Journal of Surgical Oncology 45:124-130 (1990)
Cyclophosphamide and lfosfamide Combination as Neoadjuvant Chemotherapy for Locally Advanced Nonsmall-Cell lung Cancer: A Meta-Analytic Review RAFAEL ROSELL, MD, PhD, ISABEL MORENO, MD, JOSf MAESTRE, MD, ANGEL OLAZABAL, MD, J O A N CARLES, MD, AUGUSTIN BARNADAS, MD, ALBERT ABAD-ESTEVE, MD, NURIA RIBELLES, MD, AND MERCEDES CANELA, MD From the Departments of Oncology (R.R., I.M., /.C., A.B., A.A.-E., N.R.), Thoracic Surgery (/,M,,M.C.), and Radiology (A.O.), Hospital de Badalona Germans Trias i Pujol, Universitat Autonoma de Barcelona, Barcelona, Spain
Twenty-three patients with marginally resectable and unresectable nonsmall-cell lung cancer (stages IIIA and IIIB) were treated by neoadjuvant chemotherapy. All patients received three cycles of preoperative chemotherapy with two alkylating agents, cyclophosphamide 2.5 g/m2 intravenously (i.v.) and ifosfamide 3.5 g/m2 i.v., mesna 12 g/m2 was given additionally to prevent drug hematuria. Six of 23 patients (26%) had partial response. Of the seven patients who underwent thoracotomy, two were completely resected, but with macroscopic residual disease. Mean time to progression for the whole group was 7 months. Fifteen patients had progression of disease, with local metastases only in six, and distant metastases in eight. After administering 52 chemotherapy cycles, cyclophosphamide-ifosfamide doses were cut down, as eight of 16 patients required hospitalization for fever during neutropenia nadirs. This twoalkylating (non-cisplatin) regimen, unlike cisplatin-based regimens, was ineffective, and further trials are not recommended. KEYWORDS: tumor progression rate, pathologic complete remission, resectability rate, postsurgical staging
INTRODUCTION The prognosis of locally advanced nonsmall-cell lung cancer (NSCLC) is dismal, with surgery and radiation therapy remaining the standard amenable treatment tools, but long-term survival is almost unheard of in locally advanced stages. Reports in the literature indicate that patients with completely resected stage 111 have a median survival of 12 months [I]. In a large Japanese series, Naruke et al. [2] classified 1,737 patients by postoperative stage. Five-year survival of stage IIIA was 22%, whereas survival of IIIB staged patients bottomed out at 5%. On these grounds, neoadjuvant chemotherapy might well come up with a treatment breakthrough, primarily in stage IIIA. The concept of preoperative chemotherapy for locally advanced NSCLC is appealing, and there are several theoretic considerations, such as chemotherapy plus 0 1990 Wiley-Liss, Inc.
surgery, which yielded cures in advanced Lewis lung carcinoma when neither surgery nor chemotherapy alone was effective [3]. Neoadjuvant chemotherapy may further minimize the risk of drug resistance by treating patients with a lower tumor burden and may allow an improvement in resectability rate as well as permitting in vivo assessment of drug effectiveness. The disadvantages of preoperative chemotherapy include a delay in operating if the tumor is not responsive, severe toxicity, or death. Data pooling of preoperative chemotherapy and multimodality phase I1 trials shows an overall response rate Accepted for publication June 1 1, 1990. Address reprint requests to Dr. Rafael Rosell, Chief of the Department of Oncology, Hospital de Badalona, Germans Trias i Pujol, Box 72, 08916 Badalona, Barcelona, Spain.
Neoadjuvant Chemotherapy in NSCLC
in the range of 60% to 70% with 0.8%-10% complete remissions (CR); more than 50% are able to undergo a resection following the neoadjuvant chemotherapy and 14-19 months median survival [4]. Basically, three chemotherapy combinations have been used: cisplatin plus vinblastinehindesine and mitomycin (MVP), as reported by Gralla et al. [5]; another combination for neoadjuvant chemotherapy is cisplatin plus 5-fluorouracil (FU) continuous infusion, with the possible addition of VP16 and radiotherapy [6]; and the last combination is cyclophosphamide, Adriamycin, and cisplatin (CAP) with radiotherapy [7]. Our previous studies in stages 111and IV NSCLC using high-dose cisplatin (120 mg/m2) plus vindesine with either mitomycin or ifosfamide (IFX) in 103 patients have failed to reproduce the high response rates reported by other investigators, with a 23% overall response rate and only four responders with previous bulky intrathoracic disease undergoing lung surgery after achieving radiographic partial remission [ 81. IFX has been claimed as an active drug in NSCLC, with an objective response (OR) rate greater than 15%. Giron et al. [9] reached 67% OR in 32 stage 1111 and IV patients combining IFX, mitomycin, and cisplatin. Thatcher et al. [lo] treated 45 patients with advanced NSCLC with two alkylating agents (cyclophosphamide and IFX), proving that both agents have different interactions at the DNA level, have no cross-resistance clinically, and also have different toxicity patterns. Myelosuppression is the cyclophosphamide (CTX) doselimiting toxicity, with encephalopathy being the most important potential problem with IFX [ 111. Thirty-eight percent OR was obtained with 7% CR and tolerable toxicity. Cisplatin-based regimens have made up the backbone of most clinical trials in NSCLC. Our own experience with CAP showed a 46% OR rate [12]; further, we extended our knowledge in the use of cisplatin, etoposide, and Adriamycin in comparison with cisplatin, etoposide, and epirubicin, which failed to achieve a minimum overall OR rate of only 10% [13]. Neither has the use of high-dose cisplatin proved, in our hands, to portend a reliable response rate. This prompted us to start this phase I1 study with CTX and IFX as neoadjuvant chemotherapy in stage 111, taking into account the results published by Thatcher et al. [lo] as well as the fact that this combination could be easier to handle and could be administered on an outpatient basis.
MATERIALS AND METHODS The neoadjuvant CTX-IFX trial was commenced in March 1988 and closed in August 1989. Twenty-three patients with histologically proven NSCLC and clinically demonstrated stage 111 disease were enrolled for the study. Clinical staging using TNM classification [ 141 was
125
established for all patients at diagnosis. All patients underwent plain chest roentgenography and computed tomography (CT) scan. CT was performed with 8 mm contiguous slices from the thoracic inlet level through the adrenal glands level. Contrast material was administered intravenously by bolus technique. CT images were evaluated by two expert radiologists. Mediastinal and hilar lymph nodes were interpreted as uninvolved when less than 10 mm in diameter, indeterminate when 10 to 15 mm, and probably tumor infiltrated when 15 mm or larger in size. Those excluded were patients with superior vena caval syndrome, endoscopic evidence of tracheal involvement, distant metastases, and patients unable to stand resection because of severe chronic obstructive pulmonary or cardiac disease. Other eligibility criteria included Karnofsky performance status equal or greater than 70%, leukocyte count greater than 4000/ml, platelet count greater than 100.000/ ml, and normal hepatic and renal functions. Measurable and evaluable lesions were required as well as informed consent of patients. Pretreatment evaluation included complete clinical history, comprehensive physical examination, bronchoscopy, and laboratory tests. Mediastinoscopy was carried out when mediastinal CT results were doubtful. When weight loss was observed in the 6 months prior to the trial, patients were stratified in less than or more than 6% of normal body weight. Respiratory function tests were required. Brain CT scan was compulsory in case of any neurologic signs suggesting widespread central nervous system (CNS). Bone-scanning evaluation was carried out when symptoms suggesting bone involvement were present. Treatment was comprised of three CTX-IFX cycles followed by thoracotomy . The response to chemotherapy was assessed after completing the three initial cycles. To evaluate response, all positive tests at diagnosis were repeated. Rebronchoscopy as well as CT scans were repeated in patients with partial or complete response and who met resection criteria at restaging: complete remission (CR), meaning the complete disappearance of all evidence of disease; partial response (PR), >50% reduction in the sum of the products of the greatest tumor diameter and its perpendicular; stable disease, no changes in measurable or evaluable masses; progression, any increase in size or appearance of new lesions. Survival was defined as the time from the start of chemotherapy to death. Time to relapse was measured from the date of resection to the first evidence of recurrence. Chemotherapy consisted of CTX 2.5 g/m2 plus mesna 2.5 g/m2 infused over 3 hours in 1 litre of saline. IFX 3.5 g/m2and mesna 3.5 g/m2in0.5 litre of saline was infused 90 minutes after the start of the CTX infusion. Immedi-
126
Rose11 et a].
