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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 51-59

Neoadjuvant chemotherapy in oral cancer: Current status and future possibilities


1 Department of Medical Oncology, HBCH, Sangrur, Punjab, India
2 Department of Head and Neck Surgical Oncology, HBCH, Sangrur, Punjab, India
3 Department of Medical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Submission03-Oct-2019
Date of Decision14-Nov-2019
Date of Acceptance14-Dec-2019
Date of Web Publication24-Feb-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_79_19

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  Abstract 


Eighty-five percent of oral cavity cancers present as locally advanced disease and are treated with multimodality approach. Patients who can undergo radical resection have the best outcomes, although the overall results are still unsatisfactory. Neoadjuvant chemotherapy (NACT) has been studied in oral cavity cancers with the aim of improving locoregional control and overall survival (OS) and as an organ preservation tool in resectable oral cavity cancers, It has also been studied in borderline resectable/technically unresectable tumors in order to reduce surgical margins, increase resectability, and achieve R0 resection and in unresectable tumors in order to improve disease-free survival and OS. In this review, we will critically analyze the current evidence for the use of NACT in oral squamous cell carcinoma (OSCC) and suggest an approach to select a patient who might benefit from NACT.

Keywords: Head-and-neck squamous cell carcinoma, ICT, neoadjuvant chemotherapy, oral cavity cancer, oral squamous cell carcinoma, NACT, OSCC, HNSCC


How to cite this article:
Goel A, Singla A, Prabhash K. Neoadjuvant chemotherapy in oral cancer: Current status and future possibilities. Cancer Res Stat Treat 2020;3:51-9

How to cite this URL:
Goel A, Singla A, Prabhash K. Neoadjuvant chemotherapy in oral cancer: Current status and future possibilities. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Apr 10];3:51-9. Available from: http://www.crstonline.com/text.asp?2020/3/1/51/279149




  Introduction Top


Oral squamous cell carcinoma (OSCC) constitute a significant proportion (30%) of cancers in India.[1] As per GLOBOCAN 2018 data, oral cavity cancer constitutes 10.4% of all cancers and is ranked as the most common cancer among Indian males and overall, as the second most common cancer among both sexes. Majority of these tumors (85%) present as locally advanced disease[1] and are treated with multimodality approach. Radical resection when feasible has the best outcome of all modalities,[2],[3] but the outcomes are still far from satisfactory.

Neoadjuvant chemotherapy (NACT) in oral cavity cancer may cause tumor shrinkage, which could improve locoregional control (LRC) and overall survival (OS) and may help to achieve organ preservation in resectable oral cavity cancers. NACT may also be used in patients with borderline resectable/technically unresectable tumors in order to reduce the surgical margins, increase resectability, and achieve R0 resection and in unresectable tumors to improve disease-free survival (DFS) and OS.

Surgery as the treatment option in oral cancer

Complete surgical resection with negative margins appears to be the most appropriate treatment option in OSCC. In a randomized study by Iyer et al.,[4] surgery with adjuvant treatment was compared to chemoradiation (CRT) in locally advanced head-and-neck cancers. Results in the subset of patients with OSCC showed that survival was significantly superior in patients treated with surgery and adjuvant treatment compared to CRT. The reported 5-year DFS was 68% in the surgery arm versus 12% in the CRT arm (P = 0.038).[4] Similar conclusions have been reported in the retrospective study by Gore et al.[5]

Neoadjuvant chemotherapy in resectable oral squamous cell carcinoma

NACT has been used in resectable OSCC with the intent of improving survival or preserving organs. Two large randomized studies have addressed these issues.[6],[7]

