Japanese Journal of Clinical Oncology 34:61-68 (2004)
© 2004 Foundation for Promotion of Cancer Research
Chemo-reirradiation in Persistent/Recurrent Head and Neck Cancers
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: This retrospective study was carried out to evaluate the feasibility and safety of chemo-reirradiation as a salvage treatment in patients with persistent/recurrent head and neck cancers.
Methods: From 1991 to 1999, records of 131 patients with head and neck carcinoma who had loco-regional persistent/recurrent disease following curative therapy were analyzed. Of these, 33 patients had received chemo-reirradiation. Four patients were further excluded as they had been reirradiated by brachytherapy or external radiotherapy alone. The remaining 29 patients received reirradiation along with chemotherapy. They were evaluated for toxicity profile, post-salvage survival and overall survival.
Results: The median reirradiation dose was 34 Gy (range, 12–50 Gy) and median cumulative RT dose was 104 Gy (range, 72–124 Gy). The median for chemotherapy cycles was four. Grade 2/3 mucositis, dermatitis, neutropenia were seen in 10%, 7% and 3% of patients, respectively. An overall response rate was seen in 83% of patients with complete response in 31%. All complete responders had received a cumulative RT dose of 
100 Gy. Those patients who were initially treated by external radiation alone benefited with subsequent chemo-reirradiation with a complete response rate of 54%. The median post-salvage overall survival was 9 months with the 1- and 2-year survival rates being 41% and 12%, respectively. The post-salvage disease free survival (P = 0.01) and overall survival (P = 0.008) were also significantly better in patients who were treated initially by external radiotherapy alone.
Conclusions: Chemo-reirradiation appears feasible and effective in patients treated previously with external radiotherapy but needs proper patient selection. Patients should be given optimum reirradiation dose, with cumulative doses of 100 Gy, along with chemotherapy. This study warrants the need for more prospective trials.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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More than 70% of patients with head and neck cancer (HNC) present with loco-regional advanced disease (stage III and IV) (1). Despite aggressive local therapy with surgery, radiotherapy or both, <30% of these patients remain disease free at 3 years (1). Loco-regional failures, recurrence or second primary after curative radiation therapy alone or in combination with surgery and/or chemotherapy (CT) is a significant problem (2). The prognosis of patients with recurrent HNC is grim if the tumor is left untreated, with a median survival of only 5 months (3).
Treatment options for previously irradiated patients with either local and/or regional persistent/recurrent disease are limited. Few patients are suitable candidates for curative resection. Chemotherapy is widely used for palliation of these patients but generally produces a response rate of <50% with a median survival of 5–6 months (4). The decision for instituting salvage therapy is to some extent based on the patient’s general condition and their desire for further therapy, although this involves considerable uncertainty about the likely long-term benefits and has risks of added toxicity. Reirradiation (ReRT), with or without CT, appears to be the treatment with the most potential for cure but, because of the anticipated high percentage of normal tissue injury, it is not the most commonly preferred therapeutic approach in practice and there has been, therefore, a lack of clinical trials in this area.
The present retrospective analysis was carried out to assess the efficacy of chemo-reirradiation in patients with HNC who had either persistent loco-regional disease at completion of curative radiotherapy [with/without cisplatin (CDDP) CT] or developed recurrence during follow up. The areas of interest were safety and efficacy of chemo-reirradiation, loco-regional control, post-salvage survival and overall survival.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From 1991 to 1999, records of 131 patients who had persistent or recurrent squamous cell HNC were analyzed. Of these, 55 patients were offered salvage therapy with either chemo-reirradiation (n = 33) or with CT alone (n = 22). The remaining 76 patients were not offered any salvage therapy due to either their reluctance to have further therapy, poor general condition, inability to bear the cost of additional treatment or the physician’s judgment in deciding to offer only symptomatic treatment. The analysis of 33 patients who had been planned for chemo-reirradiation is presented. All were surgically unresectable or had refused surgery. Of these, four patients did not take CT due to financial constraints (three patients were reirradiated by interstitial brachytherapy alone and one by external ReRT alone), and these were excluded from further analysis. The data on the remaining 29 patients who had received CT along with external beam ReRT is presented.
