Reference	Study Number
Kraybill, W., Harris, J., Spiro, I., Ettinger, D., Trotti, A., Lucas, D., Blum, R., Letson, D. and Eisenberg, B.: Radiation Therapy Oncology Group (RTOG) 9514: A Phase II Study of Neoadjuvant Chemotherapy (CT) and Radiation Therapy (RT) in the Management Of High Risk (HR), High Grade, Soft Tissue Sarcomas (STS) of the Extremities And Body Wall. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 815, Abs. #3276, 2003. (acc as oral pres)	95-14 (acc as oral pres)
B. Movsas, C. Scott, C. Langer, M. Werner-Wasik, N. Nicolaou, R. Komaki, M. Machtay, C. Smith, R. Axelrod and R. Byhardt: Phase III Study of Amifostine in Patients with Locally Advanced Non-Small Cell Lung Cancer (NSCLC) Receiving Chemotherapy & Hyperfractionated Radiation (CHEMO/HFXRT): Radiation Therapy Oncology Group (RTOG) 98-01. Submitted to Proceeding from Am Soc Clin Oncol (ASCO), J Clin Oncol In Press. (acc as poster disc)	98-01 (acc as poster disc)
Albain, K.S.,Scott, C., Rusch, V., Turrisi, A.T., Shepherd, F., Smith, C., Gandara, D., Johnson, D., Green, M. and Miller, R.: Phase III Comparison of Concurrent Chemotherapy Plus Radiotherapy (CT/RT) and CT/RT Followed by Surgical Resection for Stage IIIA(Pn2) Non-Small Cell Lung Cancer (NSCLC): Initial Results From Intergroup Trial 0139 (RTOG 93-09). Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 621, Abs. #2497, 2003. (acc as oral pres)	93-09 (acc as oral pres)
Sandler, H., Pajak, T., Hanks, G., Porter, A., DeSilvio, M. and Shipley, W.: Can Biochemical Failure (ASTRO Definition) Be Used as a Surrogate Endpoint for Prostate Cancer Survival in Phase III Localized Prostate Cancer Clinical Trials? Analysis of RTOG Protocol 92-02. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 381, Abs. #1529, 2003. (acc as oral pres)	92-02 (acc as oral pres)
Pilepich, M., Winter, K., Lawton, C., Krisch, R., Wolkov, H., Movsas, B., Hug, E., Asbell, S. and Grignon, D.: Phase III Trial of Androgen Suppression Adjuvant to Definitive Radiotherapy. Long Term Results of RTOG Study 85-31. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 381, Abs. #1530, 2003. (acc as oral pres)	85-31 (acc as oral pres)
Komaki, R., Swann, S., Ettinger, D., Glisson, B., Sandler, A., Movsas, B. and Byhardt, R.: Phase I Dose-Escalation Study of Thoracic Irradiation with Concurrent Chemotherapy for Patients with Limited Small Cell Lung Cancer (LSCLC). Radiation Therapy Oncology Group (RTOG) Protocol 97-12. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 631, Abs. #2539, 2003. (acc as poster disc)	97-12 (acc as poster disc) D.Ettinger will present this at ASCO
Curran, W., Scott, C., Langer, C., Komaki, R., Lee, J., Hauser, S., Movsas, B., Wasserman, T., Sause, W. and Cox, J.: Long-Term Benefit is Observed in a Phase III Comparison of Sequential vs Concurrent Chemo-Radiation for Patients with Unresected Stage III NSCLC: RTOG 94-10. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 621, Abs. #2499, 2003. (acc as oral pres)	94-10 (acc as oral pres)
Maor, M., Berkey, B., Forastiere, A., Weber, R., Goepfert, H., Morrison, W., Glisson, B., Trotti, A., Ridge, J., Chao, C., Peters, G., Lee, D., Leaf, A., Ensley, J. and Fu, K.: Larynx Preservation and Tumor Control in Stage III and IV Laryngeal Cancer: A Three-Arm Randomized Intergroup Trial; RTOG 91–11. Proc Am Soc Clin Oncol (ASCO)-Best of Oncology Session, Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), Abs. #Selected, 2003.. (acc for Best of Oncology Session)	91-11 (selected for the Best of Oncology Session)
Ford, J., Seiferheld, W., Mehta, M., Phan, S. and Curran Jr, W.: Comparison of Survival of Patients in the Phase I Study of Motexafin Gadolinium (MGd) with Radiation Therapy (RT) for Glioblastoma Multiforme (GBM), with a Matched Cohort of Patients from The RTOG RPA Glioma Database. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 106, Abs. #425, 2003.	multi-studies [UCLA run] (acc as poster disc)
