Adjuvant chemotherapy in resected lung cancer: Two-year experience in a university hospital

1Clinique d’oncologie ambulatoire; 2Centre de recherche, Centre de pneumologie, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de l’Université Laval, Quebec City, Quebec Correspondence: Dr Yves Lacasse, Centre de Pneumologie, Hôpital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, Quebec G1V 4G5. Telephone 418-656-4747, fax 418-656-4762, e-mail Yves.Lacasse@med.ulaval.ca N Bouchard, F Laberge, B Raby, S Martin, Y Lacasse. Adjuvant chemotherapy in resected lung cancer: Two-year experience in a university hospital. Can Respir J 2008;15(5):270-274.

Recent randomized trials (5,6) have confirmed the benefits of adjuvant chemotherapy in improving survival in completely resected NSCLC. A recent pooled analysis of the five largest trials indicated that the five-year absolute benefit of adjuvant cisplatin-based chemotherapy was 4.2% (5), with absolute improvements of up to 15% in the National Cancer Institute of Canada Clinical Trials Group JBR,10 trial (6). However, given the timing and nature of adjuvant chemotherapy, toxicities are of concern. In these trials, death was attributable to adjuvant chemotherapy in approximately 1% of treated patients. Chemotherapy caused febrile neutropenia in 7% to 9% of patients, while neutropenia emerged in up to 88%. Compliance with postoperative chemotherapy (defined by three or four completed cycles) in these trials was 48% to 74%.
In addition, patients with limited small-cell lung cancer (SCLC) may benefit from lung resection. Although the role of adjuvant chemotherapy has not been evaluated in prospective randomized trials, patients with SCLC who undergo complete resection are usually given postoperative chemotherapy (7).
The extent to which the results of these studies have translated into clinical practice is unknown. Our objectives were to examine the referral patterns of patients with resected lung cancer to adjuvant chemotherapy, and to compare compliance and toxicities with the current literature.

Data extraction
Sex, age, forced expiratory volume in 1 s, smoking status and major comorbidities (including chronic obstructive pulmonary disease, coronary artery disease, heart failure, chronic renal failure and diabetes) were noted. Chronic obstructive pulmonary disease was further classified according to the Global Initiative for Chronic Obstructive Lung Disease (8). Data related to the surgical procedure, including the surgeon who performed the resection, the date of surgery, the type and completeness of resection, the histological type, the final surgical staging according to the International System for Staging Lung Cancer (3), and the length of stay in hospital were extracted.
Two important dates were considered: June 1, 2004, corresponding to the publication date of the JBR.10 results at the American Society of Clinical Oncology (ASCO) meeting (5), and June 1, 2005, corresponding to the release of the results of the Adjuvant Navelbine International Trialist Association (ANITA) trial at the ASCO meeting (6). Performance status after the surgery was classified according to the five-point Eastern Cooperative Oncology Group scale (9): 0 indicating full activities without any restriction, and 4 indicating complete disability with confinement to bed or chair.
Information on whether the patient was referred to medical oncology by a surgeon, as well as the reason for not referring, was noted. Chemotherapy regimen of those who were offered adjuvant chemotherapy was recorded. For the patients who received chemotherapy at Laval Hospital, the time between surgery and initiation of adjuvant chemotherapy, the number of cycles completed and chemotherapy-related toxicities (including death) were noted. Toxicity was graded according to the common terminology criteria for adverse events (8).
Finally, in case of hospitalization during the course of therapy, the cause of hospitalization was recorded.

Statistics
Descriptive statistics (proportions or means, medians and SDs when appropriate) were used to describe the study population. Logistic regression analysis was used to investigate whether reference to medical oncology depended on the surgeon who performed the surgery. Clinical characteristics of those who received adjuvant chemotherapy were compared with those who did not receive adjuvant chemotherapy using Fisher's exact tests for the categorical variables and unpaired t tests for the continuous variables. Predictors of adjuvant chemotherapy were investigated using logistic regression analyses. The influence of each of the demographic and perioperative characteristics on the likelihood of receiving adjuvant chemotherapy was hence examined. In all the analyses, given the multitude of comparisons involved, statistical significance was set at the P<0.01 level.

RESULTS
Patients and reference patterns to medical oncology A total of 258 patients underwent surgery (Figure 1). Seven patients were excluded because of early postoperative death and two patients were excluded because of incomplete data. Data from 249 patients (59% male; mean [± SD] age of 63±9 years; 94% NSCLC; 21% stage IA; 28% stage IB; 3% stage IIA; 22% stage IIB; 12% stage IIIA; 15% stages IIIB and IV) were analyzed.
Of the 249 patients, 125 (50%) were referred to medical oncology for consideration of adjuvant chemotherapy. The reasons for not referring to medical oncology were not clearly stated in most cases (n=76; 61%). The reasons for not referring in the 48 other patients were as follows: complicated postoperative course (n=15), comorbid disease contraindicating to medical oncology believed to be too long (n=1). Reference to medical oncology was not related to the surgeon who performed the resection. Following the initial consultation in medical oncology, 14 patients were deemed ineligible for adjuvant chemotherapy because of tumour stage or comorbidities, and 11 refused to receive it.

