R e g i m e n i n M a l i g n a n t M e s o t h e l i o m a :
R e s u l t s o f a P h a s e I I S t u d y
By K. Fizazi, H. Doubre, T. Le Chevalier, A. Riviere, J. Viala, C. Daniel, L. Robert, P. Barthe´lemy, A. Fandi, and P. Ruffie´ Purpose: The aim of this open-label phase II study was to
evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in pa-tients with diffuse malignant pleural mesothelioma.
Patients and Methods: Fifteen pretreated and 55 chemo-therapy-naive patients (median age, 60 years; World Health Organization performance status of< 2) were en-rolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2followed by oxaliplatin 130 mg/m2every 3 weeks.
Results: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive
pa-tients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pre-treated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothe-lioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported.
Conclusion: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.
J Clin Oncol 21:349-354. © 2003 by American
Society of Clinical Oncology.
M
ALIGNANT MESOTHELIOMA is a tumor of the pleura
or the peritoneum.
1,2In more than 70% of patients, the
origin of the tumor is linked to a history of exposure to asbestos
fibers,
3,4especially crocidolite, which is better known as blue
asbestos. In Western Countries, concerns have arisen in recent
years regarding the increasing incidence of malignant
mesothe-lioma. This has been mainly because of the fact that this disease
is seldom curable.
5It is estimated that from 1940 to 1979,
approximately 27.5 million workers in the United States were
occasionally exposed to asbestos, with a calculated annual death
rate from malignant mesothelioma of around 2,000 in 1980
and 3,000 in the late 1990s.
6Today, the median survival of
patients is still poor, generally ranging from 4 months for
extensive malignant disease to 18 months for malignant local
pleural disease.
7Malignant mesothelioma is notoriously
re-fractory to treatment, and neither surgery nor radiotherapy
alone results in an increased survival.
8,9Although many
therapeutic options have been developed to treat the disease,
no standard therapy has emerged until now.
2,10,11Further
phase II studies of antineoplastic agents in malignant
me-sothelioma are therefore recommended.
10Raltitrexed (Tomudex; AstraZeneca, Cergy, France) is a
quinazoline folate analog that acts as a specific thymidylate
synthase inhibitor. It has demonstrated benefits in the treatment
of a variety of advanced solid tumors.
12,13In vitro studies with
raltitrexed have also demonstrated that raltitrexed has activity in
cisplatin-resistant cell lines.
14Oxaliplatin is a new platinum
deriv-ative that inhibits DNA replication through the formation of DNA
adducts. Oxaliplatin has demonstrated activity in the treatment of
advanced tumors, both in combination and in monotherapy
regi-mens.
15,16Notably, oxaliplatin has in vitro activity in
cisplatin-resistant cell lines
17,18and clinical activity in the treatment of some
cisplatin/carboplatin refractory diseases.
19-21Both in vitro and in vivo studies have demonstrated that
oxaliplatin has either a synergistic or an additive antitumor
activity when combined with thymidylate synthase inhibitors
such as raltitrexed.
22A phase I study of raltitrexed and
oxali-platin in 48 patients with advanced solid tumors determined the
recommended dose as raltitrexed 3 mg/m
2and oxaliplatin 130
mg/m
2every 3 weeks.
23This combination had shown promising
activity in the therapy of pretreated and chemotherapy-naive
malignant mesothelioma. Overall, six of 17 patients with
me-sothelioma entered in the phase I study achieved a partial
response, including four of 10 patients with cisplatin-resistant
tumors.
23The combination was well tolerated with no reported
alopecia and no major hematologic toxicity.
The aim of this phase II study was to evaluate further the
combination of raltitrexed and oxaliplatin in terms of efficacy
(objective response [OR] rates and duration, time to progression,
overall survival, and self-reported symptoms [pain in particular])
in patients with malignant pleural and peritoneal mesothelioma.
Chemotherapy-naive and pretreated patients were both studied.
From the Department of Medicine, Institut Gustave Roussy, Villejuif; Centre Franc¸ois Baclesse, Caen; AstraZeneca, Rueil-Malmaison, France; and AstraZeneca, Macclesfield, United Kingdom.
