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Keywords:

  • mesothelioma;
  • irinotecan;
  • cisplatin;
  • mitomycin C;
  • phase II;
  • first-line;
  • recurrence

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor.

METHODS.

A Phase II open-label noncomparative study was conducted to assess the safety and efficacy of the triplet combination irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in untreated patients and in those with previous exposure to chemotherapy.

RESULTS.

In 62 patients an objective response rate of 25% was observed. In the first-line setting progression-free survival measured 6.4 months (95% confidence interval [CI]: 4.5–7.3) and overall survival was 10.8 months (95% CI: 7.9–13.7). In the second-line setting progression-free survival was 7.3 months (95% CI: 3.4–11.2) and overall survival was also 7.3 months (95% CI: 4.8–9.8). Psychosocial well-being improved during chemotherapy and the main toxicity observed was neutropenia (40%).

CONCLUSIONS.

IPM appeared to have a reasonable response rate with an acceptable toxicity profile in the first- and second-line treatment of MPM. Cancer 2007. © 2006 American Cancer Society.

Malignant pleural mesothelioma (MPM) is a rapidly lethal malignancy causally associated with exposure to asbestos with a prevalence that is set to increase significantly in the US and Europe over the next 20 years.1–3 MPM is often refractory to cytotoxic treatment, which may be due to intrinsic apoptosis resistance; a variety of single agents achieve low response rates of around 20%.4–7

No reported randomized trial has yet confirmed a benefit of chemotherapy over best supportive care, although 1 trial, MSO-1 (active symptom control vs vinorelbine vs mitomycin/cisplatin/vinblastine), is currently enrolling patients.8 Two Phase III randomized trials comparing either the ‘gold standard’ doublet pemetrexed (Alimta) and cisplatin,6, 9, 10 or raltitrexed (Tomudex) and cisplatin11, 12 versus cisplatin alone confirmed a survival advantage for both doublets.13 The efficacy of radical surgery is not yet proven due to a lack of randomized evidence,14 and radical radiotherapy, although providing palliative benefit, does not improve overall survival.15 There exists only a paucity of reports of second-line therapy of MPM, thus warranting further investigation.

First-line chemotherapy with irinotecan (Campto) and cisplatin produces limited objective tumor responses in MPM.16 Several groups have reported the use of irinotecan in combination with cisplatin in nonsmall cell lung cancer17–20 and it has also been used in several other tumor types including gastric,21 neuroendocrine,22 and renal cancers.23 As mitomycin exhibits single-agent objective response in MPM,24 we explored the clinical activity of the triplet combination irinotecan, cisplatin, and mitomycin in MPM in the first-line setting. As second-line chemotherapy in individuals with MPM is underinvestigated, we also evaluated the efficacy of IPM in previously treated patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients and Methods

Between September 2000 and March 2003, patients with MPM were enrolled into a single-center trial of combined irinotecan, cisplatin, and mitomycin C (IPM). The study had appropriate institutional ethical review board approval and all patients provided written, informed consent. All recruited individuals were required to have measurable, histologically confirmed, inoperable, MPM and to be >18 years old, with Eastern Cooperative Oncology Group (ECOG) performance statuses (PS) of 0 to 2 and no uncontrolled cardiac or hepatic disease. Individuals with concurrent malignancies of another type (other than nonmelanoma skin cancer) were excluded. Hematologic and biochemical criteria included adequate bone marrow function (total leukocyte count >4 × 109 cell/L, platelet count >100 × 109 cells/L, and hemoglobin >10 g/dL) and hepatic function (alkaline phosphatase <1.5 times the upper limit of normal). Prophylactic superficial irradiation of chest drain or biopsy scars was allowed before commencement of chemotherapy, provided the patient had measurable disease outside the irradiated site. All patients had computed tomography (CT) chest scans performed at the time of enrolment and, where possible, pleural effusions were drained before beginning therapy. The International Mesothelioma Interest Group (IMIG) staging system was used25 and all patients in the second-line cohort had documented disease progression, having previously received chemotherapy with a different regimen.

