Dose-finding study of paclitaxel (Taxol1) plus cisplatin in patients with non-small cell lung cancer

LUNG

CANCER Lung Cancer 12 Suppl. 2 (1995) S1I7-S125

~

Dose-finding study of paclitaxel (Taxol l ) plus cisplatin in patients with non-small cell lung cancer 1. Klastersky*, J.P. Sculier, European Lung Cancer Working Party Department of Medicine, lnstitut Jules Bordet, I rue Heger-Bordet, /000 Brussels. Belgium

Received 7 December 1994; revision received 9 March 1995; accepted 10 March 1995

Abstract We conducted a phase I trial in advanced NSCLC to determine the optimal dosage of the new active drug paclitaxel (Taxol), in combination with high-dose ciplastin (CDDP). Taxol was infused over 3 h, followed by CDDP given over 30 min with hyperhydration. Main criteria of selection were the presence of metastatic or locally relapsing pathologically proven NSCLC, stage IIIB or IV and no prior therapy. Out of 17 treated patients, eight objective responses (47%)were documented. Significant but transient neutropenia was observed in steps III and IV. In seven patients, who received more than three courses, treatment was discontinued for severe polyneuropathy in five, cancer progression in one and unrelated disease in one. In conclusion, paclitaxel plus cisplatin, although active, was associated with severe late neurological toxicity prohibiting the administration of multiples courses.

Keywords: Paclitaxel (Taxol); High-dose ciplastin; Non-small cell lung cancer; Neutropenia

1. Introduction Non-small cell lung cancer (NSCLC) is one of the tumour types in which chemotherapy has been most extensively tested. A number of drugs have single-agent activity (greater than 10% response rate) in NSCLC, including cisplatin, vinblastine and vindesine, mitomycin C, ifosfamide and etoposide. Although patients who receive these drugs attain even higher response rates when the drugs are used in combination ITaxol is a trademark of Bristol-Myers Squibb Company • Corresponding author. Elsevier Science Ireland Ltd. SSDIOI69·5002(95)00471-C

5118

J. Klastersky et at. / Lung Cancer 12 Suppl.

2 (1995) Slt7-S125

chemotherapy (from 20-60%), the duration of response and the median survival (30-40 weeks) are short and the number of complete responses (CRs) remains low, even with aggressive and toxic schedules. However, several studies have demonstrated an improvement in survival with combination chemotherapy over best supportive care [I]. Therefore, NSCLC is a disease for which new drugs and treatment modalities are investigated in patients not previously treated by chemotherapy. Cisplatin is one of the most active drugs in NSCLC, having achieved a response rate of 14%in a cumulative number of 354 previously untreated patients. It also appears to have a dose-response effect in both NSCLC tumours and other neoplastic diseases. Results of several trials and a recent meta-analysis show that doses of 100-120 mg/m? are consistently more active than lower doses (up to 70 mg/m') [2]. On the other hand, although cisplatin-containing regimens yield reproducible response rates in the range of 30%, they have little effect on the survival of patients with NSCLC. Furthermore, no randomized study comparing cisplatin alone with a cisplatin-containing combination has shown any survival benefit. A randomized comparison of cisplatin with cisplatin plus etoposide by the European Lung Cancer Working Party showed response rates of 17%and 43%, respectively, with no significant difference in survival [3]. Paclitaxel (Taxol) is a novel cytotoxic agent extracted from the bark of the Pacific yew (Taxus brevifoliat. Phase II studies have shown that paclitaxel is an effective antineoplastic agent, especially ovarian cancer. With regard to toxicity, myelosuppression has been reversible, peripheral neuropathy has been dose-related, and hypersensitivity reactions have been obviated by lengthening the duration of infusion and by administering intensive premedication. Two recent studies have reported significant activity with paclitaxel in chemotherapy-naive patients with NSCLC [4,5]. In a phase II study by the Eastern Cooperative Oncology Group (ECOG), five partial responses (PRs) were obtained in 24 evaluable patients (21%), which represents the highest response rate recorded by ECOG with single-agent therapy in NSCLC [4]. In another phase II study performed at the M.D. Anderson Cancer Center, one CR and five PRs were observed in 25 evaluable patients (overall response, 24%) [5]. In both studies, paclitaxel, given in 24-h infusions of 250 and 200 mg/m', respectively, was reasonably well tolerated. Attempts to improve the response rate and survival of patients with NSCLC have been made by using cisplatin in combination with paclitaxel. Because these agents act through different mechanisms of action, it is possible that they may be synergistic or at least additive in NSCLC. On the other hand, there are indications that paclitaxel is not active as a salvage therapy after failure of NSCLC to cisplatin [6,7] and no positive interactions have been detected in vitro between paclitaxel and cisplatin in two NSCLC lines [8]. In a sequential phase I study, Rowinsky et al. [9] reported that administration of cisplatin followed by paclitaxel was more myelotoxic than paclitaxel followed by cisplatin. Recommended doses for paclitaxel and cisplatin were 135-170 mg/m' and 75 mg/m/, respectively. There is not much published information, so far, regarding

