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Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer
Lung Cancer 23 (1999) 19 – 30
Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer Catherine Lochrin *, Glenwood Goss, David J. Stewart, Peter Cross, Olusegun Agboola, Simone Dahrouge, Eva Tomiak, W.K. Evans Cancer Care Ontario, Ottawa Regional Cancer Centre and the Uni6ersity of Ottawa, Faculty of Medicine, Cancercare Ontario, 501 Smyth Road, Ottawa, Ont. K1H 8L6, Canada Received 26 June 1998; received in revised form 19 November 1998; accepted 30 November 1998
Abstract Objecti6es: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). Methods: Forty seven patients received thoracic radiotherapy (1.5 bid × 5 days ×4 weeks) in combination with low dose daily (3–6 mg/m2) cisplatin 9weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75 – 80 mg/m2) and vinblastine (8 – 16 mg/m2) given at 3–4 week intervals (step II). Results: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. Conclusion: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non small cell lung cancer; Hyperfractionated accelerated radiotherapy; Stage III; Cisplatin; Vinblastine; Concurrent chemotherapy; Adjuvant chemotherapy
* Corresponding author. Tel: +1-613-7377700, 6809; fax: +1-613-2473511. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 8 ) 0 0 0 9 8 - 1
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1. Introduction The 5 year survival rate of patients with locally advanced (stage III) non small cell lung cancer (NSCLC) is a dismal 1 – 10% [7]. For this stage of disease, thoracic radiation has been the primary modality of treatment. Following the 1982 report by the RTOG, once daily fractions of 2 Gy, 5 days/week for 6 consecutive weeks became the standard of practice in North America [24]. More recently, radiotherapy regimens have been modified in intensity and schedule in order to maximize tumour cell kill while maintaining acceptable toxicity. Tumour cells can proliferate rapidly [37]. Accelerated radiation therapy, a technique by which the total radiation dose is delivered within a shorter period of time, can reduce repopulation in rapidly growing tumors [17,36]. And, hyperfractionated radiation therapy, which involves delivering the total dose in a greater number of fractions, exploits the enhanced repair capacity of late-reacting normal tissues while increasing tumour cell kill. The RTOG conducted a 5-level dose escalation study using twice daily fractionation (1.2 Gy BID) in good performance status patients with stage III NSCLC. The results suggest that the survival among patients receiving a total dose of 69.6 Gy maybe improved over those receiving lower doses, without significant morbidity [4]. Other accelerated hyperfractionated schemes (CHART+HART) have resulted in improved local tumour control and survival [30]. Another potential approach to enhancing the cell kill properties of radiotherapy is to concomitantly administer a radiosensitizer such as cisplatin [27]. A randomized comparative EORTC study demonstrated a significant survival advantage for patients receiving daily cisplatin plus daily radiotherapy over radiotherapy alone [33]. More recently, the benefits of concomitant radiotherapy and chemotherapy has been also been reported by others [12]. Unfortunately, distant metastases are responsible for the first failure in 20 – 41% of patients with locally advanced NSCLC receiving curative radical radiotherapy, and ultimately occur in 49 – 79% of patients [23]. Early effective systemic therapy, if combined with optimal local treatment, could
lead to improved outcomes. Although combination chemotherapy in good performance status patients with stage IV NSCLC has demonstrated only moderate improvement in response and survival, its use in patients with regionally advanced disease is more encouraging [9]. Cisplatin based multidrug regimens, when used as induction therapy in stage III disease, yield response rates ranging from 39 and 78% [9]. Therefore, because of the radiosensitizing properties of cisplatin and vinblastine, and their known efficacy in metastatic disease, in 1993 we embarked on a pilot study of hyperfractionated accelerated radiotherapy given concurrently with low dose daily cisplatin and weekly vinblastine followed by three cycles of standard dose cisplatin and vinblastine in the treatment of patients with stage IIIA and IIIB NSCLC.
2. Patients and methods This was a prospective single arm pilot study carried out at the Ottawa Regional Cancer Centre.
2.1. Patient population All patients had cytologically or histologically confirmed, previously untreated stage III NSCLC, including squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Patients were required to have measurable disease, ECOG performance status of 0–2, adequate pulmonary (FEV1\1.25 l, DCO]50%), cardiac, renal (serum creatinine5 150 umol/l), (hepatic5 1.5× UNL), and bone marrow (Hgb] 100 g/l, WBC] 3.5× 109/l, platelet count]100 000× 109/l) functions. Patients were ineligible if they had mixed small and non small cell lung cancer, a history of neurological or renal disease, prior systemic chemotherapy, thoracic irradiation, or a previous malignancy except non-melanomatous skin cancer or carcinoma in-situ of the cervix. All eligible patients were entered consecutively. Baseline investigations included CBC and differential, tests of hepatic and renal functions, EKG and pulmonary function tests, chest X-ray,
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
CT thorax, upper abdomen and brain, and bone scan.
2.2. Treatment Treatment consisted of two sequential steps (Table 1). In step I, patients received concurrent thoracic radiotherapy and chemotherapy consisting of low dose daily cisplatin 9weekly vinblastine, and in step II patients received three cycles of standard dose chemotherapy alone as adjuvant therapy. Radiotherapy was delivered in the following hyperfractionated accelerated scheme; 1.5 Gy twice daily, a minimum of 6 h apart, on days 1 – 5, 8 – 12, 15–19 and 22– 26, for a total dose of 60 Gy. Patients concurrently received cisplatin 3 – 6 mg/m2 IV on each day of radiotherapy. Most patients also received vinblastine 2 mg/m2 IV weekly on days 1, 8, 15 and 22. Radiotherapy was delivered as soon as possible, usually within one hour, following first cisplatin administration. After a 3 – 4 week recovery period, patients received step II of the treatment consisting of cisplatin 75 – 80 mg/m2 (total dose)+ vinblastine 8–16 mg/m2 on a single day every 3 weeks for a total of three courses. Radiotherapy was administered with a 6 or 18 Mv photon energy beam. The primary lung tumour, ipsilateral hilum and mediastinum with a 2 cm margin of non-involved lung were included in the initial target volume. For tumors arising from the Table 1 Treatment schedule
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lower lung, the inferior border of the radiation field was extended to include the lower mediastinum down to the diaphragm. For upper lobe tumours, the ipsilateral supraclavicular fossa was included in the target volume. The primary tumour and bulky nodes received a minimum tumour dose of 60 Gy in 40 fractions. AP-PA beam arrangement was usually used for the initial 30 Gy, followed by oblique fields or alternate arrangement, to avoid critical organs, for the remaining 30 Gy. The maximum doses permitted to the ipsilateral whole lung, spinal cord and heart were 15 Gy, 35 Gy, and 35 Gy, respectively. To offset potential radiation oesophagitis during the course of radiation therapy, most patients received prophylactic treatment with sucralfate elixir 1 g qid, ranitidine elixir 150 mg bid, and nystatin suspension 500 000 units qid. Anti-emetic therapy generally consisted of prochlorperazine 10–20 mg p.o. daily during part I of the treatment, and dexamethasone 8–16 mg p.o. or i.v. and ondansetron 8 mg p.o. pre chemotherapy during step II.