ately after the end of the 3 hour CTX infusion, a further litre of saline was given over the next 8 hours with 6 g/m2 of mesna. As antiemetic, metoclopramide 2 mg/kg in 20 minute infusion was administered half an hour before the start of chemotherapy and 3.5 hours later. Dexamethasone 20 mg intravenously was given with the first metoclopramide dose only, and at the same time loracepam 1 mg was given orally and then again at 12 hours. Patients who did undergo surgical resection had a combined lung resection and mediastinal lymph node dissection, which included the lymph nodes at stations 1 , 2 , 3, 7, and 10 on the right and stations 4, 5 (Botallo's lymph nodes), 7, and 10 on the left [15]. Thoracotomy was carried out within the 5 weeks following the last chemotherapy cycle. Postsurgical staging was defined as follows: complete resection, an absence of residual disease on the resection margins or in the sampled upper paratracheal lymph nodes as well as evidence of marked decrease in the size of primary tumor or mediastinal lymph nodes; partiat resection, metastatic disease in the sampled upper paratracheal lymph nodes or infiltrated resection margins; unresectable disease, when resection is not feasible, implying surgical evidence of progression; complere pathological remission, no evidence of disease in any of the samples.
RESULTS Characteristics of the patient population are outlined in Table I. The median age was 63 years (range, 51 to 74 years). All patients except one were male. Eighteen patients had an 80% to 90% Kamofsky performance status; the remainder had 70% Karnofsky performance status. Squamous cell carcinoma was the most frequent histological type and was observed in 18 patients (78%), adenocarcinoma in four, and large cell carcinoma in one. According to the clinical TNM staging, 12 patients were classified as having stage IIIA and 11 as stage IIIB. Serum lactodehydrogenase level was elevated in only one patient. Weight loss greater than 6% was observed in five patients. Characteristics of the tumors are depicted in Table 11. Among the 23 cases, ten were T4 lesions, two were T3, nine T2, and two T1. There was one N3 lesion, 13 N2, four N l , and five NO. A 26% PR (95% confidence limit, 8%-44%) was achieved and stable disease in 43%. No case of CR was observed. When response was split off according to stage, 33% PR was in stage IIIA and 18% PR was in stage IIIB. PR was observed in four patients in stage IIIA, in three of nine with T2N2, and in one with T3NO (see Table 111). Seven patients (30%) underwent thoracotomy, with 86% resectability. Complete resection was performed in two patients (one lobectomy and one pneumonectomy),
TABLE I. Characteristicsof Patient Population
No. of patients Median age (range) Karnofsky performance status 60%-70% 80%-90% Squamous cell carcinoma Adenocarcinoma Large-cell carcinoma Stage IIIA
23 63 (54-74) 5 18 18 4 1
12 T3Nl (1)" T1N2 (2) T2N2 (9) 1 1 T4NO(5) T4NI (3) T4N2 (2) T3N3 ( I )
Stage IIIB
Weight loss No change < 6% > 6% a UICC
13 5 5
TNM Staging system.
TABLE 11. Characteristics of the Tumors*
~-
~~
NO NI N2 N3 Total
T1
T2
0 0 2 0 2 (9%)
0 0 9 0 9 (39%)
T3 0 1
0 1 2 (9%)
T4
Total (%)
5 3 2 0 10 (43%)
1 (4)
12 Patients 1 I Patients
Stage IIIA Stage IIIB
* UlCC
5 (22) 4 (17) 13 (56)
TNM Staging system.
TABLE 111. Analysis of Response Rate Within Different Subsets CR Stage IIIA" T3N I TIN2 T2N2 Stage llIBa T4NO T4N 1 T4N2 T3N3 a UICC
PR
SD
PD
212 419
219
111
319 I 13 I 12
215 213
315 Ill 1/1
TNM Staging system.
Three of four remaining patients with incomplete resection received postoperative irradiation. One patient with PR refused to undergo surgery. Table IV lists characteristics of patients who underwent surgery. Unfortunately, no patient was tumor free according to pathological specimens. Patient 9, for instance, was downstaged after chemotherapy, had a complete resection with gross residual macroscopic tu-
Neoadjuvant Chemotherapy in NSCLC
127
TABLE IV. PreoDerative CvcloDhosDhamide-Ifosfamide Chemotheraw in Stage 111 Non-Small-Cell Lung Cancer* Patient no. 1
5
9
Age1 sex 65 M 62 M
57
Histology
Clinical staging
Clinical response
Adenocarcinoma
T2N2
PR
Squamous carcinoma
T1N2
SD
T3N1
PR
T2N2
PR
Surgery Left upper lobectomy Right upper lobectomy
Postoperative disease status Complete resection Incomplete resection
10
64 M
Squamous carconima Large-cell carcinoma
14
64 M
Squamous carcinoma
T2N2
SD
Right Incomplete pneumonectomy resection
16
60 M
Squamous carcinoma
T2N2
PR
Right Incomplete pneumonectomy resection
17
58 M
Squamous carcinoma
T4NO
SD
Thoracotomy
M
Left Complete pneumonectomy resection Right bilobectomy Incomplete resection
Unresectable
Pathological staginga T2NO T=3cm TIN2 T = 1 cm; one N2 LN+ T3NO
Postoperative treatment
Follow-up Respiratory failure
Refused radiotherapy Radiotherapy
T2N2M1 T=4cm 5 / 6 N2 LNS; M1 = 1 cm right lower intrapulmonary met T2N2; T=4cm; 516 N2 LNf T2N2; Radiotherapy T = 6 cm; 115 N2 LNf T4N1 Radiotherapy
Survival (months) 17 16+
Bone metastases Respiratory failure
18+
Bone metastases
8
5
Asymptomatic
11+
Progessive pleural
6+
disease
*PR = partial response; SD = stable disease; LN = lymph node; met = metastases. aUICC TNM Staging system.
right pneumonectomy was needed. Residual tumor size was 6 cm in diameter, and resection was incomplete No. of evaluable cycles 65 because one of five upper paratracheal lymph nodes was Leucocyte nadir involved, whereas a large subcarinal mass of 4 cm in Grade 0 8 (35%) diameter was tumor free. I (3,000-3,900) 2 ( 9%) Tumor progression while receiving CTX-IFX chemoI1 (2,000-2,900) 4 (17%) therapy was noted in seven of 23 patients (30%), with a 111 ( I ,000- 1,900) 4 (17%) 2 months’ mean time. Mean time to progression for the IV (< 1,000) 4 (22%) whole group was 7 months. To date, 15 patients have had Platelet nadir 23 ( I 00%) Grade (> 100,000) progression, local only in six patients, bone metastases in Serum creatine (mg/dl) 23 (100%) five, liver metastases in three, and one brain and one Grade 0 (< 1.25) adrenal metastasis. Alopecia 23 (100%) Myelodepression was the dose-limiting toxicity (CTXGrade 111 IFX combination), and when 52 cycles had been adminLiver 3 (13%) Grade I1 istered to 16 patients, half had severe infection requiring Neurologic 23 (100%) hospitalization. Twenty-five percent of patients had leuGrade 0 kopenia grade 3 and 25% grade 4. After toxicity assessUrologic 23 (100%) ment in the first 16 patients, CTX and IFX doses were Grade 0 Infection 11 Episodes trimmed to 2 g/m2 and 3 g/m2,respectively. No infection episodes occurred after these dose readjustments were * CTX = cyclophosphamide; IFX = Ifosfamide. made. Toxicity is reported in Table V in a total of 65 cycles evaluated. No deaths from toxicity were observed. mor in tissue specimens, and had only one hilar lymph Neither encephalopathy nor hematuria occurred. node involved. Patient 10 underwent a right bilobectomy DISCUSSION and was , surprisingly, upstaged because an intrapulmonary mass with lcm diameter, was found in the lower Even allowing for the limited number of patients, right lobe. Patient 16 had N2 disease on CT scan, and a results still appear unpromising and bring us to our first
TABLE V. Toxicity of CTX-IFX Preoperative Chemotherapy*
128
Rose11 et al.
