1 Department of Medical Oncology A, 2 Department of Radiation Oncology, National Institute for Cancer Research, Genoa; 3 Department of Otholaryngology, San Martino Hospital, Genoa, Italy
Received 14 October 2003; revised 11 December 2003; accepted 22 December 2003
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ABSTRACT |
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In order to improve our cisplatin5-fluorouracil (5-FU)-based alternating chemo-radiotherapy regimen, in 1996 we started an investigational program to explore a modified alternating regimen including gemcitabine given both with radiosensitizing and cytotoxic intent.
Materials and methods:
Based on our previous feasibility trial, we conducted a second study testing the feasibility and activity of the following schedule: gemcitabine 800 mg/m2 on day 1 and cisplatin 20 mg/m2 on days 25 (weeks 1, 4, 7 and 10) alternated with three courses of radiotherapy (RT) (weeks 23, 56 and 89) with conventional fractionation up to 60 Gy. Gemcitabine 300 mg/m2 was also administered on the Monday of each week of RT.
Results:
Forty-seven patients with stage IV (41 patients) unresectable squamous cell carcinoma of the head and neck (SCC-HN) or who had relapsed after surgery (6 patients) were enrolled. None had previously received chemotherapy or radiotherapy. Eight patients (18%) did not complete the treatment. Main grade 34 toxicities were as follows: neutropenia (44%); neutropenia with fever (12%); thrombocytopenia (37%); anemia (30% grade 3). One patient died in therapy due to sepsis. Most patients needed hospitalization and tube-feeding or parenteral nutrition. However, 44% of patients had a weight loss >10%. Thirty-four patients had a complete response (72%). Three partial responders were rendered disease-free by surgery (final complete response rate, 79%). At a median follow-up of 38 months actuarial 3-year overall survival, progression-free survival and loco-regional control are 43%, 39% and 64%, respectively. Data of locoregional control favorably compare with those from our database of patients treated with alternating cisplatinfluorouracil and radiation within controlled clinical trials (64% versus 40%).
Conclusions:
The inclusion of gemcitabine into an alternating regimen seems to improve the results achievable with the original alternating program in stage IV patients. However, due to the high acute toxicity correlated, this intensive regimen should be managed by institutions well trained in multidisciplinary treatments.
Key words: chemo-radiotherapy, gemcitabine, head and neck, squamous cell carcinoma, stage IV
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Introduction |
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At present, using the concomitant administration of chemotherapy and radiotherapy, it is reasonable to expect a crude improvement in overall survival (OS) approaching 10% [2], most of this benefit being due to better loco-regional control. However, many questions are still unanswered. In terms of chemotherapy, we still do not know how many drugs and which ones should be used; in addition, we do not know whether a radiosensitizing strategy with low doses of drugs or full-dose chemotherapy is preferable. In terms of radiation, we know that concomitant boost and hyperfractionation are probably better than standard fractionation, at least in local control [3], but we do not actually know if such an altered fractionation radiotherapy gives a clear clinical benefit besides an increase of local toxicity, even when administered concomitantly with chemotherapy. Finally, we do not know if the addition of induction chemotherapy to a concomitant chemoradiation approach may improve the outcome mainly by reducing the risk of distant metastases. In other words, it has not been demonstrated that more intensive and toxic combined regimens achieve better long-term results, since no data from randomized trials comparing different combined approaches are available so far. However, preliminary data from some phase II trials exploring intensive chemoradiation regimens are encouraging [46].
At our institution, the standard therapeutic approach to advanced head and neck cancer is alternating cisplatin5-fluorouracil (5-FU) and radiation [79]. In 1996, in an attempt to ameliorate results achieved with this regimen, we started to explore a modified alternating regimen in which 5-FU was replaced with gemcitabine.
Gemcitabine can be considered to be a novel drug in SCC-HN since few experiences are available in this disease both in vitro [10] and in clinical trials [11]. In preclinical studies, this drug has also shown synergistic activity with cisplatin in some human solid tumors cells [12], and in SCC-HN the combination of cisplatin and gemcitabine showed interesting antitumoral activity in one clinical trial [13]. Moreover, gemcitabine, also at non-cytotoxic concentrations, has a proven in vitro [14] and clinical [15] radiosensitization activity in SCC-HN.
Here, we report the results of a phase II trial where gemcitabine was given both with radiosensitizing and cytotoxic intent together with cisplatin and radiation in a modified alternating regimen. The dose of gemcitabine chosen was based on the results of our previous feasibility trial [16] in which the median dose per week actually delivered in an alternating chemo-radiotherapy program was 500 mg/m2.
