at distant sites, most often the lungs. This
pattern of cancer death is
different from that seen in most head and neck cancer trials in which death from
local-regional disease is
far more common. It is likely that distant metastatic disease in patients with
head and neck cancer is
usually masked by local-regional disease. With improved methods to control
disease above the clavicle,
one can expect an unmasking of distant clinical disease among patients who had
occult metastatic disease
before therapy. The emerging problem of death from distant disease will require
subsequent studies that
include a systemic treatment component, particularly for those patients at
greatest risk.
Chemotherapy and radiation therapy also have the potential to avoid major loss
of organ function,
particularly in relation to the larynx. The initial thrust of the organ
preservation approach was to preserve
the larynx in patients with laryngeal cancer by using induction chemotherapy
followed by radiation.
Several trials for preserving the larynx or other organs have been performed. The benchmark study was a
randomized trial for advanced laryngeal cancer conducted by the Department of
Veterans Affairs
Laryngeal Study Group. In this trial, approximately one third of the patients
receiving induction
chemotherapy were spared total laryngectomy. Survival was nearly the same in
this group as in the group
receiving standard care, which was total laryngectomy plus postoperative
radiation therapy. Thus,
laryngeal preservation is also feasible for patients with hypopharyngeal cancer
who receive induction
chemotherapy followed by radiation.
Although the organ-preservation approach to therapy used in this study may have
important advantages
over standard surgical treatment protocols, enthusiasm must be tempered because
organ preservation does
not necessarily imply preservation of function. For example, one would not
expect to see the return of
normal laryngeal function in a patient whose advanced tumor had effaced a large
part of the organ.
Instead, one might expect to see some degree of dysphonia and possibly
compromised respiration or
aspiration with associated dysphagia. Detailed analyses of functional impairment
are currently being
performed to better assess this problem. This includes studies to validate and
develop objective measures
of phonation and to apply swallowing assessment and quality-of-life
questionnaires to patients with head
and neck cancer. The quality-of-life questionnaires also reflect the patient's
ability to tolerate therapy. It is
particularly important to monitor this among patients undergoing aggressive
treatment with chemotherapy
and radiation.
Conclusions:
The targeted superdose cisplatin program is one strategy that seems to provide
lasting disease control
without sacrificing the function of major organs. Further work is needed to
demonstrate the safety of this
technique in multiple centers and to duplicate its effectiveness. This is
currently being addressed in a
phase II multicenter trial sponsored by the National Cancer Institute for which
data management and
quality control monitoring have been subcontracted to the Radiation Therapy
Oncology Group. The goal
is for the 10 participating academic medical centers to collectively accrue 60
patients for the purpose of
determining whether the treatment is safe and whether the initial single
institutional results are
reproducible. Ultimately, randomized trials may be indicated to determine
whether this approach can
increase survival, maintain organ function, and truly improve quality of life.
References
Robbins KT. The RADPLAT treatment technique for advanced squamous-cell carcinoma
of the upper
aerodigestive tract. Current Opinion in Otolaryngology & Head and Neck Surgery
1998;6:112-119.
Brizel DM et al. Hyperfractionated Irradiation With or Without Concurrent
Chemotherapy for Locally
Advanced Head and Neck Cancer. New England Journal of Medicine 1998;338:
1798-1804
©1999, Oakstone Medical Publishing
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