Neoadjuvant chemotherapy (NACT); also called Induction chemotherapy is a treatment option in cancer therapy, in which chemotherapy is given prior to the definitive treatment like surgery or radiotherapy.
Neoadjuvant chemotherapy in cancer treatment can reduce the tumor volume, improve organ function prior to definitive treatment, permits more effective and less toxic local therapy.
Giving NACT can also address sub-clinical distant metastasis without delay and can improve local-regional control and organ preservation.
Neoadjuvant chemotherapy can also provide prognostic information about the tumor. Patients who show a good response to NACT, have good prognosis when compared to patients with poor response after chemotherapy.
Where to consider Neoadjuvant chemotherapy?
Regarding the role of NACT in head and neck cancers, there exist only a few randomized phase III trials.
Neoadjuvant chemotherapy in Oral Cancers
According to the National Comprehensive Cancer Network’s (NCCN) clinical practice guidelines, the role of NACT in Oral cavity cancers is limited only to very advanced head and neck cancers (category 3 evidence), or patients who are unfit to undergo definitive treatment like surgery or radiotherapy.
Licitra et al have studied the role of primary NACT in resectable oral cavity cancers. This was a randomized, multicenter trial enrolling 195 patients with a resectable, stage T2-T4 (> 3 cm), N0-N2, M0 untreated, squamous cell carcinoma of the oral cavity between 1989 to 1999.
Patients were randomly assigned to two arms. In the first arm, patients received three cycles of cisplatin and 5-fluorouracil followed by surgery (chemotherapy arm). The second arm patients were taken for primary surgery alone (control arm). In both arms, postoperative radiotherapy was given to high-risk patients.
After a median follow-up of 76 months, their results can be tabulated as follows:
|5 year||Loco-regional recurrence||Distant Mets||2nd primary||Overall survival||Need for segmental Mandibulectomy|
|With Good Clinical response to NACT|
|NACT followed by surgery||31%||7%||6%||55%||78%||significant p-value||31%|
They concluded that the addition of primary chemotherapy to standard surgery was not associated with any significant difference in loco-regional recurrence, distant metastasis, the chance of second primary and overall survival.
When subgroup analysis was done, they observed that patient who shown good clinical response to NACT has better and significant 5-year overall survival (78%), compared to those with poor clinical response (57%) after NACT.
The most important observation in their study was that mandible could be preserved in patients who received NACT prior to surgery and the need for a segmental mandibulectomy can be avoided. Compared to patients who went for upfront surgery, mandibular preservation was possible in 21% of patients.
The landmark trial to study the role of NACT in oropharyngeal cancers is the Groupe d’Etude des Tumeurs de la Tête Et du Cou (GETTEC) Trial.
They randomized 318 patients,
|Median Survival||5-year Overall survival||5-year Event-free survival|
|Induction chemotherapy followed by Radiotherapy||5.1 years||21%||16%|
With a median follow-up of 5 years, overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on 5 year event-free survival was smaller and of borderline significance (P = 0.11).
One of the landmark studies on the role of NACT in hypopharyngeal cancers was from the European Organisation for Research and Treatment of Cancer (EORTC). The EORTC trial included data from 194 patients of stage II/III/ IV hypopharyngeal squamous cell carcinoma.
Patients were randomized into two arms. Patients in first went for upfront surgery – total laryngectomy with partial pharyngectomy and neck dissection, followed by adjuvant radiotherapy (50Gy). Patients in second arm received two cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-fluorouracil 1000 mg/m(2) day 1-5) – followed by a reassessment. Those patients who showed a good response to chemotherapy was given a third cycle also, prior to definite radiotherapy (70Gy). Those patients in the second arm, with poor response to chemotherapy, were taken out for surgery.