2.3. Response Radiological assessment of disease response was performed 1 month after completing step I and at the beginning of each cycle during step II. When disease progression was noted in the chest, the
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patient was restaged to determine whether distant disease was also present. In the absence of local progression, patients were only investigated for disease outside the thorax if symptoms were present. Response was assessed radiologically, using a CT scan, and clinically. A complete response was defined as the complete disappearance of all tumour and resolution of all tumour-related symptoms lasting a minimum of 4 weeks, in the absence of the appearance of new lesions. Radiologic complete responses were not confirmed pathologically. A partial response was a 50% reduction in the sum of the products of the widest perpendicular diameters of measurable lesions, and/or an estimated 50% or greater reduction in the size of non-measurable but evaluable lesions, lasting a minimum of 4 weeks, in the absence of new lesions. Stable disease was the B 50% decrease and B25% increase in the sum of the products of the widest perpendicular diameters of lesions, in the absence of new lesions for at least 8 weeks. This was measured for measurable lesions and estimated for evaluable lesions. Disease progression was the] 25% increase in the size of any lesion or the appearance of new lesions. Local failure was defined as progression of an old lesion or the appearance of a new lesion within the irradiation portal; and distant progression was defined as the appearance of a new lesion outside the portal field. Recurrences falling on the boundaries of the irradiation portal were marginal failures. We followed separately local failure and distant failure to determine the site of first progression. The time to first progression was the interval between the date of documented progression at any site and the date of diagnosis. In patients who had not progressed at the time of analysis, the time to progression was censored at the last date of followup. The survival duration was the period elapsed between the date of diagnosis and the date of death. Patients alive at the time of analysis had their survival duration censored at their last follow-up. The Kaplan Meier product limit estimate was used to calculate the time to progression and survival duration [13].
tological and serum biochemistry evaluations, and weekly physical examinations for assessment of toxicity during step I. During step II, a physical examination was done prior to each course of chemotherapy and hematological and serum biochemistry evaluations were performed weekly. Chemotherapy dose adjustments were made in response to hematological, renal, and neurological toxicity. Toxicity was graded according to the NCIC CTG expanded common toxicity criteria. Step I acute toxicity was defined as any toxicity occurring prior to commencement of step II. Step II acute toxicity was defined as that which occurred during adjuvant chemotherapy or within 6 weeks of the last dose of chemotherapy. Late toxicity was any new toxicity appearing greater than 6 weeks following the last dose administration, any toxicity persisting into that period, or the appearance of permanent changes such as pulmonary fibrosis following an active process.
2.4. Toxicity
Forty-seven patients received step I, and 36 went on to receive step II. Table 3 lists the best response attained locally only, and the best overall response
Toxicity was monitored with twice-weekly hema-
3. Results Between January 1993 and August 1996, 48 patients were enrolled at the Ottawa Regional Cancer Centre. One patient refused treatment after registration because of rapid deterioration due to disease progression and is excluded from further analysis. Patients’ entry characteristics are listed in Table 2. Males made up 60% of the study population; the median age was 61.3 years (range: 34–78); the median ECOG performance status was 1; and 55% of patients were stage IIIB at diagnosis. The histological cell type of patient tumors was as follows; 34% squamous cell, 21% adenocarcinoma and 45% undifferentiated large cell. One patient believed to have stage III disease at the time of entry was retrospectively up-staged to stage IV because of the presence of a subpleural nodule at baseline. That patient remained on study and completed the treatment as intended.
3.1. Efficacy
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Table 2 Patient entry characteristics Patient characterisics Gender Age Cell type
Performance status
Staging*
N0 N2 N3
Number (%) of patients Male Female B60 \60 Squamous cell Large cell Adenocarcinoma 0 1 2 IIIA IIIB IV Tx 1 (2)
28 (60) 19 (40) 18 (38) 29 (62) 16 (34) 21 (45) 10 (21) 21 (45) 23 (49) 3 (6) 20 (43) 26 (55) 1 (2) T1 4 (9) 3 (6)
T2 8 (17) 2 (4)
T3 1 (2) 7 (15)
T4 5 (11) 14 (30) 2 (4)
* TNM 1986 classification.
for all evaluable patients. The overall objective response rate was 70% (95% CI=54 – 86%), with 21% complete responders; the local objective response rate was 74%, with 21% complete responders. Two patients had a partial response of their local disease, but disease progression elsewhere (brain metastasis at the end of step I). Some patients had a residual opacity on imaging that was significantly reduced in size from the original assessment, but that did not disappear. These patients were coded as having had a partial response, but the sustained duration of their response suggests that they may have had a complete resolution of their tumour with residual scaring visualized on imaging. Four patients are not evaluable for response assessment; one had stable disease 4 weeks after commencing therapy but was lost to follow-up shortly thereafter; two others had early deaths within 10 days of treatment, and the last was retrospectively found to have a second lung primary and was considered only evaluable for toxicity. An intent-to-treat analysis indicates that 68% of all patients attained a response. At the time of analysis, progression had been documented in 32 (71%) patients. Five (11%) pa-
tients died before disease progression could be documented, and eight (18%) were still free of progression. Of the 32 patients who had progressed, 14 (44%) failed locally as the initial site of progression, while 13 (41%) failed at a distant site first. The remainding five (15%) had simultaneous local and distant progression. The estimated median time to first progression at any site was 10.4 months. The estimated median survival duration for all patients is 17.3 months (95% CI= 10.4– 24.1). The 1, 2 and 3 year survival rates are 61, 35 and 21%, respectively (Fig. 1).
3.2. Toxicity Table 4 lists the number of patients with worst grades of acute toxicity 1–2 and 3–4 for steps I and II and for long term toxicity.
3.2.1. Acute toxicity 3.2.1.1. Esophageal. Esophagitis was the most common form of toxicity in part I and part II of the study. In part I, 28% suffered grade 3 or 4 esophageal toxicity, and in part II, 19% of patients had grade 3 or 4 esophageal toxicity. Patients experiencing esophagitis during step II did
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
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tients during step I and 15% during step II of the study. These symptoms were usually mild and were managed with oral prednisone, steroid inhalers, and broncho-dilators. If a secondary bacteria infection was suspected, patients received oral antibiotics. No patient required hospitalization for pulmonary toxicity.
Fig. 1. Kaplan Meier survival of all eligible patients (n = 47).
so either because the esophagitis from concurrent chemo-radiotherapy had not resolved, or because they developed recall esophagitis when adjuvant chemotherapy was commenced. Patients continuing to experience or reporting new symptoms of esophagitis during adjuvant chemotherapy were maintained on their sucralfate, ranitidine and nystatin therapy. Esophageal toxicity not responding to these measures was also managed with increased supportive care consisting of IV fluid administration, and occasionally, prophylactic acyclovir 400 mg/day × 5 days. Eight patients required hospital admission for supportive therapy due to severe esophagitis. One patient developed an esophageal rupture shortly after his third cycle of chemotherapy, and died.