Khuri, F., Lee, J.J., Lippman, S.M., Kim, E.S., Cooper, J., Benner, S., Vokes, E., Pajak, T., Goepfert, H. and Hong, W.K.: Isotretinoin Effects on Head and Neck Cancer Recurrence and Second Primary Tumors. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 90, Abs. #359, 2003.	9115 [MDAH run] (acc as oral pres)
Smalley, S., Benedetti, J., Williamson, S., Robertson, J., Fisher, B., Martenson, J., Benson, A., Mayer, R., Cripps, C. and Macdonald, J.: Intergroup 0144 - Phase III Trial of 5-FU Based Chemotherapy Regimens Plus Radiotherapy (XRT) in Postoperative Adjuvant Rectal Cancer. Bolus 5-FU vs Prolonged Venous Infusion (PVI) Before and After XRT + PVI vs Bolus 5-FU + Leucovorin (LV) + Levamisole (LEV) Before and After XRT + Bolus 5-FU + LV. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 251, Abs. #1006, 2003.	9403 [SWOG run] (acc as oral pres)
Wakelee, H., Stephenson, P., Keller, S., Wagner, H., Herskovic , A., Komaki, R., Marks, R., Perry, M., Livingston, R. and Johnson, D.: Post-Operative Radiotherapy (PORT) or Chemoradiotherapy (CPORT) Following Resection of Stages II and IIIa Non-Small Cell Lung Cancer (NSCLC) Leads to Higher Than Expected Risk of Death From Intercurrent Disease (DID). Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 633, Abs. #2545, 2003.	9105 [ECOG run] (acc as poster disc)

Kraybill, W., Harris, J., Spiro, I., Ettinger, D., Trotti, A., Lucas, D., Blum, R., Letson, D. and Eisenberg, B.: Radiation Therapy Oncology Group (RTOG) 9514: A Phase II Study of Neoadjuvant Chemotherapy (CT) and Radiation Therapy (RT) in the Management Of High Risk (HR), High Grade, Soft Tissue Sarcomas (STS) of the Extremities And Body Wall. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 815, Abs. #3276, 2003. (acc as oral pres) Introduction: The RTOG reported preliminary results of an intergroup Phase II trial in patients (pts) with high grade, HR STS of the extremities and body wall given CT, RT and post-resection CT in 2001. This is an update of our 2001 ASCO abstract with analysis of all patients and further follow-up. Methods: Sixty-four of 66 patients are analyzable (2.75 years median follow-up), with primary high grade 2 (19%) or 3 (81%) of 3, STS > 8 cm in diameter of the extremities (81%) and body wall (19%); and, were treated with CT (Modified MAID) and preoperative RT and received 3 cycles of post-operative CT (Modified MAID). RT, 44 GY, was given in split courses of 22 GY between cycles of CT. Results: Of fifty-two patients with clear surgical margins, 3 had local-regional recurrence. Three pts had involved margins at resection; 1 maintained local control and 2 recurred local-regionally. Five pts (8%) required amputation because of disease. Three pts had unresectable disease and 1 patient refused surgery. Nineteen pts (30%) have developed distant metastasis of which 13 had pulmonary metastasis. Fourteen pts have died, 11 because of STS, 2 due to a second primary, and 1 secondary to treatment. Reported toxicities were 80% Grade 4 hematologic toxicity, 23% Grade 4 non-hematologic toxicity, and 88% combined Grade 4 toxicity. Seventy-nine percent completed their preoperative CT and 89% completed preoperative RT. Fifty-eight percent of pts completed all therapy. Delayed wound healing was reported in 20 pts (31%). Estimated three-year survival, disease-free survival, and local-regional control were 75.1% {95% confidence interval (62.7, 87.5)}, 55.2% (42.7, 67.7), and 79.3% (69.1, 89.5), respectively. Conclusions: This combined modality treatment can be successfully delivered in a multi-institutional setting. Efficacy results are consistent with previous single institution results, but will require longer follow-up to draw definitive conclusions.

