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A phase II study of induction chemotherapy with gemcitabine (G) and cisplatin (P) in locally advanced non-small cell lung cancer: interim analysis

Gemcitabine-cisplatin (GP) combination is one of the most active and well tolerated regimens in advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the activity and toxicity of the GP regimen as a 21-day schedule in
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  Lung Cancer 34 (2001) S15–S20 A phase II study of induction chemotherapy with gemcitabine (G)and cisplatin (P) in locally advanced non-small cell lung cancer:interim analysis Antonio Santo  a, *, R. Pedersini  a , F. Pasini  a , A. Terzi  b , F. Pari  c , G. Cartei  d ,A. Sibau  e , A. Molino  a , A. Maiorino  f  , N. Panza  g , M.V. Oletti  h , S. Maluta  i ,F. Calabro`  b , G.L. Cetto  a a Department of Medical Oncology ,  Uni   ersity of Verona ,  Verona ,  Italy b Di   ision of Thoracic Surgery ,  OCM  ,  Azienda Ospedaliera ,  Verona ,  Italy c Di   ision of Medical Oncology ,  OC Carlo Poma ,  Mantua ,  Italy d Di   ision of Medical Oncology B  ,  CRO - IRCCS  ,  A  iano ,  Italy e Di   ision of Medical Oncology ,  Azienda Ospedaliera ,  Udine ,  Italy f  II Di   ision of Thoracic Surgery ,  OC Monaldi  ,  Naples ,  Italy g Di   ision of Medical Oncology ,  OC Cardarelli  ,  Naples ,  Italy h Di   ision of Medical Oncology ,  OC S  .  Gio  anni  ,  Turin ,  Italy i Di   ision of Radiotherapy ,  OCM  ,  Azienda Ospedaliera ,  Verona ,  Italy Abstract Background  :   Gemcitabine–cisplatin (GP) combination is one of the most active and well tolerated regimens in advancednon-small cell lung cancer (NSCLC). The aim of this study is to evaluate the activity and toxicity of the GP regimen as a 21-dayschedule in patients (pts) with stage IIIAN2–IIIB NSCLC.  Patients and methods :   From October 1997 to July 2000, 47 pts enteredthe study: 43 were eligible (40 men and three women); median age was 61 years (range 45–73); ECOG PS 0–1; histology wassquamous (20 pts), adenocarcinoma (12 pts), large cell (five pts), and undifferentiated (six pts); stage was IIIAN2 (14 pts, 32.56%),and IIIB (29 pts, 67.44%). Malignant pleural effusion or superior vena cava syndrome was criteria of exclusion. Inductiontreatment consisted of three cycles of GP (G 1250 mg / m 2 i.v. on days 1 and 8, and P 100 mg / m 2 on day 8 every 3 weeks).Responding and stable pts underwent surgery (S) and / or radiotherapy (RT).  Results :   Following a minimum of two cycles, 39 ptswere evaluable for response and 42 for toxicity. Two pts had complete responses (CR; 5.2%), 24 had partial response (PR; 61.5%),eight had stable disease (SD; 20.5%), and five had progressive disease (PRO; 12.8%). WHO grades 3 and 4 anaemia, neutropeniaand thrombocytopenia were observed in two, four and two pts, respectively; non-haematological toxicity was moderate. Afterinduction, stable and responding pts received either RT (18 pts) or S + RT (13 pts). Among the 16 resected pts, a radical completeresection was possible in 13 cases (81.3%), whereas tumour down-staging was observed in nine pts (56.2%).  Conclusion :   GP, as a3-week neoadjuvant schedule, appears a safe and active regimen. © 2001 Published by Elsevier Science Ireland Ltd. Keywords :   Neoadjuvant chemotherapy; Non-small cell lung cancer; Gemcitabine–cisplatin combination; Phase II study; Multimodality / locate / lungcan 1. Introduction Non small-cell lung cancer (NSCLC) accounts for75% of primary lung cancers [1]. Surgery is the stan-dard treatment for early stage NSCLC, with a 5-yearsurvival rate for patients with pathological stage I(A / B) and II (A / B) of 50–55% and 25–35%, respec-tively [2].The best therapy of IIIAN2–IIIB stage disease is stillcontroversial and further studies are required. Resultsof local treatment alone (surgery and / or radiotherapy)are dismal, with a 5-year-survival rate of about 5–15%[2].Since many of these patients die of extrathoracicrelapses, it has been hypothesised the presence of micrometastases at the time of diagnosis; for this rea- * Corresponding author. Tel.:  + 39-45-8072342; fax:  + 39-45-8341277. E  - mail address : (A. Santo).0169-5002 / 01 / $ - see front matter © 2001 Published by Elsevier Science Ireland Ltd.PII: S0169-5002(01)00400-7  A .  