[MOL] NSCLC

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American Society of Clinical Oncology 35th Annual Meeting
Day 2 - May 16, 1999

Locally Advanced NSCLC: Concurrent vs Sequential Therapy

Corey Langer, MD

The second half of the Sunday afternoon lung plenary session discussed pivotal Phase III studies in advanced disease as well as ongoing Phase II studies focused on new agents and 3-D conformal XRT.

Does Timing Influence Outcome? Concurrent vs Sequential Chemoradiation Therapy

Furuse and colleagues^[1] provided a survival update of their Phase III trial comparing concurrent chemoradiation to sequential chemoradiation. In this trial, identical doses of mitomycin, vindesine, and cisplatin were used in both arms. In the sequential arm, radiation was begun after completion of 2 cycles of MVP to a total dose of 56 Gy using a conventional schedule. In the concurrent arm, split-course RT–which could have conceivably biased the results against this arm–was delivered during MVP chemotherapy (2 cycles). This trial accrued 320 patients from August, 1992 through December 1994; all were diagnosed with unresectable stage III, and all were </= 75 years of age.

As previously reported 2 years ago at this meeting, median survival was superior for concurrent chemoradiation (16.5 months vs 13.3 months). Survival updates at 3, 4, and 5 years, presented at this meeting, confirm a persistent improvement in survival, with survival rate at 5 years 16% vs 8.9% for concurrent vs sequential therapy. The results for the concurrent arm are virtually identical to those obtained by the European Organisation for the Research and Treatment of Cancer (EORTC) and by Jeremic, in which radiosensitizing chemotherapy given concurrently with XRT was compared to radiation alone. The results of the concurrent arm also appear superior to sequential data observed by CALGB, RTOG, and CEBI, which were virtually identical to the control arm in this study (sequential MVP XRT).

Vokes and associates^[2] of the CALGB incorporated the use of more modern chemotherapy (gemcitabine, paclitaxel, vinorelbine) into locally advanced disease and uniquely evaluated both sequential and concurrent chemotherapy in a randomized Phase II trial. In this effort, the cisplatin dose was fixed at 80 mg/m² throughout. The researchers administered these agents every 3 weeks for 4 courses.

In arm 1, gemcitabine was given at 1250 mg/m² days 1 and 8, days 22 and 29, and then empirically attenuated to 600 mg/m² days 43, 50, 64, and 71. In arm 2, paclitaxel was administered at 225 mg/m² days 1 and 22, and based on previous Phase I data, attenuated to 135 mg/m² days 43 and 64 during XRT. In arm 3, vinorelbine was given at a dose of 25 mg/m² days 1, 8, 15, 22, 29, and then attenuated, based on Phase I data from the University of Chicago, to 15 mg/m² days 43, 50, 64, and 71. Total radiation dose was equivalent in each arm: 66 Gy, and was initiated day 43. The results of each of these regimens were relatively comparable, although the gemcitabine regimen yielded considerably more thrombocytopenia and esophagitis (Table I).

Table I. New Agents for Locally Advanced NSCLC

Arm	Gemcitabine	Paclitaxel	Vinorelbine
N	63	60	58
Toxicity (grade 3,4)    Thrombocytopenia    Esophagitis	30/25 36/14	6/0 31/4	0/0 13/11
Response (%)	63	50	57
Survival    Median (mos)    1-year (%)	17 63	14 63	17 67

The overall response rates to induction were also equivalent, as were 1-year survival rates (63% for gemcitabine, 63% for paclitaxel, 67% for vinorelbine). Median survival time overall in this study was 18 months, and the median time to progression overall was 10 months.

Experience Pays Off

Jin Soo Lee of the RTOG^[3] reported the effects of experience, ie, number of patients treated per institution on the outcome of therapy in patients receiving combined modality chemoradiation for locally advanced inoperable non—small-cell lung cancer (NSCLC). This study focused on 2 separate protocols, RTOG-9106 and RTOG-9204. The first study, conducted in a mixed group of patients with good and poor prognosis, implemented hyperfractionated XRT (69.6 Gy) in combination with cisplatin 50 mg/m² days 1 and 8, 29, and 36, and etoposide 50 mg/m² days 1 through 14, 29 through 42.