B. Movsas, C. Scott, C. Langer, M. Werner-Wasik, N. Nicolaou, R. Komaki, M. Machtay, C. Smith, R. Axelrod and R. Byhardt: Phase III Study of Amifostine in Patients with Locally Advanced Non-Small Cell Lung Cancer (NSCLC) Receiving Chemotherapy & Hyperfractionated Radiation (CHEMO/HFXRT): Radiation Therapy Oncology Group (RTOG) 98-01. Submitted to Proceeding from Am Soc Clin Oncol (ASCO), J Clin Oncol In Press. (acc as poster disc) RTOG conducted a randomized trial to test the ability of the radioprotector, amifostine, to reduce chemoRT esophagitis & evaluate its impact on quality of life (QOL) and patient (pt)symptom distress. 243 pts with stage II-IIIA/B NSCLC enrolled from 9/98-3/02 received induction paclitaxel (P) 225mg/m2 IV d1, 22 & carboplatin (C) AUC 6 d1, 22 followed by concurrent weekly P (50mg/m2 IV) & C (AUC 2) & hyperfractionated RT (69.6Gy/1.2Gy BID) starting d43 and were randomized at registration to +/- amifostine (A) 500mg IV 4x/week before the afternoon treatment. Eligibility stipulated KPS >70, age >18, weight loss <5%. Toxicity was assessed via NCI-CTC & EORTC/RTOG criteria, physician dysphagia logs (PDL), daily patient swallowing diaries & QOL (EORTC QLQ C30/LC-13). Swallowing area under the curve (AUC) analyses were calculated from pt diaries & PDL. 120 pts were randomized to A, 123 to no A (1 pt was ineligible). 73% received A per protocol or with minor deviation. Pre-treatment factors, toxicity endpoints and median survivals were not significantly different (Table). Grade >3 esophagitis rate was 36% with A vs. 40% without A. However, based on pt diaries, the swallowing dysfunction AUC was lower with amifostine (Z-test p=0.03), especially among females (p=0.006) and pts > 65 yrs (p=0.003). Less weight loss from baseline corresponded with A use (p=0.05). In conclusion, amifostine did not reduce grade >3 esophagitis per the NCI-CTC criteria or PDL. However, direct pt self assessment suggests a possible advantage to A that should be explored with modified A dosing/route strategies. Prospective QOL data will be analyzed and presented. Research supported by NCI & Medimmune Oncology.   Amifostine (N=120) No Amifostine (N=122) p value Avg Esophageal Length 16.6 cm 16.0 cm NS Median Survival (mo) 15.8 15.6 NS Acute Gr 3/4/5 Esophagitis 34%/2%/0% 37%/3%/0% NS Late Gr 3/4/5 NH 9%/1%/1% 8%/5%/2% NS Pt Swallowing Diary AUC 2.19 2.34 0.03 Weight change -3.2% -4.5% 0.05 NH = non-hematologic toxicity; Pt = patient; NS = not significant; AUC = area under the curve; Gr = grade

Albain, K.S., Scott, C., Rusch, V., Turrisi, A.T., Shepherd, F., Smith, C., Gandara, D., Johnson, D., Green, M. and Miller, R.: Phase III Comparison of Concurrent Chemotherapy Plus Radiotherapy (CT/RT) and CT/RT Followed by Surgical Resection for Stage IIIA(Pn2) Non-Small Cell Lung Cancer (NSCLC): Initial Results From Intergroup Trial 0139 (RTOG 93-09). Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 621, Abs. #2497, 2003. (acc as oral pres) Purpose: Pts with stage IIIA NSCLC and clinical or pathologically confirmed N2 nodes (pN2) have a poor prognosis after surgery or RT. Phase II trials of the last decade suggested improvement with concurrent CT/RT or the same followed by resection. However, the role of surgery is controversial. Thus, INT 0139 tested the value of resection after induction CT/RT vs full course CT/RT for progression-free and overall survival (PFS, OS) and patterns of failure. Methods: Pts with T1-3, pN2, M0 tumors were eligible if resection was technically feasible at registration. Pulmonary function criteria were mandated. Randomized pts received induction with cisplatin 50 mg/m2 d1,8 and etoposide 50 mg/m2 d1-5 (PE) X2 and daily RT to 45 Gy starting day 1. Arm 1 then had resection if no progression (PD), followed by PE X2; Arm 2 had uninterrupted RT to 61 Gy with 2 more cycles of PE. Results: 429 pts were randomized 3/94-11/01; 18 (4%) were ineligible. The trial was closed with sufficient events over accrual time. Data were received on 392 pts to date: 16% were 70 or older; 35%, female; and 16%, T3. Induction CT/RT compliance was very good; consolidation chemo was incomplete in 25%, Arm 1 and 11%, Arm 2. Most common grade 3/4 toxicities from CT/RT were neutropenia, emesis and esophagitis (9% Arm 1, 20% Arm 2, p=.001). Arm 1 had 14 deaths from treatment either postop (4) or during/after consolidation (10), most of which were ARDS; 3 deaths occurred with/after consolidation in Arm 2. PFS is superior on Arm 1 (log-rank p=.02): median, 14.0 vs 11.7 mos; 3-year 29% vs 19%. There were more early non-cancer deaths in Arm 1, but OS curves cross at the median (Arm 1, 22.1 mos; Arm 2, 21.7 mos), so that by year 3 the OS favors Arm 1 (38% vs 33%). More pts are alive without PD on Arm 1 (p=.003), but more died without PD on Arm 1 (p=.004). Patterns of failure were similar. Conclusions: 1) Both approaches are feasible with more treatment-related deaths on Arm 1, 2) CT/RT followed by surgery yields superior PFS, 3) longer follow-up is needed to determine if surgery significantly prolongs OS in IIIA(pN2) NSCLC.