Santo et al  .  /   Lung Cancer  34 (2001)   S  15–  S  20  S16 son, starting in the late 1980s, neoadjuvant chemother-apy has been associated with local treatment to im-prove resectability rate by down-staging the tumourand to prolong survival [3–5].Although definitive conclusions cannot yet be drawn,several phase II trials [6–8] and some published ran-domised studies [9–11] suggest that inductionchemotherapy may improve the long-term survival rate.Various combination regimens have been used,though none of them was clearly superior; in fact, theobjective RR were 50–70%, with a 4–13% of completepathological response, 45–65% of resectability, and amedian survival of 18–21 months [6–14].Recently, the introduction of new agents such asgemcitabine (G), vinorelbine, taxanes for the treatmentof NSCLC has generated great interest in the identifica-tion of more active and better tolerated combinations.In phase II studies, the gemcitabine–cisplatin combina-tion (GP) exhibited not only RR ranging from 48 to63% in stage IIIB–IV, but also a favourable safetyprofile [15–20]. On the basis of these encouraging re-sults, we deem that RR and safety can be improved if the GP combination will be used as inductionchemotherapy in patients with locally advanced, nonmetastatic disease and good performance status.The aim of this multicentric phase II trial was toevaluate the activity and toxicity of a 21-day scheduleof GP combination in locally advanced (stage IIIAN2–IIIB) NSCLC. 2. Patients and methods 2  . 1 .  Eligibility Eligibility criteria for study entry were: histologicallyor cytologically documented NSCLC; clinical stage II-IAN2 or IIIB (without malignant pleural effusion orvena cava syndrome); adequate baseline hepatic, renal,heart, and metabolic functions; pulmonary functiontests allowing surgical procedure; adequate bone mar-row reserve (WBC count   3.5 × 10 9 per l, plateletcount   100 × 10 9 per l, haemoglobin level   10 g / l,and haematocrit level   30%); age   70 years, esti-mated life expectancy   12 weeks; Eastern CooperativeOncology Group performance status of 0–1; no priorchemotherapy or radiotherapy, no second primary ma-lignancies except in situ carcinoma of the cervix oradequately controlled basal cell carcinoma of the skin;no carcinoma of the superior sulcus; female patientshad not to be pregnant or lactating; and informedconsent.Baseline evaluation included a complete medical his-tory and physical examination, complete blood cellcount, serum biochemistry, ECG, pulmonary functions.Staging procedures included chest X-ray, bron-choscopy, bone scan, CT scan of the chest, abdomenand brain.A mediastinoscopy or anterior mediastinotomy orvideo-assisted thoracoscopy, as well as a bronchoscopictranscarenal needle aspiration, was performed in allpatients in whom CT scan demonstrated enlarged me-diastinal nodes (greater than 1 cm) to confirm nodalmetastases, either N2 or N3. In patients with bulkydisease (mediastinal node greater than 2.5 cm) surgicalor bronchoscopic confirmation was not consideredmandatory. Supraclavicular adenopathy was evaluatedby needle citology or biopsy. 2  . 2  .  