K. Miller, L. Sylvester, L. R. Laufman, M. Karwal, K. Jabboury, M. Saleh, R. F. Asbury, K. Tkaczuk, A. L. Hannah, C. F. Sidor. Asco Proceedings 2007. Abstract#234 (Poster Presentation)
Phase II study of MKC-1 in patients (pts) with metastatic breast cancer (MBC) who have failed prior therapy with an anthracycline (A) and taxane (T). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 11508
L. Sylvester, L. Laufman, K. Jabboury, M. Saleh, K. Tkaczuk, F. Volterra, J. Arnott, A. Hannah, C. Sidor, K. Miller
Background: Front-line dose-intensive L-FAC has demonstrated a favorable 5-year relapse free survival pattern (ASCO 2004 #739). Tamoxifen was given for 5 years to ER+ patients after L-FAC completion. We evaluated the impact of adding tamoxifen to L-FAC. By design, this pilot study excluded low-risk patients not candidates for chemotherapy. Methods: 109 breast cancer patients were enrolled (4 excluded due to treatment violations) from 6/1989 to 1/2003: 20 Stage I (S), 52 S-II, 22 S-III, for a total of 94 patients. 11 S-IV patients were excluded from survival analysis. Adverse tumor presentations included: ER- 49, PgR- 60, P53+ 24, non-diploid 39, histological grade III 37, CerbB2+ 33. L-FAC included 72 hour (h) iv infusion 400mg/m2/day (d) 5-fluorouracil (F) modulated by iv bolus 200mg/m2/d X3 leucovorin (L), concomitantly with 24h iv d1 600-1000mg/m2 cyclophosphamide (C), 48h iv d2 + d3 60mg/m2 doxorubicin (A). S-I and S-II were given 6 courses and 8 for S-III. Increasing A + C dose level and/or shortening treatment intervals < 3 weeks with growth factors provided intensification. 40 patients received tamoxifen. Results: At a median follow-up of 74 months (range 9-214), 73 (78%) are alive (1 with relapse). Relapse free survival was: S-I 95%, S-II 81%, S-III 78%. At average course intervals of 18 days, dose intensity A/C mg/m2/wk was 24.2 / 335.4 with evidence of WHO grade III/IV stomatitis in 43%, neutropenia 59%, cumulative thrombocytopenia 50%, hand-foot syndrome 32% of patients. Aside from delayed relapse associated with tamoxifen, relapse-free survival >82 months was similar with and without tamoxifen. No relapse was observed after >53 months in ER- tumors despite showing higher frequency of adverse tumor risk factors. Conclusion: The impact of adding tamoxifen appears quite limited in a patient population with adverse tumor presentation treated with dose-intensive L-FAC.
5-year survival with dose intensive L-FAC multimodality therapy of breast cancer, K. Jabboury, A. Wong, A. Deutsch; Jabboury Foundation for Cancer Research, Houston, TX; R. Behar; Spring Branch Medical Center, Houston, TX; K. King; Sugar Land Cancer Center, Sugar Land, TX; S. Thomas, C. Reilly, P. Curtis, O. Mangini; West Houston Medical Center, Houston, TX. 2004 ASCO Annual Meeting Proceedings. Vol 22, No 14S , 2004: 739
Background: In order to enhance the activity of front-line anthracycline-based FAC (fluorouracil, doxorubicin, cyclophosphamide) chemotherapy; incremental dose intensification of A+C was implemented. F was delivered by continuous infusion (inf) along with leucovorin (L) modulation. Administration format was switched to concomitant alkylator/antimetabolite inf. Methods: From 6/1989 to 1/2003, consecutive breast cancer patients (pt), candidates for systemic chemotherapy, were treated in a pilot study with dose intensive L-FAC at a starting dose level: 72 hour (h) IV inf 400mg/m_/day (d) F modulated by IV bolus 200mg/m_/d X3 L, concomitantly with 24h IV d1 600-1000mg/m_ C, 48h IV d2 + d3 60mg/m_ A. 6 courses were given for stage (S) I and II and 8 for III. Increasing A+C dose level and/or shortening treatment intervals < 3 weeks with growth factors, provided intensification. Prior analysis (ASCO, 1996) revealed an achieved dose intensity 22.3/A, 307/C mg/m_/week. Hormone receptor positive patients received Tamoxifen (T) 20mg/d X5 years (Y) after completion of chemotherapy. 