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Materials and methods |
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Pretreatment evaluation included physical and ENT examination, complete blood counts and blood chemistry profiles, and a chest X-ray. Computerized tomography and/or sonograms were performed when indicated.
Treatment
The treatment plan is summarized in Figure 1.
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The chemotherapy regimen consisted of gemcitabine 800 mg/m2, day 1 and cisplatin 20 mg/m2/day, days 25 of weeks 1, 4, 7 and 10. Gemcitabine 300 mg/m2 was administered on day 1 of weeks 2, 3, 5, 6, 8 and 9. Cisplatin was given during a 2-h period of forced hydration and gemcitabine as a 45-min infusion. Antiemetic therapy consisted of dexametasone 8 mg intravenously (i.v.) and granisetron 3 mg i.v., before each cisplatin administration and dexametasone 8 mg or metoclopramide 20 mg i.v. when gemcitabine was administered alone.
A complete blood cell count was performed on day 1 of each week of treatment. The measurement of serum electrolytes and creatinine was performed before each cisplatin-based chemotherapy course. No prophylactic administration of granulocyte colony-stimulating factor was planned. Epoetin , 10 000 IU subcutaneously every other day, was planned starting at an hemoglobin level <10.0 g/dl.
Chemotherapy dose reductions were planned. In the case of a leukocyte count between 2900 and 2000/ml and/or neutrophil count between 1500 and 1000/ml and/or platelet count between 80 000 and 50 000/ml at the time of cisplatin-based chemotherapy, a 25% dose reduction of both cisplatin and gemcitabine was made. In the case of a leukocyte count <2000/ml and/or neutrophil count <1000/ml and/or platelet count <50 000/ml, the cisplatin-based chemotherapy was delayed for 1 week and the patient received gemcitabine at radiosensitizing dose and continued radiation.
The radiosensitizing dose of gemcitabine was reduced by 50% in the case of leukocyte count between 2000 and 1000/ml and/or neutrophil count between 1000 and 500/ml and/or platelet count between 50 000 and 25 000/ml and it was omitted in the case of leukocyte count <1000/ml and/or neutrophil count <500/ml and/or platelet count <25 000/ml.
Evaluation of response and toxicity
The method for staging was repeated to evaluate response to therapy. Response was preliminarily assessed 4 weeks after the end of treatment and definitely assessed after 12 weeks, according to World Health Organization (WHO) criteria [17]. Toxicities were evaluated according to the WHO scale [17] and recorded as the worst grade experienced by patients during the treatment.
Role of surgery
Surgery indications were not standardized. Generally a neck dissection was the rule only in patients with clinical and/or radiological evidence of persistent disease in the neck only. Neck dissection was not recommended for patients in complete response (CR) whose disease at diagnosis was staged as N23.
Statistics
The primary end point of this phase II single institution trial was CR rate assessment. Secondary end points were OS, progression-free survival (PFS) and locoregional control. The expected CR rate with alternating cisplatin 5-fluorouracil and radiation was 45% [7, 9]. Since a significant increase in severe acute mucositis is expected with the inclusion of gemcitabine, this experimental program will be considered suitable for further investigations if the level of CRs is 75%. For an
error of 0.05 and a ß error of 0.10, at least 26 complete responders are needed among the 41 patients enrolled [19].
Actuarial survival, loco-regional control and PFS are calculated according to the KaplanMeier method [20]. All patients were considered in these analyses. PFS was computed from the time of treatment beginning until the time of disease progression at any site, including the occurrence of distant metastases or second primary tumors. Patients dying without disease progression were considered to have had progressive disease at the time of death.
Loco-regional control was computed from the time of treatment beginning until the time of locoregional relapse. Patients developing metastatic disease or second tumors without locoregional relapse were censored at the time of death or last observation. Patients who did not reach the CR, including those who did not complete the treatment program for any reason, were considered locoregionally progressed at the end of treatment. OS was computed from the time of treatment beginning until the time of death or last observation.
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Results |
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Due to the severity of local reactions a 1 week delay was necessary in nine patients (19%) and 2 weeks in four (8%).
The median total dose of cisplatin actually delivered was 280 mg/m2 (87% of the planned dose) (range 160320 mg/m2). The median total dose of gemcitabine actually delivered was 4600 mg/m2 (92% of the planned dose) (range 25005000 mg/m2) and the median dose intensity was 450 mg/m2/week (87% of the planned dose intensity); it was >80% in 70% of patients.