conclusion that the current CTX-IFX given at maximum tolerated doses is ineffective as neoadjuvant approach with extremely high (30%) tumor progression rate. This percentage is similar to that found by Dautzenberg et al. [ 161 in the only prospective randomized trial testing the efficacy of presurgery Chemotherapy. Twenty-six patients were randomly assigned to either immediate surgery or upfront chemotherapy with cisplatin, vindesine, and CTX. Tumor progression rate was 36%, which prompted them to discontinue the study. In spite of the fact that our group of patients was not homogeneous, because stage IIIB was included, the results still seem fairly poor. However, Shridar et al. [ 171, who treated 21 patients with unresectable stage IIIB disease with cisplatin, continuous 5-FU infusion, and etoposide, achieved a CR rate of 73% after surgery. Gralla’s impressive results [ 181 using preoperative MVP regimen in stage IIIA have been confirmed in other series. Gralla achieved 78% OR among 72 patients with 59% complete resectability rate and 19.5 months’ median survival. In the Toronto group [I91 of 35 patients, MVP yielded 64% OR with 49% complete resectability. These results are borne out in our country by Henriquez et al. [20], who obtained 67% OR among 53 patients with 62% resectability rate. Forty-two patients were stage IIIA and 11 IIIB. Sixteen patients further received preoperative irradiation. Tumor progression during chemotherapy was observed in three patients (6%). A meaningful 33% pathological complete remission was achieved. Although these trials are encouraging, the results are not randomized investigations, and the MVP approach needs to be tested in a randomized trial. What about the chemotherapy death toll with preoperative MVP regimen? In Gralla’s series [18], there was one septic death in 72 patients. In the Toronto trial, there was significant morbidity (9 of 22 patients who underwent surgery), chemotherapy-induced sepsis in four, and late mitomycin lung injury in one. Faber et al. 161 has now updated one of the largest series using cisplatin plus 5-FU continuous infusion with the addition of etoposide and radiotherapy. Two of the 85 patients eligible for operation died of myocardial infarction during therapy [21]. The resectability rate was 97% (60 of 62 patients). Median survival of the 62 patients undergoing thoracotomy was 36 months, but overall survival was reduced to 22 months when patients dying of chemotherapy-related causes are included together with those refusing operation. Skarin et al. [7] have used preoperative CAP chemotherapy and a 88% resection rate, but one of the major deterrents to survival was systemic recurrence (66%), predominantly in the brain. In Faber’s series [6], of the 17 patients who had no residual cancer after surgery, 76% are alive. In Gralla’s experience [ 181, induction chemotherapy alone without radiation therapy is successful, producing between 10%
and 20% pathologic complete responses. This becomes important when it is admitted that most long-term survivors come from this group of pathologic complete responders. When we look at the chemoradiotherapeutic approach without surgery for stage I11 NSCLC, the Dillman et al. [22] randomized trial stands out because of superior median survival (16.5 months) for the chemoradiotherapy group in comparison to 8.5 months for those treated with irradiation alone. Niitamo-Korhonen et al. [23] obtained 66% OR with cisplatin-vindesine; radiotherapy further enhanced the tumor response to 83%. Nevertheless, these chemotherapy regimens used in combination with radiotherapy resulted in a survival similar to, but not better than, that reported after irradiation alone. A review of chemotherapeutic agents is beyond the scope of this discussion; however, some points are worth underlining. Figure 1 sums up data pooling of drugs and combinations used in NSCLC. In a study of the Southwest Oncology Group [24], IFX had 9% OR in 113 patients with extensive NSCLC, whereas other authors claim up to 32% OR [25]. Recently, Klastersky et al. [26] obtained 20% OR with high-dose cisplatin in a significant number of patients; but other authors, such as Crino et al. [27], stopped the accrual of patients in the DDP arm (24 evaluable) because of 4% OR. Carboplatin (CBDCA) interestingly has been assigned a 20% OR [28]. An Eastern Cooperative Oncology Group [29] trial found a longer survival in the carboplatin arm, with less toxicity than with the MVP arm. Kris et al. [30] has shown that the combination of EDAM, mitomycin, and vinblastine produced a 60% OR administered on an outpatient basis. Furthermore, Gralla [3 11 confirmed his good results with the MVP regimen employed on outpatient basis in 100 patients, which produced 67% OR (95% CL, 58%-76%). Cullen et al. [32] showed a 56% OR in 66 patients evaluable for response with seven patients I: 1 1%) CR using mitomycin, IFX, and cisplatin. Data pooling carried out by us shows that the activity of IFX as a single agent in NSCLC is 17% in more than 500 patients, which is similar to that reported for cisplatin (Fig. 1). However, a recent phase I1 study in 14 patients with squamous cell bronchogenic carcinoma who were treated with 4.5 g/m2 IFX over 3 days failed to produce any response [ 331. Data pooling of the principal combinations used pointed out 40% OR for the most common regimens employed, 42% for MVP among 586 patients reviewed, 43% for cisplatin plus 5-FU continuous infusion in almost 400 patients, and 32% OR for CAP in 600 patients. At present, the importance of which drugs or drug combination is more effective in NSCLC remains to be clarified. Neoadjuvant chemotherapy trials have been hampered by the absence of controls, by toxicity, and by difficulties in homogenizing staging of the disease extent. The crux
Neoadjuvant Chemotherapy in NSCLC IFX-LIVINGSTON (24) IFX-CONSTANZI (25) P-K LAST ER SKY 26) EDAM-SHUM (35) CBDCA-GATZEMEIER(28) IFX+CTX-THATCHER(lO) IFX+P-DRINGS (36) P+FU-RUSCH (37) P+IFX+MMC-CULLEN(32) P+DVA+MMC-GRALLA(31) CTX+DX+P-ROSELL (12)
I
,
303
,
-I3 __L_
129
81
.
20
I51 ,45
L
72
95 74
-.
100 31
.=+
IFX P DVA MMC IFX+X (no P) IFX+P+/-MMC CBDCA+VP16 P+FU MVP CAP
509 POOLEDRESULTS 555 364 88 482
-- -
_c_
220
-c
I
0
396 396 586
601
10 20 30 40
I
I
I
5 0 60 7 0 8 0
I
I
90 100
Fig. I . A meta-analysis of chemotherapeutic agents used in non-small-cell lung cancer. Objective response rates are indicated in percentages on the abscissa (solid bars denote 95% confidence limits) for single-agent and multiple-agent regimens. The numbers refer to number of patients. IFX, ifosfamide; P, cisplatin; EDAM, ethyl- 10-deazaaminopterin; CBDCA, carboplatin; CTX, cyclophosphamide; FU, fluorouracil; MMC, mitomycin C; DVA, vindesine; DX, doxorubicin. MVP = mitomycin, vindesine, cisplatin; CAP = cyclophosphamide, doxorubicin, cisplatin.
of the matter is how to approach neoadjuvant chemotherapy in patients staged as IIIA. Whether or not survival is enhanced by using chemotherapy before surgery in surgically resectable stage IIIA requires a randomized controlled trial such as Roth et al. [34] carried out in esophageal cancer. The results of our trial proved to be negative because the type of chemotherapy used was shown to be ineffective, as demonstrated by the high tumor progression rate, as well as the poor response rate yielded, which was significantly lower than the 50% threshold attained in stage I11 with cisplatin-based regimens. Indeed, more effective chemotherapy regimens are needed to maximize neoadjuvant approaches.
REFERENCES I . Holmes EC: Surgical adjuvant therapy of non-small-cell lung cancer. J Surg Oncol [Suppl] 1:26-33, 1989. 2. Naruke T, Goya T, Tsuchiya R, Suemasu K: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96:440-447, 1988. 3. Simpson-Herren L, Sonford AH, Holmquist JP: Effects of surgery in the cell kinetics of residual tumor. Cancer Treat Rep 60:17491760, 1976. 4. Klastersky J: Chemotherapy in non-small cell lung cancer (NSCLC). Eur J Cancer Clin Oncol 25:1035-1038, 1989. 5. Martini N, Kris MG, Gralla RJ, Bains MS, Mc Cormack PM, Kaiser LR, Burt ME, Zaman MB: The effects of preoperative chemotherapy on the resectability of non-small cell lung carcinoma with mediastinal lymph node metastases (N2MO). Ann Thorac Surg 45:370-379, 1988.