3.2.1.2. Pulmonary. Acute pulmonary toxicity consisting of shortness of breath, cough or radiological pneumonitis was observed in 25% of paTable 3 Best local and overall response (43 evaluable patients)
Complete response Partial response Stable disease Disease progression Objective response rate
Local (%)
Overall (%)
9 23 11 0 32
9 21 11 2 30
(21) (53) (26) (0) (74)
(21) (49) (26) (5) (70)
3.2.1.3. Gastrointestinal. Nausea and vomiting were usually of mild to moderate severity, but three patients required hospital admissions for severe nausea and/or vomiting during step II of treatment. Stomatitis and diarrhea was usually rare and mild, but one patient required hospital admission for hydration following a severe episode of stomatitis during his first cycle of adjuvant chemotherapy. 3.2.1.4. Local skin reactions. Twelve patients (26%) developed a local skin reaction to radiotherapy that varied from a burning sensation or an itchy rash to mild desquamation during concurrent chemo-radiotherapy. All were of grade 1 or 2. 3.2.1.5. Neurological. Five patients reported symptoms of paraesthesias during their treatment. These were of mild to moderate severity and resolved promptly. Two patients complained of decreased hearing and two others had tinnitus during adjuvant chemotherapy. Again, these symptoms were transient. 3.2.1.6. Febrile neutropenia/pneumonia. During step I of the study, one patient developed febrile neutropenia, and another developed pneumonia that required hospital admission. Both recovered promptly. During step II of the study, the incidence of febrile neutropenia was higher. Nine patients had febrile neutropenia, three of whom required oral antibiotics, and five requiring hospital admission. Of the five patients admitted, two were successfully treated and released, one developed pneumonia and died despite treatment with intravenous antibiotics, another died in a peripheral hospital from neutropenic sepsis, and one patient recovered from the infection but subsequently became comatose and died. The cause of
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Table 4 Early and late toxicity (worst grade per patient) Part I (47 patients)
Part II, 36 patients (%)
Toxicity (grade)
1–2 (%)
3–4 (%)
1–2 (%)
3–4
Esophagitis Nausea Vomiting Cough SOB Pneumonitis Pulmonary fibrosis Local reaction Fatigue Stomatitis Diarrhea Neurological Auditory Febrile neutropenia
24 29 17 7 3 1
(51) (62) (36) (15) (6) (2)
13 1 0 0 0 1
(28) (2) (0) (0) (0) (2)
10 10 6 2 2 1
(28) (28) (17) (6) (6) (3)
7 3 1 0 0 0
(19) (8) (3) (0) (0) (0)
12 13 3 2 2 0
(26) (28) (6) (4) (4) (0)
0 4 1 0 0 0 2
(0) (9) (2) (0) (0) (0) (4)
8 1 1 3 4
(22) (3) (3) (8) (11)
8 1 0 0 0 9
(22) (3) (0) (0) (0) (25)
death was undetermined, but may have been related to leptomeningeal involvement by tumour.
3.2.1.7. Cardio6ascular. One patient developed superficial thrombophlebitis, and two others (one of whom had a history of cardiac abnormalities) developed a deep venous thrombosis and required hospital admission for management. None of these events were thought to be related to the treatment. Another patient died of congestive heart failure with secondary chest infection. The onset of symptoms occurred after 4 days of radiotherapy and was thought to be unrelated to treatment. 3.2.2. Late toxicity 3.2.2.1. Esophageal. Five patients suffered symptoms of esophageal toxicity following the end of treatment. In three, the symptoms consisted of odynophagia, persisting following the end of treatment. These manifestations eventually resolved with supportive therapy. In the other two patients symptoms reappeared after a period of quiescence. One patient developed a tracheosophageal fistula 2 months after treatment. A stent was inserted, at which time the fistula enlarged, and the patient became confused and dis-
Late toxicity, 47 patients (%)
5 (11)
1 (2) 1 (2) 22 (47%)
oriented, probably related to sepsis, and died a few days later. Death was thought to be related to the fistula. The other patient developed an esophageal stricture that required dilation 1 year after his treatment. This procedure caused perforation of the esophagus, resulting in a septic death. There was no evidence of tumor invading the esophagus in either patient. All five patients experiencing late esophageal toxicity had been treated early on in the study, prior to the implementation of prophylactic therapy.
3.2.2.2. Pulmonary. Virtually all patients who had a moderately extended survival duration (51%) exhibited long term pulmonary toxicity consisting of fibrosis and/or consolidation in the radiation field on chest X-ray. Three patients had late evidence of pleural effusion in the absence of local disease progression, and two had pericardial effusion. These symptoms were thought to have been inflammatory effusions secondary to radiotherapy or due to a redistribution of bloodflow following radiation therapy. Table 5 lists the grade of hematological toxicity as a percentage of the number of weeks evaluated during step I, and cycles evaluated during step II. Hematological toxicity was mild during concurrent chemo-radiation, and more significant during
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adjuvant chemotherapy. Grade 3 – 4 leukopenia and granulocytopenia were seen in 31, and 28% of cycles in Part II, respectively. Thrombocytopenia and anemia occurred at grade 3 – 4 in 3% of cycles. The median nadir values of white blood count, granulocyte count, platelet count, and hemoglobin levels are given for the weeks in Part I and the cycles in Part II. Of the 47 patients who started treatment, 42 (89%) completed the 4 weeks of combination therapy. Of these 42 patients, 36 went on to receive adjuvant chemotherapy, and 22 (47%) patients completed the entire planned therapy. Of the 25 patients who did not complete treatment, three died of causes unrelated to therapy, 11 discontinued treatment because of deteriorating performance status related to treatment toxicity (primarily esophagitis), three patients refused further treatment, five progressed while on treatment, and three died of treatment related toxicity (pneumonia, neutropenic sepsis, esophageal rupture). Following the end of treatment, there were two treatment related deaths related to esophageal toxicity.
4. Discussion The criteria for grading toxicity vary widely between studies, especially with respect to esophagitis. These variations do not allow for direct comparisons of the incidence of toxicity between studies. Nonetheless, regardless of the scale used, studies of radiotherapy alone and espe-
cially those of combination radiotherapy/ chemotherapy commonly report esophagitis to be a significant form of acute toxicity. Furthermore, the rate of gastro-intestinal toxicity is significantly increased in studies combining chemotherapy with radiotherapy [25]. The rate of esophageal toxicity reported in these studies varies greatly from 9 to 66%, probably in part due to the heterogeneity of the toxicity scales [14,16,19,22,32,34,35]. Under the NCIC CTG expanded common toxicity criteria used in this study, grade 3 esophagitis is the presence of dysphagia or odynophagia lasting more than 14 days despite treatment. The percentage of patients reporting some degree of esophagitis during concurrent therapy was 79%; 28% at grade 3–4. Although the differences in scales preclude a direct comparison of the results, the incidence of acute esophagitis observed in this study is seemingly higher than would have been expected from radiotherapy alone. The hyperfractionated accelerated schedule of radiotherapy coupled with the radiosensitisation of cisplatin likely increased the incidence of acute toxicity. During the adjuvant chemotherapy part of the study, we observed a significant incidence of recall esophagitis. In fact, 47% complained of esophagitis during part II of the study; 19% at grades 3–4, and 11% remained symptomatic or developed symptoms at least 6 weeks after completion of all therapy. Esophagitis was usually managed with increased supportive therapy, but occasionally required hospital admission for parenteral nutritional support. There were three deaths attributable to esophageal toxicity. One of the
Table 5 Hematological toxicity Part I (135–139 evaluable weeks)
White blood cells Granulocytes Platelets Hemoglobin
Grade 1–2 (%)
Grade 3–4 (%)
24
4
7 12 22
2 1 1
Part II (71–74 evaluable cycles) Median nadir (×109/l)
Grade 1–2 (%)
Grade 3–4 (%)
Median nadir (×109/l)
5.3
35
31
2.8
4.3 272 124
20 25 68
28 3 3
2.2 229 104
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