109 pt, ages 25-81 (median 51), were enrolled: 20 SI, 35 SIIA, 19 SIIB, 8 SIIIA, 16 SIIIB, and 11 SIV. 50 (46%) were hormone receptor negative. Results: 29 (30%) non-metastatic pt underwent upfront mastectomy at pt/surgeon discretion. Breast conservation was addressed and successful in all upfront lumpectomy (45) pt., and neoadjuvant L-FAC in 6/6 SII and 15/18 SIII. 72 pt received radiation (64 after breast conservation, 8 to chest wall). Two intramammary failures were seen (3%). The median follow up is 56 months (M). The estimated 5Y disease free survival: 81% SI, 76% SII, 78% SIII. 4/11 SIV were treated, as IV NED and 3 remain relapse free at 3, 8, and 9Y. 5Y survival is 89%SI, 89%SII, and 83% SIII. By 1998, 3 pt developed AML/MDS (at 15, 26, and 36M from initiation of L-FAC) and accordingly, subsequent treatment was given in a dose dense manner only, without additional cases observed. 11/98 (11%) had a 2nd breast cancer develop; 2 while on T. Conclusions: L-FAC is highly effective in the treatment of breast cancer and allows a high rate of breast conservation. The addition of taxane therapy is currently being evaluated.
Jabboury K, Wong A, Deutsch A, Garcia O, Habboubi N. Phase I Trimetrexate (TMTX) Modulation of Weekly 24-Hour Infusional Fluorouracil (FU) / Leucovorin (LV); an Active Minimally Myelosuppressive Regimen. Proc Annu Meet Am Soc Clin Oncol; 21:A, 2002.
Jabboury K, Wong A, Deutsch A, Garcia O, Habboubi N. Different toxicity outcome that is dose-schedule-dependent in sequential trimetrexate modulation of weekly fluorouracil/leucovorin. Proc Annu Meet Am Assoc Cancer Res; 43:A2755, 2002.
Sequential trimetrexate (TMTX) modulation of IV bolus (IVB) fluorouracil/leucovorin (FU/LV) has shown a significant anti-tumor effect. Conti et al. (94) demonstrated that the maximally tolerated dose (MTD) for weekly TMTX followed 24 hour (H) later by FU/LV/IVB X 6 q 8 weeks (WK) was 110/500/500mg/m2. Grade (G) 3/4 diarrhea was the principal toxicity in 17% of patients (PT). In a phase I study, we evaluated courses(C) of sequential TMTX modulation of weekly 24H infusional FU with LV X 3 q 4 WK. Intra patient dose escalation was permitted. A total of 32 patients with epithelial malignancies were treated; 19 males, median (M) age 66, M ECOG performance 1, 18 with prior radiation, 18 with prior chemotherapy. LV dose was fixed at 500mg/m2. FU dose was not escalated beyond 2300mg/m2. The MTD of TMTX was reached at 600mg/m2 when FU and LV were delivered by concomitant 24H infusion. The limiting toxicities were G 3/4 vomiting, diarrhea, and nephrotoxicity. To simplify administration schedule, LV was administered by IVB at the recommended level of TMTX/FU/LV of 550/2300/500mg/m2 with a differing toxicity profile. LV by IVB schedule appears less toxic, and may allow TMTX dose escalation > 600mg/m2/WK X 3 Q 4 WK. Moreover, 24H infusional FU permits 5-fold escalation of TMTX compared to FU IVB.
Jabboury KW, Behar RA, Wong A, King KW, McKowen RL, Paxton TP, Mangini O, Deutsch AS. Concomitant ICE-FL radiochemotherapy showing favorable outcome in stage III non-small cell lung cancer. Proc Annu Meet Am Assoc Cancer Res; 41:A4407, 2000.