Treatment was administered on an outpatient basis as follows: intravenous (i.v.) irinotecan 100 mg/m2, cisplatin 40 mg/m2, mitomycin-C 6 mg/m2 administered on Day 1, with irinotecan 100 mg/m2, cisplatin 40 mg/m2 administered on Day 15 of a 28-day cycle. Patients in the second-line setting or those with a PS of 2 were treated with irinotecan 70 mg/m2. Antiemetic granisetron 1 mg i.v. and dexamethasone 8 mg i.v. were coadministered routinely with each cycle. Blood cell counts and chemistry panels were repeated with every treatment. Treatment was delayed by 1 week in the event of bone marrow suppression (total leukocyte count <3 × 109 cells/L, neutrophil count <1.5 × 109 cells/L, or platelet count <100 × 109 cells/L).

Assessment of Response

Patients were assessed for response by thoracic CT scans after each cycle of chemotherapy. Although there is debate regarding the best assessment of response in MPM,5 we used the newer guidelines to evaluate the response to treatment in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST26). If there were no separately identifiable mass lesions then the thickness of the circumferential pleural tumor was measured at 3 separate levels on transverse sections, as previously described for the assessment of response to treatment in mesothelioma. The sum of the measurements was taken as the baseline sum longest diameter and repeat measurements were made at the same levels on subsequent scans.

Duration of response was defined as the interval from the time that the criteria for partial response (PR) were first met to the time that criteria for progressive disease were first met, taking as reference the smallest sum longest diameter recorded since treatment started. Duration of stable disease (SD) was defined as the interval from the start of treatment to the time that criteria for progressive disease were first met, taking as reference the smallest sum longest diameter recorded since treatment started.

Quality of Life

Quality of life was assessed in all patients at baseline (before chemotherapy) and subsequently at 8 and 12 weeks. The Rotterdam Symptom Check-List (RSCL) was used,27 as it has been found to be useful previously in individuals with MPM.28–30 A single questionnaire covered general and respiratory symptoms, psychologic well-being, and physical activity. Patient scores of improvement, deterioration, or no change in quality-of-life indices were collated individually and recorded.

Statistical Considerations

An objective response of at least 20% was considered sufficient to encourage further investigation of IPM, and conventional statistical considerations indicate that an open study of 14 patients would have a 95% chance or greater of detecting at least 1 response if the true response were 20% or greater. If at least 1 response occurred in the first 14 patients, it was planned to increase the number of patients to assess the response rate with more precision up to a total of 62 individuals. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS) using the product limit estimator.31 For survival distributions stratified according to objective tumor response, comparison employed the log-rank statistical test. For quality of life analysis, the changes between RSCL scores (within patient) at the different time points were compared using the Wilcoxon signed ranks test.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics: First- and Second-line IPM

Forty-nine patients were enrolled for treatment with IPM as first-line chemotherapy and 13 were enrolled for treatment with IPM in the second-line setting. Of these 13 patients, previous regimens received were vinorelbine (9 patients), vinorelbine/oxaliplatin (3 patients), and cisplatin/pemetrexed (1 patient). The median interval between the end of the first course and the start of the second was 6 months. Responses to non-IPM first-line therapy included 2 patients who had PRs (15%), 6 with SD (46%), and 5 patients with progressive disease (PD; 39%). A summary of patient characteristics for the first- and second-line studies is provided in Table 1.

Table 1. Patient Characteristics for Patients Receiving IPM in the First- and Second-Line Settings
 No. of patients
First-lineSecond-line
  1. IPM indicates irinotecan, cisplatin, and mitomycin-C; ECOG, Eastern Cooperative Oncology Group, IMIG, International Mesothelioma Interest Group (this is most accurate when surgically assessed, although approximated CT criteria were used here).

Total4913
Age median (range)61 (44–75)56 (49–68)
Sex
 Men4011
 Women92
ECOG performance status
 0282
 1164
 257
IMIG stage
 I10
 II71
 III192
 IV2110
Histologic subgroup
 Epithelioid3610
 Sarcomatoid62
 Biphasic71

Objective Responses: First-line IPM

In patients treated first-line with IPM, objective responses were measurable in 43 patients (6 were unevaluable), as summarized in Table 1A. No complete remissions were observed. PRs were observed in 16 (37%) patients, with SD in 23 (54%) patients, and PD seen in 4 (9%) patients. A typical response to PR is shown in Figure 2A,B.

