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Chemotherapy Alone vs. Chemotherapy Plus High Dose Multiple Antioxidants in Patients with Advanced Non Small Cell Lung Cancer

Department of Medical Oncology (A.K.P., M.B., A.S., R.P., N.K.B., V.K.), Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, INDIA
Department of Medicine (R.G., A.M.), Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, INDIA
Department of Surgery (S.B.), Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, INDIA
Department of Radiotherapy (B.K.M.), Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, INDIA
Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (K.N.P.)

Address reprint requests to: Prof. Vinod Kochupillai, Chief, Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences (AIIMS), New Delhi 110 029, INDIA. E-mail: vinodkochupillai{at}yahoo.com

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer.

Methods: 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test.

Results: An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms.

Conclusions: These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.

Key words: lung cancer, chemotherapy, antioxidants, beta-carotene, vitamin C, vitamin E

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Non small cell lung cancer (NSCLC) is the commonest cancer with high mortality rates throughout the world [1]. Current treatment modalities do not yield satisfactory results [2,3]. Therefore, innovations are needed to improve the management of NSCLC. Several in vitro studies suggest that certain antioxidants may enhance the effects of cytotoxic therapy [4–7]. Clinical trials using antioxidants as an adjunct to chemotherapy, however, have been sparse. It is primarily because of the concern that antioxidants might counteract the effect of cytotoxic agents especially those, which mediate their action by generating free radicals such as alkylating agents, antimetabolites and radiation [8]. In theory, antioxidants may decrease the efficacy of these agents by quenching free radicals. This concern, however, may not be justified as several studies have demonstrated that antioxidants enhance the growth-inhibitory effects of X-irradiation and chemotherapeutic agents on tumor cells, depending upon the dose, form and type of antioxidant, chemotherapeutic agent and tumor [4–7]. It has been reported that antioxidants such as mesna and amifostine do not decrease the efficacy of chemotherapy even though they exert their effect by quenching free radicals [9,10].

In vitro studies conducted in our own lab demonstrated that a mixture of three antioxidants (vitamins C, E and beta carotene) significantly enhanced paclitaxel/carboplatin induced apoptosis in human lung squamous cancer cell line H520 [11]. This has led us to investigate the role of high dose multiple antioxidants as an adjunct to chemotherapy in the management of human non-small cell lung carcinoma.

	PATIENTS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
The protocol of this trial was approved by the institute ethics committee. Patients were enrolled after fully informed consent was obtained. The primary end point was overall survival, and the secondary end points were the rates of complete and overall response and toxicity.

Previously untreated patients aged 65 years or less with cytologically or histologically confirmed advanced stage (IIIb or IV) non-small-cell lung cancer; with measurable lesions; Karnofsky’s Performance Status (KPS) of 60 or above; with a life expectancy of at least three months were included. Patients were required to have adequate organ function as defined by a leukocyte count of at least 4000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a hemoglobin level of at least 9.5 g per deciliter (5.9 mmol per liter), aspartate aminotransferase and alanine aminotransferase levels of no higher than 100 IU per milliliter, a serum creatinine level of no higher than 1.2 mg per deciliter (106 µmol per liter), and a creatinine clearance of at least 60 ml per minute.

The exclusion criteria included prior interstitial pneumonitis, pulmonary fibrosis, myocardial infarction within the preceding three months, and uncontrolled diabetes mellitus. Patients with massive pleural or peritoneal effusion, and those with symptomatic brain metastases requiring whole-brain irradiation were excluded from the study. Pregnant or lactating mothers were also excluded.

Staging of the tumor was based on the results of physical examination, chest radiography, fiberoptic bronchoscopy with biopsy and/or cytologic examination, computed tomography (CT) of the chest, and ultrasonography or CT of the abdomen. Other tests like CT brain, radionuclide bone scanning, and bone marrow aspiration or biopsy were carried out whenever clinically indicated.

Patients were chosen from regular cancer outpatients of our hospital. From September 1998 to July 2004, 136 patients of stage IIIb or IV NSCLC were randomly assigned to one of the two arms after detailed medical history and physical examination. Patients in chemotherapy arm (n = 72) received chemotherapy alone while patients in combination arm (n = 64) received multiple high-dose antioxidants and chemotherapy. The randomization was carried out by ‘sealed envelope’ procedure.

Patients in both the arms, after standard pre-medication, received paclitaxel 225 mg/m2 over three hours on the first day and carboplatin dosed to an AUC of 6 using Calvert’s formula on the second day [12]. The carboplatin dose was recalculated according to the patient’s most recent creatinine clearance value before each chemotherapy cycle. Chemotherapy was repeated every three weeks for a maximum of six cycles. Patients in combination arm received an oral dose of high-dose multiple antioxidants two days prior to the initiation of chemotherapy, and continued for the entire period of treatment. The doses of antioxidant vitamins were vitamin C as ascorbic acid (6100 mg/day, vitamin E as dl-alpha tocopherol succinate (1050 mg/day) and synthetic beta-carotene (60 mg/day). The preparation of vitamin E also contained selenium, copper sulfate and zinc sulfate. The doses of antioxidants were based on available literature [13]. After the completion of chemotherapy, antioxidant doses were tapered to half over a period of one month and continued for the entire observation period. Patient compliance was assessed by checking the empty blister packets of antioxidants and patient’s recall.