All patients who completed the treatment program received 60 Gy of radiotherapy.
Acute toxicity
Forty-three patients were evaluated for acute toxicity. Details of the side-effects and their frequency are reported in Table 3.
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Eighty-one per cent of patients developed severe mucositis. In 44% of patients oral nutrition was completely impossible. Generally the highest grade of mucosal toxicity appeared during week 5 of treatment. Tube-feeding and/or parenteral nutrition including partial supports were necessary in 40 patients (93%) and almost half of these patients needed hospitalization during the treatment program. Nevertheless, a weight loss ranging between 10% and 20% was recorded in 44% of patients. All these patients, however, recovered to oral nutrition in 49 weeks (median, 6 weeks) from the end of combined treatment despite a persistent xerostomia.
Grade IIIII cutaneous reactions were observed in 77% of patients.
Activity
According to the protocol rules, response was preliminarily evaluated 1 month after the end of treatment and definitively assessed after 3 months.
Thirty-four patients obtained a CR (72%) and five patients a partial response (11%). Eight patients (17%) were not evaluable for the reasons listed above. Three partial responders with clinically evident residual disease on the neck were rendered disease-free after a radical neck dissection. Thus, the final CR rate was 79% (95% in the evaluable patients).
Events observed at a median follow-up of 38 months are listed in Table 4.
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Fifteen per cent of patients died because of locoregional tumor, 23% because of distant metastatic disease or second primary neoplasms and 21% due to comorbidity or toxicity (one patient).
Three-year OS, PFS and loco-regional control were 43%, 39% and 64%, respectively (Figure 2). Excluding from the analyses the eight patients who did not complete the planned treatment, 3-year OS, PFS and loco-regional control were 51%, 47% and 77%, respectively (Figure 3).
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No severe late effects, such as osteoradionecrosis, mucosal ulceration or necrosis, fibrosis or larynx strictures occurred in any long-term survivors. None needed permanent tube-feeding or gastrostomy.
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Discussion |
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The only difference between the regimen employed in the present study and the original alternating cisplatinfluorouracil and radiation regimen first tested at our institute [7] is the use of gemcitabine, both with cytotoxic and radiosensitizing intent, instead of 5-fluorouracil.
The intention-to-treat CR rate (72%), the actuarial local control (64% at 3 years) and OS achieved (43% at 3 years) are remarkable if we consider that patients enrolled in the present trial had poor-prognosis head and neck cancer. Particularly, 77% of patients had T4 previously untreated, or relapsed after surgery, unresectable disease. We can say that one in every two patients who complete this treatment program is still potentially curable despite the very advanced disease.
Moreover, these data favorably compare in terms of activity with those from our database of patients with stage IV disease treated with alternating cisplatinfluorouracil and radiation within controlled clinical trials (Table 5). In fact, a 30% statistically significant increase in CR rate has been obtained with the gemcitabine-based regimen. This is the difference that we considered satisfactory in the statistical hypothesis. Even long-term local control appears better with this new combined approach (64% versus 40%), although the impact on OS seems to be less significant (43% versus 35%), which may be correlated with the higher incidence of distant failures (metastases and second primaries) observed in the present trial (23% versus 10%). This finding is common to other recent phase II trials testing intensive combined regimens [4, 5]. It is possible that the improved local control achieved by these regimens gave more time to the already existing micrometastases to develop and for second primary tumors to arise. This behavior might support the need to improve the activity of systemic therapy by the use of additional multiagent chemotherapy given before combined treatment and/or the use of biological therapies.
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Eight patients (17%) did not complete the planned therapy program (unevaluable patients) including four patients who died during treatment. The magnitude of this percentage might be considered strictly depending on the intensity of the treatment program. However, we would like to stress that this percentage is comparable with that observed in our experience with the original alternating cisplatinfluorouracil and radiation program which is an easier and less toxic treatment (Table 5). A possible explanation for this finding may be that the characteristics of head and neck cancer patients play a significant role in treatment compliance as well. Most of these patients have concomitant illnesses and they may interrupt the treatment program or die for a number of miscellaneous reasons not necessarily related to the tumor or therapy. Actually, the number of patients who did not complete the planned treatment in our studies is higher than that reported in other phase II trials with aggressive combined programs but, in our opinion, the reason for that should be looked for in a different selection of patients. In fact, in one of the most recently published phase III randomized trials [22], the rate of patients who did not complete the planned treatment in the two chemoradiation arms was even higher (27% and 15%, respectively).