The first study by Licitra et al.[6] in 2003 had two arms, with the standard arm consisting of surgery followed by postoperative radiation to high-risk patients and the experimental arm including induction chemotherapy followed by the same sequence as in the standard arm. The induction chemotherapy used was three cycles of cisplatin 100 mg/m2 and 5-fluorouracil (5FU) 1000 mg/m2 (120-h infusion administered every 21 days) (CF regimen). A total of 195 patients were randomized: 98 to the surgical arm and 97 to the induction chemotherapy arm. In this study, 64% of patients completed the planned three cycles of chemotherapy, 37% of patients had Grade 3/4 toxicities with three patients (3%) having toxic deaths. This was a negative study, with no difference in the OS between the two arms (5-year OS in both arms was 55%).[6] The long-term results of this study reported by Bossi et al.,[8] after a median follow-up of 11.5 years, confirmed the same results. NACT failed to have an impact on LRC, distant metastasis, and OS.[8]

Another study by Zhong et al.,[7] with a similar chemotherapy regimen, also failed to show a benefit for induction therapy. In this study, locally advanced resectable oral cancer patients were randomized to either upfront surgery followed by postoperative radiation or two cycles of a docetaxel, cisplatin, and 5FU (TPF) regimen followed by surgery and adjuvant radiation. It is important to note that the doses of cisplatin and 5FU were 75 mg/m2 and 750 mg/m2 in the Zhong study, respectively, which were lower than the doses used in the study by Licitra et al. Two hundred and fifty-six patients were enrolled, and after a median follow-up period of 2.5 years, there was no difference in either the OS (hazard ratio [HR], 0.977; 95% confidence interval [CI], 0.634–1.507; P = 0.918) or the DFS (HR, 0.974; 95% CI, 0.654–1.45; P = 0.897).[7] It is to be noted that 98.3% of patients completed the planned two cycles of chemotherapy, with only 9% having Grade 3 toxicities and none having Grade 4 toxicity. Thus, it can be concluded that induction chemotherapy did not result in a statistically significant improvement in OS or DFS in resectable oral cancers.

Does neoadjuvant chemotherapy help in organ preservation in resectable oral cavity cancers?

The role of induction chemotherapy in laryngeal cancers for organ preservation has been extensively studied.[9] There are limited data, however, for organ preservation in oral cancers. In the study by Licitra et al.,[6] it was seen that mandibular resection could be avoided in 21% of patients who received induction chemotherapy (52% in control arm vs. 31% in chemotherapy arm). In addition, postoperative radiotherapy (RT) was administered in 33% of patients in chemotherapy arm versus 46% in control arm. Preservation of the mandible during surgery could lead to an improved cosmesis and improved functional outcomes.[10],[11]

Similarly, in a study done by Chinn et al.,[12] in which they evaluated the role of induction selection (IS)-concurrent CRT protocol versus primary surgical extirpation in resectable OSCC, they showed a statistically significantly better OS, DFS, and LRC in the surgical cohort, showing the failure of organ preservation approach to lead to a survival benefit in resectable OSCC. The limitations of the study should be kept in mind while interpreting the results, i.e., a small IS cohort and the retrospective nature of the study.

Induction chemotherapy for mandibular preservation in resectable OSCC is being studied in our institute by Dr. Chaukar et al. in a Phase III trial. The same group conducted a Phase II study. This was presented at a Foundation for Head and Neck Oncology 2015 meeting at Nagpur, India. The authors showed that with this approach, mandibular preservation could be achieved in 49% of patients without compromising the local control (unpublished data).

Can we choose patients with good prognosis?

Response to induction chemotherapy also seems to be a favorable prognostic factor.[6],[7] In the study by Licitra et al., patients with a pathological complete response (CR) had a 10-year OS of 76.2% compared to 41.3% in those without a pathological CR (P = 0.0004).[6] Similarly, in the study by Zhong et al., there was a significant positive correlation between pathological response and clinical response. A favorable pathological response post-NACT predicts a better outcome with regard to OS, distant metastasis-free survival (DMFS), DFS, and locoregional recurrence-free survival.

Furthermore, in the study by Zhong et al.,[7] the subgroup analysis showed improved OS (HR, 0.418; 95% CI, 0.179–0.974; P = 0.043) and DMFS (HR, 0.418; 95% CI, 0.179–0.974; P = 0.043) in patients with N2 disease who received NACT.