Treatment plan G 1250 mg / m 2 was administered as a 30-min i.v.infusion in 250-ml saline solution on days 1 and 8. P100 mg / m 2 was infused over 30 min in hypertonic salinesolution on day 8. Courses were repeated every 3weeks. Before G infusion, i.v. corticosteroids were ad-ministered to avoid a flu-like syndrome; P was adminis-tered after G, with adequate i.v. hydration (2500-mlsaline solution plus potassium chloride and magnesiumsulphate) and parenteral administration of 5-HT3 re-ceptor antagonist. 2  . 3  .  Dose modification The doses of G and / or P were adjusted to the out-comes of blood counts immediately before the infusion,according to the following guidelines: on day 8 of eachcycle patients received 75% of the dose if the WBCcount was  3.5  2.5 × 10 9 per l (and neutrophil count  1 × 10 9 per l) or the platelet count was  100  75 × 10 9 per l; treatment was delayed for 1 week if the WBCor platelet counts were   2.5 × 10 9 and 75 × 10 9 per l,respectively. Dose adjustments for subsequent cycleswere made for both G and P. On day 1 of each newcycle, if recovery was not complete, the treatment wasdelayed for 1 week and growth factors were adminis-tered. After 1 week, if the WBC count was   35  2.5 × 10 9 per l (and neutrophil count  1 × 10 9 per l) orthe platelet count   100  75 × 10 9 per l, patients re-ceived 75% of the dose; if WBC count was   2.5 × 10 9 per l or platelet count was   75 × 10 9 per l, thechemotherapy was stopped and the patient was evalu-ated for local treatment. 2  . 4  .  Study design Following surgical and medical staging, patients re-ceived two cycles of the GP combination; afterwards achest X-ray was obtained: in case of stable disease (SD)or response, a third cycle was given. In case of progres-sive disease (PRO), patients were removed from thestudy (Fig. 1).  A .  Santo et al  .  /   Lung Cancer  34 (2001)   S  15–  S  20   S17 After the third cycle, a full medical re-staging withCT scan was performed. Responsive and stable patientsunderwent surgery and radiotherapy (if resectable) orradiotherapy alone. In the case of PRO, patients wereremoved from the study. Surgery was associated withsystemic mediastinal node dissection and not only withmediastinal node sampling. Nodal stations wereclassified according to the ATS criteria (Mountain / Dresler: Eighth World Conference on Lung Cancer,10–15 August 1997, Dublin, Ireland). 2  . 5  .  Treatment e  aluation Tumor response evaluated after at least two cycles of the GP combination was classified according the WorldHealth Organisation (WHO) criteria.A complete response (CR) was defined as the com-plete disappearance of all abnormalities on the CTscan. A partial response (PR) was defined as a reduc-tion of more than 50% in the sum of the two perpendic-ular diameters of the primary tumour and hilar andmediastinal nodes (if enlarged). SD was defined as aless than 50% reduction or a less than 25% increase inthe sum of the two perpendicular diameters per site.PRO was defined as more than 25% increase in the sumof the two perpendicular diameters per site.Toxicity was evaluated after at least one cycle of theGP combination and graded according to the WHOcriteria. Table 1Patients’ characteristics%Number of patients47Enrolled patients43Eligible patients61Age (years) MedianRange 45–73Sex 9340M3 7F25PS (ECOG) 58.1401 18 41.86Histology Squamous cell 20 46.527.912Adenocarcinoma5 11.6Large cellUndifferentiated 6 13.92.31Stage IIIA T1N29T2N2 20.9T3N2 4 9.3Stage IIIB T4N0–1 6 13.923.3T4N2 10T1–4N3 13 30.3N2 bulky (CT 62.827scan) 3. Results 3  . 1 .  