Sandler, H., Pajak, T., Hanks, G., Porter, A., DeSilvio, M. and Shipley, W.: Can Biochemical Failure (ASTRO Definition) Be Used as a Surrogate Endpoint for Prostate Cancer Survival in Phase III Localized Prostate Cancer Clinical Trials? Analysis of RTOG Protocol 92-02. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 381, Abs. #1529, 2003. (acc as oral pres) Prostate cancer has a long natural history and a survival endpoint for clinical trials requires a long interval between the end of patient accrual and endpoint reporting. PSA-defined failure could potentially be used as a surrogate endpoint for survival, substantially shortening the time required for reporting results. Prentice defines criteria that a surrogate marker must satisfy to be useful in clinical trials. Treatment must be prognostic (1) for the true endpoint (i.e. prostate cancer survival) and (2) the surrogate endpoint (i.e. PSA failure), (3) the surrogate must be prognostic for the true endpoint (i.e., PSA failure is associated with prostate death), and (4) the full effect of the treatment on the true endpoint is explained by the surrogate (i.e., prostate cancer survival must be the same by protocol treatment arms once PSA failure has occurred). This analysis assesses whether PSA failure (ASTRO definition) meets these criteria in the RTOG 92-02 clinical trial and can be used as a surrogate marker. Men with locally advanced prostate cancer (T2C-T4) PSA <150 ng/ml were eligible and serial PSA measurements were collected. Patients received goserelin and flutamide two months before and during radiation and were randomized to no further therapy (STAD) or 24 months of additional goserelin alone (LTAD). 1554 patients were entered, the median follow-up is 5.8 years, and 142 of 448 deaths were prostate cancer related. Of the four Prentice criteria, the first three were met. Importantly, however, the fourth criterion was not satisfied -- for those who failed biochemically, the relative risk of prostate cancer related death for patients treated with LTAD is 1.5 (p=0.05) times greater than STAD, indicating that the significance of a PSA failure event is not the same for each of the protocol arms. Thus, PSA failure may not be a satisfactory surrogate marker for prostate cancer survival in randomized clinical trials when the treatments have different duration of androgen deprivation. Supported by NCI grants: RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115.

