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Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma A significant factor in local control and distant metastasis

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195
Adoptive lmmunotherapy for
Nonsmall Cell Lung Carcinoma
A Fourth Treatment Modality, Complicated Radiation
Sensitizer, or None of the Above
Daniel D. Karp, M.D.
Michael B. Atkins, M.D.
Division of Hematology/Oncology, Tupper Research Institute, New England Medical Center,
Boston, Massachusetts.
N
Address for reprints: Michael B. Atkins, MD.,
Department of Medicine, Division of Aduli Hernatology/Oncology, New England Medical Center, 750 Washington Street, Box 542, Boston,
MA 02111.
Received April 10, 1996; accepted April 17,
1996.
0 1996 American Cancer Society
onsmall cell lung carcinoma (NSCLC) is the most frequent cause
of cancer mortality in the world. The incidence continues to rise
globally by 0.5% per year and, in 1996, several million patients will be
diagnosed worldwide with this disease. In Western countries, between
one-third and half of the patients will have intermediate stage disease
with involvement of lobar or bronchial lymph nodes (Stage 11) or
mediastinal (Stage 111) disease at diagnosis. Unfortunately, the great
majority of these patients succumb to their illness. While surgery
alone can produce 5-year survivals of 40 to 54% of patients with
Stage I1 disease,' single modality treatment, either surgery or radiation
therapy, in Stage IIIA or IIIB NSCLC offers very little hope for long
term success. Surgery alone is associated with a 3-year survival of
only 9% of patients with mediastinal lymph node disease2 and radiation alone produces only 5% long term ~urvival.~
Historically, chemotherapy has been relegated to the palliation of patients with Stage IV
disease. These disappointing survival data have prompted intensive
investigations of combination modality therapy for patients with intermediate stage NSCLC.
Such multiple combination modality regimens have been developed
over the past decade and have produced considerable improvement in
survival rates relative to single modality therapy. Radiation therapy has
enhanced long term local control when added to surgery in patients
with IIIA and resected IIIB disease. Combinations of chemotherapy and
radiation earlier in the disease process have produced durable responses
and long term survival-even in some patients with highly unfavorable
disease. For example, in 1990 the Cancer & Acute Leukemia Group B
(CALGB) Study of Dillman et al. showed a marked sunival advantage
for patients with unresectable Stage 111 NSCLC treated with 2 cycles of
vinblastine and cisplatin prior to 6,000 centigray (cGy)thoracic radiation
(TRT).4In addition, Schaake-Koning et al., in a 3-arm study of 308 patients, showed a marked superiority of low dose daily or weekly cisplatin
given simultaneously with 5500 cGy TRT in unresectable patients5 Survival at 3 years was 13 to 16% for the cisplatinlradiation groups versus
only 2% for the radiation only group.
Other studies have also shown an important role for adding chemotherapy to surgery and TRT. Rose11 et al. reported results of a
196
CANCER July 15,1996 / Volume 78 / Number 2
randomized study from Barcelona in which 60 patients
with Stage IIIA NSCLC received either 3 cycles of cisplatin, ifosfamide, and mitomycin C (PIM) prior to
surgery or surgery alone.fiBoth groups received postoperative TRT (5000 cGy). The chemotherapy group
had a median survival of 26 months versus 8 months
for the control arm ( P < 0.001). In addition, a study
comparing cyclophosphamide, etoposide, and cisplatin prior to surgery versus surgery alone in patients
with IIIA NSCLC had to be stopped early due to the
markedly better median survival of the chemotherapy
~
published Lung Cangroup (64 vs. 11 m o ~ )A.recently
cer Study Group Protocol involving cyclophosphamide, adriamycin, and cisplatin (CAP) in patients with
completely resected Stage I1 and 111 NSCLC, produced
a median time to progression of 19.5 months and a
median survival of 32.7 months8 In a Southwest Oncology Group (SWOG) study conducted by Albain et
al. with patients for whom surgery was not judged to
be the first option due to mediastinal (N2) or contralatera1 (N3) involvement, more than 80% were able to
undergo tumor resection following neoadjuvant cisplatin and etoposide plus 4500 cGy TRT and 19 of 89
undergoing resection (21%) had no viable tumor in
the ~ p e c i m e n The
. ~ overall 3-year survival of 26% in
this report is quite encouraging. Other groups have
administered concurrent chemotherapy (cisplatin and
etoposide) and radiation therapy in doses as high as
5940 cGy prior to surgery in patients with Stage IIIB
disease with 45% of the patients having no viable tumor in the surgical specimen and a projected 5-year
survival of more than 50%.’03”
Despite these apparent advances, the majority of
patients with intermediate NSCLC still eventually succumb to their disease. Better treatment strategies are
still necessary. Any putative benefit from novel treatment strategies, however, must be judged in comparison to the multimodality regimens described above. In
addition, as survival rates will vary markedly between
clinically and surgically staged patientsLZ
and patterns
of spread and sites of failure will vary according to
cell type, the reader must examine treatment groups
critically when attempting to compare various adjuvant studies. Ideally, randomized studies of sufficient
size are needed to control for these inherent biases.