Patients ’   characteristics From October 1997 to July 2000, 47 patients withlocally advanced NSCLC from eight Italian institutionswere enrolled into the study. Four patients weredeemed ineligible: one patient had bone metastases andthe other three had a PS  1. Of the 43 eligible patients,four were excluded from our analysis because of nondisease-related death (two pts) and severe complications(two pts). On the whole, 39 patients were evaluable forresponse and 42 were assessable for toxicity. The char-acteristics of the 43 eligible patients are listed in Table1. Median age was 61 years (range 73–45); 40 weremen; ECOG performance status was 0 in 25 patients(58.14%) and 1 in 18 patients (41.86%); histology in-cluded 12 adenocarcinomas (27.9%), 20 squamous cellcarcinomas (46.5%), five large cell carcinomas (11.6%)and six undifferentiated carcinomas (13.9%); stage wasIIIAN2 in 14 patients (32.56%) and IIIB in 29 patients(67.44%).Mediastinoscopy was performed in 16 patients(37.2%), because the remaining patients had bulky N2– N3 disease. 3  . 2  .  Chemotherapy Overall, 119 cycles were delivered, 102 (85.7%) of which were administered at full doses. Full doses of chemotherapy were given to 30 of the 43 eligible pa-tients (70%). Fig. 1. Study design.  A .  Santo et al  .  /   Lung Cancer  34 (2001)   S  15–  S  20  S18Table 2Haematological and non-haematological toxicityGrade WHO32 4 Haematological  Granulocytopenia 6 (14.3)8 (19) 4 (9.5)4 (9.5) 2 (4.7)Anaemia 8 (19)3 (7.1)5 (12) 2 (4.7)Thrombocytopenia Non - haematological  10 (23.2)Emesis 3 (7.1) – 3 (7.1)5 (11.9) – Fever – Infection – – 4 (9.5)Dyspnea 1 (2.3) –  – 3 (7.1) – Oral mucositis2 (4.7)Cutaneous – 1 (2.3)2 (4.7)6 (14.3) – Alopecia – Paresthesias – 3 (7.1) – 5 (11.9) – Fatigue – Diarrhoea – –  – –  – Serum creatinineNumber (%) of patients evaluable after at least one cycle of GPcombination. After induction chemotherapy responding and stablepatients underwent surgery and / or radiotherapy. 3  . 3  .  Surgery Before induction chemotherapy, the disease was con-sidered to be technically resectable or marginally re-sectable for the T factor, but inoperable due to themediastinal node enlargement in 31 cases. Sixteen pa-tients underwent surgery: lobectomy was performed ineight patients, sleeve lobectomy in one, and pneumec-tomy in seven. Complete resection was possible in 13patients (81.3%). The remaining three patients had his-tological microscopic residual tumours.Six of the patients previously considered inoperable(19%) underwent complete resection due to chemother-apy cytoreduction. 3  . 4  .  Radiotherapy Thirteen of 31 patients who underwent radiotherapyto the chest received this treatment as adjuvant therapy.The median dose delivered was 54 Gy (range 40–69).Radiation dose was prescribed to the intersection pointof the beams with correction for air transmissionthrough the lung. All patients were treated by linearaccelerator and conventional radiotherapy, with a dailydose of 2 Gy 5 days per week. A large volume wasirradiated with 40–44 Gy and a smaller volume (boost)with a median dose of 14 Gy so that a total mediandose of 54 Gy was delivered. No significant complica-tions were observed. Among the 18 evaluable patients,we observed one CR and six PR (ORR 38.8%). Of theremaining 11 patients, eight had SD and three had localPRO. 4. Discussion The GP combination, with a 21-day or 28-day sched-ule, is among the most active and best toleratedchemotherapy regimens in stage IV and in poor prog-nosis stage IIIB NSCLC, as reported by many phase IIstudies showing RR exceeding 50% [16–18].Recently, in three randomised clinical trials, Sandleret al. [21], Cardenal et al. [22] and Crino` et al. [23]compared the GP combination with a standard treat-ment (P, P-epotoside and P-ifosphamide-mytomicin, re-spectively). In all of the three studies, RR wassignificantly higher in the GP arm, and in two of thesestudies [24], time to progression (TTP) was also im-proved significantly.The GP combination used as a 4-week schedule forthe treatment of metastatic disease