All these patients had been initially treated by curative radiotherapy doses with or without cisplatin CT. All patients for chemo-reirradiation had a Karnofsky performance score (KPS) of 70 or more, with no evidence of metastatic disease and had no major (grade-3/4) late normal tissue (mucosal and skin) reactions from previous radiation. All had undergone a pre-treatment evaluation, including a complete hemogram and biochemistry profile, chest X-ray PA view, pathological proof of recurrence, ultrasonography of abdomen, bone scintigraphy when indicated, direct laryngoscopic evaluation and a contrast enhanced treatment planning scan of head and neck region when required.
The ReRT consisted of a course of external radiotherapy (XRT) along with CT. The ReRT treatment portals were individualized with margins of 1.5–2 cm around the gross persistent/recurrent primary tumor and/or lymph nodes. The dose to the spinal cord was kept within the tolerance level and every attempt was made not to give more than 5–6 Gy to the cord during the ReRT treatment. Thus, the cumulative dose to the spinal cord from initial RT and ReRT was kept below 50 Gy. The lymph nodes overlying the spinal cord were treated either by electrons or contrast enhanced computed tomography (CECT)-based treatment planning system (TSG Radplan) plan. The chemotherapy used was CDDP (35 mg/m2 iv infusion day-1 weekly or 100 mg/m2 iv infusion day-1 every 3–4 weeks), either alone or in combination with 5-fluorouracil (5FU) (375 mg/m2 iv bolus day-1 weekly or 375 mg/m2 iv bolus days 1–5 every 3–4 weeks).
The responses were assessed at 6 weeks after the completion of chemo-reirradiation by clinical examination and direct laryngoscopic evaluation. The acute and late toxicities were scored as per the RTOG toxicity criteria. There were no definite guidelines of dose reduction protocols and it was the treating physician’s discretion to decrease the ReRT doses in case of severe acute toxicity.
Statistical analysis was done using the SPSS version 10.0 for Windows (SPSS Inc. Chicago, IL). The last follow up date was in December 2002 and final statistical analysis was done in March 2003. Post-salvage survivals were calculated from the last date of salvage treatment to progression of disease, date of death or last contact with patient. Comparison of factors affecting ReRT dose, response and tumor control at the time of last analysis was done using chi-square test and survival analysis by Kaplan–Meier estimates. Patients who were lost to follow up at the time of last analysis were considered as an event (worst-case scenario).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics
Patient characteristics are shown in Table 1. Half of these patients were initially treated by XRT alone while the remaining half received CDDP (35 mg/m2 iv infusion day-1 weekly) either as neoadjuvant (n = 7) or concurrent (n = 7) with radiation. Sixty-nine percent (20/29) of the patients who had initially achieved a complete response (CR) developed recurrence either at the primary (60%), lymph node (LN, 25%) or both (15%) sites. Nine patients (31%), who had a partial response (PR) to initial radical treatment, were also subsequently reirradiated. All patients had a pathological proof of persistent/recurrent disease, i.e. squamous cell carcinoma. A majority (66%) of these patients developed recurrence after 6 months of initial treatment.
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Salvage Interventions
The salvage interventions offered to these patients are described in Table 2. The median duration between initial XRT and ReRT was 13 months (range, 3–90) and 59% of the patients received ReRT 12 months or more after the initial RT.
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All patients received CT along with ReRT. The CT given was either CDDP + 5FU, in 17/29 patients (59%), or CDDP alone, in 12/29 (41%) patients. Forty-two percent of patients received initial CT (CDDP + 5FU, n = 11; CDDP alone, n = 1) followed by the same CT along with ReRT. Forty-eight percent of patients received CT along with ReRT (CDDP alone, n = 10; CDDP + 5FU, n = 4). Three patients (10%) received initial CT (CDDP + 5FU, n = 2; CDDP alone, n = 1) followed by ReRT. The median number of chemotherapy cycles was 4 (range, 2–10).
The median ReRT dose was 34 Gy (range, 12–50) and 45% (13/29) of the patients received >40 Gy. The dose per fraction for ReRT was between 180 and 200 cGy. The cumulative dose (initial RT dose + ReRT dose) was 104 Gy median and 86% (25/29) of patients received a cumulative RT dose of 100 Gy or more. It was noted that ReRT and cumulative RT doses were influenced by the initial XRT–ReRT interval and the ReRT field area (Table 3). There was a tendency to give a higher ReRT dose (>40 Gy) if the interval between the initial treatment and ReRT was >12 months, (P = 0.004). Also, the majority of these patients (interval >12 months) received a cumulative RT dose of 100 Gy or more (P = 0.017). As expected, there was a tendency to give a higher ReRT dose to smaller ReRT field areas, although this was not found to be statistically significant (Table 3). However, in terms of cumulative RT doses, a smaller field size received a cumulative dose of 100 Gy or more and was significant at P = 0.01.