We have previously reported that frontline infusional ICE-FL showed a significant activity in lung cancer. Tumor regression > 50% was observed in 92% of small cell (SC) and 84% of non-small cell (NSC) histology. Moreover, the feasibility of concomitant thoracic irradiation was demonstrated (AACR 1997 #2202). In this pilot study, 57 patients (PTS) (32 males) were treated including 42 NSC:stage (STG) I&II 3, STG III 19, STG IV 20, and 15 SC:limited 7, extensive 8. Concomitant thoracic irradiation (median 6300cGy, range 4500-6720) was given to STG III NSC and limited SC PTS simultaneously with courses 3 & 4 of a total of 6. ICE-FL is administered as a 7-day(d) I.V. continuous infusion of cisplatin (total [T] 100mg/m2),with I.V. hydration, ifosfamide/mesna daily 1 hour(h) IV infusion (IVI) x 7 (T 5g/ m2), etoposide daily 1h IVI x 7d (T 250mg/m2), 5-FU 240mg/m2/24h x 7d and leucovorin 200mg/m2 daily short IVI x 7d with G-CSF 5-10 mcg/ kg/d/sc as of d9. At a median follow-up(F/U) of 14 months(m) (1-72), 47 PTS died, however, 38% of deaths were not lung cancer related. There were no treatment related deaths. The median survival for STG IV NSC was 14m (a 53% 1-year survival), and for limited SC 21m (72% 1-year survival). Additionally, the data on 19 STG III NSC PTS, at a median F/U of 29m, revealed that 64% of PTS did not relapse, however, 9/12 (75%) of deaths were from causes unrelated to lung cancer. In this series, though STG III NSC PTS have a significant potential of surviving lung cancer with ICE-FL radiochemotherapy, there is a higher risk of dying from comorbidity.
Jabboury K, Wong A, Deutsch A, Garcia O, Cleary J, Oster W. Trimetrexate Modulation of Weekly 24-Hour Infusional Fluorouracil/Leucovorin: A Phase I/II Study in Advanced Malignancies. Proc Annu Meet Am Soc Clin Oncol; 19:A870, 2000.
Trimetrexate (TMTX) modulation of IV bolus fluorouracil/leucovorin (FU/LV) demonstrated significant activity in gastrointestinal cancer with prior fluoropyrimidine exposure. TMTX maximally tolerated dose (MTD) was 110mg/m2 (Conti et al. 94). TMTX has moderate diverse anti-tumor activity, however, the optimal dose schedule remains unclear. We evaluated sequential TMTX modulation of weekly 24-hour(h) infusional FU/LV in a phase I/II intra-patient dose escalation study. Each course (C) consisted of weekly 1h IV infusion of TMTX d1, followed by 24h simultaneous FU/LV IV infusion d2 without oral LV rescue X 3 weeks every 4 weeks. So far, a total of 18 patients (PT) are registered with advanced malignancies [9 colon, 2 non-small cell lung, 1 small cell lung, 1 breast, 2 prostate, 1 hepatocellular, 1 unknown primary, 1 pancreas]. Median (M) age was 63 (45-73), 10 males, M ECOG performance status 1 (0-2). 11 patients had prior radiation and 12 prior FU chemotherapy regimens. A total of 77 courses [M3 (1-14)] were given. LV dose is fixed at 500mg/m2. 8 dose levels (DL) have been evaluated: TMTX/FU/m2/DL was 80/1800/DL1, 110/1800/DL2, 110/2300/DL3, 130/2300/DL4, 175/2300/DL5, 200/2300/DL6, 250/2300/DL7, and 300/2300/DL8. NCI toxicity [> grade(G) 2] were only seen in 3/9 PT (4/18C) at DL7 and were not treatment limiting. Other toxicities G1&2/C included: anemia/10, leukopenia/11, thrombocytopenia/28, mucositis/18, diarrhea/3, nausea/13, vomiting/2, hand-foot syndrome/2, skin rash/1, fever/2 and headache/4. Responses were seen at all dose levels in 6/16 evaluable patients with colon 3 PR, 3 SD, hepatocellular 1 PR, and non-small cell lung cancer 2 PR. So far, the MTD has not been reached, however, the infusional schedule of FU/LV allowed doubling the MTD dose of TMTX when given with IV bolus FU/LV. This dose schedule of TMTX/FU/LV is well tolerated, appears active and can lend itself to combination with other agents in view of its limited toxicity profile.
Wong A, Jabboury K, Edwards M, McKowen R, Behar R, King K, Ghafir S, Mangini O, Hendricks S, Pardo D. Paucity of Relapse Following ICE-FL with Concomitant Thoracic Irradiation in Stage III Non-Small Cell Lung Cancer. Proc Annu Meet Am Soc Clin Oncol; 18:A2034, 1999.