Results of the EORTC trial is summarized below:
|Overall survival||Recur at||Distant Mets||Laryngectomy-free survival|
|NACT followed by RT/Sx||11%||3.7y||38%||13%||14%||19%||38%||22%||9%|
|Abbreviations: DFS (Disease-free survival), LFS (Laryngectomy free survival), RT (Radiotherapy), Sx (Surgery), s (significant), ns (Non-significant)|
The patients were followed up for a median period of 10.5 years. Though there was a significant difference in median overall survival (1.6 years extra with NACT followed by RT) there was no significant difference in 10-year overall survival. At the end of 10 years, larynx could be preserved in 9% of patients.
“Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer” from the Department of Veterans Affairs Laryngeal Cancer Study Group is the most important trial which established the role of neoadjuvant chemotherapy in laryngeal cancers.
This randomized trial included 332, stage III/IV laryngeal cancer patients. The trial design was similar to the EORTC trial.
Patients were randomly assigned to two arms; one group received three cycles of chemotherapy (Cisplatin with 5-fluorouracil) followed by definitive radiotherapy (66 to 76 Gy) or surgery with adjuvant radiotherapy. Clinical tumor response was assessed after two cycles of chemotherapy, and patients with a good clinical response received the third cycle of chemotherapy, which was followed by definitive radiation therapy. Patients with no clinical response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy.
Results of the VA trial can be summarized as follows
|DFS||2yr OS||Recur at primary||Recur at regional||Distant Mets||Laryngectomy-free survival|
|NACT followed by RT||65%||68%||12%||8%||11%||39%|
|Abbreviations: DFS (Disease-free survival), OS (Overall survival), RT (Radiotherapy), s (significant), ns (Non-significant)|
At a median follow-up of 33 months, no significant difference was observed in disease-free survival and 2-year overall survival.
Patterns of recurrence differed significantly between the two groups, with more local recurrences and fewer distant metastases in the chemotherapy group than in the surgery group.
36 percent of patients in chemotherapy arm required total laryngectomy as a salvage option, while larynx could be preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease.
This study established the role of NACT followed by definite RT in advanced laryngeal cancers as an effective organ preservation strategy, without compromising overall survival.
Another important trial to study role of induction chemotherapy in laryngeal cancers came again from the French GETTEC group.
The GETTEC trial in the larynx, included 68 patients of T3 laryngeal squamous cell carcinoma.
The trial arms were same as that in VA trial, one arm patients received total laryngectomy followed by radiotherapy and other arm patients received induction chemotherapy, followed by radiotherapy in good responders, and by total laryngectomy plus radiotherapy in poor responders.
|2 year DFS||2 year OS||8 year Laryngectomy-free survival|
|Induction chemo followed by Radiotherapy||62%||69%||42%|
15 of the 36 (42%) patients in the induction chemotherapy group did not have a laryngectomy. But survival and disease-free survival were significantly worse in the induction chemotherapy group than in the surgery group.
Preservation of larynx at an expense of survival was the conclusion of GETTEC trial and the trial concluded against using induction chemotherapy as a standard treatment for laryngeal cancers.
The RTOG 91-11 trial studied different modalities of radiotherapy in locally advanced laryngeal cancers.
With a primary endpoint larynx of larynx preservation, 547 patients were randomly assigned to one of three groups. Group A received radiotherapy alone, Group B went for radiotherapy with concurrent administration of cisplatin, and Group C received induction cisplatin plus 5-fluorouracil followed by radiotherapy.
|5yr||DFS||OS||Intact larynx||LR control||Distant Mets|
|C: IC followed by RT||38%||58%||75%||61%||15%|
|p-value||0.02(C vs A)|
0.006(B vs A)
|NS||0.005(B vs C)|
0.001(B vs A)
|0.004(B vs C)|
0.001(B vs A)
|0.03(B vs A)|
With a median follow-up period was 3.8 years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin differed significantly from the patients who received induction chemotherapy followed by radiotherapy or radiotherapy alone.
Rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin. Both chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups.
The rate of high-grade toxic effects was greater with the chemotherapy-based regimens. The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy.
The RTOG 91-11 trial concluded that, in patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.
Which drug regimen for Neoadjuvant chemotherapy?