Progression-Free and Overall Survival: First-line IPM

Of the patients receiving first-line IPM, 44 were evaluable for PFS (5 patients were censored). Median PFS from first treatment was 6.4 months (95% CI: 4.5–7.3), as shown in Figure 1A. In all, 59 patients were evaluable for survival, of which 17 were censored. The median OS from first treatment was 10.8 months (95% confidence limits were 7.9–13.7 months), as shown in Figure 1B.

thumbnail image

Figure 1. (A) Kaplan-Meier curve of progression-free survival (PFS) for patients receiving first-line irinotecan, cisplatin, and mitomycin-C (IPM. (B) Kaplan-Meier curve of overall survival (OS) for patients receiving first-line IPM. (C) Kaplan-Meier curve of PFS for patients receiving second-line IPM. (D) Kaplan-Meier curve of OS for patients receiving second-line IPM.

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Objective Responses: Second-line IPM

In patients receiving second-line IPM, there were no complete responses. PRs were seen in 2 of 10 evaluable patients (20%), of whom 1 patient originally had stable disease after 12 cycles of vinorelbine. Two patients had previously progressed after 4 and 12 cycles of vinorelbine, respectively. SD was observed in 5 patients (50%) and progressive disease in 2 patients (20%). Table 2 summarizes response to second-line IPM stratified according to histologic subtype.

Progression-Free and Overall Survival: Second-line IPM

In patients receiving second-line IPM, the median PFS was 7.3 months (95% CI: 3.4–11.2) as shown in Figure 1C. OS from the first cycle of IPM was 7.3 months (95% CI: 4.8–9.8) as shown in Figure 1D. Median OS from commencement of first-line chemotherapy to death after second-line IPM was 15.1 months (n = 13, 95% confidence limits were 2.5–27.7 months), as shown in Figure 2B.

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Figure 2. (A) An illustration of a partial response (PR) in an individual receiving irinotecan, cisplatin, and mitomycin-C (IPM) in the second-line setting. (B) Kaplan-Meier curve of overall survival (OS) for patients from first treatment, receiving second-line IPM.

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Dose Intensity and Toxicity

There were no treatment-related deaths. In the first-line setting, observed grade 1/2 toxicities were: malaise in 10 patients, neutropenia in 10 patients, anemia in 5 patients, thrombocytopenia in 3 patients, nausea and vomiting in 3 patients, neuropathy in 2 patients, and mucositis in 2 patients. Grade 3/4 toxicities were: neutropenia in 25 patients, leucopenia in 4 patients, thrombocytopenia in 3 patients, diarrhea in 2 patients, and malaise in 1 patient. In the second-line setting, grade 1/2 toxicities were: malaise in 10 patients and neutropenia in 3 patients. Grade 3/4 toxicities were: neutropenia in 4 patients, anemia in 2 patients, thrombocytopenia in 1 patient, nausea and vomiting in 2 patients, and malaise in 1 patient. There were no significant differences in toxicity profiles between the first- and second-line administration of IPM. In the first-line setting, 3 or more cycles of chemotherapy were received by 32 (65%) patients and in the second-line cohort 7 (54%) patients completed 3 or more cycles.

Quality of Life

All patients were asked to complete the RSCL questionnaire immediately before treatment (baseline) and at 8 and 12 weeks after treatment began on the day that chemotherapy was administered. No information was available on change over time in RSCL for 25% of the patients (21% baseline only, 5% did not provide RSCL scores at any time). Among the remaining 74% of patients, 49% had RSCL measured at both 8 and 12 weeks. Psychological well-being had improved between baseline and Week 8 (P = .02), although the subsequent changes between Week 8 and Week 12 were not statistically significant. Physical symptoms showed little difference between baseline and Week 8, with approximately equal numbers of patients improving or deteriorating. However, between Weeks 8 and 12, two-thirds of patients found their physical symptoms worsened (P = .005). Activity scores showed no statistically significant pattern of improvement or deterioration over time. Despite worsening of physical symptoms, when patients were asked to give an overall evaluation of their quality of life at baseline, 8 weeks and 12 weeks, the majority found it excellent, with only 3 or 4 patients describing it as poor (Fig. 3).