deaths occurred in a patient who had a history of diabetes since the age of 11 and who may have had underlying vascular disease. All three deaths occurred early on in the study, following which we vigorously administered prophylactic treatment for esophagitis, consisting of sucralfate elixir 1 gm qid, ranitidine elixir 150 mg bid and nystatin suspension 500 000 units qid, and we discontinued investigating patients endoscopically for esophageal symptoms. These preventative measures eliminated life threatening esophageal toxicity, and allowed successful completion of the treatment in most patients. Acute pulmonary manifestations consisting of cough, shortness of breath or pneumonitis were recorded in 25% of patients during their treatment (part I or II). Symptomatic pulmonary toxicity was treated with bronchodilators, steroids, antibiotics and oxygen, as indicated. Most patients (47%) developed radiological evidence of pulmonary fibrosis or consolidation in the radiation field; an expected outcome of pulmonary radiotherapy. The incidence and intensity of neurological toxicity, including peripheral neuropathy and ototoxicity was that expected from cisplatin based regimens [3,28]. There was no long term neurological deficits from treatment. Hematological toxicity consisted primarily of leukopenia, neutropenia, and decreased hemoglobin levels. The incidence and severity of hematological toxicity is similar to that observed in studies of chemotherapy alone, without induction therapy. Most patients with stage IIIA or IIIB disease are not curable, and the expected median survival duration ranges between 9 and 18 months, depending on treatment [21]. Radiotherapy has been the standard treatment for stage III NSCLC. Recently, three large randomized comparative trials demonstrated the benefits of sequential induction chemotherapy and radiotherapy over radiotherapy alone. Two trials used induction chemotherapy consisting of cisplatin and vinblastine followed by radiotherapy alone [8,31]. Both observed a significant improvement in survival duration in the multi-modality arm. Another trial investigated the use of a cisplatin based chemotherapy regimen administered for three cycles before and after radiotherapy [15]. In that
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study, the rate of distant metastases was reduced and overall survival improved in the multi-modality arm. These findings are supported by the results of two other comparative studies [5,38]. Furthermore, two recent meta-analyses of randomized clinical trials comparing radiotherapy to combination chemotherapy and radiotherapy have demonstrated a survival advantage at years 1 and 3 for combined modality therapy [18,26]. The meta-analyses grouped together all combination therapies without distinguishing between concurrent and sequential therapies. The benefit imparted by concurrent therapy is potentially different from that with sequential therapy. Low dose chemotherapy given with radiotherapy might be expected to enhance the effects of radiotherapy while providing modest, if any, systemic control of the disease. In contrast, the objective of sequential chemotherapy is to control occult systemic disease, although it may also contribute to control of local disease. Most studies comparing concurrent therapy to radiotherapy alone have reported a reduction in the rate of local recurrence and improved overall survival in the combination arm, but no difference in the control of distant metastases [2,12,32,34], suggesting that the improved survival is due to improved local control and not systemic control. This is further supported by the fact that the few studies that did not observe an improvement in the rate of local relapse from combination therapy also failed to demonstrate improved survival [1,20,35]. Sequential therapy has also been demonstrated to be superior to radiotherapy alone with respect to survival in several randomized trials [2,6,8,15,38]. Some of these studies report a reduction in the incidence of distant metastases with sequential therapy [2,6,15], while others do not [8,19,38]. Interestingly, contrary to studies of concurrent chemotherapy, an improvement in survival did not always correlate with a detectable decrease in the rate of distant metastases. A review of studies of induction (sequential) chemotherapy by Green reported that this approach appears to reduce the rate of distant metastases, but that local control remains the limiting factor [10]. Therefore, the mechanism by which sequential chemotherapy and radiotherapy
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effects survival has not been clearly defined. If, however, sequential chemotherapy reduces the risk of distant relapse, and concomitant therapy controls local disease, then the combination of both therapeutic approaches may improve overall control of the disease. In the present study, we combined two radiosensitizers, cisplatin and vinblastine, with concurrent radiotherapy to improve local tumour control, and subsequently administered three courses of standard chemotherapy in an attempt to reduce the risk of distant relapse. The first site of relapse was local in 44% of patients, distant in another 41%, and both in 15%. These results are similar to those reported in other studies of concurrent therapy [1,20,22,32]. Therefore, it is not clear whether the addition of adjuvant chemotherapy contributed to tumour control. This could only be tested in a randomized study. One might speculate that the low dose chemotherapy given concurrently with radiotherapy would induce resistance to later standard dose chemotherapy. If one hypothesized that the use of sequential chemotherapy improves survival, without significantly reducing the proportion of first metastases at a distant site because it impacts on both local disease and occult distant metastases, then the combination of concurrent and sequential therapy would be expected to result in an improved survival over concurrent therapy alone. Our results are in keeping with this hypothesis. The time to first progression, at any site, was 10.4 months, the estimated median survival duration was 17.2 months, and the 1, 2 and 3 year survival rates were 61, 35, and 21%, respectively. These survival rates appear improved when compared to studies of concurrent or sequential chemotherapy alone. One final note; studies of adjuvant therapy with surgery for resectable disease suggest that chemotherapy delivered in the neoadjuvant setting [29] produces superior results to that given post surgically [11]. If the optimal timing for chemotherapy is prior to the therapy that is aimed at controlling local disease then, extrapolating from that data, it may be argued that induction chemotherapy followed by concurrent therapy might have produced superior results in these patients with stage III,
non-resectable disease. Single arm, phase II studies usually have a limited number of patients but can provide useful information on the feasibility and toxicity of a regimen. The therapeutic benefit may be hypothesized, but it can only be evaluated in comparative studies. Therefore, when reporting on phase II studies of small sample sizes, caution must be exercised before drawing conclusions concerning efficacy of the regimen. Within the limitations of this study, we can say that the combination of concurrent vinblastine-cisplatin chemotherapy and hyperfractionated accelerated radiotherapy followed by sequential chemotherapy is both feasible and tolerable, and appears to provide adequate tumour control. However, the toxicity and inconvenience to the patient was significant, because of the elevated incidence of acute esophagitis, and because of the prolonged treatment duration, respectively. The risk to benefit ratio of this kind of therapy needs to be evaluated in studies which incorporate a quality of life assessment to determine the value of increasing treatment intensity/duration. Encouragingly, however, there appears to be a small subset of patients with locally advanced disease who will survive more than 5 years. Although the follow up duration in our study does not allow us to report on the 5 years survival rate, at the time of analysis, four patients (8%) are alive after 40 months, while two are progression free after 43 months, and 53 months, respectively. These patients have been without treatment for more than 3–4 years. Therefore, if combined modality therapy can increase the rate of long term survival within the limits of acceptable toxicity, then the diminished quality of life suffered during treatment may be justifiably offset by the prolonged treatment free and overall survival. References [1] Blanke C, Ansari R, Mantravadi R, et al. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small cell lung cancer: a hoosier oncology group protocol. J Clin Oncol 1995;13:1425 – 9.