J. Klastersky et al. / Lung Cancer 12 Suppl. 2 (/995 ) S1/ 7-S1 25

SI19

the optimal dosage and efficacy of the combination of paclitaxel and cisplatin in NSCLC. Three recent abstracts presented at the 1994 ASCO meeting , deal with paclitaxel plus carboplatin in NSCLC; an objective response was observed in 18 (29%) of 82 patients [10-12]. Rowinsky et al. investigated the maximum tolerated doses (MTDs) of paclitaxel, given by 24-h infusion, and cisplatin when administered with granulocyte colonystimulating factor (G·CSF) support. Responses were achieved in patients with NSCLC, head and neck cancer and oesophageal cancer. The authors concluded that administration of G-CSF with this regimen results in higher neutrophil counts, briefer neutropenia and fewer hospitalizations as compared with paclitaxel/cisplatin alone. Peripheral neuropathy was dose-limiting at 300 mg/m/ paclitaxel in combination with 75 mg/m? cisplatin. A detailed study of peripheral neuropathy from paclitaxel and cisplatin combination, including electrophysiological investigations, was recently published by Chaudhry et al. [14]; it confirms that peripheral neuropathy is likely to be the limiting toxicity of paclitaxel plus cisplatin combination chemotherapy. The present study was undertaken in previously untreated patients with NSCLC: (I) to determine the MTD of paclitaxel when administered as a 3-h intravenous infusion in combination with cisplatin every 3 weeks; (2) to evaluate the nature, frequency, severity and duration of adverse events associated with this drug combination; and (3) to evaluate the combination's antitumour efficacy.

2. Patients and methods To be eligible for the study, patients had to have histologically proven metastatic or locally relapsed NSCLC (stage IIIB or IV), be 18-75 years of age, and have a Karnofsky performance status of at least 60%. Prior to chemotherapy, the neutrophil count had to be at least 1500/JLI and the platelet count at least 100 000/JLI. Serum levels of bilirubin and creatinine could not be greater than 1.25 times the normal value. All patients provided informed consent, and all were accessible to prolonged follow-up. Exclusion criteria were as follows: extensive irradiation during the last 4 weeks prior to chemotherapy, CNS metastases, cardiac arrhythmia or heart failure, myocardial infarction during the last 6 months, history for first- or second-degree heart Table 1 Schedule of drug administration Dose level

Paclitaxel (mg/m2)

Cisplatin (mg/m2)