Therefore, despite the preliminary results from phase II studies that seem to encourage aggressive multimodality treatment strategies, in our opinion, the above reported considerations still strongly support the need for adequate phase III studies comparing more aggressive versus less aggressive chemo-radiotherapy programs to definitively assess the role of treatment intensification.
However, to achieve the optimal administration of concomitant chemo-radiotherapy, a high level of experience in this field, as well as the availability of a multidisciplinary team to provide appropriate supportive care, are of crucial importance. In fact, we have recently demonstrated a correlation between treatment institution and outcome [23]. This finding may represent a bias in large multicenter randomized trials, particularly when aggressive strategies are compared to more standard treatments, unless careful selection of the treating institutions is made.
In summary, the inclusion of gemcitabine into an alternating chemo-radiotherapy program, at least in the schedule we tested in this trial, produces formidable acute toxicity, but it is manageable by an experienced team. This more aggressive approach seems to mainly improve locoregional control if compared to the original alternating program. Distant metastases, second primary tumors and comorbidity represented the first cause of death in this trial.
The role of this aggressive combined approach, as well as of others, definitely needs to be addressed in randomized trials.
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FOOTNOTES |
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REFERENCES |
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2. Pignon JP, Bourhis J, Domenge C et al. Chemotherapy added to loco-regional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data. Lancet 2000; 355: 949955.[CrossRef][ISI][Medline]
3. Fu KK, Pajak TF, Trotti A et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation radiotherapy and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinoma: preliminary reports of RTOG 9003. Int J Radiat Oncol Biol Phys 2000; 48: 716.[ISI][Medline]
4. Adelstein DJ, Saxton JP, Lavertu P et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 2002; 20: 14051410.
5. Vokes EE, Kies MS, Haraf DJ et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000; 18: 16521661.
6. Vokes EE, Stenson K, Rosen FR et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 2003; 21: 320326.
7. Merlano M, Vitale V, Rosso R et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992; 327: 11151121.[Abstract]
8. Merlano M, Benasso M, Corvò R et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996; 88: 583589.
9. Corvò R, Benasso M, Sanguineti G et al. Alternating chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck. Cancer 2001; 92: 28562867.[CrossRef][ISI][Medline]
10. Braakhuis BJ, van Dongen GA, Vermorken JB et al. Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (gemcitabine) against human head and neck cancer. Cancer Res 1991; 51: 211214.[Abstract]
11. Catimel G, Vermorken JB, Clavel M et al. A phase II study of gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994; 5: 543547.[Abstract]
12. Peters GJ, Bergman AM, Ruiz van Haperen VWT et al. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995; 22: 7279.
13. Hitt R, Castellano D, Hidalgo M et al. Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck. Ann Oncol 1998; 9: 13471349.[Abstract]
14. Shewach DS, Lawrence TS. Gemcitabine and radiosensitization in human tumor cells. Invest New Drugs 1996; 14: 257263.[ISI][Medline]
15. Eisbruch A, Shewach DS, Bradford CR et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 2001; 19: 792799.
16. Benasso M, Merlano M, Sanguineti G et al. Gemcitabine, cisplatin, and radiation for advanced, unresectable squamous cell carcinoma of the head and neck. A feasibility study. Am J Clin Oncol 2001; 24: 618622.[CrossRef][ISI][Medline]
17. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207214.[ISI][Medline]
18. Ang KK, Kaander JHAM, Peters LJ. Radiotherapy for head and neck cancers. Philadelphia, PA: Lea & Febiger 1994.
19. Thall PF, Simon R, Ellenberg SS. A two-stage design for choosing among several experimental treatments and a control in clinical trials. Biometrics 1989; 45: 537547.[ISI][Medline]
20. Kaplan EL, Meyer P. Non-parametric estimation for incomplete observation. J Am Stat Assoc 1958; 53: 457474.[ISI]
21. LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys 1995; 31: 10491092.[Medline]
22. Adelstein DJ, Li Y, Adams GL et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003; 21: 9298.
23. Benasso M, Lionetto R, Corvò R et al. Impact of the treating institution on the survival of patients with head and neck cancer treated with concomitant alternating chemotherapy and radiation. Eur J Cancer 2003; 39: 18951898.[CrossRef][ISI][Medline]