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30 [2] Brodin O, Nou E, Mercke C, et al. Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish lung cancer study group. Eur J Cancer 1996;32A:1893–900. [3] Carenza L, Villani C, Framarino dei Malatesta M, et al. Peripheral neuropathy and ototoxicity of dichlorodiamineplatinum: instrumental evaluation. Preliminary results. Gynecol Oncol 1986;25:244–9. [4] Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TF. A randomized phaseI/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with ] 69.6 Gy in favorable patients with radiation therapy oncology group stage III non-small-cell lung carcinoma: report of radiation therapy oncology group 83–11. J Clin Oncol 1990;8:1543–55. [5] Crino L, Latini P, Meacci M, et al. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Annals Oncol 1993;4:847–51. [6] Crino L, Meacci M, Corgna E, et al. Long term results in locally advanced inoperable non small cell lung cancer (NSCLC): a randomised trial of induction chemotherapy (CT) plus radiotherapy (RT) vs radiation alone. [Abstract] Lung Cancer 1991;75:161. [7] Damstrup L, Poulsen HS. Review of the curative role of radiotherapy in the treatment of non-small cell lung cancer. Lung Cancer 1994;11:153–78. [8] Dillman R, Herndon J, Seagren S, Eaton WJ, Green M. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia groupB (CALGB) 8433 trial. J Nat Cancer Inst 1996;88:1210–5. [9] Green M. Chemotherapy and radiation in the nonoperative management of stage III non-small-cell lung cancer: the right chemotherapy works in the right setting. In: DeVita VT, Hellman S, Rosenberg SA, editors. Important Advances in Oncology. Philadelphia: J.B. Lippincott, 1993:125 – 37. [10] Green M. The rold of induction chemotherapy before radiation therapy in non-operative management of stage III NSCLC. Lung Cancer 1994;11:S55–65. [11] Holmes EC. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma. Chest 1995;106:293S–6S. [12] Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol 1996;14:1065 –70. [13] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:481. [14] Le Pechoux C, Arriagada R, LeChevalier T, Bretel J. Concurrent cisplatin-vindesine and hyperfractionated thoracic radiotherapy in locally advanced nonsmall cell lung cancer. Int J Rad Oncol Biol Physics 1996;35:519–25. [15] LeChevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiother-
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Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer Catherine Lochrin *, Glenwood Goss, David J. Stewart, Peter Cross, Olusegun Agboola, Simone Dahrouge, Eva Tomiak, W.K. Evans Cancer Care Ontario, Ottawa Regional Cancer Centre and the Uni6ersity of Ottawa, Faculty of Medicine, Cancercare Ontario, 501 Smyth Road, Ottawa, Ont. K1H 8L6, Canada Received 26 June 1998; received in revised form 19 November 1998; accepted 30 November 1998
Abstract Objecti6es: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). Methods: Forty seven patients received thoracic radiotherapy (1.5 bid × 5 days ×4 weeks) in combination with low dose daily (3–6 mg/m2) cisplatin 9weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75 – 80 mg/m2) and vinblastine (8 – 16 mg/m2) given at 3–4 week intervals (step II). Results: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. Conclusion: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non small cell lung cancer; Hyperfractionated accelerated radiotherapy; Stage III; Cisplatin; Vinblastine; Concurrent chemotherapy; Adjuvant chemotherapy
* Corresponding author. Tel: +1-613-7377700, 6809; fax: +1-613-2473511. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 8 ) 0 0 0 9 8 - 1
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C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
1. Introduction The 5 year survival rate of patients with locally advanced (stage III) non small cell lung cancer (NSCLC) is a dismal 1 – 10% [7]. For this stage of disease, thoracic radiation has been the primary modality of treatment. Following the 1982 report by the RTOG, once daily fractions of 2 Gy, 5 days/week for 6 consecutive weeks became the standard of practice in North America [24]. More recently, radiotherapy regimens have been modified in intensity and schedule in order to maximize tumour cell kill while maintaining acceptable toxicity. Tumour cells can proliferate rapidly [37]. Accelerated radiation therapy, a technique by which the total radiation dose is delivered within a shorter period of time, can reduce repopulation in rapidly growing tumors [17,36]. And, hyperfractionated radiation therapy, which involves delivering the total dose in a greater number of fractions, exploits the enhanced repair capacity of late-reacting normal tissues while increasing tumour cell kill. The RTOG conducted a 5-level dose escalation study using twice daily fractionation (1.2 Gy BID) in good performance status patients with stage III NSCLC. The results suggest that the survival among patients receiving a total dose of 69.6 Gy maybe improved over those receiving lower doses, without significant morbidity [4]. Other accelerated hyperfractionated schemes (CHART+HART) have resulted in improved local tumour control and survival [30]. Another potential approach to enhancing the cell kill properties of radiotherapy is to concomitantly administer a radiosensitizer such as cisplatin [27]. A randomized comparative EORTC study demonstrated a significant survival advantage for patients receiving daily cisplatin plus daily radiotherapy over radiotherapy alone [33]. More recently, the benefits of concomitant radiotherapy and chemotherapy has been also been reported by others [12]. Unfortunately, distant metastases are responsible for the first failure in 20 – 41% of patients with locally advanced NSCLC receiving curative radical radiotherapy, and ultimately occur in 49 – 79% of patients [23]. Early effective systemic therapy, if combined with optimal local treatment, could
lead to improved outcomes. Although combination chemotherapy in good performance status patients with stage IV NSCLC has demonstrated only moderate improvement in response and survival, its use in patients with regionally advanced disease is more encouraging [9]. Cisplatin based multidrug regimens, when used as induction therapy in stage III disease, yield response rates ranging from 39 and 78% [9]. Therefore, because of the radiosensitizing properties of cisplatin and vinblastine, and their known efficacy in metastatic disease, in 1993 we embarked on a pilot study of hyperfractionated accelerated radiotherapy given concurrently with low dose daily cisplatin and weekly vinblastine followed by three cycles of standard dose cisplatin and vinblastine in the treatment of patients with stage IIIA and IIIB NSCLC.
2. Patients and methods This was a prospective single arm pilot study carried out at the Ottawa Regional Cancer Centre.
2.1. Patient population All patients had cytologically or histologically confirmed, previously untreated stage III NSCLC, including squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Patients were required to have measurable disease, ECOG performance status of 0–2, adequate pulmonary (FEV1\1.25 l, DCO]50%), cardiac, renal (serum creatinine5 150 umol/l), (hepatic5 1.5× UNL), and bone marrow (Hgb] 100 g/l, WBC] 3.5× 109/l, platelet count]100 000× 109/l) functions. Patients were ineligible if they had mixed small and non small cell lung cancer, a history of neurological or renal disease, prior systemic chemotherapy, thoracic irradiation, or a previous malignancy except non-melanomatous skin cancer or carcinoma in-situ of the cervix. All eligible patients were entered consecutively. Baseline investigations included CBC and differential, tests of hepatic and renal functions, EKG and pulmonary function tests, chest X-ray,
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
CT thorax, upper abdomen and brain, and bone scan.
2.2. Treatment Treatment consisted of two sequential steps (Table 1). In step I, patients received concurrent thoracic radiotherapy and chemotherapy consisting of low dose daily cisplatin 9weekly vinblastine, and in step II patients received three cycles of standard dose chemotherapy alone as adjuvant therapy. Radiotherapy was delivered in the following hyperfractionated accelerated scheme; 1.5 Gy twice daily, a minimum of 6 h apart, on days 1 – 5, 8 – 12, 15–19 and 22– 26, for a total dose of 60 Gy. Patients concurrently received cisplatin 3 – 6 mg/m2 IV on each day of radiotherapy. Most patients also received vinblastine 2 mg/m2 IV weekly on days 1, 8, 15 and 22. Radiotherapy was delivered as soon as possible, usually within one hour, following first cisplatin administration. After a 3 – 4 week recovery period, patients received step II of the treatment consisting of cisplatin 75 – 80 mg/m2 (total dose)+ vinblastine 8–16 mg/m2 on a single day every 3 weeks for a total of three courses. Radiotherapy was administered with a 6 or 18 Mv photon energy beam. The primary lung tumour, ipsilateral hilum and mediastinum with a 2 cm margin of non-involved lung were included in the initial target volume. For tumors arising from the Table 1 Treatment schedule
21
lower lung, the inferior border of the radiation field was extended to include the lower mediastinum down to the diaphragm. For upper lobe tumours, the ipsilateral supraclavicular fossa was included in the target volume. The primary tumour and bulky nodes received a minimum tumour dose of 60 Gy in 40 fractions. AP-PA beam arrangement was usually used for the initial 30 Gy, followed by oblique fields or alternate arrangement, to avoid critical organs, for the remaining 30 Gy. The maximum doses permitted to the ipsilateral whole lung, spinal cord and heart were 15 Gy, 35 Gy, and 35 Gy, respectively. To offset potential radiation oesophagitis during the course of radiation therapy, most patients received prophylactic treatment with sucralfate elixir 1 g qid, ranitidine elixir 150 mg bid, and nystatin suspension 500 000 units qid. Anti-emetic therapy generally consisted of prochlorperazine 10–20 mg p.o. daily during part I of the treatment, and dexamethasone 8–16 mg p.o. or i.v. and ondansetron 8 mg p.o. pre chemotherapy during step II.