Thus, these trials by Licitra et al. and Zhong et al.[6],[7] have given us many insights. In the Zhong study, there was a trend toward a lower incidence of distant metastasis for patients who received NACT as compared to patients undergoing upfront surgery (5.5% vs. 8.7%); there was increased mandibular preservation seen in the study by Licitra et al. as well as a lesser need of adjuvant RT.[6] In the NACT arm, patients who had a favorable pathological response had an improved survival as compared to those with an unfavorable response or those in the non-NACT group.

However, the lack of benefit of NACT on OS must be viewed in the context of these studies being underpowered. In the study by Licitra et al., the planned sample size of 258 patients guaranteed 90% power to detect a 20% absolute risk reduction in the chemotherapy group. However, only 198 patients were finally enrolled due to the difficulty in accruing patients. For this reason, the power of the study was reduced to 78%. Similarly, the study by Zhong et al., with a sample size of 256 patients, had a power of 83%.

In summary, multiple studies have failed to demonstrate improvement in LRC or OS with NACT in resectable OSCC, however the effect of NACT on reducing distant metastasis, mandibular preservation in tumors without gross invasion of the mandible, and disease control in patients with higher nodal stage seems interesting and warrants further investigation. We will need large and adequately powered studies, preferably in the Indian setting to answer this question clearly.

Neoadjuvant chemotherapy in locally advanced technically unresectable oral squamous cell carcinoma

The definition of unresectability is an unsettled issue which is influenced by subjective criteria, and hence is prone to variation. Technical unresectability is a complex interplay between the disease status, anatomical site of involvement, surgical skills, quality of life issues, and ability to achieve an R0 resection.[3] Patil et al.[13] have defined technical unresectability as:

  1. Buccal mucosa primary, with diffuse margins and peritumoral edema going up to or above the level of the zygomatic arch and without any satellite nodules
  2. Tongue primary (anterior 2/3rd), with the tumor extending up to or below the level of the hyoid bone
  3. Extension of tumor originating in the anterior two-thirds of the oral tongue to the vallecula
  4. Extension of tumor into the high infratemporal fossa, as defined by the extension of tumor above an axial plane passing at the level of the sigmoid notch
  5. Extensive skin infiltration impacting the achievement of negative margins.


Patil et al. analyzed 721 patients with technically unresectable OSCC, all of whom received two or three drugs (taxane + platinum ± 5FU) as NACT followed by resection in resectable cases. Nearly 43% of the patients had downsizing of disease and subsequently underwent surgery. R0 resection was achieved in all patients; the three-drug regimen achieved resectability in 66.21% and the two-drug regimen in 40.34%. The LRC rate at 2 years was 20.6% for the whole cohort; 32% in patients undergoing surgery and 15% in patients undergoing nonsurgical treatment (P = 0.0001). The median OS was 19.6 months (95% CI, 9.59–25.21 months) in patients undergoing surgery and 8.16 months (95% CI, 7.57–8.76) in patients who received nonsurgical treatment (P = 0.0001).[13]

In a retrospective analysis by Rudresha et al.,[14] in patients with T4a technically unresectable OCSCC treated with two-drug NACT, the median OS of patients who underwent surgery followed by adjuvant local therapy (n = 15) was 16.9 months (95% CI, 15.2–19.8 months) and for those treated with nonsurgical local therapy (n = 65) was 8.8 months (95% CI, 6.8–10.6 months) (P < 0.001).

Patil et al.[15] in another retrospective analysis of 123 patients with technically unresectable OCSCC, showed increased resectability and OS in patients post-NACT who underwent resection. Nearly 21% of patients received the three-drug regimen and the rest received the two-drug regimen consisting of a taxane and platinum. The response rates with the three- and two-drug regimen were 32% and 27.37%, respectively. Resectability was achieved in 68% of patients after the three-drug regimen and 37.89% patients after the two-drug regimen. The estimated median OS was not reached in patients who had a clinical response and underwent resection as opposed to 8 months in patients treated with a nonsurgical modality post-NACT (P = 0.0001).