Assessment of Response and Toxicity
History and physical examination, and complete blood count and serum chemistry were performed at every visit. Chest radiographs were performed at the baseline and then after every chemotherapy cycle. CT scan of chest and upper abdomen was done at the baseline and after three and six cycles. Brain CT scan and bone scan were performed when clinically indicated.

Patients were assessed every week for the first six weeks and then every two weeks over the entire treatment period (or more frequently, if clinically indicated). Toxicity assessment was done as per the "National Cancer Institute common toxicity criteria" [14].

Responding patients (stage IIIb) were assessed for the resectability of tumors after three cycles. Tumors were removed surgically if they were found to be operable. Others showing a response were to complete six cycles followed by radiotherapy. Patients showing disease progression at any stage were taken off the study and were offered second line chemotherapy; however, none of these patients opted for the same and were managed symptomatically.

Complete response (CR) was defined as disappearance of all clinical and radiological evidence of tumor for a minimum of four weeks; partial response (PR) as 50% or greater decrease in the sum of the products of the perpendicular diameters of the lesions for a minimum of four weeks with no increase in the size of any existing lesion or the appearance of new lesions; stable disease as any regression of the lesions not meeting the criteria for partial or complete remission; and progressive disease as a 25% or greater increase in the sum of the products of the perpendicular diameters of the lesions or appearance of new lesions.

Follow-up
Patients were followed up and evaluated clinically and radiologically every month. CT scan of the chest (including upper abdomen) was done every three months.

Statistical Analysis
Patients’ characteristics, prognostic variables, response rates, and toxicities were compared with the use of Chi Square Test or Fisher’s Exact Test, as applicable; and for comparing age distribution, the Student’s t-test was used. Survival was measured from the date of randomization to the date of death or to the date of the most recent follow-up. Survival curves were calculated by the Kaplan-Meier method and compared within the two groups with the use of the log-rank test [15].

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Patients Characteristics
Age, gender, history of smoking & alcohol intake, stage and histology of tumor, and performance status were comparable in chemotherapy arm and combination arm (Table 1). Compliance with the prescribed medications was adequate. All patients were repeatedly counseled to stop smoking and they were not smoking during the study period.

Response to the Treatment
The overall response rate in chemotherapy arm was 33% (24/72) with all responses being partial. In combination arm the response rate was 37% (24/64) including two complete responses. On statistical analysis, the difference in the response rates between the two arms is not significant (p = 0.28) (Table 2).

Survival and Survival Time
In chemotherapy arm, overall survival (OS) is 32.9% at one year and 11.1% at two years; median survival (MS) is 9 months. In combination arm, OS at one and two years are 39.1% and 15.6% respectively and MS is 11 months (Table 2). The difference in survival between the two groups is not significant statistically (p = 0.20).

Toxicity
The main cumulative toxicities were peripheral neuropathy and alopecia. The common non-cumulative toxicities were hematological (neutropenia, thrombocytopenia, and anemia) and gastrointestinal (diarrhea/constipation). Grade III and IV toxicities were similar in the two arms. Of note, the incidence of gastrointestinal toxicity was high in both arms (27% in chemotherapy arm and 26% in combination arm) and the incidence of hematological toxicity was low (9% and 8% respectively). All patients in our study developed significant alopecia during treatment.

	DISCUSSION

 
Non-small cell lung cancer accounts for 75–80% of all lung cancers with a majority of patients presenting in advanced stage, beyond surgical cure. Despite extensive research, the prognosis of such patients continues to be less than satisfactory with a five-year survival rate of about 8% [16]. Several combination chemotherapy regimens have been evaluated. However, to date response rates (RR) continue to be around 35% with no evidence of complete responses (CR). The median survival (MS) time is often less than ten months, and one- and two-year survival rates have remained at about 35% and 10%, respectively [17].

In the present study, patients receiving chemotherapy alone showed similar results with a RR of 33% with 24 patients showing PR and none showing CR, MS time of 9 months and OS at one and two years of 32.9% and 11.1%, respectively. Patients receiving antioxidant mixture and chemotherapy showed a RR of 37% with 24 patients showing PR and two showing CR, MS time of 11 months, OS at one and two years of 39.1% and 15.6%, respectively. Although clinical outcome in combination arm does not appear to be statistically significant in comparison to that observed in chemotherapy arm, these results do not substantiate the fear of oncologists that antioxidants in conjunction with chemotherapy might reduce the efficacy of therapy by protecting cancer cells.

There was no difference in the toxicity profile in the two arms. The pattern of toxicity seen in our study was different from that reported in other similar studies [18–21]. Twenty six to 28% of all patients suffered from grade III or IV diarrhea. This is in contrast to the reported pattern where about two-thirds of patients experience significant hematological toxicity while the incidence of severe diarrhea is less than one percent. The reasons for the different toxicity profile in our patients as compared to western population are not clear.