2.3. Response Radiological assessment of disease response was performed 1 month after completing step I and at the beginning of each cycle during step II. When disease progression was noted in the chest, the
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patient was restaged to determine whether distant disease was also present. In the absence of local progression, patients were only investigated for disease outside the thorax if symptoms were present. Response was assessed radiologically, using a CT scan, and clinically. A complete response was defined as the complete disappearance of all tumour and resolution of all tumour-related symptoms lasting a minimum of 4 weeks, in the absence of the appearance of new lesions. Radiologic complete responses were not confirmed pathologically. A partial response was a 50% reduction in the sum of the products of the widest perpendicular diameters of measurable lesions, and/or an estimated 50% or greater reduction in the size of non-measurable but evaluable lesions, lasting a minimum of 4 weeks, in the absence of new lesions. Stable disease was the B 50% decrease and B25% increase in the sum of the products of the widest perpendicular diameters of lesions, in the absence of new lesions for at least 8 weeks. This was measured for measurable lesions and estimated for evaluable lesions. Disease progression was the] 25% increase in the size of any lesion or the appearance of new lesions. Local failure was defined as progression of an old lesion or the appearance of a new lesion within the irradiation portal; and distant progression was defined as the appearance of a new lesion outside the portal field. Recurrences falling on the boundaries of the irradiation portal were marginal failures. We followed separately local failure and distant failure to determine the site of first progression. The time to first progression was the interval between the date of documented progression at any site and the date of diagnosis. In patients who had not progressed at the time of analysis, the time to progression was censored at the last date of followup. The survival duration was the period elapsed between the date of diagnosis and the date of death. Patients alive at the time of analysis had their survival duration censored at their last follow-up. The Kaplan Meier product limit estimate was used to calculate the time to progression and survival duration [13].
tological and serum biochemistry evaluations, and weekly physical examinations for assessment of toxicity during step I. During step II, a physical examination was done prior to each course of chemotherapy and hematological and serum biochemistry evaluations were performed weekly. Chemotherapy dose adjustments were made in response to hematological, renal, and neurological toxicity. Toxicity was graded according to the NCIC CTG expanded common toxicity criteria. Step I acute toxicity was defined as any toxicity occurring prior to commencement of step II. Step II acute toxicity was defined as that which occurred during adjuvant chemotherapy or within 6 weeks of the last dose of chemotherapy. Late toxicity was any new toxicity appearing greater than 6 weeks following the last dose administration, any toxicity persisting into that period, or the appearance of permanent changes such as pulmonary fibrosis following an active process.
2.4. Toxicity
Forty-seven patients received step I, and 36 went on to receive step II. Table 3 lists the best response attained locally only, and the best overall response
Toxicity was monitored with twice-weekly hema-
3. Results Between January 1993 and August 1996, 48 patients were enrolled at the Ottawa Regional Cancer Centre. One patient refused treatment after registration because of rapid deterioration due to disease progression and is excluded from further analysis. Patients’ entry characteristics are listed in Table 2. Males made up 60% of the study population; the median age was 61.3 years (range: 34–78); the median ECOG performance status was 1; and 55% of patients were stage IIIB at diagnosis. The histological cell type of patient tumors was as follows; 34% squamous cell, 21% adenocarcinoma and 45% undifferentiated large cell. One patient believed to have stage III disease at the time of entry was retrospectively up-staged to stage IV because of the presence of a subpleural nodule at baseline. That patient remained on study and completed the treatment as intended.
3.1. Efficacy
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Table 2 Patient entry characteristics Patient characterisics Gender Age Cell type
Performance status
Staging*
N0 N2 N3
Number (%) of patients Male Female B60 \60 Squamous cell Large cell Adenocarcinoma 0 1 2 IIIA IIIB IV Tx 1 (2)
28 (60) 19 (40) 18 (38) 29 (62) 16 (34) 21 (45) 10 (21) 21 (45) 23 (49) 3 (6) 20 (43) 26 (55) 1 (2) T1 4 (9) 3 (6)
T2 8 (17) 2 (4)
T3 1 (2) 7 (15)
T4 5 (11) 14 (30) 2 (4)
* TNM 1986 classification.
for all evaluable patients. The overall objective response rate was 70% (95% CI=54 – 86%), with 21% complete responders; the local objective response rate was 74%, with 21% complete responders. Two patients had a partial response of their local disease, but disease progression elsewhere (brain metastasis at the end of step I). Some patients had a residual opacity on imaging that was significantly reduced in size from the original assessment, but that did not disappear. These patients were coded as having had a partial response, but the sustained duration of their response suggests that they may have had a complete resolution of their tumour with residual scaring visualized on imaging. Four patients are not evaluable for response assessment; one had stable disease 4 weeks after commencing therapy but was lost to follow-up shortly thereafter; two others had early deaths within 10 days of treatment, and the last was retrospectively found to have a second lung primary and was considered only evaluable for toxicity. An intent-to-treat analysis indicates that 68% of all patients attained a response. At the time of analysis, progression had been documented in 32 (71%) patients. Five (11%) pa-
tients died before disease progression could be documented, and eight (18%) were still free of progression. Of the 32 patients who had progressed, 14 (44%) failed locally as the initial site of progression, while 13 (41%) failed at a distant site first. The remainding five (15%) had simultaneous local and distant progression. The estimated median time to first progression at any site was 10.4 months. The estimated median survival duration for all patients is 17.3 months (95% CI= 10.4– 24.1). The 1, 2 and 3 year survival rates are 61, 35 and 21%, respectively (Fig. 1).
3.2. Toxicity Table 4 lists the number of patients with worst grades of acute toxicity 1–2 and 3–4 for steps I and II and for long term toxicity.
3.2.1. Acute toxicity 3.2.1.1. Esophageal. Esophagitis was the most common form of toxicity in part I and part II of the study. In part I, 28% suffered grade 3 or 4 esophageal toxicity, and in part II, 19% of patients had grade 3 or 4 esophageal toxicity. Patients experiencing esophagitis during step II did
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tients during step I and 15% during step II of the study. These symptoms were usually mild and were managed with oral prednisone, steroid inhalers, and broncho-dilators. If a secondary bacteria infection was suspected, patients received oral antibiotics. No patient required hospitalization for pulmonary toxicity.
Fig. 1. Kaplan Meier survival of all eligible patients (n = 47).
so either because the esophagitis from concurrent chemo-radiotherapy had not resolved, or because they developed recall esophagitis when adjuvant chemotherapy was commenced. Patients continuing to experience or reporting new symptoms of esophagitis during adjuvant chemotherapy were maintained on their sucralfate, ranitidine and nystatin therapy. Esophageal toxicity not responding to these measures was also managed with increased supportive care consisting of IV fluid administration, and occasionally, prophylactic acyclovir 400 mg/day × 5 days. Eight patients required hospital admission for supportive therapy due to severe esophagitis. One patient developed an esophageal rupture shortly after his third cycle of chemotherapy, and died.