In a retrospective study by Joshi et al.,[16] the efficacy and impact of induction chemotherapy in T4b oral cavity cancers was investigated. One hundred and ten patients were offered induction chemotherapy and then assessed for resectability at the end of two cycles of chemotherapy. Post-induction, these patients either underwent surgical or nonsurgical local intervention depending on their response to NACT. Nearly 20% of the patients received the three-drug regimen, whereas the rest of the patients received the two-drug regimen. Twenty-eight patients had a partial response, 49 patients had stable disease, and 23 patients progressed. Resectability was achieved in 34 (30.9%) of the 110 patients. The estimated median OS in patients who underwent surgery was 18 months (95% CI, 13.6–22.46 months) and for those treated with nonsurgical treatment was 6.5 months (95% CI, 5.6–7.4 months) (P = 0.0001). Patients with masticator space involvement were divided into two subgroups based on the extension of tumor above (29 patients) and below (79 patients) in an axial plane at the level of mandibular notch. It was interesting to note that in the logistic regression analysis, only involvement of the masticator space below the jugular notch (P = 0.02) was an independent variable predicting the achievement of resectability.

Similarly, Liao et al. studied the role of meticulous surgery in those patients where the tumor involvement of the masticator space was restricted to a plane below the jugular notch. The results were impressive with a 5-year OS rate of 47%.[17]

Thus, the use of induction chemotherapy in T4 cancer which fits the criteria of technical unresectability is safe and feasible and may lead to complete surgical resection in approximately 40% of patients. This approach is likely to lead to a survival advantage in patients who undergo surgery and should be considered the standard of care in this setting.

Although the three-drug regimen achieved greater resectability, it has much higher toxicity and might not be feasible in a resource-constrained setting. In such a setting, the two-drug regimen may be considered. A trial is underway at our center comparing the two-drug to the three-drug regimen in the NACT setting.

To summarize, this group of patients should be aggressively treated with NACT with an aim of achieving resectability, which has shown to improve survival. No studies have used targeted therapy (epidermal growth factor receptor inhibitors) or immunotherapy in this setting, despite both showing survival advantage in advanced metastatic/recurrent disease.

Neoadjuvant chemotherapy in unresectable OSCC

As discussed above, the definition of resectability is an unsettled issue, but those patients not falling within the category of technically unresectable should be kept in this category. Although there are limited data exclusively in patients with unresectable disease, some of the trials which included these patients among others need a mention here and are discussed below.

Two large randomized trials, the TAX 323 and 324,[18],[19] compared the three-drug TPF regimen with PF and showed superiority of the three-drug regimen in terms of OS and PFS in patients with locally advanced head-and-neck cancer. There were some limitations which should be kept in mind while interpreting these results. Oral cavity cancers constituted around 17% and 15% of patients, respectively, in these trials, and both the trials used a non-standard approach of local therapy, i.e., RT alone and CRT with concurrent carboplatin, respectively. The outcomes were also not compared with the outcomes from the standard of care which is surgery. Therefore, direct extrapolation to OSCC patients may not be possible. These studies clearly demonstrate the advantage of using three-drug over the two-drug regimen for induction. However, feasibility of using TPF chemotherapy in this setting remains low in the Indian context.

Two other trials have evaluated NACT followed by CRT in head-and-neck cancer. The PARADIGM trial compared three cycles of TPF NACT followed by docetaxel or carboplatin-based CRT versus CRT with two cycles of cisplatin alone. Patients were eligible if their tumor was either unresectable or of low surgical curability on the basis of advanced tumor stage (III or IV) or regional-node stage (II or III, except T1N2), or if they were a candidate for organ preservation. The trial was stopped early due to slow enrollment. The 3-year OS was similar, 73% versus 78% for NACT followed by CRT versus CRT alone (P = 0.77).[20] The DeCIDE study compared CRT alone to two cycles of NACT followed by CRT with docetaxel-based regimens in locally advanced head-and-neck SCC. Although OS was similar in both arms (HR, 0.91; 95% CI, 0.59–1.41), the NACT arm had a lower incidence of distant failure (P = 0.043).[21] Similar to the PARADIGM study, the DeCIDE study also did not meet its accrual target.