Pilepich, M., Winter, K., Lawton, C., Krisch, R., Wolkov, H., Movsas, B., Hug, E., Asbell, S. and Grignon, D.: Phase III Trial of Androgen Suppression Adjuvant to Definitive Radiotherapy. Long Term Results of RTOG Study 85-31. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 381, Abs. #1530, 2003. (acc as oral pres) RTOG (Radiation Therapy Oncology Group) Protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression using goserelin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy. Eligible patients were those with palpable primary tumor extending beyond the prostate (Clinical Stage T3) or those with regional lymphatic involvement. Patients who have undergone prostatectomy were eligible if there was histologically documented penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement. Stratification was based on histological differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either radiotherapy and adjuvant goserelin (Arm I) or to radiotherapy alone followed by observation and application of goserelin at the time of relapse (Arm II). In Arm I the drug was to be started during the last week of radiation therapy and was to be continued indefinitely or until signs of progression. From 1987 to 1992 when the study was closed, 977 patients were entered: 488 on Arm I and 489 on Arm II. As of December 2002, the median follow-up for all patients reached 7.3 years and for live patients10 years. Adjuvant androgen suppression has resulted in significant improvement in all end points (see table below).   Arm Estimated 5 year rate Estimated 10 year rate P value Local Failure I 15% 23% P<0.0001   II 30% 39%   Distant Metastases I 15% 25% P<0.0001   II 29% 39%/td>   b NED PSA <1.5 I 55% 30% P<0.0001   II 21% 9%   Absolute Survival I 76% 53% P<0.0043   II 71% 38%

Komaki, R., Swann, S., Ettinger, D., Glisson, B., Sandler, A., Movsas, B. and Byhardt, R.: Phase I Dose-Escalation Study of Thoracic Irradiation with Concurrent Chemotherapy for Patients with Limited Small Cell Lung Cancer (LSCLC). Radiation Therapy Oncology Group (RTOG) Protocol 97-12. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 631, Abs. #2539, 2003. (acc as poster disc) Accelerated RT was shown to improve local control (LC) and survival among pts with LSCLC, but local failure was still unacceptably high. To increase LC and survival, a multi-institutional phase I radiation dose-escalation study was undertaken by the RTOG. Previously untreated, pathologically confirmed SCLC pts with limited stage and KPS > 70 were enrolled between 2/98 and 1/02. Pts originally received cisplatin (P), 60 mg/M2 IV and etoposide (E) 120 mg/M2 IV days 1-3, repeated every 3 wks x 4 cycles with concurrent thoracic radiation therapy (TRT) during the first 2 cycles of PE. TRT was given 1.8 Gy daily to 36 Gy followed by a small boost field encompassing only the gross disease. Boost TRT was delivered with escalations of 1.8 Gy twice daily (Bid) during the final days to establish the maximum tolerated dose (MTD). The first arm used a boost of 3 Bid Fx 1.8 Gy for a TD of 50.4 Gy. Escalations of Bid TRT during the last 5, 7, 9, and 11 days permitted TDs of 54 Gy 57.6 Gy 61.2 Gy and 64.8 Gy , all in a total time of 5 wks. A 50% rate of acute Gr 3 or 4 acute esophagitis was considered dose-limiting. 64 pts were enrolled: 2 of the first 8 receiving 50.4 Gy developed Gr 3 acute esophagitis. Dose of E was changed to 240 mg/M2 PO on days 2 & 3 with same TRT dose of 50.4 Gy: 10 pts were treated with acceptable toxicity. Progressive dose escalations were possible until the 64.8 Gy arm when 3 of 8 pts (which exceeded the stopping rules for the trial) had Gr 3 acute esophagitis. Therefore, the MTD was determined to be 61.2 Gy, in 34 Fx of 1.8 Gy when given concurrently with this regimen of PE, which has been proposed as a phase II study through RTOG.

Curran, W., Scott, C., Langer, C., Komaki, R., Lee, J., Hauser, S., Movsas, B., Wasserman, T., Sause, W. and Cox, J.: Long-Term Benefit is Observed in a Phase III Comparison of Sequential vs Concurrent Chemo-Radiation for Patients with Unresected Stage III NSCLC: RTOG 94-10. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 621, Abs. #2499, 2003. (acc as oral pres) A three-arm randomized trial studied whether the concurrent delivery of cisplatin-based chemotherapy with thoracic radiotherapy (TRT) improves survival when compared with the sequential delivery of these therapies for pts with locally advanced, unresected stage II-III NSCLC. 