3.2.1.2. Pulmonary. Acute pulmonary toxicity consisting of shortness of breath, cough or radiological pneumonitis was observed in 25% of paTable 3 Best local and overall response (43 evaluable patients)
Complete response Partial response Stable disease Disease progression Objective response rate
Local (%)
Overall (%)
9 23 11 0 32
9 21 11 2 30
(21) (53) (26) (0) (74)
(21) (49) (26) (5) (70)
3.2.1.3. Gastrointestinal. Nausea and vomiting were usually of mild to moderate severity, but three patients required hospital admissions for severe nausea and/or vomiting during step II of treatment. Stomatitis and diarrhea was usually rare and mild, but one patient required hospital admission for hydration following a severe episode of stomatitis during his first cycle of adjuvant chemotherapy. 3.2.1.4. Local skin reactions. Twelve patients (26%) developed a local skin reaction to radiotherapy that varied from a burning sensation or an itchy rash to mild desquamation during concurrent chemo-radiotherapy. All were of grade 1 or 2. 3.2.1.5. Neurological. Five patients reported symptoms of paraesthesias during their treatment. These were of mild to moderate severity and resolved promptly. Two patients complained of decreased hearing and two others had tinnitus during adjuvant chemotherapy. Again, these symptoms were transient. 3.2.1.6. Febrile neutropenia/pneumonia. During step I of the study, one patient developed febrile neutropenia, and another developed pneumonia that required hospital admission. Both recovered promptly. During step II of the study, the incidence of febrile neutropenia was higher. Nine patients had febrile neutropenia, three of whom required oral antibiotics, and five requiring hospital admission. Of the five patients admitted, two were successfully treated and released, one developed pneumonia and died despite treatment with intravenous antibiotics, another died in a peripheral hospital from neutropenic sepsis, and one patient recovered from the infection but subsequently became comatose and died. The cause of
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Table 4 Early and late toxicity (worst grade per patient) Part I (47 patients)
Part II, 36 patients (%)
Toxicity (grade)
1–2 (%)
3–4 (%)
1–2 (%)
3–4
Esophagitis Nausea Vomiting Cough SOB Pneumonitis Pulmonary fibrosis Local reaction Fatigue Stomatitis Diarrhea Neurological Auditory Febrile neutropenia
24 29 17 7 3 1
(51) (62) (36) (15) (6) (2)
13 1 0 0 0 1
(28) (2) (0) (0) (0) (2)
10 10 6 2 2 1
(28) (28) (17) (6) (6) (3)
7 3 1 0 0 0
(19) (8) (3) (0) (0) (0)
12 13 3 2 2 0
(26) (28) (6) (4) (4) (0)
0 4 1 0 0 0 2
(0) (9) (2) (0) (0) (0) (4)
8 1 1 3 4
(22) (3) (3) (8) (11)
8 1 0 0 0 9
(22) (3) (0) (0) (0) (25)
death was undetermined, but may have been related to leptomeningeal involvement by tumour.
3.2.1.7. Cardio6ascular. One patient developed superficial thrombophlebitis, and two others (one of whom had a history of cardiac abnormalities) developed a deep venous thrombosis and required hospital admission for management. None of these events were thought to be related to the treatment. Another patient died of congestive heart failure with secondary chest infection. The onset of symptoms occurred after 4 days of radiotherapy and was thought to be unrelated to treatment. 3.2.2. Late toxicity 3.2.2.1. Esophageal. Five patients suffered symptoms of esophageal toxicity following the end of treatment. In three, the symptoms consisted of odynophagia, persisting following the end of treatment. These manifestations eventually resolved with supportive therapy. In the other two patients symptoms reappeared after a period of quiescence. One patient developed a tracheosophageal fistula 2 months after treatment. A stent was inserted, at which time the fistula enlarged, and the patient became confused and dis-
Late toxicity, 47 patients (%)
5 (11)
1 (2) 1 (2) 22 (47%)
oriented, probably related to sepsis, and died a few days later. Death was thought to be related to the fistula. The other patient developed an esophageal stricture that required dilation 1 year after his treatment. This procedure caused perforation of the esophagus, resulting in a septic death. There was no evidence of tumor invading the esophagus in either patient. All five patients experiencing late esophageal toxicity had been treated early on in the study, prior to the implementation of prophylactic therapy.
3.2.2.2. Pulmonary. Virtually all patients who had a moderately extended survival duration (51%) exhibited long term pulmonary toxicity consisting of fibrosis and/or consolidation in the radiation field on chest X-ray. Three patients had late evidence of pleural effusion in the absence of local disease progression, and two had pericardial effusion. These symptoms were thought to have been inflammatory effusions secondary to radiotherapy or due to a redistribution of bloodflow following radiation therapy. Table 5 lists the grade of hematological toxicity as a percentage of the number of weeks evaluated during step I, and cycles evaluated during step II. Hematological toxicity was mild during concurrent chemo-radiation, and more significant during
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
26
adjuvant chemotherapy. Grade 3 – 4 leukopenia and granulocytopenia were seen in 31, and 28% of cycles in Part II, respectively. Thrombocytopenia and anemia occurred at grade 3 – 4 in 3% of cycles. The median nadir values of white blood count, granulocyte count, platelet count, and hemoglobin levels are given for the weeks in Part I and the cycles in Part II. Of the 47 patients who started treatment, 42 (89%) completed the 4 weeks of combination therapy. Of these 42 patients, 36 went on to receive adjuvant chemotherapy, and 22 (47%) patients completed the entire planned therapy. Of the 25 patients who did not complete treatment, three died of causes unrelated to therapy, 11 discontinued treatment because of deteriorating performance status related to treatment toxicity (primarily esophagitis), three patients refused further treatment, five progressed while on treatment, and three died of treatment related toxicity (pneumonia, neutropenic sepsis, esophageal rupture). Following the end of treatment, there were two treatment related deaths related to esophageal toxicity.