To summarize, the benefit of induction chemotherapy in clinical practice compared with the present standard CRT remains controversial in inoperable/unresectable disease.

Urgently needed are predictive biomarkers that can identify patients that might benefit from the reduction of the risk of future distant metastases by the sequential chemotherapy approach. It seems, for example, that patients with present versus absent lower neck nodal involvement have a significantly lower 5-year DMFS rate (34.3% vs. 55.2%, P = 0.008) as shown decades ago.[22] These numbers might be different today as therapeutics (chemotherapy and RT) have evolved. Other potential predictive biomarkers are being evaluated, such as p53 or GDF15.[23]

Regimen for preoperative chemotherapy in oral cancer

The three-drug combination of TPF seems to be the most appropriate regimen for preoperative chemotherapy. Noronha et al.[24] retrospectively compared various chemotherapy regimens. Patients had received either a two-drug combination using taxane (either paclitaxel or docetaxel) and platinum (either cisplatin or carboplatin) or a three-drug combination of TPF. The response rate was statistically significantly higher with the three-drug combination: 50% versus 22% with the two-drug regimen (P = 0.004). Comparing the taxane-based regimens, docetaxel had a 30.3% response rate, whereas paclitaxel had a response rate of 17.2% (P = 0.018). There was no statistically significant difference in the response rate between patients receiving either carboplatin or cisplatin.[24] A comparison of a cisplatin and 5FU-based combination versus a three-drug TPF regimen has not been studied in oral cancers in the preoperative setting. However, corollaries can be drawn from the TAX 323 and 324 studies, where these two regimens were compared in locally advanced head-and-neck cancers as induction chemotherapy before definitive CRT.[18],[19] In both studies (TAX 323 and 324), the use of a three-drug combination (TPF) showed a better response rate and better OS. In TAX 323, the median OS was 18.8 months in the TPF arm, whereas it was 14.5 months in the PF arm (P = 0.02).[18] Similarly, in the TAX 324 study, the median OS was 71 months in the TPF arm, whereas it was 30 months in the PF arm (P = 0.006).[19] An individual patient data meta-analysis done by Blanchard et al.[25] confirmed these findings. In both TAX 323 and 324 studies, oral cancer patients were included, though the proportion was below 20%.[18],[19] From these two studies and an earlier study from our center,[24] it can be concluded that the TPF regimen may be the preferred regimen of choice for preoperative chemotherapy.[24]

Number of cycles of preoperative chemotherapy

How many cycles should be given before preoperative surgery is an open question. In the era of cisplatin and 5FU, Paccagnella et al.[26] showed that the response to induction chemotherapy improves until the fourth cycle. Hence, it could be said that when CF is used as the induction chemotherapy, four cycles are required. However, the number of cycles required with the TPF regimen is not known. To the best of our knowledge, there is no study comparing the two cycles of TPF with a higher number of cycles. In TAX 323 and 324 studies, four and three cycles of TPF were used, respectively.[18],[19] In the PARADIGM study, three cycles of TPF were used.[20] In DeCIDE, two cycles of TPF were used.[21] Similarly, two cycles of TPF were used by Zhong et al.[7] Thus, it seems that at least two cycles and a maximum of four cycles can be used when TPF is administered as preoperative chemotherapy. Clinical experience with NACT in our setting would favor the use of three cycles of induction chemotherapy followed by surgery to avoid the chance of progression due to a delayed surgery after four cycles although there are no data to prove the same.