610 patients with newly diagnosed, unresected stage II-III NSCLC, KPS >70, and wt loss < 5% were enrolled in a phase III trial comparing two concurrent chemotherapy (CHM) and TRT regimens to a sequential CHM and TRT approach between 7/94 & 7/98. The sequential arm ((SEQ) included cisplatin (P) 100 mg/m2 days (D) 1 and 29 & vinblastine 5 mg/m2/weekly x 5 with 60 Gray (Gy) TRT beginning D 50, and Arm 2 used the same CHM with 60 Gy TRT beginning D 1 (CON-QD). Arm 3 employed P 50 mg/m2 D 1, 8, 29, & 36 with oral etoposide 50 mg BID x 10 weeks 1, 2, 5, & 6 with 69.6 Gy in 1.2 Gy BID fractions beginning D 1 (CON-BID). Of the 595 analyzable patients, the rates of acute grade 3-4 non-hematologic (N-H) toxicity rates were higher with concurrent than sequential therapy, but late toxicity rates were similar. With minimum and median potential follow-up times of 4.0 and 6.0 years, the median & 4-yr survivals are 14.6 mo & 12% (SEQ), 17.0 mo & 21% (CON-QD RT),& 15.2 mo & 17% (CON-BID RT). The CON-QD RT arm has better survival than the SEQ arm (p=0.046). This report demonstrates the long-term survival benefit of the concurrent delivery of cisplatin-based CHM with TRT as compared with the sequential delivery of these therapies. ARM MST 4-Yr Surv P Value vs SEQ SEQ 14.6 Mo 12% CON-QD RT 17.0 Mo 21% 0.046 CON-BID RT 15.2 Mo 17% 0.296

Maor, M., Berkey, B., Forastiere, A., Weber, R., Goepfert, H., Morrison, W., Glisson, B., Trotti, A., Ridge, J., Chao, C., Peters, G., Lee, D., Leaf, A., Ensley, J. and Fu, K.: Larynx Preservation and Tumor Control in Stage III and IV Laryngeal Cancer: A Three-Arm Randomized Intergroup Trial; RTOG 91–11. Proc Am Soc Clin Oncol (ASCO)-Best of Oncology Session, Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), Abs. #Selected, 2003.. (acc for Best of Oncology Session) Purpose/Objective: To evaluate induction chemotherapy followed by radiation (control) versus concomitant chemotherapy and radiotherapy versus radiation therapy alone in the treatment of stage III and low-volume stage IV glottic and supraglottic cancers. Endpoints for evaluating the trial were laryngectomy free-survival (LFS), laryngectomy preservation rate (LPR), patterns of relapse, treatment-related adverse events, and overall survival. Materials/Methods: Between August 1992 and May 2000, 547 patients were enrolled in our study. Patients were eligible for the study if they had a new diagnosis of a potentially resectable stage III or IV squamous carcinoma of the glottic or supraglottic region; patients with a T1 or a high-volume T4 tumor were excluded from the study. Patients were randomly assigned to 3 treatment arms. Patients in arm 1 received 3 cycles of induction cisplatin 100 mg/m2 once and 5-fluorouracil 1000 mg/m2 /day for 5 days every 3 weeks. In responding patients, this treatment was followed by 70 Gy of radiation in 35 fractions for 49 days. Patients in arm 2 received concurrent cisplatin 100 mg/m2 on days 1, 22, and 43 of radiation treatment (70 Gy/35 fractions for 49 days). Patients in arm 3 received radiation only at 70 Gy/35 fractions for 49 days. Patients with a neck node > 3 cm or with multiple neck nodes underwent a neck dissection 8 weeks after completion of therapy. After excluding 30 patients from the study, 517 remained for analysis (173 in arm 1, 172 in arm 2, and 172 in 3). Sixty eight percent of the 517 patients had supraglottic cancer. Pretreatment patient and tumor characteristics were very similar in the 3 treatment arms. Results: At 2 years, LFS for the patients treated with concomitant chemotherapy and radiotherapy was significantly better than for patients treated with radiotherapy alone (p = 0.018). The LPR was significantly greater in arm 2 compared with arms 1 and 3. The number of laryngectomies at 2 years was 43, 21, and 49 for the induction, concomitant and radiotherapy arms respectively. Loco-regional control at 2 years for patients in arm 2 (78%) was significantly better than either arm 1 (61%), or arm 3 (56%), p < 0.01. Ten patients in the study died of treatment toxicity; 5 died in the induction chemotherapy arm and 5 died in the concomitant chemotherapy and radiation arm. Acute grade 4 and 5 toxicity was 31%, 21%, and 5% in treatment arms 1, 2, and 3 respectively (<0.0001). Late grade 4 and 5 toxicity was 9%, 8% and 10% in the 3 arms (not significant). Overall survival was very similar for the patients in the 3 treatment arms (~75% at 2 years). Conclusions: Concomitant chemotherapy and radiotherapy was superior for LPR and loco-regional control compared with induction chemotherapy followed by radiotherapy and compared to radiotherapy alone. Patients on concomitant treatment had a superior LFS compared to patients treated with radiation alone. There was no significant difference between induction chemotherapy and radiotherapy alone using these criteria. Better local control with the concomitant treatment arm did not improve survival. (presented at ASTRO 2002 Meeting)