-I 1

135 135

75

If needed

2 3 4

200 200

100 100 100

3-6 3- 6 3- 6 3- 6

170

120

No. of patients

8120

J. Klastersky et 01. / Lung Cancer 12 Suppl. 2 ( 1995) SlJ 7-S125

block, polyneuropathy (greater than WHO grade II) and active infection , dementia or other severe neurological disease. It was decided to evaluate responses following three courses of paclitaxel-cisplatin chemotherapy. Treatment would be discontinued in patients showing disease progression. Partial responders would be treated until the optimal response was obtained, and complete responders would receive four courses of maintenance therapy. The treatment plan is summarized in Table I. The study was designed to define the MTD of paclitaxel in combination with cisplatin. MTD was defined as the dose at which two or more of six patients had one of the following: neutrophil count less than 5OO/,.Ll for more than 7 days; febrile neutropenia (body temperature at least 38.2°C, neutrophil count less than 500/,.Ll); grade IV thrombocytopenia (less than 25 OOO//Ll); grade III mucositis for more than 7 days; other grade III toxicities (except pain, emesis, and alopecia) ; no haematological recovery by day 35; persistent non-haematological toxicity greater than grade II (except pain, emesis, and alopecia) on retreatment date. All patients underwent continuous cardiac monitoring during treatment and received premedication (dexamethasone, promethazine and cimetidine) for possible hypersensitivity reactions. In addition, standard antiemetic prophylaxis was administered with metoclopramide, dexamethasone and lorazepam. Paclitaxel was administered over 3 h, followed by cisplatin, which was administered over 30 min. Hyperhydration was performed over 24 h with mannitol and 4 I of 5% dextrose and 0.45% saline. 3. Results Patient characteristics, clinical results and data relevant to haematological and non-haematological toxicity are summarized in Tables 2a and 2b. The first three patients, who received cisplatin and paclitaxel at doses of 100 mg/m? and 135 mg/rrr', respectively, were all men with stage IV NSCLC. After three courses, two patients achieved PRs lasting 8 and 14 months as therapy was continued. The third showed disease progression after three courses and survived 2.5 months. None of these patients received any further therapy. No serious neutropenia or thrombocytopenia occurred in this group. The most serious early toxicities were alopecia and nausea and/or vomiting (WHO grade II, except one patient with WHO grade III alopecia). No other serious side effects were observed in these patients; one patient had grade I mucositis, and two patients had infection , none of which were severe. One patient (no. 2) developed grade III peripheral neuropathy after nine courses; he also presented transient reactions, considered to represent hypersensitivity to the treatment after the seventh course, and which were controlled by corticoids during the following courses. The second group of patients consisted of one man and two women with stage IV NSCLC who received three courses of cisplatin/paclitaxel at doses of 100 mg/m? and 170 mg/m', respectively. One patient experiencing no change in tumour was treated subsequently with another chemotherapy and survived for 7.5 months. The two other patients had disease progression after three courses and later received radi-

(3)

(9) (7)

2 2 0 0 0 I 0 I 0 (l)

(2)

I (I)

(l )

0 I (I) 0 0 0 0 I (3)b

3 (2)

1652 14 233

(2)

2 2 0 3 2 0 0 2 0

3 (4) 2 (l) 0 0 0 0 0 2 (3) 0

(3) (3)

4810 II 277

2088 13 141

3 (l) 3 (l) 0 0 0 0 0 0 I (3)d

1941 14 272

7.5 CT+RT

2.5 CT

14 None

3440 II 132

-

-

-

F 47 Sq 0 60 IV Li 3 Progression

5

M 59 Sq 4 90 IV L 3 No change

4

M 39 Ad 28 60 IV B,A,K,N 3 Progression

3

M 63 Sq II 70 IV L 9 Partial 14 8 None

2

M 62 Sq 12 70 IV B 5 Partial 8 rOO None

I

0 0 0

I (l)

3 (2) 0 0 0 0

822 15 117

9 RT

-

F 61 Ad 14 80 IV B 3 Progression

6

Cisplatin 100 mg/m 2 + paclitaxel 170 mg/m 2

Sqesquamous cell carcinoma, Ad=adenocarcinoma; PS=performance status, +B=bone, Lelung, Aeadrenals. Keekidney, N=lymph nodes, Br=brain, Skeskin, Li=liver, CT=chemotherapy, Sesurgery, RTeeradiotherapy, "highest WHO grade after three courses (no . of course), bhypotension,
Clinical course Sex Age, years Histology Weight loss (%) Karnofsky PS Stage Metastases+ No courses Response Response duration, mo Survival, Further therapy Haematological toxicity Nadir neutrophils Day of nadir Lowest platelet count (x 10(0) Side effects" Alopecia Nausea/vomiting Nephrotoxicity Neurotoxicity Hypersensitivity Mucositis Cardiotoxicity Infection Others

Patients

Cisplatin 100 mg/m ' + pacl itaxel 135 rng/rn/

Table 2 (a) Patient characteristics and results of treatment

~

en ;::;

~

I

CI:l

CI:l

-"

'0

~ ......

---""'

CI:l

.,.:§,....

~

-'"..

~ :.

~

r-

<,

I::l ,....