Our interest in antioxidants originated from the pre-clinical studies, which showed that pretreatment with antioxidants, such as vitamin C, beta carotene, alpha tocopherol succinate and retinoic acid, significantly enhanced the growth inhibitory effects of cisplatin, dacarbazine, tamoxifen and several other anticancer agents on human melanoma and parotid carcinoma cells [6,7]. In a study with mice transplanted with adenocarcinoma of the breast, vitamin A (retinyl palmitate) or synthetic beta-carotene in combination with (x)-irradiation or cyclophosphamide increased the cure rate from 0% to over 90% [22].

Clinical studies investigating the role of antioxidants as an adjunct to chemotherapy and/or radiotherapy are limited. In a non-randomized clinical trial, 18 patients with small cell lung cancer received multiple antioxidant treatment with chemotherapy and/or radiation [23]. The median survival time for the whole group was 16.8 months, not inferior to the standard therapy. Thus addition of antioxidants was found to be safe in this study. In a case report, two patients of advanced epithelial ovarian cancer received high dose antioxidant therapy in addition to the carboplatin and paclitaxel chemotherapy [24]. Both patients were disease-free at three and three and half years, respectively.

In another study, thirty-two ‘high risk’ breast cancer patients, aged 32–81 years, were given adjuvant nutritional intervention (a combination of Vitamins C, E, beta-carotene, Selenium, essential fatty acids and Coenzyme Q10) and followed for 18 months [25]. None of the patients died during the study period or showed signs of distant metastases. The quality of life of these patients was improved and six patients showed apparent partial remission. Antioxidant supplementation (beta-carotene 45 mg, alpha-tocopherol 825 mg and ascorbic acid 450 mg daily for three weeks) before conditioning therapy in bone marrow transplant patients led to no difference in relapse rates [26]. In another study with 65 patients of bladder carcinoma treated with BCG immunotherapy, supplementation with mega-dose combination of vitamin A (40,000 units), vitamin B6 (100 mg), vitamin C (2000 mg), vitamin E (400 units) and Zinc (90 mg) led to decreased recurrence rates at 10 months of follow up (40% vs. 80%) compared to patients receiving RDA values of these agents [27]. These variations in clinical studies may be due to differences in doses, type and number of antioxidants. Therefore, it is essential to define the optimal number, type and dose of antioxidants for a maximal benefit when used as an adjunct to standard therapy.

Pre-clinical data showed that antioxidant vitamins reduce the frequency and severity of toxicity associated with (x)-irradiation and chemotherapeutic agents. For instance, vitamin E has been shown to decrease adriamycin-induced toxicity in rabbits [28]; vitamin E in combination with pentoxifyllin has been reported to significantly regress the radiation-induced fibrosis [29]. In the current study, however, no such protection was seen when we used paclitaxel and carboplatin. It would thus appear that the protective effect of antioxidants on normal cells might not be against all anticancer agents.

There are certain limitations in the present study that should be considered while interpreting the findings. The antioxidants (beta carotene, vitamin E and vitamin C) could not be used in their biologically active forms due to constraints of commercial availability. For example, the 9-cis isomer of beta-carotene found in natural preparations may be a more potent antioxidant [30] compared to the all-trans isomer used by us. Similarly, d--tocopherol succinate is considered more active form than the synthetic form (dl)-alpha-tocopherol succinate used by us [31]. Thus, there is a possibility that the results might improve if more active forms of antioxidant vitamins are used. Also, the antioxidant preparation used by us contained other compounds like copper sulfate, manganese sulfate, zinc sulfate and selenium, which might have affected the results. For instance, selenium has its own antioxidant properties, which might have confounded the results [32]. Another limitation of the present study is that the serum levels of the antioxidants were not estimated. In order to establish an optimal dose response relationship, it is essential that future studies utilizing antioxidant preparations be based on pharmacokinetic data.

Large-scale phase III clinical trials in relatively homogeneous patient populations receiving well-specified conventional treatment regimen alone and in combination with high-dose multiple antioxidants are needed to clarify the true potential of antioxidants in the management of human malignancies.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
In conclusion, antioxidant supplementation during paclitaxel/carboplatin containing chemotherapy in NSCLC appears to be safe and the results of the present study do not support the hypothesis that antioxidant vitamins could compromise the efficacy of standard chemotherapy. There is a possibility that these agents could be potentially useful in the management of NSCLC. Larger controlled trials are required to ascertain their exact role.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
This study has been partially funded by a grant obtained from the Terry Fox Foundation, Canada. We acknowledge the secretarial contributions by Mr. Brijesh Bhardwaj for the article.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Preliminary results of this study were presented as abstracts at ASCO 2001 Meeting, New Orleans, and UICC Congress 2002, Oslo, Norway.

Received January 16, 2004. Accepted November 25, 2004.

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TOP FOOTNOTES ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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