Ford, J., Seiferheld, W., Mehta, M., Phan, S. and Curran Jr, W.: Comparison of Survival of Patients in the Phase I Study of Motexafin Gadolinium (MGd) with Radiation Therapy (RT) for Glioblastoma Multiforme (GBM), with a Matched Cohort of Patients from The RTOG RPA Glioma Database. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 106, Abs. #425, 2003. Aim: To compare the survival of patients with GBM treated in the phase I study of motexafin gadolinium in combination with radiation, with a matched cohort of patients from the RTOG Recursive Partitioning Analysis (RPA) glioma database. Methods: Data were available for 33 cases treated on the phase I trial. These were matched with 33 cases from the RTOG database according to the following prognostic factors: Karnofsky Performance Status, extent of surgery, histology, and age (within 5 years). Kaplan-Meier survival curves were generated. A matched pair Cox analysis of overall survival was done and the generalized Wilcoxon (Peto-Prentice) test was used for a nonparametric comparison. Results: Kaplan-Meier estimate of median survival time for the RTOG cases was 12.0 months compared to 17.6 months for the cases treated with motexafin gadolinium. The Cox analysis of overall survival yielded a hazard ratio of 2.0 in favor of the motexafin gadolinium treated cases (p=0.07). The generalized Wilcoxon test also resulted in a one-sided p-value of 0.07. Discussion: Studies of chemotherapy for GBM suggest at best a median survival benefit in the range of 3 months, yet chemotherapy is routinely given to many patients; therefore, a survival benefit of 5.6 months is of interest. The numbers of patients are small, but they were well matched for the major prognostic factors. Conclusion: The results of this well matched case control comparison showed a potential survival benefit of 5 to 6 months from the use of motexafin gadolinium in combination with standard radiation therapy for Glioblastoma Multiforme. This result should be further investigated with either a larger phase II trial or a randomized trial in a multi-center setting.

Khuri, F., Lee, J.J., Lippman, S.M., Kim, E.S., Cooper, J., Benner, S., Vokes, E., Pajak, T., Goepfert, H. and Hong, W.K.: Isotretinoin Effects on Head and Neck Cancer Recurrence and Second Primary Tumors. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 90, Abs. #359, 2003. Based on results of a landmark trial by Hong et al (NEJM, 1990) showing a significant second primary tumor (SPT) reduction with short-term, high-dose 13-cis-retinoic acid (isotretinoin) in stage I-IV head and neck squamous cell carcinoma (HNSCC) patients, in 1991 we launched the present large-scale phase III trial of low-dose, long-term isotretinoin in stage I, II HNSCC patients definitively treated with radiation therapy or surgery. 1384 patients were registered and 1190 were eligible and randomized to receive either isotretinoin or placebo for 3 years and were followed for 4 more years. Patients were stratified by stage, smoking status, and primary tumor site. The last patient completed treatment in September 2002. There was no significant difference in overall survival, or SPT- or recurrence-free survival (p=0.79, 0.99, and 0.18, respectively). There was a provocative pattern of decreased recurrences, however in the isotretinoin arm (versus placebo). This effect was lost after treatment stopped, suggesting a cause-and-effect relationship with isotretinoin. The annual SPT rate was 4.7% in both arms. Overall SPT demographics included higher SPT rates in the pharynx than the larynx or oral cavity; in current than in former or never smokers; and in stage II than in stage I cases (all p<0.01). Overall recurrence demographics included higher recurrence rates in stage II than in stage I cases (p<0.01), in the oral cavity than in the pharynx, and in the pharynx than in the larynx (p=0.01) and no correlation between recurrence and smoking status (p=0.69). There was no smoking status-by-treatment interaction. The percentages of SPTs (n=260) in the lung, oral cavity, larynx, and pharynx were 30%, 17%, 8%, and 6%, respectively. Based on the provocative differential between the recurrence and SPT effects of isotretinoin, we are analyzing molecular tumor characteristics to better distinguish between SPTs and recurrences. Our present clinical results also support a potential role in the head and neck for retinoid combinations, which currently are being tested in ongoing clinical and mechanistic (e.g., cyclin D1 polymorphism) studies. (Supported by NCI P01 CA52051 to WKH)