~

~

c:::

~

is''

>::

Patients

0 0 0 4 (I) 22 (I) Id

I (I)

2 (I) 2 (I)

8k IIIk

no l

37 days None

-

Death

I

o If (2)

o

Ie (4)

I t (3) 0 0 0

o

3 (2) 2 (2) 0 0 0 0 0

2064 20 174

3 (2) 2 (I)

3360 16 287

0

()

2& (4)

o

2 (4) 0 0 0

o

3 (2) 0

3 (2) I (5) 1 (8) I (5) 0 0 0

163

8

11 20 9 77

18(4)

o

1(6) 0 0 0

o

3 (2) 2 (5)

3775 12 225

CT

6 None

3 (I) 0 0 0 0 0 3 (3) J (3) 31

3 (2 ) 0 0 0 0 0 0 0 2h

-

-

3 (I) 3 (I ) 0 2 (5) 0 0 0 0 0

950 16

1/2 10

286 13

4

-

-

5 14+ None

Partial

4

Li N 5 Partial 6 14+ RT

IV

IV B 8 Partia l 10+ 10+ None

IV

1178

Partial 17+ 17+ None

8

IV Li ,B

IV Li 3 Partial 15+ 15+ S+ RT

IV

N 6 Partial 5 10 CT+RT

IV

A

-

0

o

0 0 0 0 0

1 (I)

3 (I)

2/93 15

12+ CT+RT

-

M 58 Ad 0 80 iliA 0 3 No change

F 41 Ad 0 80 IV B,Sk ,L 3 Pro gessio n

M 66 Sq 9 100 IV Br,B 3 No change

F 54 Sq 0 100

M 55 Ad 0 70

M 56 Sq 0 100

M 69 Ad 0 90

M 45 Sq 6 80

F 47 Sq 0 80

M 66 Ad 7 70

16

15

14

12 13

II

10

9

8

7

2 (2) 0 0 0 0 0 3 (2) 0 0

4446 1

9+ CT

-

M 56 Ad 4 70 IV B,Br 2 No change

17

Cis platin 120 mg/m 2 + paclitaxel 200 mg/rn?

Sq= squ amous cell ca rcin oma, Ade adenocarcincma: PS=performance status , +B =bone, L= lung, A= adrenals, K=kidney, N= lymph nodes, Br=brain , Sk e skin, Li=/iver, C'I'ecbernotberapy, Sesurgery, RT =radiotherapy, "highest WHO grade a fter thre e courses (No. of course), bhypotens ion, cdiarr hea, dtransient hype rbilirubinemia, "xerostmia. fskin rash, 8diarrhea , "phelbitis-exerostoamia. icellulitis from extrav asation, jgrad e I" toxicit y during third co urse, kduring first course, 'only two courses given ; arythmia developed pr ior to third course.

Sex Age, years Histology Weight loss (%) Karnofsky PS Stage Metastases» No course s Respo nse Response duration , mo Surviva l, mo Fur ther therapy Haematological toxic ity Nadir neutrophils Day of nadir Lowest platelet count (x 1000) Side effects" Alopec ia Nausea/vomiting Neph rotoxicity Neurotoxicity Hypersen sitivity Muco sitis Ca rdiotoxicity Infection Others

-Clinica l co urse

Cisplat in 100 mg/m 2 + paclitaxel 200 mg/m ?

Table 2b Patient characte ristics and results of treatment en

~

~

"I

...~

"-

G:

~

t",

'",... ...-e

-§

'".,... '" v,

,..,"

Q

~

t"-

<,

~

',..."

""

~

s~

>;