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Response
The clinical overall response rate (CR + PR) was seen in 24/29 (83%) patients, of which 31% (9/29) had achieved a CR after completion of treatment. The average duration for all CR was 15 months (range, 2–33). It was further seen that of the nine patients who achieved a CR, six had maintained ultimate tumor control (i.e. sustenance of disease-free response at the time of last analysis). However, no difference was seen in the ultimate tumor control rate at the primary versus the nodal sites. We assessed various host, disease and treatment-related factors that could influence the response rates (at completion of ReRT protocol) and ultimate tumor control in these patients (Table 4).
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No correlation was found between previous disease-free interval (DFI) and CR achievement. However, in terms of ultimate tumor control, patients developing recurrence after 6 months or more had a better sustenance of response (5/6) versus those recurring in less than 6 months (1/3). The overall response rate to the ReRT protocols was correlated with the initial treatment protocols that the patients had received. It was seen that patients who were initially treated by RT alone had shown a better overall response rate (13/15, 87%) when they were subsequently treated by chemo-reirradiation. Seven out of these 13 patients (54%) had achieved a CR. On the other hand, patients who were initially treated by XRT along with CDDP-based protocols showed an overall response rate of 71% (10/14) and only two out of these 10 patients (20%) achieved a CR (P = 0.09). Of the nine patients who achieved a CR, it was seen that six received a ReRT dose of 40 Gy or more and the remaining three patients received a dose of <40 Gy. However, in terms of cumulative RT dose it was seen that 6/9 complete responders receiving 100 Gy or more had an ultimate tumor control and none of the patient who received <100 Gy achieved a CR.
Survival
The median follow up for all patients was 10 months as of last follow up, done in December 2002. The average post-ReRT disease-free survival (DFS) was 6 months (range, 0–29) and one-year cause-specific DFS was 19%. Only 6/29 (21%) patients were free of disease while the remainder had a persistence/recurrence of disease at the time of last analysis. Of these, 12 patients were lost to follow up with disease and considered dead at the time of analysis (Table 5). The median post-salvage overall survival (OS) was 9 months (range, 1–29). The one-year and two-year post-salvage OS were 41% and 12%, respectively. Of the nine patients who achieved a CR, one patient who was disease free died due to cardiac illness, two developed re-recurrence and succumbed to disease and one was lost to follow up with disease. Five patients were alive and disease free at the time of last analysis.
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Further analysis was done to identify factors that could influence post-salvage survival. Patients who were initially treated by RT alone did significantly better both in terms of post-salvage DFS, P = 0.01 (Fig. 1) and post-salvage OS (median, 18 months), versus those who were initially treated by RT + CT protocol (median, 5 months), P = 0.008 (Fig. 2).
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The patterns of failure following ReRT protocols were as follows. Of the nine patients with CR, two failed at the primary site (one died due to co-morbid condition after achieving a CR by salvage chemotherapy following ReRT and the other was lost to follow up with disease); one patient failed at LN site and later died due to disease; one failed at both primary and LN sites and was subsequently treated by salvage chemotherapy + surgery (RND) but succumbed to disease later. Of the 15 partial responders, six had persistent loco-regional disease and later succumbed to disease; two patients also developed distant metastases (one pleural effusion + axillary LN; one supraclavicular + axillary LN) apart from loco-regional persistent disease and died due to disease; the remaining seven patients were lost to follow up with disease. Of the five non-responders, one died due to disease and the remaining four were lost to follow up with residual disease.