We conducted a pilot study for front-line therapy in lung cancer with ICE-FL: A 7-day(d) I.V. Continuous infusion of cisplatin [total (T) 100mg/m2] with I.V. Hydration, ifosfamide/mesna daily 1 hour(h) infusion * 7(T 5g/m2), etoposide daily 1h infusion x 7 (T 250mg/m2), 5FU 240mg/m2/d I.V. Continuous infusion x 7 and leucovorin 200mg/m2/d short I.V. Infusion x 7, with filgrastim support 5-10mcg/kg/d/sc starting on d 9. We have reported earlier (AACR 1997 #2202) the activity of the program demonstrating >=50% initial tumor regression in 92% of small cell(SC) and 84% of non-small cell(NSC) lung cancer patients(Pt). As of 11/98, a total of 56 consecutive lung cancer Pt were analyzed: Median(M) age 60(35--82), 25 females. The study included 15 SC (8 limited and 7 extensive stage) and 41 NSC (1 IB, 1 II, 5 IIIA, 12 IIIB, 22 IV). A total of 6 ICE-FL courses/Pt were planned. Concomitant thoracic irradiation was delivered (28 Pt) along with courses 3 + 4 of ICE-FL in limited stage SC and stages II, III, and selected stage IV Pt, in daily fractions for a M of 6300cGy(4500--6720). At a M follow-up of 23 months(mo) for stage III, only 5/17 relapsed, however, additional 5/17 died because of comorbidity without relapse. The overall survival for stage III was 53%(IIIA 80%, IIIB 42%). The M time to relapse was 7 mo(6--10). The survival pattern compares favorably with other front-line programs in stage III NSC.<.P>
Jabboury K, Wong A, Curtis P, Thomas S, Reilly C, Behar R, King K, Mangini O, Hendricks S, Pardo D. Freedom from Relapse with Dose Intensive L-FAC in Breast Cancer. Proc Annu Meet Am Soc Clin Oncol; 18:A362, 1999.
Dose intensive L-FAC: Fluorouracil infusion 400--450mg/m2/24h, day (d) 1--3 modulated by I.V. Bolus leucovorin 200mg/m2/d, d 1--3, cyclophosphamide 600--1000mg/m2/24h d 1, and doxorubicin 60mg/m2/48h d 2 + 3 followed by filgrastim support, has shown a 36% complete pathological response and 28% minimal microscopic residue in neoadjuvant therapy (ASCO 1997 #611). By 11/98, 61 patients(Pt) median(M) age 49(29--80) completed L-FAC for a total of 389 courses. 18 Pt were subsequently started on tamoxifen 20mg/d x 5 years. 31 of 53 underwent breast preservation surgery followed by radiotherapy including tumor bed boost to at least 6100cGy given at the conclusion of L-FAC. To date, at a M follow-up (F/U) of 41 months(mo) (minimum F/U of 12 mo), only 5 of 53 non-metastatic Pt relapsed at a M of 21 mo(15--34) with the following break down: [EMBEDDED TABLE] In this concomitant infusional alkylator/antimetabolite, time-compressed schedule(M course interval 20d, minimal 11d), the dose intensity of doxorubicin was 23mg/m2/week. Total doxorubicin dose delivered was 360mg/m2 for stage I + II and 500mg/m2 for stage III without evidence of clinical cardiomyopathy. Cyclosphosphamide delivered dose intensity was 330mg/m2/wk for a total of 5300mg/m2. 2 Pt developed acute myeloid leukemia and one myelodysplasia. Survival outcome of dose intensive L-FAC compares favorably with other breast cancer front line programs.
Jabboury K, Wong A, Curtis P, Thomas S, Behar R, Mangini O, Roy M, Rogers L, Hendricks S, Pardo D. Paucity of early relapses; an additional indicator of the high activity of front-line dose intensive L-FAC in breast cancer. Proc Annu Meet Am Soc Clin Oncol; 17:A567, 1998.