6. Faber LP, Kittle CF, Warren WH, Bonomi PD, Taylor SG, Reddy S, Lee M-S: Preoperative chemotherapy and irradiation for stage 111 non-small cell lung cancer. Ann Thorac Surg 47:669-677, 1989. 7. Skarin A, Jochelson M, Sheldon T, Malcolm A, Oliynyk P, Overholt R, Hunt M, Frei I11 E: Neoadjuvant chemotherapy in marginally resectable stage IIIMO non-small cell lung cancer: long-term follow-up in 41 patients. J Surg Oncol 40:266-274, 1989. 8. Rosell R, Abad-Esteve A, Moreno I, Barnadas A, Carles J, Fernandez C, Ribelles N , Culubret M: A randomized study of two vindesine plus cisplatin containing regimens with the addition of mitomycin or ifosfamide in patients with advanced non-small cell lung cancer. Cancer 65: 1692-1699, 1990. 9. Giron CG, Ordofiez A, Jalon JI, Baron MG: Combined chemotherapy with ifosfamide, mitomycin and cisplatin in advanced non-small cell lung cancer. Cancer Treat Rep 71:851-853, 1987. 10. Thatcher N, Smith DB, Lind MJ, Anderson H, Barclay J , Chopra MP, Fitzgerald MD: Double alkylating agent therapy with ifosfamide and cyclophosphamide for advanced non-small cell lung cancer. Cancer 61:34-18, 1988. 1 1 . Watkin SW, Husband DJ, Green JA, Warenuis HM: Ifosfamide encephalopathy: A reappraisal. Eur J Cancer Clin Oncol25: 13031310, 1989. 12. Rosell R, Abad-Esteve A, Roig J, Moreno I, Fernandez C, Ribas M: The role of combination cyclophosphamide, doxorubicin and cisplatin (CAP) chemotherapy in advanced non-small-cell lung cancer. Tumori 73:345-349, 1987. 13. Rosell R, Abad-Esteve A, Morera J, Monras P, Moreno I, Ruiz J, Fernandez C, Ribas M: A randomized study comparing platinum, doxorubicin and VP-16 with platinum, 4’-epidoxorubicin and VP-16 in patients with non-small-cell lung cancer. Am J Clin Oncol (CCT) 10:245-248, 1987. 14, Mountain CF: A new international staging system for lung cancer. Chest [Suppl] 89:225-232, 1986. 15. Naruke T, Suemasu K , Ishiwaka S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76:832-838, 1970.
130
Rose11 et al.
16. Dautzenberg B, Chastang CL, Lebeau B, Coetmeur AD, Benichou J, Postal MJ: A randomized phase 11 trial of neoadjuvant
17.
18. 19.
chemotherapy in resectable bronchogenic non small cell carcinoma. Short term results. In Jacquillat CI, Weil M, Khayat D (eds): “Neo-adjuvant Chemotherapy”. London: John Libbey Eurotext Ltd, 1988, pp 365-370. Shridar KS, Thurer R, Kim Y, Fountzilas G, Davila E, Donnelly E, Charyulu KKN, Saldana MJ, Thompson T, Benedetto P, Raskin N , Beattie EJ: Multimodality treatment of non-small cell lung cancer: response to cisplatin, VP-16, and 5-FU chemotherapy and to surgery and radiation therapy. J Surg Oncol 38:193215, 1988. Gralla RJ: Multi-modality therapy for stage 111 non-small cell lung cancer. Am Soc Clin Oncol, Educational Booklet, San Francisco, 1989, pp. 27-31. Burkes R, Ginsberg R, Shepherd F, Blackstein M, Goldberg M, Waters P, Patterson A, Todd T, Pearson F, Cooper J, Jones D: Neo-adjuvant trial with MVP (mitomycin-C +vindesine cisplatin) chemotherapy for stage 111 (TI-3, N2, MO) unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol8:221, 1989. Henriquez Lopez I, Muiioz Galindo L, Ortiz de Urbina D, Calvo FA: Neoadjuvant chemotherapy (NAC) with cisplatin (CDDP), vindesine (VDS) and mitornycin C (MMC) in locally advanced non-small cell lung cancer (NSCLC). 5th European Conf on Clinical Oncology,-1989, p 67. Collins C. Weiden PL: Cardiotoxicitv of 5-fluorouracil. Cancer Treat Rep 71:733-736, 1987. Dillman RO, Seagren SL, Propert K, Eaton WL, Frei EF, Green MR: Protochemotherapy improves survival in regional non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol7:195, 1988. Niitamo-Korhonen S , Holsti P, Holsti RL, Pyrhonen S, Mattson K: A comparison of cis-platinum-vindesine and cis-platinumetoposide combined with radiotherapy for previously untreated localized inoperable non-small cell lung cancer. Eur J Cancer Clin Oncol 25:1039-1043, 1989. Livingston RB: Treatment of advanced non-small cell lung cancer: The Southwest Oncology Group experience. Semin Oncol [Suppl] 15:3741, 1988. Costanzi JJ, Gagliano R, Lukas D, Panettiere FJ, Hokanson JA: lfosfamide in the treatment of recurrent or disseminated lung cancer. Cancer 41:1715-1719, 1978. Klastersky J , Sculier JP, Bureau G, Libert P, Ravez P, Vandermoten G, Thiriaux J, Lecomte J, Cordier R, Dabouis G, Brohee D, Themelin L, Mommen P: Cisplatin versus cisplatin plus etoposide in the treatment of advanced non-small cell lung cancer. J Clin Oncol 7:1087-1092. 1989.
+
20.
21, 22. 23.
24. 25. 26.
27. Crino L, Meacci L, Corgna E, Buzzi F, Di Costanzo I;, Darwish S, Tonato M: A randomized trial of 3 cisplatin containing regimens for advanced non small cell lung cancer. Proc V World Conf Lung Cancer 4: 119, 1988. 28. Garzemeier U, Hossfeld DK, Heuhauss R, Achterrath W, Lenaz L: Phase I1 trial with carboplatin in patients with advanced unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 8:237, 1989. 29. Bonomi PD, Finkelstein DM, Ruckdeschel JC, BIum RH, Green MD, Mason B, Hahn R, Tormey DC, Harris J, Comis R, Glick J: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. J Clin Oncol 7: 1602-161 3, 1989. 30. Kris MG, Gralla RJ, Potanovich LM, Marks LA, Heelan RT: Incorporating 10-ethyl- 10-deazaaminopterin (EDAM) into combination therapy with mitomycin and vinblastine for patients with advanced non-small cell lung cancer. Proc Am SOCClin Oncol 8:227, 1989. 31. Gralla RJ, Kris MG, Potanovich LM, Marks LA, Healan RT: Enhancing the safety and efficacy of the MVP regimen (mitomycin vinblastine t cisplatin) in 100 patients with inoperable non-small cell lung cancer. Proc Am Soc Clin Oncol8:227, 1989. 32. Cullen MH, Joshi R, Chetiyawardana AD, Woodroffe CM: Mitomycin, ifosfamide and cis-platin in non-small cell lung cancer: treatment good enough to compare. Br J Cancer 58:359361, 1988. 33. Banks J, Anderson EG, Smith AP: Failure of response to ifosfamide in squamous cell bronchogenic carcinoma. Cancer Chemother Pharmacol 23:128, 1989. 34. Roth JA, Pass HI, Flanagan MM, Graeber GM, Rosenberg JC, Steinberg S: Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 96:242-248, 1988. 35. Shum KY, Kris MG, Gralla RJ, Burke T, Marks LD, Heelan RT: Phase I1 study of 10-ethyl- 10-deaza-aminopterin in patients with stage 111 and IV non-small-cell lung cancer. J Clin Oncol 64-50, 1988. 36. Drings P: European experience with ifosfamide in non-small cell lung cancer. Sem Oncol (Suppl 3) 16:22-30, 1989. 37. Rusch V, Weiden P, Hill L: Patterns of relapse following neo-adjuvant therapy for regionally inoperable non-small cell lung cancer. Lung Cancer [Suppl] 4:A-161. 1988.