~

N N

J. Klastersky et 01. / Lung Cancer /2 Suppl. 2 (/995) SII7-S/25

Sl23

ation therapy (with the addition of cisplatin in one patient). The survival was 9 and 7 months, respectively. Neutropenia was more pronounced with this schedule of cisplatin/paclitaxel, but a neutrophil count less than 100/1t1 was observed in only one patient (on day 15 after chemotherapy). Thrombocytopenia was not encountered. Non-haematological side effects included grade III alopecia (three patients), grades I and III nausea and vomiting (two patients) and mild neurotoxicity, grade I mucositis, mild hypotension and diarrhoea (one patient each). No nephrotoxicity, hypersensitivity, cardiotoxicity or infection was seen in this group of patients. The next group comprised five men and one woman with stage IV NSCLC who received cisplatin and paclitaxel at doses of 100 and 200 mg/rrr', respectively. All these patients had PRs and were continued on therapy for four to eight additional courses. One patient experienced neutropenia and another one had thrombocytopenia (77 OOO/ltl) documented during the third course of therapy. Nonhaematological side effects included alopecia (all patients) , and grade I or II nausea and vomiting (four patients) . In one patient (no. 11), grade II neurotoxicity and diarrhoea was seen during the fourth course of therapy. One patient , a 66-year-old man with a right upper-lobe adenocarcinoma and unilateral adrenal metastasis, died of massive hemoptysis 37 days after receiving cisplatin and paclitaxel. He had lost 7% of his weight prior to entry and performance status was 70%. Except for chronic obstructive pulmonary disease, his past medical history was unremarkable. He developed fever on day 7 after chemotherapy and was rehospitalized with fatigue, hypotension, and hyponatremia (117 mmol/l). The following day (day 8 after chemotherapy) he developed atrial fibrillation and had two cardiac arrests (grade IV cardiotoxicity); he was successfully resuscitated and given artificial ventilation until his death. On day 18, he developed bilateral pneumonia; Candida sp was found in the sputum and urine requiring treatment with teicoplanin, ceftazidime and fluconazole. After 7 days, fluconazole was changed to amphothericin B because of the persistence of yeasts in the sputum and urine; 5 days later, teicoplanin, and ceftazidime were changed to amikacin and ciprofloxacin after Staphylococcus epidermidis and Pseudomonas cepacia were found in the sputum. He also experienced a rise in his serum creatinine, from an initial value of 0.7 mg% to 2.5 mg% on day 10 before returning to normal (0.9 mg%) on day 18. His serum level of bilirubin also increased, from an initial value of 1.0 mg% to 6.9 mg% on day 10, before returning to normal on day 22 (1.2 mg%). No clear explanation could be found for these renal and liver abnormalities; they might have been related to chemotherapy or to the circulatory, ventilatory and infectious problems the patient was having. No other side effects were seen in the other patients in this group . The last group is made, up to now, to five patients: two women and three men, with two squamous cell carcinomas and three adenocarcinomas; four of these patients had a stage IV disease and one was staged IlIA but was not operable. These patients received cisplatin and paclitaxel at doses of 120 and 200 mg/m/, respectively. One patient presented a partial remission and in another (no. 17), a minor response was seen after two courses but the patient was taken out of the study because he developed atrial fibrillation just prior to the third course; in two other patients

S124

J. Klastersky et 01. / Lung Cancer 12 Suppl. 2 (1995) S1J7-S125

no change of the tumor was seen; one patient progressed. Further chemotherapy was given to two patients, radiotherapy to one, and one has received chemotherapy combined with radiotherapy. Three patients presented with granulocytopenia on days 13, 10 and 16 but moderate thrombocytopenia was seen in only one patient. Alopecia was observed in all patients and nausea and/or vomiting in two. Neurotoxicity was seen in one patient and another one presented a thrombophlebitis. In one patient (no. 14), grade III cardiac toxicity (atrial fibrillation and heart failure) and infection (Ps. aeruginosa bacteremia) occurred during the third course of therapy, which was not continued beyond that course.