The second trial, a randomized Phase II trial, evaluated the same regimen in exclusively good-prognosis patients and also evaluated standard vinblastine and cisplatin induction followed by concurrent single daily fractionated XRT, with 3 additional doses of cisplatin during XRT. A total of 239 patients were evaluated. They were broken down into 2 groups: Group A, those institutions that enrolled 5 or more patients (n=147), and Group B, those that did not (n=92).

Of note, there was no significant difference in baseline demographic status between the 2 groups. However, there was a significant improvement in survival in both studies for those institutions that enrolled more patients. In the RTOG-9106 trial, median survival for group A was 20.5 months vs 14.8 months for Group B. In the RTOG-9204 trial, median survival in Group A was 25.7 months vs 13.4 months in Group B.

The Las Vegas Effect

In the "question and answer" session, Dr. Ackerly raised the issue of the "Las Vegas effect," where deleterious outcome in a particular institution might potentially lead to poor patient accrual and an inferior overall outcome. However, the data presented did not necessarily corroborate this concern. Moreover, the protocol completion rate in both groups, when analyzed on the basis of the first 4 patients accrued, was no different between Groups A and B, strongly suggesting that toxicities were probably comparable. The reason for the difference in survival remains unclear, although it strongly suggests that institutions experienced with combined modality therapy appear to be much more comfortable implementing such programs and may be better equipped to support patients through the toxicities of treatment, with earlier, more aggressive intervention. In addition, institutions with more experience may be more willing to accept toxicities that less experienced institutions would consider onerous.

A Novel Approach to XRT Dose Escalation

Finally, in an effort to improve local control and limit toxicity, Hayman^[4] mounted a dose-escalation trial using 3-D conformal XRT. Patients were grouped by effective target volume. Maximum tolerated doses have not been reached in any of the "bins" evaluated, with a range of 69.3 Gy to date for 31% to 40% effective target volume to as high as 100.29 Gy for the smallest effective volume (</=12%). How to best combine chemotherapy with 3-D conformal XRT remains to be seen, but such efforts may ultimately enable us to customize delivery of XRT to specific patients, based on tumor volume and location, in an effort to improve local control and minimize toxicity.

Table II. Current Safe RT Dose Level for Effective Treatment Volume

Bin	1	2	3	4	5
Veff (%)	</= 12	12-18	18-24	24-31	31-40
RT dose (Gy)	102.9	92.4	84	75.6	69.3

Future trials will elucidate the optimal way to combine chemotherapy with altered fractionation and altered dose delivery approaches. That goal has not yet been reached, but based on this study, it is not unreasonable to believe that it will be achieved within the next 3 to 5 years.

Finally, as these data mature, the role of new agents in combination with XRT in locally advanced NSCLC will need to be explored in greater depth and ultimately compared in Phase III trials with standard treatment (cisplatin plus/minus etoposide or vinblastine).

References

1. Furuse K, Fukuoka M, Takada Y, et al. Phase III Study of Concurrent Vs. Sequential Thoracic Radiotherapy (TRT) in Combination with Mitomycin (M), Vindesine (V) and Cisplatin (P) in Unresectable Stage III Non-Small Cell Lung Cancer (NSCLC): Five-Year Median Follow-Up Results [Abstract 1770]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
2. Vokes EE, Leopold KA, Herndon JE, et al. A Randomized Phase II Study of Gemcitabine or Paclitaxel or Vinorelbine with Cisplatin as Induction Chemotherapy (Ind CT) and Concomitant Chemoradiotherapy (XRT) for Unresectable Stage III Non-Small Cell Lung Cancer (NSCLC) (CALGB Study 9431) [Abstract 1771]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
3. Lee JS, Scott CB, Komaki R, et al. Effects of the Number of Patients Treated Per Institution on the Outcome of Therapy in Patients with Locally-Advanced Inoperable Non-Small Cell Lung Cancer: RTOG91-06 and RTOG92-04 Experience [Abstract 1773]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
4. Hayman JA, Martel MK, Randall K, et al. Dose Escalation in Non-Small Cell Lung Cancer (NSCLC) Using Conformal 3-Dimensional Radiation Therapy (C3DRT): Update of a Phase I Trial [Abstract 1772]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.

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