Patients receiving adjuvant chemotherapy
One hundred patients finally received chemotherapy. Comparisons between those who received chemotherapy and those who did not are shown in Table 1. The results of the regression analyses are shown in Table 2. Tumour stage and performance status were the most powerful predictors of adjuvant chemotherapy. Histological type, longer length of stay, date of surgery and older age were the other predictors. Of note, 29 of the 61 patients (48%) with stage II lung cancer did not receive adjuvant chemotherapy.

Compliance and toxicity
Sixty patients received adjuvant chemotherapy at Laval Hospital, and contributed to the toxicity and compliance analyses. The 40 remaining patients were transferred to their community hospital where they received adjuvant chemotherapy after the indication was ascertained at Laval Hospital. Treatment was initiated 47 days (median) after surgery ( Figure 2). Chemotherapy mainly consisted of cisplatin-vinorelbine (n=23; 38%), cisplatin-etoposide (n=13; 22%) and carboplatinpaclitaxel (n=12; 20%) ( Table 3). Sixty-six per cent of patients completed all four scheduled cycles. There was no treatment-related death. Complete data on toxicity were available for 48 patients. Table 4 gives the proportion of patients

DISCUSSION
We report the results of a retrospective analysis conducted in a university-affiliated hospital regarding the prescription of adjuvant chemotherapy in resected lung cancer patients. Although compliance was high and toxicity was acceptable, we found that one-half of those who were submitted to lung resection for lung cancer did not receive adjuvant chemotherapy. Poor performance status, increasing age and increasing hospital length of stay at the time of surgical resection decreased the probability of adjuvant chemotherapy. There appeared to be no bias with the referring surgeon. Kassam et al (10) have reported the results of a similar analysis that was limited to the patterns of reference to medical oncology for consideration of adjuvant chemotherapy in completely resected NSCLC. They found that from May 2003 to May 2004, only 31% (36 of 115) of patients were referred for adjuvant therapy. During the subsequent year, 63% (56 of 89) of patients were referred. Of 92 patients referred to medical oncology, only 42 (46%) received adjuvant chemotherapy. The main reason for not prescribing treatment was patient refusal (50%). Our study found a 50% rate of being referred to medical oncology. Eighty per cent of these patients received therapy and only 9% refused it.
The most obvious limitation of our study is that the data were obtained retrospectively, with limited information on those who received chemotherapy in community hospitals. In the reference analysis, we nevertheless considered every consecutive patient who had undergone resection for lung cancer. Our results are similar to those observed by Kassam et al (10), despite different methodologies. Our data were mainly collected after the ASCO meeting in May 2004, when medical evidence favouring adjuvant chemotherapy was released, and included a small number of patients with SCLC who all received, with one exception, adjuvant chemotherapy. In addition, we considered patients with incomplete resection, a situation in which the benefits of adjuvant therapy are unclear (11).
The eligibility criteria in the International Adjuvant Lung Cancer (IALT) trial specified that patients had to be randomly assigned to treatment group or control group within sixty days after surgery (12). Similarly, one inclusion criterion from the NCIC BR.10 trial (6) and from the ANITA trial (13) was that chemotherapy had to be commenced within six weeks of surgery. Our study showed that treatment was initiated 47 days (median) after surgery. Good collaboration is necessary among surgeons, pathologists and oncologists to be able to initiate treatment within a reasonable delay. Whether any delay would decrease the benefit of adjuvant chemotherapy remains unknown but is likely.
Regarding compliance to chemotherapy, only 50% of patients received the predicted four cycles of chemotherapy in the ANITA (13) and NCIC BR.10 trials (6). We observed a 66% full-compliance rate. The differences may be related to our inclusion of patients with SCLC. Nevertheless, our results confirm the application of adjuvant chemotherapy in day-today practice. In the NCIC BR.10 trial, hospitalization was required in 19% of patients for medical problems related to toxicity (6). These data were not available for the other two trials (12,13). We found that 15% were hospitalized because of side effects.

CONCLUSION
Adjuvant chemotherapy is gaining acceptance in clinical practice. Although one-half of those who were submitted to lung resection for lung cancer did not receive adjuvant chemotherapy, the results of the present study confirm the feasibility of adjuvant chemotherapy in routine care of patients with lung cancer. Toxicity to adjuvant chemotherapy was similar to that observed in published clinical trials. More patients, especially those with stages II and IIIA NSCLC, should be referred to medical oncology for consideration of adjuvant chemotherapy. Further study should focus on the factors associated with reference to medical oncology.
SUPPORT: This study originated from Laval Hospital and was supported by local funds.