It is in this context that we must view the study
by Ratto et al. in this issue of
This study
examined the potential benefit of adding a new therapeutic modality, adoptive immunotherapy (AI), to the
conventional treatment approaches. They investigated
the value ofAI with autologous tumor infiltrating lymphocytes (TIL) and outpatient low-dose interleukin-2
(IL-2) in 113patients with resected Stage 11, IIIA, or IIIB
NSCLC. Patients enrolled in this study had autologous
tumor obtained at the time of initial surgery dissociated and cultured in IL-2 to generate autologous TIL.
Approximately 6 to 8 weeks following surgery, patients
whose cultures grew out TIL (80% of initial group),
were randomized to receive either observation or TIL
+ IL-2 (Stage 11) or either chemotherapy with cisplatin
and vinblastine or A1 (Stage 111) with both arms then
receiving involved field radiation therapy at approximately Day 60 (120 days post surgery). The authors
report a significant improvement in overall survival
favoring the A1 group as a whole. Subset analysis
showed that the survival benefit was concentrated in
patients with Stage IIIB disease. While median survival
remained constant at approximately 22 months for
patients with all stages of disease receiving AI, median
survival declined from 31 months for Stage I1 patients
to 7.3 months for Stage IIIB patients in the control
group. Fifty percent of patients who received A1 are
projected to remain alive at 2 years compared with
only 30% of the control patients. The survival curves
for the 2 arms diverged early and after about 6 months
tended to decline in parallel indicating that both early
recurrence and death were more common in the control group. Furthermore, local recurrence rates were
significantly lower in the A1 group relative to the control group and, in contrast to most prior reports, did
not appear to be affected by the completeness of the
surgical resection. The authors propose that these data
support a role for A1 delaying local recurrence and
prolonging survival in patients with Stage IIIB NSCLC
treated with delayed postoperative radiation therapy.
Despite the intriguing nature of these results, they
must be reviewed with caution. Although the two
treatment groups seemed to have been balanced for
the major risk factors, the specifics of performance
status, a major predictor of outcome, were not provided. In addition, the sample sizes were small (16
patientdarm for Stage IIIB patients), consequently unknown factors, including chance events, could conceivably have contributed to the observed survival differences. This point is emphasized when one considers that the IIIB population receiving “standard
therapy” had a much greater incidence of early local
recurrence and an extremely short survival compared
with patients receiving the combined modality regimen mentioned earlier7~9-’L
and that this decrease in
local recurrence relative to the control arm is largely
responsible for the significant benefit attributable to
AI. One wonders to what extent the delay in radiation
therapy in this control group until approximately Day
120 postsurgery or adverse events related to chemotherapy could have contributed to these poor results.
Furthermore, the lack of benefit for A1 in earlier stage
disease is troubling as one would anticipate that such
Therapies for NSCLC/Karp and Atkins
patients with lower volume disease might be best
suited to obtain benefit from an immunotherapy approach. These results, in particular, argue against a
systemic effect of the A1 which the investigators originally hoped to document and highlight the need for
confirmation of these finding:;.