Submitted May 21, 2002; accepted September 30, 2002.
Address reprint requests to Karim Fizazi, MD, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France, email: fizazi@igr.fr.
© 2003 by American Society of Clinical Oncology. 0732-183X/03/2102-349/$20.00
349
Journal of Clinical Oncology,Vol 21, No 2 (January 15), 2003: pp 349-354 DOI: 10.1200/JCO.2003.05.123
The toxicity profile of the raltitrexed/oxaliplatin combination
during all cycles was also explored.
PATIENTS AND METHODS
Study Design
This was an open-label, noncomparative, two-center, phase II study of raltitrexed plus oxaliplatin in patients with diffuse malignant mesothelioma. The study was conducted in accordance with Good Clinical Practice and approved by the ethics committees of the two participating centers.
Patients
Patients with a histologically proven diagnosis of malignant mesothelioma of the pleura or peritoneum were eligible for the study if they met the following inclusion criteria: (1)ⱖ18 years of age, with a life expectancy ofⱖ12 weeks; (2) World Health Organization performance status ofⱕ2; (3) satisfactory baseline hematologic and organ function; (4) at least one measurable lesion (bidimensionallyⱖ2 cm or unidimensionally⬎0.5 cm); and (5) had given their written informed consent for participation in the trial. Two groups of target patients were defined: pretreated patients (maximum of two previous regimens) and chemotherapy-naive patients.
Patients were considered ineligible for the study if they had any of the following exclusion criteria: (1) other malignancies, except for adequately treated carcinoma-in-situ of the uterine cervix or basal squamous cell carcinoma of the skin or if previous malignancy was more than 5 years earlier and there were no signs or symptoms of recurrence; (2) uncontrolled infections, pleural effusion, or any serious coexisting medical illness; (3) peripheral neuropathy (⬎ grade 1, National Cancer Institute common toxicity criteria [NCI-CTC] scale); and (4) abnormal hematologic parameters (WBC count⬍4.0⫻109/L or absolute neutrophil count⬍2.0⫻109/L,
hemoglobin⬍9.0 g/dL [or⬍8.0 g/dL in cases of inflammatory anemia], platelet count⬍100⫻109/L) or biochemistry parameters (bilirubin⬎1.5⫻
upper limit of normal range [ULN], serum creatinine⬎ 1.5 ⫻ULN or creatinine clearance⬍60 mL/min, and AST or ALT⬎2.5⫻ULN [⬎5⫻ ULN if known liver involvement]).
Treatment
Patients received raltitrexed 3 mg/m2as a 15-minute intravenous infusion
followed 45 minutes later by oxaliplatin 130 mg/m2as a 2-hour infusion.
This treatment cycle was repeated every 3 weeks. Antiemetic and symptom-atic therapies were permitted, with the exception of any vitamin supplement containing folic acid. Full supportive care and treatment were instituted immediately after the first signs of chemotherapy-associated toxicity. Pa-tients were to be withdrawn from the study as a result of any of the following: (1) objective disease progression (according to protocol criteria); (2) unac-ceptable toxicity or adverse event; (3) patient unwilling or unable to continue (drop outs); (4) patient lost to follow-up; and (5) investigator decision that it was in the patient’s best interest not to continue.
Dose Modification
The dose of raltitrexed and/or oxaliplatin was modified in the conditions of toxicity described below. Once the dose had been reduced, all subsequent cycles were administered at the reduced dose.
Toxicity present on the day of treatment. In the event of ongoing unacceptable or clinically relevant toxicity, dosing was delayed for a maximum of 14 days until all signs of toxicity had resolved or were resolving (with the exception of asymptomatic liver transaminases).
Toxicity during intervals. Further doses of chemotherapy were modified on the basis of the worst grade of toxicity seen during the previous cycle.
Hematologic toxicity and febrile neutropenia. Each drug was adminis-tered at 75% of the full dose after grade 3 or 4 febrile neutropenia or after grade 3 or 4 hematologic toxicity that required a delay of between 1 and 2 weeks for the resolution of toxicity.