often required omis-sion of the G dose on day 15 because of haematologicaltoxicity [18]. Other phase II studies in advanced diseaseHaematological and non-haematological toxicity arelisted in Table 2. During chemotherapy, leucopenia wasthe predominant toxicity: grade 3 and 4 neutropeniaand anaemia were observed in ten (23%) and six (14%)patients, respectively. Packed red cell trasfusions wererequired in four patients (9.5%). Grades 3 and 4 throm-bocytopenia was observed in five patients (11%). Neu-tropenic fever occurred in three patients (7.1%). Emesiswas mild, and only three patients experienced WHOgrade 3 vomit. One patient presented grade 3 dyspneaand another one grade 4 cutaneous toxicity (2.3%).Other toxicities were not recorded.One patient died of ictus cerebri after two courses of the GP combination; one died of myocardial infarctionbefore the third cycle of chemotherapy; one developedpericarditis after one cycle; one developed severe cuta-neous allergic reaction after the first G administration.Twenty-six out of the 39 patients who received atleast two cycles of the GP combination responded (twoCR, 24 PR), for an overall response rate (ORR) of 66.6%. Eight patients (20.5%) had stable disease andfive patients (12.8%) PRO (Table 3). Table 3Objective response (CT scan)Stage IIIB TotalResponse Stage IIIA N2 – CR 2 (8) 2 (5.1)13 (52)11 (78) 24 (61.5)PRSD 8 (20.6)2 (14) 6 (24)1 (7) 4 (16)PRO 5 (12.8)Number (%) of patients evaluable after at least two cycles of GPcombination.  A .  Santo et al  .  /   Lung Cancer  34 (2001)   S  15–  S  20   S19 showed that a 3-week schedule was associated withlower haematological toxicity without a reduction of the RR (  45%) [18,20,22].On the basis of these data, we are testing the activityof the GP regimen in an earlier phase of the disease. Infact, in the metastatic setting, an increased RR seldomtranslates into appreciable survival improvement [23].However, in marginally resectable disease, the reduc-tion of the size of the tumour and down-staging mightbe important to obtain complete resection and improve-ment in long-term survival [25].Moreover, we used a 21-day schedule as inductiontreatment postponing also P to day 8 for two reasons:first, the patient showed a better psychological compli-ance (the first dose of G is usually well tolerated andpatients are more inclined to accept the treatment withP); and secondly, the single dose of G seldom causedneutropenia or thrombocytopenia at day 8. Accord-ingly, most of our patients (85.7%) completed the entirecycle of chemotherapy.Many phase II studies of the GP combination asinduction chemotherapy in locally advanced NSCLC,using a 4-week schedule with G administered weekly(days 1, 8 and 15), showed a high rate of ORR (  60%)[25–29]. However, the pattern of toxicity varied accord-ing to the schedule used [30]. For instance, haematolog-ical toxicity (neutropenia and thrombocytopenia) wassuch that in the study reported by Van Zandwijk et al.[29], the third dose had to be withheld or reduced inmore than 50% of patients. On the other hand, a lowerrate of haematological toxicity was reported by Rubioet al. [31], Isla et al. [32] and Migliorino et al. [33] whoused a 3-week schedule with G given on days 1 and 8.In the present study, the GP combination showed agood activity and was well tolerated. The ORR was66.6% among the 39 evaluable patients (24 PR and twoCR). Sixteen of the responsive patients underwentsurgery: 13 patients had a histologically complete resec-tion (81%). Nine of these (56%) were downstaged.These results are comparable to those reported by VanZandwijk et al. [29] who obtained a complete resectionrate of 71% and negative mediastinal nodes in 53% of the 17 operated patients.The data about toxicity are even more