Margins after neoadjuvant chemotherapy

R0 resection is the mainstay of treatment in advanced oral cancers. A positive or close surgical margin is considered as a high-risk factor for recurrence in oral cancer. Both the studies of NACT in resectable OSCC by Licitra et al.[6] and Zhong et al.[7] used pre-NACT tumor extension to calculate the resection volume. However, in the study by Licitra et al., the final surgical choice was left to the judgment of the responsible surgeon on the basis of the actual extent at the time of surgery; also, a macroscopic safe margin of at least 1.5 cm was mandatory. Similar margin was kept in the study by Zhong et al. In their study, margin negativity was achieved in all treated patients in both arms; there was no difference in LRC between the two study groups (30.5% and 31.3%). In contrast, histologically positive margins were noted in four patients in the NACT arm and 12 patients in the control arm, although LRC did not differ between the two arms.

In contrast, in the study by Patil et al. in technically unresectable tumors,[13] surgical resection planned was according to the post-NACT volume. It is interesting to note that only about 3% of patients had close margins, defined as <5 mm, and all patients achieved negative margins.

Whether giving NACT will affect the margin status and will lead to greater negative margins was studied in a matched-pair analysis done by Prabhash et al.[9] The study failed to show any difference in margin positivity rate between upfront operated patients and post-NACT patients, In the Licitra study with revised margin, the extent of locoregional disease was similar in both arms, suggesting that post-NACT revised margin does not impact LRC.

Surgical complications after neoadjuvant chemotherapy

The toxicity associated with NACT can contribute to postoperative mortality and morbidity. A study by Prabhash et al.[13] tried to answer this question in a retrospective analysis, and they found that postoperative major or minor complication rate did not increase following NACT in head-and-neck cancer. There was a concern of increased blood loss following surgery, which needs to be confirmed in further studies. In the study by Licitra et al., two patients in the NACT arm underwent transoral resection without neck dissection because of increased surgical risk and six patients could not undergo planned surgery because of death from toxicity. In the study by Zhong et al., NACT did not increase the surgical or postsurgical complications.

Selecting a post-neoadjuvant chemotherapy regimen

No consensus exists yet regarding the optimal post-TPF regimen, although evidence suggests that some options confer high toxicity without additional benefit. RT alone has the largest body of evidence in cases where organ preservation is the primary objective,[27],[28] yet other regimens (RT plus carboplatin, PF, or cetuximab) have shown encouraging results in the post-NACT setting in smaller studies.[29],[30] However, Phase III randomized trials are imperative to further establish the role of these regimens in sequential chemotherapy and CRT treatment.

The inclusion of cisplatin in both TPF (75 mg/m2 every 3 weeks) and the follow-up CRT (100 mg/m2 every 3 weeks) regimen has been generally associated with low adherence and unacceptably high rates of toxicity.[31],[32] A study of 65 patients randomized to receive either high-dose (100 mg/m2 every 3 weeks) or weekly (40 mg/m2) cisplatin plus RT following four cycles of TPF was terminated early because only 32% of all patients were able to receive the full planned cisplatin dose due to toxicity.[32] No difference in OS rate was observed at 2 years between the two arms.[32] Although the vast majority of patients included in this study were still able to receive >90% of the planned dose of RT,[32] this study suggested that it is inadvisable to administer high cumulative cisplatin doses (300 mg/m2) post-TPF due to associated toxicity issues and low adherence to the systemic component of the treatment. The randomized, Phase II TREMPLIN study in previously untreated patients with Stages III to IV laryngeal/hypopharyngeal SCC administered three cycles of the TAX 323/EORTC 24971 TPF regimen.[29] Poor responders (<50% tumor shrinkage) underwent salvage surgery. Responders (50% tumor shrinkage) were randomly assigned to conventional RT (70 Gy) with concurrent cisplatin (100 mg/m2/day) on days 1, 22, and 43 of RT or concurrent cetuximab (400 mg/m2 loading dose followed by 250 mg/m2/week) during RT. Many patients ended participation in the trial before receiving the RT-based portion of the treatment. However, those who did and were randomized to the cetuximab and RT arm had fewer treatment interruptions and a higher rate of treatment completion than those randomized to the cisplatin and RT arm.[27],[29] Despite that, more relapses occurred in the cetuximab/RT arm than in the cisplatin/RT arm (the majority of which could be salvaged by surgery) with no difference in OS.