4. Discussion Cisplatin is one of the most active drugs available for the treatment of NSCLC. In our own studies and meta-analysis, the response rate to cisplatin is in the range of 22-25%. There is some indication that, at least in patients with limited (i.e. stage III) disease, higher doses of cisplatin might yield higher response rates and that the addition of etoposide might bolster responsiveness as compared with cisplatin alone. Nevertheless, there is no evidence that higher cisplatin doses or the addition of etoposide improves survival [3]. Paclitaxel has achieved response rates of 20-30% in NSCLC. Since paclitaxel exerts its cytostatic effect through a different mechanism than cisplatin, and because paclitaxel does not share the nephrotoxic or ototoxic potential of cisplatin, it appears reasonable to use these drugs in combination. In designing such a combination, we recognized that both drugs are associated with some haematological toxicity and have neurotoxic potential. In this dose-finding study, we observed eight (47%) PRs in 17 patients with stage IV NSCLC treated with cisplatin-paclitaxel at different dose intensities; no changes were observed in four patients and four others experienced disease progression after receiving three courses. In addition, one patient died of massive hemoptysis 37 days after treatment; that event was preceded by several medical complications beginning on day 8 after chemotherapy, among which were atrial fibrillation, bradycardia, cardiac arrests, need for mechanical ventilation, possible bacterial and fungal diseases, and a rise in serum creatinine and bilirubin. However, the overall status of that patient, including serum creatinine and bilirubin levels, stabilized a few days prior to his death. Because of these complications, the patient's response to treatment could not be adequately assessed. Very striking in this study is the relative lack of haematological toxicity. Severe neutropenia, i.e. neutrophil counts lower than 5OO/ILI, were observed in only two patients. Infection was observed in three patients but was not severe. Thrombocytopenia was seen in one patient in this series and was moderate (77 000/1L1). The most frequent and severe non-haematological side effects were alopecia and nausea and/or vomiting. All of these toxicities were below grade IV. Neurotoxicity, consisting of peripheral neuropathies, occurred so far in five out of seven patients who received three or more courses of therapy with cisplatin-paclitaxel. Nephrotoxicity was not seen in this series; only two patients out of the 12 who received at least three courses of chemotherapy had a mild and transient elevation

J. Klastersky et af. / Lung Cancer 12 Suppl. 2 (1995) SJJ7-S125

SI25

of the serum creatinine (grade I). In one patient after one course and in the other after eight courses. In conclusion, paclitaxel plus cisplatin, although active in NSCLC, was associated with late neurological toxicity, prohibiting the administration of prolonged therapy.

References [I] Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; II: 1866-1872. [21 Donnadieu N, Paesmans M, Sculier JP. Chemotherapy of non-small lung cancer according to disease extent: a meta-analysis of the literature. Lung Cancer 1991; 7: 243-252. [3] Klastersky J, Sculier JP, Lacroix H et al for the European Organization for Research and Treatment of Cancer Lung Working Party. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8: 1556-1562. [4] Chang Ay, Kim K, Glick J et al. Phase II study of Taxol, merbarone, and piroxantrone in stage IV non-small cell lung cancer: the Eastern Cooperative Oncology Group results. J Natl Cancer Inst 1993; 85: 388-394. [51 Murphy WK, Fosselia FV, Winn RJ et al. Phase II study of Taxol in patients with untreated advanced non-small cell lung cancer. J Natl Cancer Inst 1993; 85: 384-388. [6] Ruckdeschel J, Wagner Jr H, Williams C et al. Second-line chemotherapy for resistant, metastatic, non-small cell lung cancer (NSCLC): the role of taxol (Tax). Proc ASCO 1994; 14: Abstract 1200. [71 Murphy WK, Winn RJ, Huber M et al. Phase II study oftaxol (T) in patients (PT) with non-small cell lung cancer (NSCLCL) who have failed platinum (P) containing chemotherapy (CTX). Proc ASCO 1994; 14: Abstract 1224. [8] Viallet J, Boucher L, Gallant G. In vitro interactions between palcitaxel (TAX) and other agents in human non-small cell lung cancer (NSCLCL) cell lines: antagonism with etoposide (VP-16) and doxorubicin (DOX). Proc ASCO 1994; 14: Abstract 1233. [9] Rowinsky EK, Gilbert MR, McGuire WP et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991; 9: 1692-1703. [10] Israel VK, Zaretsky S, Natale RB. Phase 1111 trial of combination carboplatin and taxol in advanced non-small cell lung cancer (NSCLC). Proc ASCO 1994; 14: Abstract 1175. [II] Paul DM, Johnson DH, Hande KR et al. Carboplatin (C) and Taxo1 (T): a well tolerated regimen for advanced non-small cell lung cancer (NSCLC). Proc ASCO 1994; 14: Abstract 1121. [12] Langer CJ, Leighton J, Comis R et al. Taxol and carboplatin (CBDCA) in combination in stage IV and IIIB non small-cell lung cancer (NSCLC): a phase II trial. Proc ASCO 1994; 14: Abstract 1122. [13] Rowinsky EK, Chaudry V, Forastiere AA et al. Phase I and pharmacological study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J Clin Oncol 1993; II: 2010-2020. [141 Chaudry V, Rowinsky EK, Sartorius SE et al. Peripheral neuropathy from Taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994; 35: 304-311.