We reported earlier (ASCO 1997 #611) the association, in stage III breast cancer(bc), of high incidence of pathological complete remission with early survival benefit following dose intensive L-FAC: Fluorouracil infusion 400--450mg/m2/24h day(d) 1--3 modulated by i.v. bolus leucovorin 200mg/m2/d d 1--3, cyclophosphamide 600--1000mg/m2/24h d 1, and doxorubicin 60mg/m2/48h d 2+3, followed by filgrastim support. Program details, including alkylator dose intensity, were described earlier (ASCO 1996 #261). By 10/97, 59 patients(Pt) completed L-FAC. Median(M) age was 49, (29--75). Breast conservation was achieved in 13/15 neoadjuvant L-FAC Pts, in addition to 19 with up-front breast conservation surgery. Radiotherapy, including tumor bed boost, to at least 6100cGy, was delivered at the conclusion of L-FAC. Tamoxifin maintenance 20mg/d x 5 years post L-FAC was given to 18 Pts. To date, with a 32 month M follow-up(F/U), 5/56 Pt relapsed (3 stage IV Pt not included) with a relapse free survival(RFS) of 91%, showing the following break down: [EMBEDDED TABLE] Two Pts developed a contralateral breast cancer, 1 Pt acute myeloid leukemia, and another myelodysplasia. Early treatment outcome data of dose intensive L-FAC compares favorably with other frontline programs in non-metastatic bc.
Jabboury K, Roy M, Rogers L, Jones L, Mangini O. Survival benefit: early evidence with frontline dose intensive L-FAC in breast cancer. Proc Annu Meet Am Soc Clin Oncol; 16:A611, 1997.
We report interim follow-up on frontline L-FAC; fluorouracil (F) infusion 400-450 mg/m2/24 h day (d) 1-3 modulated by IV bolus leucovorin (L) 200 mg/m2/d d 1-3, cyclophosphamide (C) 600-1000 mg/m2/24 h d l, and doxorubicin (A) 60 mg/m2/48 h d 2+3. Details of the program were described earlier (Proc ASCO; 15:A261, 1996). By July 1996 a total of 45 patients (Pt) were registered; Median (M) age 51, and M Zubrod performance status 0 (0-2). Neoadjuvant L-FAC was given to 15 Pt; 2 with stage (S) II , 8 with S III, and 5 with S IV. An average of 5 (2-8) preoperative courses was given achieving a dose intensity (mg/m2/wk) of 24.2 for A and 357 for C. Surgical staging in 14 Pt showed no residual disease (CRp) in 5 (36%), minimal microscopic residue (micro) in 4 (28%) and partial response in 5 (36%). At present the M follow-up for S III (5 adjuvant, 8 neoadjuvant, 6 S IIIA, 7 S IIIb) reached 24 months from surgery and all remain disease free. Despite the limited number of treated Pt, the high incidence of major histopathological responses and early disease-free survival pattern compares favorably with historical FAC: CRp 7%, micro 10% (Cancer Res; 46:2578, 1986) and approx 65% disease-free at 24 months (Cancer; 62:2507, 1988). Modification of frontline doxorubicin combination chemotherapy to L-FAC shows a promising therapeutic outcome.
Jabboury K, Rogers L, Loh A, Mangini O. Dose-intensive L-FAC: an observed increased frequency of complete pathological remission (Crp) in breast cancer. Proc Annu Meet Am Soc Clin Oncol; 15:A261, 1996.
We incorporated infusional fluorouracil (F), modulated by leucovorin (L), into dose-intensive doxorubicin (A) and cyclophosphamide (C) combination, limited by mucosal toxicity grade greater than 2 and delayed granulocyte/platelet recovery. From 6/89 - 5/95, a total of 34 patients (pts), with median (M) age of 49 (29-80), and M Zubrod performance status of 0 (0-2) were treated. A total of 215 courses of L-FAC were administered at a starting dose of C 600-1000 mg/m2/24 hr d1, A 60 mg/m2/48 hr d2+d3, F 400-450 mg/m2/24 hr d1-d3, with L 200 mg/m2/d iv short infusion d1-d3. Dose escalation of A and C and treatment interval reduction less than 21d were attempted. Filgrastim support was used in 66% of courses. 6 adjuvant courses were given for stage I (high risk) and II, while treatment was extended to a cumulative A approx 500 mg/m2 for stages greater than or equal to III. Tamoxifen 20 mg/d was initiated after chemotherapy for estrogen receptor positive tumors. The overall A and C dose intensity (DI) were 22.3 and 307 mg/m2/wk, respectively. Pre-operative L-FAC (average of 5 courses) was administered to 10 pts with locally advanced/regionally metastatic disease with average DI A: 27.9 and C: 348. Surgical staging revealed no viable tumor in 5 pts, or a 63% CRp, microscopic residue in 2, and partial response in 3, without relapse, including additional 4 pts with greater than or equal to 10 positive axillary lymph nodes at a M of 20 months (range 5-71). Toxicity profile/course included WHO grades: greater than or equal to 3 oral mucositis in 17%, 4 thrombocytopenia in 22%, 4 neutropenia in 48%. Mucosal toxicity resulted in treatment interval delay greater than or equal to 24d in 21/27 courses. This repeated observation of CRp warrants further evaluation of this regimen.