+
Cyclophosphamide and lfosfamide Combination as Neoadjuvant Chemotherapy for Locally Advanced Nonsmall-Cell lung Cancer: A Meta-Analytic Review RAFAEL ROSELL, MD, PhD, ISABEL MORENO, MD, JOSf MAESTRE, MD, ANGEL OLAZABAL, MD, J O A N CARLES, MD, AUGUSTIN BARNADAS, MD, ALBERT ABAD-ESTEVE, MD, NURIA RIBELLES, MD, AND MERCEDES CANELA, MD From the Departments of Oncology (R.R., I.M., /.C., A.B., A.A.-E., N.R.), Thoracic Surgery (/,M,,M.C.), and Radiology (A.O.), Hospital de Badalona Germans Trias i Pujol, Universitat Autonoma de Barcelona, Barcelona, Spain
Twenty-three patients with marginally resectable and unresectable nonsmall-cell lung cancer (stages IIIA and IIIB) were treated by neoadjuvant chemotherapy. All patients received three cycles of preoperative chemotherapy with two alkylating agents, cyclophosphamide 2.5 g/m2 intravenously (i.v.) and ifosfamide 3.5 g/m2 i.v., mesna 12 g/m2 was given additionally to prevent drug hematuria. Six of 23 patients (26%) had partial response. Of the seven patients who underwent thoracotomy, two were completely resected, but with macroscopic residual disease. Mean time to progression for the whole group was 7 months. Fifteen patients had progression of disease, with local metastases only in six, and distant metastases in eight. After administering 52 chemotherapy cycles, cyclophosphamide-ifosfamide doses were cut down, as eight of 16 patients required hospitalization for fever during neutropenia nadirs. This twoalkylating (non-cisplatin) regimen, unlike cisplatin-based regimens, was ineffective, and further trials are not recommended. KEYWORDS: tumor progression rate, pathologic complete remission, resectability rate, postsurgical staging
INTRODUCTION The prognosis of locally advanced nonsmall-cell lung cancer (NSCLC) is dismal, with surgery and radiation therapy remaining the standard amenable treatment tools, but long-term survival is almost unheard of in locally advanced stages. Reports in the literature indicate that patients with completely resected stage 111 have a median survival of 12 months [I]. In a large Japanese series, Naruke et al. [2] classified 1,737 patients by postoperative stage. Five-year survival of stage IIIA was 22%, whereas survival of IIIB staged patients bottomed out at 5%. On these grounds, neoadjuvant chemotherapy might well come up with a treatment breakthrough, primarily in stage IIIA. The concept of preoperative chemotherapy for locally advanced NSCLC is appealing, and there are several theoretic considerations, such as chemotherapy plus 0 1990 Wiley-Liss, Inc.
surgery, which yielded cures in advanced Lewis lung carcinoma when neither surgery nor chemotherapy alone was effective [3]. Neoadjuvant chemotherapy may further minimize the risk of drug resistance by treating patients with a lower tumor burden and may allow an improvement in resectability rate as well as permitting in vivo assessment of drug effectiveness. The disadvantages of preoperative chemotherapy include a delay in operating if the tumor is not responsive, severe toxicity, or death. Data pooling of preoperative chemotherapy and multimodality phase I1 trials shows an overall response rate Accepted for publication June 1 1, 1990. Address reprint requests to Dr. Rafael Rosell, Chief of the Department of Oncology, Hospital de Badalona, Germans Trias i Pujol, Box 72, 08916 Badalona, Barcelona, Spain.
Neoadjuvant Chemotherapy in NSCLC
in the range of 60% to 70% with 0.8%-10% complete remissions (CR); more than 50% are able to undergo a resection following the neoadjuvant chemotherapy and 14-19 months median survival [4]. Basically, three chemotherapy combinations have been used: cisplatin plus vinblastinehindesine and mitomycin (MVP), as reported by Gralla et al. [5]; another combination for neoadjuvant chemotherapy is cisplatin plus 5-fluorouracil (FU) continuous infusion, with the possible addition of VP16 and radiotherapy [6]; and the last combination is cyclophosphamide, Adriamycin, and cisplatin (CAP) with radiotherapy [7]. Our previous studies in stages 111and IV NSCLC using high-dose cisplatin (120 mg/m2) plus vindesine with either mitomycin or ifosfamide (IFX) in 103 patients have failed to reproduce the high response rates reported by other investigators, with a 23% overall response rate and only four responders with previous bulky intrathoracic disease undergoing lung surgery after achieving radiographic partial remission [ 81. IFX has been claimed as an active drug in NSCLC, with an objective response (OR) rate greater than 15%. Giron et al. [9] reached 67% OR in 32 stage 1111 and IV patients combining IFX, mitomycin, and cisplatin. Thatcher et al. [lo] treated 45 patients with advanced NSCLC with two alkylating agents (cyclophosphamide and IFX), proving that both agents have different interactions at the DNA level, have no cross-resistance clinically, and also have different toxicity patterns. Myelosuppression is the cyclophosphamide (CTX) doselimiting toxicity, with encephalopathy being the most important potential problem with IFX [ 111. Thirty-eight percent OR was obtained with 7% CR and tolerable toxicity. Cisplatin-based regimens have made up the backbone of most clinical trials in NSCLC. Our own experience with CAP showed a 46% OR rate [12]; further, we extended our knowledge in the use of cisplatin, etoposide, and Adriamycin in comparison with cisplatin, etoposide, and epirubicin, which failed to achieve a minimum overall OR rate of only 10% [13]. Neither has the use of high-dose cisplatin proved, in our hands, to portend a reliable response rate. This prompted us to start this phase I1 study with CTX and IFX as neoadjuvant chemotherapy in stage 111, taking into account the results published by Thatcher et al. [lo] as well as the fact that this combination could be easier to handle and could be administered on an outpatient basis.
MATERIALS AND METHODS The neoadjuvant CTX-IFX trial was commenced in March 1988 and closed in August 1989. Twenty-three patients with histologically proven NSCLC and clinically demonstrated stage 111 disease were enrolled for the study. Clinical staging using TNM classification [ 141 was
125
established for all patients at diagnosis. All patients underwent plain chest roentgenography and computed tomography (CT) scan. CT was performed with 8 mm contiguous slices from the thoracic inlet level through the adrenal glands level. Contrast material was administered intravenously by bolus technique. CT images were evaluated by two expert radiologists. Mediastinal and hilar lymph nodes were interpreted as uninvolved when less than 10 mm in diameter, indeterminate when 10 to 15 mm, and probably tumor infiltrated when 15 mm or larger in size. Those excluded were patients with superior vena caval syndrome, endoscopic evidence of tracheal involvement, distant metastases, and patients unable to stand resection because of severe chronic obstructive pulmonary or cardiac disease. Other eligibility criteria included Karnofsky performance status equal or greater than 70%, leukocyte count greater than 4000/ml, platelet count greater than 100.000/ ml, and normal hepatic and renal functions. Measurable and evaluable lesions were required as well as informed consent of patients. Pretreatment evaluation included complete clinical history, comprehensive physical examination, bronchoscopy, and laboratory tests. Mediastinoscopy was carried out when mediastinal CT results were doubtful. When weight loss was observed in the 6 months prior to the trial, patients were stratified in less than or more than 6% of normal body weight. Respiratory function tests were required. Brain CT scan was compulsory in case of any neurologic signs suggesting widespread central nervous system (CNS). Bone-scanning evaluation was carried out when symptoms suggesting bone involvement were present. Treatment was comprised of three CTX-IFX cycles followed by thoracotomy . The response to chemotherapy was assessed after completing the three initial cycles. To evaluate response, all positive tests at diagnosis were repeated. Rebronchoscopy as well as CT scans were repeated in patients with partial or complete response and who met resection criteria at restaging: complete remission (CR), meaning the complete disappearance of all evidence of disease; partial response (PR), >50% reduction in the sum of the products of the greatest tumor diameter and its perpendicular; stable disease, no changes in measurable or evaluable masses; progression, any increase in size or appearance of new lesions. Survival was defined as the time from the start of chemotherapy to death. Time to relapse was measured from the date of resection to the first evidence of recurrence. Chemotherapy consisted of CTX 2.5 g/m2 plus mesna 2.5 g/m2 infused over 3 hours in 1 litre of saline. IFX 3.5 g/m2and mesna 3.5 g/m2in0.5 litre of saline was infused 90 minutes after the start of the CTX infusion. Immedi-
126
Rose11 et a].