Gastrointestinal toxicity. The dose of oxaliplatin was reduced to 75% in the presence of grade 3 diarrhea or grade 3 vomiting, despite adequate antiemetic treatment (a 5-hydroxytryptamine-3 inhibitor plus a corticoste-roid), and to 50% in the presence of grade 4 vomiting, despite adequate
antiemetic treatment. The dose of raltitrexed was reduced to 75% after grade 2 diarrhea or grade 3 mucositis or to 50% after grade 3 diarrhea or grade 4 mucositis. Treatment was stopped after grade 4 diarrhea.
Neurologic toxicity. The dose of oxaliplatin was reduced according to the presence of neurologic toxicity. If paraesthesia was permanently present between cycles or if paraesthesia was associated with pain or functional impairment lasting for more than 7 days, the dose of oxaliplatin was reduced to 100 mg/m2 (and to 80 mg/m2if paraesthesia with pain reoccurred).
Treatment with both drugs was stopped if paraesthesia with pain or functional impairment was permanent between cycles.
Renal toxicity. The dose of raltitrexed was reduced and dosing delayed by 1 week if creatinine clearance wasⱕ65 mL/min (dose reduced to 75% and 50% of dose at 55 to 65 mL/min and 25 to 54 mL/min, respectively). Raltitrexed treatment was stopped if creatinine clearance was less than 25 mL/min.
Patient Evaluation
The medical history of the patient was recorded (including details of prior exposure to asbestos), and a full physical examination was performed within 14 days of the first treatment cycle. Physical examinations were also performed before each treatment cycle.
Efficacy Assessment
Target lesions were defined and measured within 14 days of the first treatment administration and were at least 2 cm in their largest diameter (with the exception of pleural lesions, which were a minimum thickness of 0.5 cm measured perpendicular from the thoracic wall). The target lesions were measured in the two largest perpendicular diameters and the area conven-tionally calculated as the product of these diameters. In the case of both bidimensional and unidimensional measurements in the same patient, bidi-mensional measurement was used to assess response. The total tumor size in one site was calculated as the sum of the areas of all target lesions in this site (or the sum of the thickness of pleural lesions). Tumor response was assessed by computed tomography scan every three cycles of chemotherapy until disease progression. All ORs were confirmed with a further computed tomography scan at least 4 weeks after their first documentation
Definitions of ORs follow. Complete response was defined as the complete disappearance of all known disease, determined by two observations not less than 4 weeks apart. Partial response was defined as a reduction of at least 50% in tumor size (relative to initial tumor size), determined by two observations not less than 4 weeks apart, with no appearance of new lesions or progression of any lesion. Progressive disease was defined as an increase in the size of one or more lesions of 25% or more, or the appearance of a new lesion. Stable disease (or no change) was defined as no complete response, partial response, or progressive disease demonstrated during the first 9 weeks of treatment. The best overall response was defined as the best response from start of treatment to progression. All ORs were assessed by an external review panel.
Evaluation of symptomatic response was made using patient self-assess-ment at baseline and at weekly intervals during the study on a 100-mm visual analog scale (VAS; where 0 mm was the least possible symptom and 100 mm was the worst possible symptom).24Five parameters were assessed—pain,
asthenia, activity, shortness of breath, and appetite. Patients were considered to be symptomatic if they had a baseline value of at least 20 mm. A positive change in symptom intensity was defined as an improvement in the intensity measurements of at least 50% from baseline for at least 3 consecutive weeks. A positive change was only recorded for patients who were symptomatic at baseline. A negative change in symptom intensity was defined as a deterioration of the intensity measurement by any degree relative to baseline (and exceeding 20 mm on the VAS) for at least 3 consecutive weeks. Each patient was classified as a symptomatic responder or nonresponder for each symptom. The symptomatic response rate was defined as:
Number of symptomatic responders
Number of eligible patients who received⫽1 cycle⫻100% (1)
Tolerability Assessments
Biochemistry assessments, including serum creatinine levels, were per-formed within 14 days before the first course of treatment and thereafter
before each cycle. If serum creatinine levels were abnormal, creatinine clearance was performed or calculated on the basis of the serum creatinine value. In addition, creatinine clearance was routinely calculated before each cycle, including the first course, for all patients over 70 years of age or for patients with a body-surface area of 1.5 m2or more. Hematology
assess-ments were performed within 14 days before the first course of treatment and thereafter weekly during study. Adverse events were recorded during treatment and for 3 weeks after the final cycle. They were recorded and classified according to NCI-CTC recommendations, with the investigator providing an assessment of the relationship of each adverse event to study treatment. All patients with grade 3 or 4 NCI-CTC toxicity at the end of the treatment period were followed up until they had returned to grade 1 or 2 unless, in the investigator’s opinion, the patient was never likely to improve because of the nature of the underlying disease.