Jabboury K, Rogers L, Loh A, Mangini O. Complete pathological remission (Crp) in breast cancer: an early frequent finding with dose-intensive L-FAC, leucovorin (L)/fluorouracil (F), doxorubicin (A), and cyclophosphamide (C). Proc Annu Meet Am Soc Clin Oncol; 14:A222, 1995.
To improve the therapeutic outcome of A-based front-line combination chemotherapy, we incorporated high dose L modulation of infusional F into dose-intensive A and C combination, limited by mucosal toxicity grade greater than 2 and delayed granulocyte/platelet recovery. The resultant dose-intensity (DI) was described earlier (ASCO 13:A95, 1994). A total of 27 patients (pts), Median (M) age of 54 (29-80) and M Zubrod performance status of 1 (0-2), were treated from 6/89 to 10/94. 163 courses of L-FAC were delivered at a starting dose of C 600-1000 mg/m2/24 hr d1, A 60 mg/m2/48 hr d2+3, F 400-450 mg/m2/24 hr d1-3 with L 200 mg iv bolus/d d1-3. Treatment interval reduction was less than 21 d and dose escalation of A and C were attempted. 64% of courses were supported by filgrastim. The overall average A and C DI were 21.9 and 306 mg/m2/wk, respectively. Pre-operative L-FAC (average of 5 courses) was administered to 8 pts with locally advanced/regionally metastatic disease with DI (mg/m2/wk) average of A: 24.4 and C: 339. Surgical staging revealed no viable tumor in 5/8 pts (63% CRp, 95% confidence interval of 31-86%), microscopic residue in 2/8, and partial response in 1/8 without relapse noted, including additional 4 pts with greater than or equal to 10 positive axillary lymph nodes at a M of 20 mo. Toxicity profile/courses included WHO grades: greater than or equal to 3 oral mucositis in 17%, 4 thrombocytopenia in 9%, 4 neutropenia in 41%. Mucosal toxicity resulted in treatment interval delay greater than or equal to 24 d in 20/26 courses. Despite the early nature of the data, the repeated observation of CRp in pts treated with dose-intensive L-FAC appears to be suggestive of significant therapeutic efficacy.
Jabboury K, Rogers L, Ghaffir S, Mangini O. ICE-FL: a 7-day infusional regimen in lung cancer with early activity and feasibility of concomitant radiotherapy.Proc Annu Meet Am Assoc Cancer Res; 36:A1435, 1995.
As of April 1991, we initiated a pilot study of a 7-day (d) iv infusion of continuous infusion cisplatin (Total [T] 100 mg/m2) with concomitant iv hydration (greater than or equal to 2 L/d), ifosfamide/mesna daily 1 hr infusion x 7 (T 5 g/m2), etoposide daily 1 hr infusion x 7 (T 250 mg/m2), 5FU 240 mg/m2/24 hr x 7, and leucovorin 200 mg/m2 daily short infusion x 7. Filgrastim support (5-10 ug/kg/d/sc) was started on day 9. Early data were reported (ASCO Proceedings 12:354, 1993). 23 patients (pts) with a median (M) age of 60 years, M Zubrod performance status 1 (1-4), received 113 courses (C; M of 6C/pt) at a M interval of 27 d. This group included 9 pts with small-cell (SC; 4 limited and 5 extensive disease) and 14 pts non-SC (10 pts stage IV) histology. After chemotherapy induction 22 C were given concomitantly with 11 radiotherapy fields (M4600 cGy [2800-5600]). 17/19 pts responded (CR + PR) to chemotherapy (4 pts had no evaluable disease). M survival of all pts and for stage IV non-SC histology was 290 days. The following WHO grade III/IV toxicities/C were observed: neutropenia 29%, thrombocytopenia 52%, anemia 30%, vomiting 21%, diarrhea 4%. Hypomagnesemia less than 1.5 mg/dL occurred in 46% of C. In pts receiving greater than or equal to 6 C neuropathy was noted. Treatment interval greater than 21 d was due to delayed platelet recovery in 45 C. 62% of C were delivered as outpatient. Only 1/7 pts receiving mediastinal radiochemotherapy sustained temporary grade III esophagitis. The activity demonstrated in this limited analysis warrants further evaluation in earlier disease presentation.