Prabhash et al.[11] showed the feasibility of cisplatin-based chemoradiation post-NACT. They showed that around 97% of patients completed RT and around 82% of patients received five or more cycles of weekly cisplatin with manageable Grade 3 toxicities and with only 4% patients developing Grade 3 rise in creatinine post-CRT. They concluded that weekly cisplatin-based CRT seems a feasible approach in the Indian setting after NACT followed by surgery.

Finally, carboplatin or PF can also be paired with RT as post-NACT regimens, as used in TAX 324 and in the Italian trial. Both combination treatments demonstrated favorable safety results, and the majority of patients completed those regimens.[19] However, no results are available directly comparing the combination of RT with cisplatin versus RT plus carboplatin or PF. From the meta-analyses performed until now, comparing carboplatin/RT and cetuximab/RT to cisplatin/RT in the LA SCCHN setting,[33],[34],[35] it can be concluded that the standard cisplatin-based CRT should remain the standard of care until equivalence with carboplatin or cetuximab has been prospectively demonstrated. Moreover, none of these regimens have been fully investigated in the post-NACT setting. As immune checkpoint inhibitors gain approval and are increasingly tested in combination with other therapies, their potential role in follow-up therapy will require examination. Immunotherapies' toxicity profiles are encouraging and may become a key factor in determining their place within the treatment paradigm.

Neoadjuvant chemotherapy in the recurrent setting

Surgical excision of locoregionally recurrent head-and-neck cancers is associated with a median DFS of 17.9 months.[12] Very few patients with recurrences are candidates for R0 resection, and most of these patients receive palliative treatment or CRT with dismal outcomes. NACT, when used in upfront technically unresectable tumors, leads to resection in 43% of patients with improvement in OS. Whether NACT can work in recurrent tumors was studied by Prabhash et al.[13] in a retrospective analysis. The authors analyzed forty patients with recurrent locally advanced technically unresectable head-and-neck cancer who were treated with two cycles of NACT. There was no benefit of NACT in improving outcome in these patients. Certain caveats should be kept in mind while interpreting these results. Majority of the patients (>75%) had a disease-free interval (DFI) below 10 months and 50% of patients had DFI below 6 months, suggesting an aggressive biology of disease; 75% of patients received two-drug taxane + platinum, and only 25% patients received the three-drug regimen. The benefit of NACT in patients with a longer DFI is not known, and studies in this subgroup of patients are required to answer this question.

Role of HPV and neoadjuvant chemotherapy

HPV positivity confers a favorable prognosis in oropharyngeal tumors treated with RT or CRT. It is known that the positive effect of HPV is negated by increasing stage and increasing tobacco exposure. NACT has shown benefit in technically unresectable cancers. Around 80% of patients with oral cavity SCC are smokers. The prognostic value of HPV and p16 positivity has been demonstrated in the induction chemotherapy (paclitaxel/carboplatin or TPF) setting in head-and-neck cancers, where patients with HPV-positive disease had a higher overall response rate and more than double the 5-year survival rates versus patients with HPV-negative disease.[36],[37] The data on the impact of HPV positivity on treatment outcomes in patients with oral cancer are limited.

Prabhash et al. in a retrospective analysis studied 124 patients with technically unresectable oral cavity SCC. The patients were treated with two cycles of NACT, and the authors assessed the difference in outcome between the HPV-positive and HIV-negative cohorts. They found higher response rates, a higher proportion of patients underwent surgical resection, and there was a higher 2-year OS in the HPV-positive cohort. The findings are in contrast to previous studies which studied the outcome difference between these two cohorts in patients with head-and-neck cancers and found no differential outcomes in patients with oral cavity cancers treated with RT or CRT. These differences may be due to higher proportion of HPV-positive patients and a younger median age in the study by Prabhash et al., as well as the fact that they studied outcomes with NACT, whereas others studied outcomes with RT or CRT. Additional large studies will be required to definitively answer this question, to guide whether routine HPV testing needs to be done in all patients with oral cavity SCC, and whether these two cohorts should be treated differently.