Assuming the data are valid, what potential mechanisms are involved?Some investigators have reported
activity for IL-2 based immunotherapy in NSCLC with
occasional responses being observed in clinical trials
involving IL-2 alone or IL-2 with lymphokine activated
killer cells (LAK) in patients with metastatic disease.l4l 5 Krigel et al. observed 3 responses including
a complete response in 73 patients treated on an outpatient ECOG protocol involving IL-2 either alone or
in combination with interferon p.I6These investigators
also noted a longer than anticipated median survival,
although stringent patient selection criteria may have
contributed to this finding. Therefore, it is conceivable
that the A1 could have produced additive antitumor
effects, especially in this earlier stage patient population. Unfortunately, most other reports involving patients with metastatic NSCLC (including IL-2 + TIL
protocols) have been less sanguine. 1 7 ~ 1 8Alternatively,
A1 could have hastened resolution of any immunosuppressive effect of surgery (especially relative to postop chemotherapy) facilitating host immune mediated
control of tumor progression. However, whether surgery produces clinically relevant immunosuppression
which can be abrogated by immunotherapy is still a
matter of conjecture. In any event, the confinement
of benefit in the study by Ratto et al. to those patients
with more extensive or even residual mediastinal disease and the total lack of systemic benefit for any subset argues against a systemic effect of A1 as was initially
postulated. In fact, the data indicate that A1 may have
exerted its beneficial effects through principally local
mechanisms; either through the concentration of infused TIL in the chest as suggested by the authors,
or the potentiation of the action of the subsequent
involved field radiation therapy. This latter hypothesis
is particularly intriguing because of its potential implication for the treatment of othler diseases. Nonetheless, an explanation for how such an effect could be
mediated is clearly lacking and there has been remarkably little preclinical or clinical investigation evaluating this hypothesis. While Cameron et al. reported synergy for IL-21TIL and local radiation therapy in a murine MC-38 carcinoma hepatic metastases model,’’ in
these experiments the radiation was administered
prior to rather than after the IL-;!/TIL therapy. Clearly
more investigations into the existence and potential
mechanisms of any synergistic interaction between A1
and subsequent radiotherapy are warranted.
197
Although IL-2 + TIL therapy appears superior to
IL-2 alone in animal tumor models“ and in some
Phase I1 clinical trials”.2zthe value of this combination
has never been proven in any clinical setting. In fact,
the improved response rates reported by Rosenberg
et al. could have been due to selection bias inherent in
their study design."^" In their study, tumor responses
were usually transient, and did not correlate with the
amount of infused TlL. Conversely, responses were
reported in some patients who had progressed following IL-2 alone indicating potential non-cross resistance. Randomized controlled studies comparing IL2 plus TIL to similarly selected patients receiving
IL-2 alone would be necessary to document any true
response advantage related to the addition of TIL. One
such study using selected CD8+ TIL in patients with
metastatic renal cell cancer is currently underway, and
results are eagerly anticipated. Similarly,the contribution of TIL to the results in the present study by Ratto
et al. is unproven and needs to be formally tested. The
fact that there was no correlation between response
and the number or cytolytic activity of the infused TIL
supports a limited role for the TIL. Consequently, even
if the results are valid, there is no definitive proof that
the generation of TIL, a laborious and technically difficult process, is a necessary component of the regimen.
In conclusion, the results of this randomized study
by Ratto et al. raise many intriguing questions. Despite
the fact that patients with Stage IIIB disease in the
control group did worse than expected and sample
sizes were too small to be definitive, the potential benefit for AI observed in this study cannot be readily
dismissed. In light of the significance of the public
health problem posed hy NSCLC and the still limited
benefit of current treatment strategies, confirmatory
studies are warranted. In addition, investigation of the
potential mechanism of any favorable interactions between AI/IL-2 and radiation therapy is also indicated.
If results can be confirmed, we may eventually be able
to add another modality to our treatment armamentarium for this disease which might enhance the benefits already observed with combinations of chemotherapy, radiation therapy, and surgery. In addition, this
approach, if promising, may be applicable to other
disease settings.
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prognostic, paranasopharyngeal, local, factors, extension, carcinoma, distant, metastasis, values, nasopharyngeal, significance, control
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