RESULTS
Of a total of 72 patients recruited into the study, two patients
were not eligible, one because of absence of measurable lesions
at inclusion and the other because of a nonconfirmation of
mesothelioma diagnosis. According to the European
Organiza-tion for Research and Treatment of Cancer classificaOrganiza-tion, 24
patients (34%) had a poor prognosis mesothelioma (three or
more of the following risk factors: male, WBC count
⬎
8.3
⫻
10
9/L, performance status
ⱖ
1, sarcomatoid tumor, and probable
or possible histologic diagnosis).
The number of patients eligible for analysis of time-related
parameters was 70 (55 chemotherapy-naive and 15 pretreated
patients; Table 1). Sixty-four patients (91%) had a pleural
mesothelioma, of whom 66% had tumor-lymph
node-metas-tasis International Mesothelioma Interest Group stage III or
IV, and the majority presented with epithelial tumors (46
patients, 65.7%). Of the 15 pretreated patients, all had
previously received cisplatin. Chest pain (79% of patients)
and dyspnea (74.3% of patients) were the most frequently
reported disease-related symptoms.
Efficacy
The assessment of response was performed on the overall
population of 70 eligible patients and on the 57 patients who
received three or more treatment cycles and who were fully
assessable for response. Of the 70 patients, 14 patients (20% of
the eligible population) had a partial response, 32 patients (46%)
had stable disease, and 22 patients (31%) had progressive disease
(two of the 70 patients were nonassessable in terms of response).
The overall OR rate was 20% (95% confidence interval [CI],
11.4% to 31.3%) in the eligible population and 24.6% (95% CI,
14.1% to 37.8%) in the assessable population. No difference was
seen in the OR rate for chemotherapy-naive and pretreated
patients (OR for both was 20%). Median response duration in the
14 patients exhibiting partial responses was 35 weeks (95% CI,
26 to 66 weeks). The overall median time to disease progression
was 18 weeks (95% CI, 13 to 22 weeks). In chemotherapy-naive
patients, the median time to progression was 17 weeks (95% CI,
11 to 21 weeks; Fig 1), whereas in pretreated patients, it was 27
Table 1. Patient Characteristics at Enrollment
No. of
Patients %
No. of patients recruited and eligible 70 Sex Male 51 Female 19 Age, years Median 60 Range 43-74 Chemotherapy-naı¨ve patients 55 78.6 Pretreated patients 15 21.4 Asbestos exposure 37 52.9* Thrombocytosis,⬎400,000/L 29 41.4 Histologic subtype Epithelial 46 65.7 Sarcomatoid 3 4.3 Mixed 12 17.1
Other, not classified 8 11.4
Missing 1 1.4
WHO performance status
0 14 20 1 43 61.4 2 13 18.6 Primary site Pleura 64 Peritoneum 6
Abbreviation: WHO, World Health Organization. *For the 70 eligible patients with 14 missing data.
Fig 1. Time to disease progression by group of treat-ment.
weeks (95% CI, 13 to 31 weeks). The symptomatic response
rate, as assessed using the VAS, was 36% for shortness of breath,
30% for pain, 23% for activity, 21% for appetite, and 20% for
asthenia in the 70 eligible patients (Table 2).