4. Discussion The criteria for grading toxicity vary widely between studies, especially with respect to esophagitis. These variations do not allow for direct comparisons of the incidence of toxicity between studies. Nonetheless, regardless of the scale used, studies of radiotherapy alone and espe-
cially those of combination radiotherapy/ chemotherapy commonly report esophagitis to be a significant form of acute toxicity. Furthermore, the rate of gastro-intestinal toxicity is significantly increased in studies combining chemotherapy with radiotherapy [25]. The rate of esophageal toxicity reported in these studies varies greatly from 9 to 66%, probably in part due to the heterogeneity of the toxicity scales [14,16,19,22,32,34,35]. Under the NCIC CTG expanded common toxicity criteria used in this study, grade 3 esophagitis is the presence of dysphagia or odynophagia lasting more than 14 days despite treatment. The percentage of patients reporting some degree of esophagitis during concurrent therapy was 79%; 28% at grade 3–4. Although the differences in scales preclude a direct comparison of the results, the incidence of acute esophagitis observed in this study is seemingly higher than would have been expected from radiotherapy alone. The hyperfractionated accelerated schedule of radiotherapy coupled with the radiosensitisation of cisplatin likely increased the incidence of acute toxicity. During the adjuvant chemotherapy part of the study, we observed a significant incidence of recall esophagitis. In fact, 47% complained of esophagitis during part II of the study; 19% at grades 3–4, and 11% remained symptomatic or developed symptoms at least 6 weeks after completion of all therapy. Esophagitis was usually managed with increased supportive therapy, but occasionally required hospital admission for parenteral nutritional support. There were three deaths attributable to esophageal toxicity. One of the
Table 5 Hematological toxicity Part I (135–139 evaluable weeks)
White blood cells Granulocytes Platelets Hemoglobin
Grade 1–2 (%)
Grade 3–4 (%)
24
4
7 12 22
2 1 1
Part II (71–74 evaluable cycles) Median nadir (×109/l)
Grade 1–2 (%)
Grade 3–4 (%)
Median nadir (×109/l)
5.3
35
31
2.8
4.3 272 124
20 25 68
28 3 3
2.2 229 104
C. Lochrin et al. / Lung Cancer 23 (1999) 19–30
deaths occurred in a patient who had a history of diabetes since the age of 11 and who may have had underlying vascular disease. All three deaths occurred early on in the study, following which we vigorously administered prophylactic treatment for esophagitis, consisting of sucralfate elixir 1 gm qid, ranitidine elixir 150 mg bid and nystatin suspension 500 000 units qid, and we discontinued investigating patients endoscopically for esophageal symptoms. These preventative measures eliminated life threatening esophageal toxicity, and allowed successful completion of the treatment in most patients. Acute pulmonary manifestations consisting of cough, shortness of breath or pneumonitis were recorded in 25% of patients during their treatment (part I or II). Symptomatic pulmonary toxicity was treated with bronchodilators, steroids, antibiotics and oxygen, as indicated. Most patients (47%) developed radiological evidence of pulmonary fibrosis or consolidation in the radiation field; an expected outcome of pulmonary radiotherapy. The incidence and intensity of neurological toxicity, including peripheral neuropathy and ototoxicity was that expected from cisplatin based regimens [3,28]. There was no long term neurological deficits from treatment. Hematological toxicity consisted primarily of leukopenia, neutropenia, and decreased hemoglobin levels. The incidence and severity of hematological toxicity is similar to that observed in studies of chemotherapy alone, without induction therapy. Most patients with stage IIIA or IIIB disease are not curable, and the expected median survival duration ranges between 9 and 18 months, depending on treatment [21]. Radiotherapy has been the standard treatment for stage III NSCLC. Recently, three large randomized comparative trials demonstrated the benefits of sequential induction chemotherapy and radiotherapy over radiotherapy alone. Two trials used induction chemotherapy consisting of cisplatin and vinblastine followed by radiotherapy alone [8,31]. Both observed a significant improvement in survival duration in the multi-modality arm. Another trial investigated the use of a cisplatin based chemotherapy regimen administered for three cycles before and after radiotherapy [15]. In that
27
study, the rate of distant metastases was reduced and overall survival improved in the multi-modality arm. These findings are supported by the results of two other comparative studies [5,38]. Furthermore, two recent meta-analyses of randomized clinical trials comparing radiotherapy to combination chemotherapy and radiotherapy have demonstrated a survival advantage at years 1 and 3 for combined modality therapy [18,26]. The meta-analyses grouped together all combination therapies without distinguishing between concurrent and sequential therapies. The benefit imparted by concurrent therapy is potentially different from that with sequential therapy. Low dose chemotherapy given with radiotherapy might be expected to enhance the effects of radiotherapy while providing modest, if any, systemic control of the disease. In contrast, the objective of sequential chemotherapy is to control occult systemic disease, although it may also contribute to control of local disease. Most studies comparing concurrent therapy to radiotherapy alone have reported a reduction in the rate of local recurrence and improved overall survival in the combination arm, but no difference in the control of distant metastases [2,12,32,34], suggesting that the improved survival is due to improved local control and not systemic control. This is further supported by the fact that the few studies that did not observe an improvement in the rate of local relapse from combination therapy also failed to demonstrate improved survival [1,20,35]. Sequential therapy has also been demonstrated to be superior to radiotherapy alone with respect to survival in several randomized trials [2,6,8,15,38]. Some of these studies report a reduction in the incidence of distant metastases with sequential therapy [2,6,15], while others do not [8,19,38]. Interestingly, contrary to studies of concurrent chemotherapy, an improvement in survival did not always correlate with a detectable decrease in the rate of distant metastases. A review of studies of induction (sequential) chemotherapy by Green reported that this approach appears to reduce the rate of distant metastases, but that local control remains the limiting factor [10]. Therefore, the mechanism by which sequential chemotherapy and radiotherapy
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effects survival has not been clearly defined. If, however, sequential chemotherapy reduces the risk of distant relapse, and concomitant therapy controls local disease, then the combination of both therapeutic approaches may improve overall control of the disease. In the present study, we combined two radiosensitizers, cisplatin and vinblastine, with concurrent radiotherapy to improve local tumour control, and subsequently administered three courses of standard chemotherapy in an attempt to reduce the risk of distant relapse. The first site of relapse was local in 44% of patients, distant in another 41%, and both in 15%. These results are similar to those reported in other studies of concurrent therapy [1,20,22,32]. Therefore, it is not clear whether the addition of adjuvant chemotherapy contributed to tumour control. This could only be tested in a randomized study. One might speculate that the low dose chemotherapy given concurrently with radiotherapy would induce resistance to later standard dose chemotherapy. If one hypothesized that the use of sequential chemotherapy improves survival, without significantly reducing the proportion of first metastases at a distant site because it impacts on both local disease and occult distant metastases, then the combination of concurrent and sequential therapy would be expected to result in an improved survival over concurrent therapy alone. Our results are in keeping with this hypothesis. The time to first progression, at any site, was 10.4 months, the estimated median survival duration was 17.2 months, and the 1, 2 and 3 year survival rates were 61, 35, and 21%, respectively. These survival rates appear improved when compared to studies of concurrent or sequential chemotherapy alone. One final note; studies of adjuvant therapy with surgery for resectable disease suggest that chemotherapy delivered in the neoadjuvant setting [29] produces superior results to that given post surgically [11]. If the optimal timing for chemotherapy is prior to the therapy that is aimed at controlling local disease then, extrapolating from that data, it may be argued that induction chemotherapy followed by concurrent therapy might have produced superior results in these patients with stage III,
non-resectable disease. Single arm, phase II studies usually have a limited number of patients but can provide useful information on the feasibility and toxicity of a regimen. The therapeutic benefit may be hypothesized, but it can only be evaluated in comparative studies. Therefore, when reporting on phase II studies of small sample sizes, caution must be exercised before drawing conclusions concerning efficacy of the regimen. Within the limitations of this study, we can say that the combination of concurrent vinblastine-cisplatin chemotherapy and hyperfractionated accelerated radiotherapy followed by sequential chemotherapy is both feasible and tolerable, and appears to provide adequate tumour control. However, the toxicity and inconvenience to the patient was significant, because of the elevated incidence of acute esophagitis, and because of the prolonged treatment duration, respectively. The risk to benefit ratio of this kind of therapy needs to be evaluated in studies which incorporate a quality of life assessment to determine the value of increasing treatment intensity/duration. Encouragingly, however, there appears to be a small subset of patients with locally advanced disease who will survive more than 5 years. Although the follow up duration in our study does not allow us to report on the 5 years survival rate, at the time of analysis, four patients (8%) are alive after 40 months, while two are progression free after 43 months, and 53 months, respectively. These patients have been without treatment for more than 3–4 years. Therefore, if combined modality therapy can increase the rate of long term survival within the limits of acceptable toxicity, then the diminished quality of life suffered during treatment may be justifiably offset by the prolonged treatment free and overall survival. References [1] Blanke C, Ansari R, Mantravadi R, et al. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small cell lung cancer: a hoosier oncology group protocol. J Clin Oncol 1995;13:1425 – 9.
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