ately after the end of the 3 hour CTX infusion, a further litre of saline was given over the next 8 hours with 6 g/m2 of mesna. As antiemetic, metoclopramide 2 mg/kg in 20 minute infusion was administered half an hour before the start of chemotherapy and 3.5 hours later. Dexamethasone 20 mg intravenously was given with the first metoclopramide dose only, and at the same time loracepam 1 mg was given orally and then again at 12 hours. Patients who did undergo surgical resection had a combined lung resection and mediastinal lymph node dissection, which included the lymph nodes at stations 1 , 2 , 3, 7, and 10 on the right and stations 4, 5 (Botallo's lymph nodes), 7, and 10 on the left [15]. Thoracotomy was carried out within the 5 weeks following the last chemotherapy cycle. Postsurgical staging was defined as follows: complete resection, an absence of residual disease on the resection margins or in the sampled upper paratracheal lymph nodes as well as evidence of marked decrease in the size of primary tumor or mediastinal lymph nodes; partiat resection, metastatic disease in the sampled upper paratracheal lymph nodes or infiltrated resection margins; unresectable disease, when resection is not feasible, implying surgical evidence of progression; complere pathological remission, no evidence of disease in any of the samples.
RESULTS Characteristics of the patient population are outlined in Table I. The median age was 63 years (range, 51 to 74 years). All patients except one were male. Eighteen patients had an 80% to 90% Kamofsky performance status; the remainder had 70% Karnofsky performance status. Squamous cell carcinoma was the most frequent histological type and was observed in 18 patients (78%), adenocarcinoma in four, and large cell carcinoma in one. According to the clinical TNM staging, 12 patients were classified as having stage IIIA and 11 as stage IIIB. Serum lactodehydrogenase level was elevated in only one patient. Weight loss greater than 6% was observed in five patients. Characteristics of the tumors are depicted in Table 11. Among the 23 cases, ten were T4 lesions, two were T3, nine T2, and two T1. There was one N3 lesion, 13 N2, four N l , and five NO. A 26% PR (95% confidence limit, 8%-44%) was achieved and stable disease in 43%. No case of CR was observed. When response was split off according to stage, 33% PR was in stage IIIA and 18% PR was in stage IIIB. PR was observed in four patients in stage IIIA, in three of nine with T2N2, and in one with T3NO (see Table 111). Seven patients (30%) underwent thoracotomy, with 86% resectability. Complete resection was performed in two patients (one lobectomy and one pneumonectomy),
TABLE I. Characteristicsof Patient Population
No. of patients Median age (range) Karnofsky performance status 60%-70% 80%-90% Squamous cell carcinoma Adenocarcinoma Large-cell carcinoma Stage IIIA
23 63 (54-74) 5 18 18 4 1
12 T3Nl (1)" T1N2 (2) T2N2 (9) 1 1 T4NO(5) T4NI (3) T4N2 (2) T3N3 ( I )
Stage IIIB
Weight loss No change < 6% > 6% a UICC
13 5 5
TNM Staging system.
TABLE 11. Characteristics of the Tumors*
~-
~~
NO NI N2 N3 Total
T1
T2
0 0 2 0 2 (9%)
0 0 9 0 9 (39%)
T3 0 1
0 1 2 (9%)
T4
Total (%)
5 3 2 0 10 (43%)
1 (4)
12 Patients 1 I Patients
Stage IIIA Stage IIIB
* UlCC
5 (22) 4 (17) 13 (56)
TNM Staging system.
TABLE 111. Analysis of Response Rate Within Different Subsets CR Stage IIIA" T3N I TIN2 T2N2 Stage llIBa T4NO T4N 1 T4N2 T3N3 a UICC
PR
SD
PD
212 419
219
111
319 I 13 I 12
215 213
315 Ill 1/1
TNM Staging system.
Three of four remaining patients with incomplete resection received postoperative irradiation. One patient with PR refused to undergo surgery. Table IV lists characteristics of patients who underwent surgery. Unfortunately, no patient was tumor free according to pathological specimens. Patient 9, for instance, was downstaged after chemotherapy, had a complete resection with gross residual macroscopic tu-
Neoadjuvant Chemotherapy in NSCLC
127
TABLE IV. PreoDerative CvcloDhosDhamide-Ifosfamide Chemotheraw in Stage 111 Non-Small-Cell Lung Cancer* Patient no. 1
5
9
Age1 sex 65 M 62 M
57
Histology
Clinical staging
Clinical response
Adenocarcinoma
T2N2
PR
Squamous carcinoma
T1N2
SD
T3N1
PR
T2N2
PR
Surgery Left upper lobectomy Right upper lobectomy
Postoperative disease status Complete resection Incomplete resection
10
64 M
Squamous carconima Large-cell carcinoma
14
64 M
Squamous carcinoma
T2N2
SD
Right Incomplete pneumonectomy resection
16
60 M
Squamous carcinoma
T2N2
PR
Right Incomplete pneumonectomy resection
17
58 M
Squamous carcinoma
T4NO
SD
Thoracotomy
M
Left Complete pneumonectomy resection Right bilobectomy Incomplete resection
Unresectable
Pathological staginga T2NO T=3cm TIN2 T = 1 cm; one N2 LN+ T3NO
Postoperative treatment
Follow-up Respiratory failure
Refused radiotherapy Radiotherapy
T2N2M1 T=4cm 5 / 6 N2 LNS; M1 = 1 cm right lower intrapulmonary met T2N2; T=4cm; 516 N2 LNf T2N2; Radiotherapy T = 6 cm; 115 N2 LNf T4N1 Radiotherapy
Survival (months) 17 16+
Bone metastases Respiratory failure
18+
Bone metastases
8
5
Asymptomatic
11+
Progessive pleural
6+
disease
*PR = partial response; SD = stable disease; LN = lymph node; met = metastases. aUICC TNM Staging system.
right pneumonectomy was needed. Residual tumor size was 6 cm in diameter, and resection was incomplete No. of evaluable cycles 65 because one of five upper paratracheal lymph nodes was Leucocyte nadir involved, whereas a large subcarinal mass of 4 cm in Grade 0 8 (35%) diameter was tumor free. I (3,000-3,900) 2 ( 9%) Tumor progression while receiving CTX-IFX chemoI1 (2,000-2,900) 4 (17%) therapy was noted in seven of 23 patients (30%), with a 111 ( I ,000- 1,900) 4 (17%) 2 months’ mean time. Mean time to progression for the IV (< 1,000) 4 (22%) whole group was 7 months. To date, 15 patients have had Platelet nadir 23 ( I 00%) Grade (> 100,000) progression, local only in six patients, bone metastases in Serum creatine (mg/dl) 23 (100%) five, liver metastases in three, and one brain and one Grade 0 (< 1.25) adrenal metastasis. Alopecia 23 (100%) Myelodepression was the dose-limiting toxicity (CTXGrade 111 IFX combination), and when 52 cycles had been adminLiver 3 (13%) Grade I1 istered to 16 patients, half had severe infection requiring Neurologic 23 (100%) hospitalization. Twenty-five percent of patients had leuGrade 0 kopenia grade 3 and 25% grade 4. After toxicity assessUrologic 23 (100%) ment in the first 16 patients, CTX and IFX doses were Grade 0 Infection 11 Episodes trimmed to 2 g/m2 and 3 g/m2,respectively. No infection episodes occurred after these dose readjustments were * CTX = cyclophosphamide; IFX = Ifosfamide. made. Toxicity is reported in Table V in a total of 65 cycles evaluated. No deaths from toxicity were observed. mor in tissue specimens, and had only one hilar lymph Neither encephalopathy nor hematuria occurred. node involved. Patient 10 underwent a right bilobectomy DISCUSSION and was , surprisingly, upstaged because an intrapulmonary mass with lcm diameter, was found in the lower Even allowing for the limited number of patients, right lobe. Patient 16 had N2 disease on CT scan, and a results still appear unpromising and bring us to our first
TABLE V. Toxicity of CTX-IFX Preoperative Chemotherapy*
128
Rose11 et al.