Toxicity
The acute toxicities consisted of mucosal, skin and myelosuppression. One patient developed grade III neutropenia leading to septicemia and succumbed to it despite conservative treatment. Acute grade III mucosal reactions were seen in three patients and grade III skin reactions in two patients, which were managed by conservative treatment. As this is a retrospective analysis the late toxicities were not well documented for all re-irradiated tissue in all patients. Overall, 25 patients had some form of documented late effects (Table 6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The management of loco-regional persistent/recurrent disease in the head and neck region is a difficult therapeutic problem. Surgery may constitute an effective salvage treatment, but for the majority of cases, local extension of the disease contraindicates surgery (5–8). Traditionally, chemotherapy has been used for palliation of symptoms in these cases. Commonly used single agents like CDDP, 5FU, methotrexate and bleomycin have documented response rates of ~15–20%, while combinations such as CDDP + 5FU or hydroxyurea (HU) + 5FU have reported slightly superior response rates ranging from 21% to 32% (9), but a dismal gain in survival of 5–6 months only (10), which suggests the need for other therapeutic approaches. ReRT with brachytherapy with or without XRT or CT has been explored especially in nasopharynx, oral cavity, oropharynx and/or lymph nodes to improve response rates (35–75%) and possibly survival (2 years OS, 32–48%) (11–16) but anatomic constraints and large tumor volume often precludes the use of this technique in other HNC sites (8,17). However, in most series of ReRT using interstitial implants, a high rate of soft tissue necrosis and fistula (33–48%) are reported (18,19). Therefore, the major concern for the radiotherapists has been to decide what dose of ReRT is to be delivered in a previously irradiated site with an acceptable rate of normal tissue complications.
External ReRT with CT appears to be promising. In the literature, highly heterogeneous publications concerning external ReRT of HNC are reported. These studies are difficult to interpret and compare because of the heterogeneity in the selection of patients and tumors (including variegated recurrent sites, different histologies and metastatic disease) and the type of re-treatment used (brachytherapy and/or CT and/or surgery), the DFI taken for the ReRT protocols, the ReRT and the cumulative RT doses delivered, the endpoints evaluated (CR rate, tumor control, symptom free survival etc.) and the toxicity documentation (6,8,10,11,18,20–25). Our study involved a relatively more homogenous group of patients who had been initially treated with curative XRT doses (median, 70 Gy) with or without CDDP; all patients were reirradiated by XRT with CDDP ± 5FU for non-metastatic recurrent cancers confined to oral cavity, oropharynx and laryngopharynx with a squamous cell carcinoma histology; we also provide information on response rates, survival, toxicity and prognostic factors. The salient features and results of important phase I/II studies of ReRT with concomitant chemotherapy are described in Table 7.
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Three studies have used 5FU + HU (6,21,22), while one study used CDDP + 5FU (26) along with split-course XRT, with RT doses ranging from 9 to 60 Gy. These authors reported response rates of 41–75% with 1- and 2-year survival ranging from 15 to 56%. In the present study CDDP ± 5FU has been used along with continuous XRT course with median dose of 32 Gy (range, 12–50 Gy). The overall response rate in the present study is 83% (CR rate, 31%) with 1- and 2-year survival being 41% and 12%, respectively, which is comparable with that reported in literature.
In the current study, the rate of acute (grade 3) mucositis (10%) and skin reactions (7%) were acceptable and were lower than those reported in literature. This could be attributed to the lower doses of ReRT used in our patients. Hematological grade 3 toxicity was seen in only one patient (3%), who subsequently died due to septicemia. The frequency and severity of late toxicity after ReRT has been reported in a limited number of studies. In our study, severe late toxicity (grade 3) due to XRT, in the form of mucosal dryness and subcutaneous fibrosis was seen in 4 and 14%, respectively, which again is comparable to that documented in literature (Table 7).
Most of the investigators have tried to identify various prognostic factors such as age, sex, performance status, initial tumor site, type of recurrence, DFI from initial treatment to recurrence, interval between initial RT and ReRT, ReRT dose, cumulative RT dose that could influence the local control and possibly survival. Some authors have documented a higher probability of tumor control in patients with recurrent nasopharyngeal and laryngeal cancers (11,13,20,27,28), while others did not find any statistically significant difference in the response rate, ultimate tumor control or survival at various initial primary sites (10,23). In the present study too, no difference in the tumor response or survival was seen in relation to the primary site of initial lesion.
Emami et al. (23) reported that the type of recurrence has an influence on the ultimate tumor control, with better response seen for lesions that recurred at primary site (21%) as compared to nodal recurrence (10%), while other authors (6,10) and our study did not find any correlation between the type of recurrence and survival.