Overall median survival from the start of treatment (Fig 2) and
from diagnosis of mesothelioma was 32 weeks (95% CI, 24 to 40
weeks) and 51 weeks (95% CI, 45 to 63 weeks), respectively. In
chemotherapy-naive patients, median survival was 31 weeks
(95% CI, 23 to 40 weeks) from the start of treatment and 49
weeks (95% CI, 40 to 52 weeks) from diagnosis of
mesotheli-oma. In pretreated patients, median survival was 44 weeks (95%
CI, 24 to 40 weeks) from the start of treatment and 226 weeks
(95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma.
For the 70 eligible patients, overall 1-year survival was 26%
(95% CI, 15.5% to 36.4%): 22% (95% CI, 10.9% to 33.2%) in
chemotherapy-naive patients and 40% (95% CI, 15.2% to
64.8%) in pretreated patients.
Tolerability
The safety analysis considered all 72 patients. Twenty patients
(16 chemotherapy-naive patients and four pretreated patients)
withdrew from the treatment because of adverse events.
Toler-ability data are listed in Table 3. Patients received a median (
⫾
SD) of 4.6 cycles (
⫾
2.2) of the raltitrexed/oxaliplatin
combi-nation. Out of 72 patients, 19 (26%) and 21 (29%) required a
dose reduction for raltitrexed and oxaliplatin, respectively.
Although paraesthesia (neurologic toxicity) was reported in
most patients, in only two patients (2.8%) was the event reported
as being of grade 3 (severe) intensity. An increase in ALT was
reported frequently (62.5%) but was never clinically relevant.
Four cases of grade 4 adverse events were reported, one each of
asthenia, dysphagia, dehydration, and heart failure (which was
not related to therapy). Grade 3/4 hematologic toxicity was
unusual; neutropenia (grade 3) and leucopenia (grade 3) were
Table 2. Global Symptomatic Response Rate
Response
Chemotherapy-Naı¨ve Patients (n⫽55)
Pretreated Patients
(n⫽15) Total (N⫽70)
No. % No. % No. %
Normal activity scale
Symptomatic responder 13 23.6 3 20.0 16 22.8 Nonresponder 39 70.9 12 80.0 51 72.9 Missing 3 5.5 3 4.3 Asthenia scale Symptomatic responder 10 18.2 4 26.7 14 20.0 Nonresponder 42 76.3 11 73.3 53 75.7 Missing 3 5.5 — — 3 4.3 Pain scale Symptomatic responder 19 34.5 2 13.3 21 30.0 Nonresponder 33 60.0 13 86.7 46 65.7 Missing 3 5.5 — — 3 4.3
Shortness of breath scale
Symptomatic responder 19 34.5 6 40.0 25 35.7 Nonresponder 33 60.0 9 60.0 42 60.0 Missing 3 5.5 — — 3 4.3 Appetite scale Symptomatic responder 10 18.2 5 33.3 15 21.4 Nonresponder 42 76.3 10 66.7 52 74.3 Missing 3 5.5 — — 3 4.3
Fig 2. Survival duration from start of treatment with raltitrexed and oxaliplatin by group of treatment.
reported by five (6.9%) and four (5.6%) patients, respectively,
and anemia (grade 3) by three patients (4.2%). There were no
grade 3 or 4 events of thrombocytopenia. There was no alopecia,
and no treatment-related deaths occurred.
DISCUSSION
The efficacy of the raltitrexed/oxaliplatin regimen reported in
the phase I trial with ORs in six of 17 patients
23,25has been
supported by the results from this phase II trial. The overall
response rate assessed on an intent-to-treat basis in pretreated
and chemotherapy-naive patients with malignant mesothelioma
was reported as 20% in this study. Evaluation of response criteria
is currently a subject of debate in mesothelioma. This response
rate, which was obtained using strict criteria, is relatively
encouraging when considered in the context of the results
obtained with other regimens, including cisplatin-based
thera-pies. A review of chemotherapy in malignant mesothelioma
2identified only a few agents with significant activity. No drugs
have consistently induced a response rate of greater than 20%.
Some combination regimens have been reported as inducing
higher response rates in small phase II trials.