Smalley, S., Benedetti, J., Williamson, S., Robertson, J., Fisher, B., Martenson, J., Benson, A., Mayer, R., Cripps, C. and Macdonald, J.: Intergroup 0144 - Phase III Trial of 5-FU Based Chemotherapy Regimens Plus Radiotherapy (XRT) in Postoperative Adjuvant Rectal Cancer. Bolus 5-FU vs Prolonged Venous Infusion (PVI) Before and After XRT + PVI vs Bolus 5-FU + Leucovorin (LV) + Levamisole (LEV) Before and After XRT + Bolus 5-FU + LV. Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 251, Abs. #1006, 2003. 5-FU based chemoradiotherapy is standard therapy for T3,4N0 or node positive rectal cancer. Intergroup 864751 suggested improved relapse free (RFS) and overall (OS) survival when 5-FU was delivered by PVI during XRT. INT 0144 compared this approach vs consistent use of PVI before and after XRT vs biochemically modulated 5-FU which avoided central lines. Eligibility criteria included: complete resection of T3,4N0M0 or T1-4NOM0 rectal adenocarcinoma, registration 20-70 days after resection, adequate CBC, liver function studies, and general medical condition, and signed IRB approved consent. From 3/1994-8/2000 1917 pts were randomized to: arm 1-bolus 5-FU 2 five day cycles q28d before (500mg/m2/d) and after (450mg/m2/d) XRT (50.4-54 Gy) plus 5-FU via PVI 225mg/m2/d during XRT; arm II-PVI (300 mg/m2/d) 42 d before and 56 d after identical XRT + PVI as arm I; or, arm III-bolus 5-FU, LV (20 mg/m2) in 2 five day cycles q 28 d before(425mg/m2 5-FU) and after (380mg/m2 5-FU) XRT + bolus 5-FU (400mg/m2) + LV d 1-4 of wk 1,5 of XRT. Arm III received LEV 150mg/d d1-3,14-16 each cycle before and after XRT. 4.6% were ineligible. Pts were stratified by operation type, T and N stage, and time from surgery. Arms were well balanced for other prognostic factors including age, gender, and performance status. Median follow-up of living pts was 4.6 yrs. Major deviations occurred in 2.4%. Toxicity was similar in arms I-III with <1% lethal toxicity in each arm. Grade 3-4 GI/hematologic toxicity by arms was: arm I 66%/42%; arm II 68%/27%; arm III 43%/50%. RFS and OS were similar in all arms with 3 yr RFS 68-69%; p = 0.45 and 3 yr OS 81-83%; p = 0.21 based on Cox regression model stratified for variables used in randomization. There were no significant interactions between treatment and gender, race, or T and N prognostic group. We conclude that any of these 3 arms are acceptable for clinical practice. They produce very similar RFS and OS with slightly differing toxicity profiles with differing needs for central lines.

Wakelee, H., Stephenson, P., Keller, S., Wagner, H., Herskovic , A., Komaki, R., Marks, R., Perry, M., Livingston, R. and Johnson, D.: Post-Operative Radiotherapy (PORT) or Chemoradiotherapy (CPORT) Following Resection of Stages II and IIIa Non-Small Cell Lung Cancer (NSCLC) Leads to Higher Than Expected Risk of Death From Intercurrent Disease (DID). Proceeding from Am Soc Clin Oncol (ASCO), Chicago, IL, J Clin Oncol, [22] (May 31-June 3, 2003), pg. 633, Abs. #2545, 2003. In order to determine the influence of adjuvant therapy on the risk of DID following resection of stages II and IIIa NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently with PORT (5040 cGy in 28 daily fractions). Four hundred eighty-eight patients were accrued to the study, 242 to the PORT only arm and 246 to the CPORT arm. Median follow up was 82 months (range 21-127 months). Deaths due to cancer in each treatment arm were similar (p=0.77), as were DID (45 (18.6%) PORT and 46 (18.7%) CPORT, p=0.81). The overall 4 year actuarial rate of DID was 16.9%: 15.4% for patients who received PORT and 18.4% for those randomized to CPORT. The overall result is significantly different than the expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status, of 10.1% (p<0.002). Within the study population, the risk of DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or wei ght loss in the previous 6 months. Male gender was associated with an increased risk of DID in univariate analysis (p = 0.04), but was not significant after accounting for age. In this study, the risk of DID following resection of stages II and IIIa NSCLC appears to be increased in patients who received PORT or CPORT. This effect may be due to sequelae of these adjuvant therapies Ã?