conclusion that the current CTX-IFX given at maximum tolerated doses is ineffective as neoadjuvant approach with extremely high (30%) tumor progression rate. This percentage is similar to that found by Dautzenberg et al. [ 161 in the only prospective randomized trial testing the efficacy of presurgery Chemotherapy. Twenty-six patients were randomly assigned to either immediate surgery or upfront chemotherapy with cisplatin, vindesine, and CTX. Tumor progression rate was 36%, which prompted them to discontinue the study. In spite of the fact that our group of patients was not homogeneous, because stage IIIB was included, the results still seem fairly poor. However, Shridar et al. [ 171, who treated 21 patients with unresectable stage IIIB disease with cisplatin, continuous 5-FU infusion, and etoposide, achieved a CR rate of 73% after surgery. Gralla’s impressive results [ 181 using preoperative MVP regimen in stage IIIA have been confirmed in other series. Gralla achieved 78% OR among 72 patients with 59% complete resectability rate and 19.5 months’ median survival. In the Toronto group [I91 of 35 patients, MVP yielded 64% OR with 49% complete resectability. These results are borne out in our country by Henriquez et al. [20], who obtained 67% OR among 53 patients with 62% resectability rate. Forty-two patients were stage IIIA and 11 IIIB. Sixteen patients further received preoperative irradiation. Tumor progression during chemotherapy was observed in three patients (6%). A meaningful 33% pathological complete remission was achieved. Although these trials are encouraging, the results are not randomized investigations, and the MVP approach needs to be tested in a randomized trial. What about the chemotherapy death toll with preoperative MVP regimen? In Gralla’s series [18], there was one septic death in 72 patients. In the Toronto trial, there was significant morbidity (9 of 22 patients who underwent surgery), chemotherapy-induced sepsis in four, and late mitomycin lung injury in one. Faber et al. 161 has now updated one of the largest series using cisplatin plus 5-FU continuous infusion with the addition of etoposide and radiotherapy. Two of the 85 patients eligible for operation died of myocardial infarction during therapy [21]. The resectability rate was 97% (60 of 62 patients). Median survival of the 62 patients undergoing thoracotomy was 36 months, but overall survival was reduced to 22 months when patients dying of chemotherapy-related causes are included together with those refusing operation. Skarin et al. [7] have used preoperative CAP chemotherapy and a 88% resection rate, but one of the major deterrents to survival was systemic recurrence (66%), predominantly in the brain. In Faber’s series [6], of the 17 patients who had no residual cancer after surgery, 76% are alive. In Gralla’s experience [ 181, induction chemotherapy alone without radiation therapy is successful, producing between 10%
and 20% pathologic complete responses. This becomes important when it is admitted that most long-term survivors come from this group of pathologic complete responders. When we look at the chemoradiotherapeutic approach without surgery for stage I11 NSCLC, the Dillman et al. [22] randomized trial stands out because of superior median survival (16.5 months) for the chemoradiotherapy group in comparison to 8.5 months for those treated with irradiation alone. Niitamo-Korhonen et al. [23] obtained 66% OR with cisplatin-vindesine; radiotherapy further enhanced the tumor response to 83%. Nevertheless, these chemotherapy regimens used in combination with radiotherapy resulted in a survival similar to, but not better than, that reported after irradiation alone. A review of chemotherapeutic agents is beyond the scope of this discussion; however, some points are worth underlining. Figure 1 sums up data pooling of drugs and combinations used in NSCLC. In a study of the Southwest Oncology Group [24], IFX had 9% OR in 113 patients with extensive NSCLC, whereas other authors claim up to 32% OR [25]. Recently, Klastersky et al. [26] obtained 20% OR with high-dose cisplatin in a significant number of patients; but other authors, such as Crino et al. [27], stopped the accrual of patients in the DDP arm (24 evaluable) because of 4% OR. Carboplatin (CBDCA) interestingly has been assigned a 20% OR [28]. An Eastern Cooperative Oncology Group [29] trial found a longer survival in the carboplatin arm, with less toxicity than with the MVP arm. Kris et al. [30] has shown that the combination of EDAM, mitomycin, and vinblastine produced a 60% OR administered on an outpatient basis. Furthermore, Gralla [3 11 confirmed his good results with the MVP regimen employed on outpatient basis in 100 patients, which produced 67% OR (95% CL, 58%-76%). Cullen et al. [32] showed a 56% OR in 66 patients evaluable for response with seven patients I: 1 1%) CR using mitomycin, IFX, and cisplatin. Data pooling carried out by us shows that the activity of IFX as a single agent in NSCLC is 17% in more than 500 patients, which is similar to that reported for cisplatin (Fig. 1). However, a recent phase I1 study in 14 patients with squamous cell bronchogenic carcinoma who were treated with 4.5 g/m2 IFX over 3 days failed to produce any response [ 331. Data pooling of the principal combinations used pointed out 40% OR for the most common regimens employed, 42% for MVP among 586 patients reviewed, 43% for cisplatin plus 5-FU continuous infusion in almost 400 patients, and 32% OR for CAP in 600 patients. At present, the importance of which drugs or drug combination is more effective in NSCLC remains to be clarified. Neoadjuvant chemotherapy trials have been hampered by the absence of controls, by toxicity, and by difficulties in homogenizing staging of the disease extent. The crux
Neoadjuvant Chemotherapy in NSCLC IFX-LIVINGSTON (24) IFX-CONSTANZI (25) P-K LAST ER SKY 26) EDAM-SHUM (35) CBDCA-GATZEMEIER(28) IFX+CTX-THATCHER(lO) IFX+P-DRINGS (36) P+FU-RUSCH (37) P+IFX+MMC-CULLEN(32) P+DVA+MMC-GRALLA(31) CTX+DX+P-ROSELL (12)
I
,
303
,
-I3 __L_
129
81
.
20
I51 ,45
L
72
95 74
-.
100 31
.=+
IFX P DVA MMC IFX+X (no P) IFX+P+/-MMC CBDCA+VP16 P+FU MVP CAP
509 POOLEDRESULTS 555 364 88 482
-- -
_c_
220
-c
I
0
396 396 586
601
10 20 30 40
I
I
I
5 0 60 7 0 8 0
I
I
90 100
Fig. I . A meta-analysis of chemotherapeutic agents used in non-small-cell lung cancer. Objective response rates are indicated in percentages on the abscissa (solid bars denote 95% confidence limits) for single-agent and multiple-agent regimens. The numbers refer to number of patients. IFX, ifosfamide; P, cisplatin; EDAM, ethyl- 10-deazaaminopterin; CBDCA, carboplatin; CTX, cyclophosphamide; FU, fluorouracil; MMC, mitomycin C; DVA, vindesine; DX, doxorubicin. MVP = mitomycin, vindesine, cisplatin; CAP = cyclophosphamide, doxorubicin, cisplatin.
of the matter is how to approach neoadjuvant chemotherapy in patients staged as IIIA. Whether or not survival is enhanced by using chemotherapy before surgery in surgically resectable stage IIIA requires a randomized controlled trial such as Roth et al. [34] carried out in esophageal cancer. The results of our trial proved to be negative because the type of chemotherapy used was shown to be ineffective, as demonstrated by the high tumor progression rate, as well as the poor response rate yielded, which was significantly lower than the 50% threshold attained in stage I11 with cisplatin-based regimens. Indeed, more effective chemotherapy regimens are needed to maximize neoadjuvant approaches.
REFERENCES I . Holmes EC: Surgical adjuvant therapy of non-small-cell lung cancer. J Surg Oncol [Suppl] 1:26-33, 1989. 2. Naruke T, Goya T, Tsuchiya R, Suemasu K: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96:440-447, 1988. 3. Simpson-Herren L, Sonford AH, Holmquist JP: Effects of surgery in the cell kinetics of residual tumor. Cancer Treat Rep 60:17491760, 1976. 4. Klastersky J: Chemotherapy in non-small cell lung cancer (NSCLC). Eur J Cancer Clin Oncol 25:1035-1038, 1989. 5. Martini N, Kris MG, Gralla RJ, Bains MS, Mc Cormack PM, Kaiser LR, Burt ME, Zaman MB: The effects of preoperative chemotherapy on the resectability of non-small cell lung carcinoma with mediastinal lymph node metastases (N2MO). Ann Thorac Surg 45:370-379, 1988.