interesting.Grades 3 and 4 anaemia, neutropenia and thrombocy-topenia were observed in 14, 23 and 11% of the pa-tients, respectively, consistently with similar studiesusing a 21-day schedule [31–33].Non-haematological toxicity was moderate: grade 3vomiting and dyspnea were observed in 7 and 2% of cases, respectively; one patient presented exfoliativedermathitis after the first dose of G, requiring with-drawal from the study.This schedule allowed a good quality of life duringchemotherapy, without causing any delay of the localtreatment (surgery or radiotherapy) or unexpected in-crease in morbidity.In conclusion, the GP combination with P on day 8is an active induction regimen in locally advancedNSCLC (unresectable or marginally resectable), withan ORR of 66%.The 3-week schedule showed a lower haematologicaltoxicity profile compared to the 4-week schedule, andwas well tolerated on an outpatient basis. The combina-tion of the GP regimen with surgery and radiotherapywas not associated with unexpected toxicity. Due to theshort follow-up no conclusions can be drawn on TTPand overall survival. References [1] Shepherd FA. Future direction in the treatment of non-small-celllung cancer, department of Medicine, Toronto Hospital Ontario,Canada. Semin Oncol 1994;21(Suppl. 4):48–62.[2] Mountain CF. Lung cancer staging: 1997 revisions. In: AntypasG, editor. Second International Congress on Lung Cancer,Crete, Greece, 1996. Bologna: Monduzzi Editore, 1996: 11–13.[3] Tonato M. The role of Neoadjuvant chemotherapy in NSCLC.Chest 1996;109:93–5.[4] Dillman RO. Improved survival in stage III non-small-cell lungcancer: seven years follow up of cancer and leukemia group B(CALGB) 8433 Trial. J Natl Cancer Inst 1996;88:1210.[5] le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy aloneversus combined chemotherapy and radiotherapy in unresectablenon-small cell lung carcinoma. Lung Cancer 1994;10(10):239–44.[6] Martini N, Flehinger BJ. The role of surgery in N2 lung cancer.Surg Clin North Am 1987;67:1037–49.[7] Sugarbaker DJ. Advances in the treatment of NSCLC. In:ASCO Educational Book, vol. 13, 1994:183–95.[8] Pujol JL, Michel FB. Neoadjuvant chemotherapy of non smallcell bronchial cancers. Presse Med 1991;20:418–22.[9] Pass HI, Progrebniak HW, Steinberg SM, et al. Randomizedtrial of neoadjuvant therapy for lung cancer: interim analysis.Ann Thorac Surg 1992;53(6):992–8.[10] Roth JA, Fossella F, Komaki R. A randomized trial comparingperioperative chemotherapy and surgery with surgery alone inresectable stage IIIA non-small cell lung cancer. J Natl CancerInst 1994;86:673.[11] Rossel F, Gomez-Codina J, Camps C, et al. A randomized trialcomparing preoperative chemotherapy plus surgery with surgeryalone in patients with non-small cell lung cancer. New Engl JMed 1994;330:153–8.[12] Martini N, Kris MG, Flehinger BJ, et al. Preoperativechemotherapy for stage IIIA (N2) lung cancer: the Sloan Ketter-ing experience with 136 patients. Ann Thorac Surg1993;55:1365–74.[13] Elias AD, Skarin AT, Gonin R. Neoadiuvant treatment of stageIIIA non small cell lung cancer: long term results. Am J ClinOncol 1994;17:26–36.[14] Burkes RL, Shepherd FA, Ginsberg R. Induction chemotherapywith MVP on patients with stage IIIA (T1-3, N2, M0) unre-sectable non small cell lung cancer (NSCLC): the Torontoexperience. Proc ASCO 1994;13:327 Abstr.[15] Cardenal F, Rosel R, et al. Gemcitabine + cisplatin versusetoposide + cisplatin in advanced non small cell lung cancerpatients: preliminary randomized phase III results. Proc ASCO1997;16:458 abstr.[16] Abratt RA, Bezwoda WR, Goedhals L, et al. Weekly Gem-citabine with monthly Cisplatin: effective chemotherapy for ad-vanced non-small-cell lung cancer. J Clin Oncol 1997;5:744–9.
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