26Interestingly,
other regimens combining an antimetabolite, such as
gemcitab-ine or pemetrexed, with either cisplatin or carboplatin have also
shown promising activity.
27Very recently, the results of a phase
III trial of cisplatin with and without pemetrexed have been
reported in abstract form, and a better survival rate was reported
in the combination arm.
28The efficacy/toxicity ratio of the raltitrexed/oxaliplatin
regi-men compares favorably with that of other regiregi-mens of
chemo-therapy or chemoimmunochemo-therapy previously used in our
institu-tions.
1,25Interestingly, in this trial and the phase I trial of the
same regimen,
23,25there were responses even in pretreated
patients, including some with cisplatin-refractory disease. These
results are consistent with the in vitro activities of each agent
against cisplatin-resistant cell lines.
14,17,18Overall, the median
survival times are consistently within the range reported in the
literature for active therapy and are superior to the 5- to 6-month
survival time reported for untreated patients.
1The raltitrexed/oxaliplatin regimen in this phase II trial had a
manageable toxicity profile that was consistent with previous
phase I and phase II trials using the same combination.
23,29No
toxic deaths were observed in this study. The principal toxicity
observed was asthenia, which has been previously reported with
this regimen. Although a transaminase increase occurred often, it
was never clinically relevant. There were no reports of alopecia.
Grade 3 anemia and neutropenia were observed in only 4.1%
and 6.9% of patients, respectively, and severe thrombocytopenia
was not encountered. These data indicate that the regimen had
little myelosuppressive activity. In contrast, the combination of
cisplatin and gemcitabine resulted in a 38% incidence of grade 3
leucopenia and a 19% incidence of grade 4 thrombocytopenia in
a phase II study of patients with malignant mesothelioma,
26and
the combination of oxaliplatin and fluorouracil resulted in a 42%
incidence of grade 3/4 neutropenia in a phase III study of
patients with advanced colorectal cancer.
16Moreover, the
regi-men is administered as an outpatient infusion, in contrast to some
cisplatin-based regimens.
In summary, the raltitrexed/oxaliplatin combination seems to
be associated with a favorable risk/benefit profile in patients with
diffuse, malignant pleural mesothelioma. The outpatient regimen
seems to have produced significant efficacy along with an
acceptable tolerability profile. The results from this study have
prompted the European Organization for Research and
Treat-ment of Cancer to conduct a phase III randomized trial of
cisplatin with or without raltitrexed. Promise for the future may
lie in combined-treatment modalities, which are expected to
provide superior alternatives to current treatments.
ACKNOWLEDGMENT
We thank Gregoire Edorh for monitoring the Centers and Muriel Licour for analysis of the data.
Table 3. Most Common Adverse Events in Total Population (Nⴝ72) According to NCI-CTC Grade
Adverse Event
Grade 1 Grade 2 Grade 3 Grade 4 No. of Patients % No. of Patients % No. of Patients % No. of Patients % Asthenia 8 11.1 31 43.0 14 19.4 1 1.3 Nausea 31 43.0 16 22.2 6 8.3 — — Paraesthesia 41 56.9 8 11.1 2 2.7 — — Weight decrease 24 33.3 20 27.7 2 2.7 — — ALT increase 17 23.6 20 27.7 8 11.1 — — Vomiting 17 23.6 19 26.3 3 4.1 — — Anorexia 15 20.8 14 19.4 9 12.5 — — Distal paraesthesia 34 47.2 3 4.1 — — — — Anemia 17 23.6 15 20.8 3 4.1 — — Neutropenia 12 16.6 8 11.1 5 6.9 — — Leucopenia 12 16.6 8 11.1 4 5.5 — — Diarrhea 12 16.6 5 6.9 4 5.5 — — Fever 8 11.1 12 16.6 — — — — Constipation 17 23.6 2 2.7 — — — — AST increase 12 16.6 5 6.9 1 1.3 — — Thrombocytopenia 17 23.6 — — — — — — Lockjaw 12 16.6 1 1.3 — — — — Dysaesthesia 11 15.2 — — — — — — Abdominal pain 5 6.9 2 2.7 2 2.7 — —
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