6. Faber LP, Kittle CF, Warren WH, Bonomi PD, Taylor SG, Reddy S, Lee M-S: Preoperative chemotherapy and irradiation for stage 111 non-small cell lung cancer. Ann Thorac Surg 47:669-677, 1989. 7. Skarin A, Jochelson M, Sheldon T, Malcolm A, Oliynyk P, Overholt R, Hunt M, Frei I11 E: Neoadjuvant chemotherapy in marginally resectable stage IIIMO non-small cell lung cancer: long-term follow-up in 41 patients. J Surg Oncol 40:266-274, 1989. 8. Rosell R, Abad-Esteve A, Moreno I, Barnadas A, Carles J, Fernandez C, Ribelles N , Culubret M: A randomized study of two vindesine plus cisplatin containing regimens with the addition of mitomycin or ifosfamide in patients with advanced non-small cell lung cancer. Cancer 65: 1692-1699, 1990. 9. Giron CG, Ordofiez A, Jalon JI, Baron MG: Combined chemotherapy with ifosfamide, mitomycin and cisplatin in advanced non-small cell lung cancer. Cancer Treat Rep 71:851-853, 1987. 10. Thatcher N, Smith DB, Lind MJ, Anderson H, Barclay J , Chopra MP, Fitzgerald MD: Double alkylating agent therapy with ifosfamide and cyclophosphamide for advanced non-small cell lung cancer. Cancer 61:34-18, 1988. 1 1 . Watkin SW, Husband DJ, Green JA, Warenuis HM: Ifosfamide encephalopathy: A reappraisal. Eur J Cancer Clin Oncol25: 13031310, 1989. 12. Rosell R, Abad-Esteve A, Roig J, Moreno I, Fernandez C, Ribas M: The role of combination cyclophosphamide, doxorubicin and cisplatin (CAP) chemotherapy in advanced non-small-cell lung cancer. Tumori 73:345-349, 1987. 13. Rosell R, Abad-Esteve A, Morera J, Monras P, Moreno I, Ruiz J, Fernandez C, Ribas M: A randomized study comparing platinum, doxorubicin and VP-16 with platinum, 4’-epidoxorubicin and VP-16 in patients with non-small-cell lung cancer. Am J Clin Oncol (CCT) 10:245-248, 1987. 14, Mountain CF: A new international staging system for lung cancer. Chest [Suppl] 89:225-232, 1986. 15. Naruke T, Suemasu K , Ishiwaka S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76:832-838, 1970.
130
Rose11 et al.
16. Dautzenberg B, Chastang CL, Lebeau B, Coetmeur AD, Benichou J, Postal MJ: A randomized phase 11 trial of neoadjuvant
17.
18. 19.
chemotherapy in resectable bronchogenic non small cell carcinoma. Short term results. In Jacquillat CI, Weil M, Khayat D (eds): “Neo-adjuvant Chemotherapy”. London: John Libbey Eurotext Ltd, 1988, pp 365-370. Shridar KS, Thurer R, Kim Y, Fountzilas G, Davila E, Donnelly E, Charyulu KKN, Saldana MJ, Thompson T, Benedetto P, Raskin N , Beattie EJ: Multimodality treatment of non-small cell lung cancer: response to cisplatin, VP-16, and 5-FU chemotherapy and to surgery and radiation therapy. J Surg Oncol 38:193215, 1988. Gralla RJ: Multi-modality therapy for stage 111 non-small cell lung cancer. Am Soc Clin Oncol, Educational Booklet, San Francisco, 1989, pp. 27-31. Burkes R, Ginsberg R, Shepherd F, Blackstein M, Goldberg M, Waters P, Patterson A, Todd T, Pearson F, Cooper J, Jones D: Neo-adjuvant trial with MVP (mitomycin-C +vindesine cisplatin) chemotherapy for stage 111 (TI-3, N2, MO) unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol8:221, 1989. Henriquez Lopez I, Muiioz Galindo L, Ortiz de Urbina D, Calvo FA: Neoadjuvant chemotherapy (NAC) with cisplatin (CDDP), vindesine (VDS) and mitornycin C (MMC) in locally advanced non-small cell lung cancer (NSCLC). 5th European Conf on Clinical Oncology,-1989, p 67. Collins C. Weiden PL: Cardiotoxicitv of 5-fluorouracil. Cancer Treat Rep 71:733-736, 1987. Dillman RO, Seagren SL, Propert K, Eaton WL, Frei EF, Green MR: Protochemotherapy improves survival in regional non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol7:195, 1988. Niitamo-Korhonen S , Holsti P, Holsti RL, Pyrhonen S, Mattson K: A comparison of cis-platinum-vindesine and cis-platinumetoposide combined with radiotherapy for previously untreated localized inoperable non-small cell lung cancer. Eur J Cancer Clin Oncol 25:1039-1043, 1989. Livingston RB: Treatment of advanced non-small cell lung cancer: The Southwest Oncology Group experience. Semin Oncol [Suppl] 15:3741, 1988. Costanzi JJ, Gagliano R, Lukas D, Panettiere FJ, Hokanson JA: lfosfamide in the treatment of recurrent or disseminated lung cancer. Cancer 41:1715-1719, 1978. Klastersky J , Sculier JP, Bureau G, Libert P, Ravez P, Vandermoten G, Thiriaux J, Lecomte J, Cordier R, Dabouis G, Brohee D, Themelin L, Mommen P: Cisplatin versus cisplatin plus etoposide in the treatment of advanced non-small cell lung cancer. J Clin Oncol 7:1087-1092. 1989.
+
20.
21, 22. 23.
24. 25. 26.
27. Crino L, Meacci L, Corgna E, Buzzi F, Di Costanzo I;, Darwish S, Tonato M: A randomized trial of 3 cisplatin containing regimens for advanced non small cell lung cancer. Proc V World Conf Lung Cancer 4: 119, 1988. 28. Garzemeier U, Hossfeld DK, Heuhauss R, Achterrath W, Lenaz L: Phase I1 trial with carboplatin in patients with advanced unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 8:237, 1989. 29. Bonomi PD, Finkelstein DM, Ruckdeschel JC, BIum RH, Green MD, Mason B, Hahn R, Tormey DC, Harris J, Comis R, Glick J: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. J Clin Oncol 7: 1602-161 3, 1989. 30. Kris MG, Gralla RJ, Potanovich LM, Marks LA, Heelan RT: Incorporating 10-ethyl- 10-deazaaminopterin (EDAM) into combination therapy with mitomycin and vinblastine for patients with advanced non-small cell lung cancer. Proc Am SOCClin Oncol 8:227, 1989. 31. Gralla RJ, Kris MG, Potanovich LM, Marks LA, Healan RT: Enhancing the safety and efficacy of the MVP regimen (mitomycin vinblastine t cisplatin) in 100 patients with inoperable non-small cell lung cancer. Proc Am Soc Clin Oncol8:227, 1989. 32. Cullen MH, Joshi R, Chetiyawardana AD, Woodroffe CM: Mitomycin, ifosfamide and cis-platin in non-small cell lung cancer: treatment good enough to compare. Br J Cancer 58:359361, 1988. 33. Banks J, Anderson EG, Smith AP: Failure of response to ifosfamide in squamous cell bronchogenic carcinoma. Cancer Chemother Pharmacol 23:128, 1989. 34. Roth JA, Pass HI, Flanagan MM, Graeber GM, Rosenberg JC, Steinberg S: Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 96:242-248, 1988. 35. Shum KY, Kris MG, Gralla RJ, Burke T, Marks LD, Heelan RT: Phase I1 study of 10-ethyl- 10-deaza-aminopterin in patients with stage 111 and IV non-small-cell lung cancer. J Clin Oncol 64-50, 1988. 36. Drings P: European experience with ifosfamide in non-small cell lung cancer. Sem Oncol (Suppl 3) 16:22-30, 1989. 37. Rusch V, Weiden P, Hill L: Patterns of relapse following neo-adjuvant therapy for regionally inoperable non-small cell lung cancer. Lung Cancer [Suppl] 4:A-161. 1988.
+