Baker FL, Sanger LJ, Rodgers RW, Jabboury K, Mangini OR. Cell proliferation kinetics of normal and tumour tissue in vitro: quiescent reproductive cells and the cycling reproductive fraction. Cell Prolif; 28(1):1-15, 1995.
Current methods for measuring the cell kinetics of human tumours are made and interpreted within the context of a simplistic two compartment model for cell proliferation, consisting of cells that are cycling and those that are not. It is now recognized that the non-cycling compartment of many tumours is heterogeneous, composed of non-reproductive end-stage cells and reproductive cells that are dormant/quiescent. We have developed an in vitro analysis that distinguishes for the first time quiescent reproductive cells from non-reproductive end-stage cells and have integrated this analysis with monolayer clonogenic and suicide assays to simultaneously quantitate the duration of the cell cycle and reproductive cells that are: cycling, quiescent, clonogenic, and non-reproductive end-stage cells. We have defined a new parameter, the Cycling Reproductive Fraction (CRF), which is the cycling cell population referenced specifically to the reproductive cell population. Measurements of CRF from 72 tumour biopsies and from 5 normal foreskins showed that CRF approached 100% in some tumours; however, CRF showed near normal values (< 1%) in others suggesting that cell cycle control may be maintained in some tumours. Because of CRF's improved specificity, we believe that CRF may enhance classification, prognostication, and the optimization and prediction of response to chemotherapy.
Jabboury K, Rogers L, Ghaffir S, Mangini O. ICE-FL: a promising 7-day infusional regimen of ifosfamide (I)/mesna, cisplatin (C), etoposide (E), and 5-fluorouracil (F)/leucovorin (L), in lung cancer. Proc Annu Meet Am Soc Clin Oncol; 12:A1193, 1993.
Optimization of therapeutic outcome may rely on the delivery schedule of several chemotherapeutic agents, including ICE-FL. Therefore, schedule design can target the potential advantage in favorable pharmacokinetics to result in improved activity or toxicity profile. Moreover, a prolonged radiosensitizer exposure may favorably affect concomitant radiation. We began a pilot study of a 7-day (d) iv infusion of continuous infusion C (total [T] 100 mg/m2) with concomitant iv hydration (greater than or equal to 2 liters/d), I/mesna daily, 1-hr infusion (T 5 g/m2), E daily 1-hr infusion (T 250 mg/m2), F 240 mg/m2/24 hr x 7, and L 200 mg/m2/d short infusion x 7. Filgrastim support (5-10 ug/kg/d/sc) was started on d 9, until adequate neutrophil recovery. Ondansetron antiemetic coverage was used for all patients (pts). 9 concomitant radiotherapy courses were delivered. 11 pts were treated, 7 with non-small cell (NSC) histology and 4 with small cell (SC) histology. Median (M) age was 60 yr (range, 35-67). M Zubrod performance status was 1 (1-4). M 4 (1-10) courses were given at M interval of 29 d (18-43). M number of metastatic sites was 1 (1-4). 7/9 pts with measurable disease responded (1 CR, 6 PR; 3 SC, 4 NSC), 2 SD, and 2 NSC pts with nonmeasurable disease had greater than 70% reduction in tumor markers, for M response duration of 6 mo. M survival was 9 mo. Of 48 courses analyzed, the following WHO grade III/IV toxicities were observed: neutropenia 38%, thrombocytopenia 21%, anemia 15%, vomiting 31% and diarrhea 4%. Only grade II oral mucositis (15%) and nephrotoxicity (19%) were noted. Hypomagnesemia was seen in 67% of courses. Microhematuria was detected in 1 course. Neuropathy was observed in 9 pts and in 4 was treatment limiting. Delayed platelet recovery was also treatment limiting. 48% of courses were delivered as outpatient. This program appears to be associated with promising activity and acceptable toxicity level. Further evaluation is underway.