Response evaluation post neoadjuvant chemotherapy

The Response Evaluation Criteria in Solid Tumors (RECIST) criteria have been widely used for response assessment both in general clinical practice and clinical trials. However, in RECIST, the focus is on unidimensional imaging and volumetric changes are not included. Prasad et al. have shown that the treatment response was graded differently based on volumetric measurement as opposed to unidimensional imaging of tumor burden in head-and-neck cancers.[15] Thus, reliance on RECIST criteria alone for assessing response might have an implication on the treatment algorithm in head-and-neck cancers. In the study by Zhong et al., 8.1% of patients had a CR by RECIST, whereas 13.4% achieved a pathological CR. Prabhash et al.[16] in their study have shown that there is no correlation between the radiological response and the postoperative pathological response. They showed that 35% of patients with stable disease as per RECIST criteria could undergo surgery with negative margins. Furthermore, both the positive and negative predictive values of radiological response (combination of CR + PR) for the prediction of pathological CR are below 50%. This implies that radiological response alone cannot accurately judge the actual pathological response within the tumor. Consequently, relying on radiological criteria alone could conceivably limit the ability to distinguish responders from non-responders. Thus, there is an urgent need to develop new criteria for predicting response in head-and-neck cancer patients receiving NACT.

Compliance and tolerability of induction chemotherapy

In a routine practice report by Patil et al.,[13] 15.8% of patients discontinued induction chemotherapy after the first cycle. The reasons for discontinuation were mainly logistic issues, but toxicity was an issue in 0.7% of patients.[13] In a prospective study by Zhong et al.,[7] only 1.7% of patients could not complete the planned two cycles of the TPF regimen. Overall, it seems that TPF is well tolerated as preoperative chemotherapy and only 1%–2% of patients cannot receive a second cycle due to toxicity. Notably, the TAX 323/EORTC 24971 regimen was associated with a more favorable safety profile than the previously standard PF regimen.[18],[19]

However, in routine practice, discontinuation due to other reasons seems an issue, especially in the developing world. Selection of patients for TPF is important. The low mortality rate in randomized trials may partly be due to the stringent inclusion and exclusion criteria and partly because the patients included in the trials were younger and fitter than the patients seen in routine practice. Not surprisingly, TPF is associated with high mortalities in routine practice. A mortality rate associated with TPF as high as 15.3% has been reported from California.[38]


  Potential Predictive Biomarkers for Neoadjuvant Chemotherapy in Oral Cancers Top


As discussed earlier, a significant proportion of patients with OSCC have a response to NACT. These patients have been shown to have better LRC, DFS, and OS. In addition, unresectable OSCC may be rendered resectable after NACT. The identification of tumor response predictors may allow a more rational selection of therapeutic strategies, sparing unnecessary toxicities to patients who would not benefit from NACT. It could further lead to the development of new drug regimens to overcome primary resistance to NACT. Multiple studies have proposed biomarkers for predicting response to chemotherapy, but none of them are validated sufficiently to allow use in clinical practice.


  Summary Top


Current evidence suggests that there is a limited role for NACT in locally advanced resectable oral cancer and should not be used outside of a well-designed clinical trial. The addition of NACT has failed to demonstrate an improvement in local control rates and OS in resectable OSCC. The improvement in the distant metastasis rate among a select group of patients requires further validation. There is a need to standardize the definition of resectable advanced OSCC for both clinical practices and for inclusion in future clinical trials. Patients with technically unresectable oral cavity cancers may have responses to the tune of 70% with aggressive three-drug regimen (TPF), and a third of these patients may benefit from subsequent surgical treatment. The patients with good response and subsequent resections have better outcomes. In view of limited benefit with NACT, newer strategies need to be conceived in order to improve the outcome in patients with advanced OSCC. There is an emergent need to generate Indian data from prospective randomized trials to substantiate the benefit of induction chemotherapy in resectable and technically unresectable OSCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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