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Figure 3. Changes in the 3 scales of psychological well-being, physical and activity from (A) baseline to 8 weeks and from (B) 8 weeks to 12 weeks. The histograms are based on the 31 patients who had completed the Rotterdam Symptom Check-List (RSCL) at all 3 time points.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

IPM demonstrates useful clinical activity in MPM, is well tolerated in the first- and second-line settings, and is associated with evidence of symptomatic benefit. Although it is difficult to compare between this study and the previous Phase II and III trials, there is now extensive previous experience in MPM with doublets giving a wide range of outcomes, and these triplet data are at the top of this range. We suggest that a randomized study comparing the triplet and doublet approaches is warranted and, in addition, as the responses and survival outcomes in the small second-line cohort here were notable and the toxicities were reasonable, IPM is worthy of study in a larger Phase II study in this group experiencing recurrence.

There are few published clinical trials examining the efficacy of chemotherapy in the second-line setting in MPM32, 33 and we found that IPM exhibits moderate activity in previously treated patients, with an objective response rate of 20%, tumor stabilization of 50%, and an OS of 7.3 months; patients survived on average for 15.1 months from first treatment. It appears that IPM may be extending survival; however, patient selection could account for this apparently longer survival time. All of the patients receiving IPM in the second-line setting were classified as low-risk according to the EORTC prognostic score5 and the median survival of this low-risk group is higher than for high-risk, and therefore suggests some degree of selection bias. It is not known what survival of low-risk patients might be in the absence of chemotherapy, an important question that may be answered by the MSO-1 Phase III clinical trial. Such bias may underlie the perceived effectiveness of all therapies, including extrapleural pneumonectomy, that have yet to be validated by randomized trials.

The use of IPM, which is now routine in patients with MPM at our institution, derives from a number of previous studies. The highest response rates have generally been observed with cisplatin-containing regimens.9, 32, 34 Nakano et al16 administered irinotecan (60 mg/m2 on Days 1, 8, and 15), with cisplatin (60 mg/m2 on Day 1), in a 28-day schedule to 15 patients leading to a partial response rate of 26.7% with a PFS of 5.3 months and OS of 7 months. Mitomycin-C, bioreduced under hypoxic conditions, has been explored in combination with cisplatin in a nude mouse xenograft model.35 A randomized Phase II conducted by the Cancer and Leukemia Group B treated 35 patients with cisplatin and mitomycin or doxorubicin.36 Cisplatin and mitomycin was associated with a response rate of 26%, compared with 14% for the cisplatin and doxorubicin doublet; the PFS was 3.6 months and OS 7.7 months, respectively, with no differences between arms.

As the incidence of MPM is increasing, we are faced with the challenge of treating more patients, including those with recurrence. Agents that are active in the first-line setting are not necessarily active later,37 and the diffuse nature of the disease implies a limited role for both surgical and radiotherapeutic techniques, and thus further impact will be made using combination cytotoxic regimens. Despite many efforts on the use of chemotherapy in the palliative setting, only limited evidence exists on which to base recommendations.6, 7 In summary, IPM is a well-tolerated regimen with measurable activity both in the first- and second-line settings and warrants further investigation.

Table 2. Response to First-Line and Second-Line Therapy With IPM According to Histological Subtype
ResponseNo. ofevaluablepatientsPercentResponse rate by histologic subtype
EpithelioidSarcomatoidBiphasic
  1. IPM indicates irinotecan, cisplatin, and mitomycin-C; PR, partial response; SD, stable disease; PD, progressive disease.

  2. Response to first-line (top) and second-line (lower) therapy with IPM according to histological subtype. For the patients treated second-line, previous chemotherapy consisted of either vinorelbine, (9 patients), vinorelbine/oxaliplatin (3 patients), cisplatin/pemetrexed (1 patient). Median interval between the end of the first course and the start of the second was 6 months. Responses to non-IPM first-line therapy included 2 patients who had PRs (15%), 6 with SD (46%), 5 patients with PD (39%).

First-line
 PR16371141
 SD23541715
 PD49400
Second line
 PR330201
 SD550500
 PD220110

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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