In the present study the DFI, i.e. the interval between initial treatment and recurrence, did not influence the CR rates to chemo-reirradiation. Gandia et al. (21) also found no correlation between DFI and CR rates, while others have found that a long DFI correlated with increased CR rates (23,29). However, when we correlated DFI to ultimate tumor control, it was seen that patients with recurrence after 6 months or more had a better sustenance of response (CR, 5/6) than those recurring in <6 months (1/3). The prognostic significance of duration between the two irradiations (i.e. interval between initial RT and ReRT) influencing CR rates is also controversial. Some authors have reported a significant correlation for 6 months (14) and 1–2 years (8,18,24,25), while others do not report such an association (6,10,21,22). In the present study too, no correlation was seen. The dose of ReRT used in various studies varied widely from 9 to 75 Gy with different fractionation schedules, treatment breaks and CT used. Most of the studies, however, documented a better outcome (response rates of 41–75% and 2-year OS rates of 16–22%) with a total ReRT dose of 50 Gy or more (6,8,10,18,23,25). However, in the majority of these studies there were treatment breaks (either planned or unplanned) and the toxicity rates were also higher (Table 7). In our study the median ReRT dose given was 34 Gy (range, 12–50 Gy), but without any treatment breaks, with an equivalent response rate (83%) and 2-year OS (12%) but lower toxicity. However, in some studies the cumulative RT dose was taken as a reference (subcutaneous tissue, 110 Gy, spinal cord, <50 Gy) to curtail the ReRT dose and thereby the anticipated late toxicities. In our study the median cumulative RT dose was 104 Gy (range, 72–124 Gy). The lower ReRT and the cumulative RT doses in our study reflect the treating physicians’ apprehension in giving higher tumoricidal doses concomitantly with CDDP-based CT in patients with persistent/recurrence within 6 months, probably because of the anticipated higher tissue toxicities. However, all patients in our study who achieved a CR to ReRT (9/29) had received a cumulative RT dose of 100 Gy or more, thereby suggesting that a cumulative dose of >100 Gy is necessary for obtaining tumor control, even if the ReRT is combined with CT.
The irradiation technique used by various authors in recurrent HNC was relatively homogenous, placing stringent fields taking gross tumor plus 1.5–2 cm margins and respecting the spinal cord tolerance to <50 Gy (6,23,24). Few studies tested the field size or the volume of irradiation as a predictive factor of outcome but none correlated it with the ReRT and cumulative RT doses delivered. Langlois et al. (14) found that local control was obtained more frequently when the cumulative surface area of the irradiation was <100 cm2. Similarly, De Crevoisier et al. (10) also found a field area of <125 cm2 as a prognostic factor affecting response and overall survival. In our study, however, we did not find any significant correlation between field size (median area, 36 cm2) with response and survival. However, we did find that smaller field areas received higher ReRT and cumulative RT doses (P = 0.03) (Table 3).
An interesting fact came out in our study. Those patients who were initially treated by XRT + CDDP showed a poorer response rate, post-salvage DFS and OS versus those who received XRT alone initially when they were subsequently treated by ReRT + CDDP-based CT protocols. This was found to be statistically significant (Figs 1 and 2), thereby suggesting the probable development of chemoresistant mechanisms in patients treated initially by RT + CT protocols. Such a finding has not been reported in other ReRT series. Probably the resistant recurrent tumors may respond if they receive higher doses of RT, which can be given by interstitial brachytherapy and conformal external RT techniques (3D-CRT and IMRT), or they can be treated with hyperthermia along with external RT and hyperbaric oxygen.
The conclusions drawn from our study and literature are that ReRT with CDDP-based CT in previously irradiated patients with recurrent HNC is feasible, with good response rates and acceptable toxicity, and produces lasting tumor control for some patients. In the unresectable group, or if surgery would result in unacceptable morbidity, ReRT protocols should be considered. Patients should be carefully selected: favorable sites such as larynx and nasopharynx; small tumor size; a relatively longer period since previous irradiation (preferably 6 months); no major late complications due to initial RT. Radiation portals must be tight to avoid excessive irradiation of normal tissues. Although the optimum ReRT dose/schedule has yet to be defined, the reirradiation dose should be optimum, ranging from 60 to 70 Gy with cumulative RT doses of 100 Gy or more, along with CT. The need of chemo-reirradiation should be tested in prospective trials, more so for those patients who are initially treated with chemoradiotherapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Yoodhvir Singh Nagar, J-260, J-Block, Saket, New Delhi 110017, India. E-mail: ysnagar{at}yahoo.com
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Received October 31, 2003; accepted December 24, 2003
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