TAX 323 trial and TAX 324 trials are the two landmark trials which studied which chemotherapy regimen is best for induction chemotherapy in head and neck cancers. GORTEC 2000-01, trial studied which chemotherapy regimen is ideal in laryngeal cancers.
TAX 323 trial included 358 patients of unresectable stage III/IV, M0 head and neck squamous cell carcinomas. Patients were randomly assigned into two groups. Group I received a three-drug regimen TPF (docetaxel 75mg/m2 and cisplatin 75mg/m2, day 1; 5-fluorouracil 750mg/m2 by continuous infusion, days 1 to 5) while group II received two-drug regimen PF (Cisplatin 100mg/m2 on day 1, followed by 5FU 1000mg/m2 days 1-5) every 3 weeks for four cycles. Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy. The primary endpoint was progression-free survival.
At end of 32.5 months median follow-up, patients who received TPF regimen had a significant clinical response (33% vs 20%), median progression-free survival (11 vs 8 months), median overall survival (19 vs 15 months) compared to those who received PF regimen.
Grade III/IV toxicities and death due to toxicities were significantly higher with PF regimen than with TPF. It was unclear whether this was due to the low dosage of Cisplatin and 5-fluorouracil used in TPF arm.
TAX 324 trial included 501 patients, both resectable and unresectable, stage III, IV, M0 head and neck squamous cell carcinomas.
In the TPF arm, patients received Docetaxel 75mg/m2 and Cisplatin 100mg/m2, day 1; 5FU 1000mg/m2 by continuous infusion, days 1 to 5. In PF arm, patients received Cisplatin 100mg/m2 on day 1, followed by 5FU 1000mg/m2 days 1-5 every 3 weeks for three cycles. Patients who were showing less than 25% clinical response at the end of the second cycle were taken out of study for salvage surgery. Rest of the patients received concurrent chemoradiotherapy (CCRT) with 70-74Gy radiation and weekly Carboplatin at end of 3rd. Those patients who had N3 disease, residual disease after CCRT received salvage surgery.
With a median follow-up of 72.2 months, they found that induction chemotherapy with TPF provides better long term survival benefit compared to PF in locally advanced head and neck squamous cell carcinoma. Better overall survival was observed with larynx followed by hypopharynx, oropharynx, oral cavity. TAX 324 trial concluded that patients who are candidates for induction chemotherapy should be treated with TPF regimen.
|5 yr overall survival||Median survival||Progress free survival|
|TPF||52%||70.6 months||38 months|
|PF||42%||34.8 months||13.2 months|
The GORTEC 2000-01 trial studied TPF vs PF regimen in 213 operable previously untreated stage-III or -IV larynx or hypopharynx squamous cell carcinoma who are candidates for total laryngectomy. With a similar study design as that of TAX 324 trial, patients were randomly assigned into two arms, one receiving TPF and another PF regimen.
The primary endpoint was a three-year larynx preservation rate. Secondary endpoints included larynx dysfunction-free survival (LDFFS), overall survival (OS), disease-free survival (DFS), loco-regional control rate (LCR), cause of death, and later toxicity rates.
After a median follow-up of 105 months, they observed that induction chemo with TPF increased larynx preservation and larynx dysfunction free survival. But there was no significant difference in OS, DFS, LRC.
Larynx preservation rate
|Larynx dysfunction-free survival||OS DFS, LRC|
Gr-III/IV late toxicities
|5 year(%)||10 year(%)||5 year(%)|
A meta-analysis by Blanchard et al, regarding TPF versus PF regimen in locally advanced head and neck squamous cell carcinoma, included five randomized trials representing 1,772 patients were identified. The analysis showed that TPF regimen is better over PF as induction chemotherapy. But its precise role in the management of locally advanced head and neck squamous cell carcinoma remains to be determined.
When to consider Neoadjuvant chemotherapy?
Role of induction chemotherapy prior to definitive radiotherapy was studied in PARADIGM Trial, DeCIDE Trial, TTCC Trial and the RTOG 91-11 Trial. Randomized studies by Licitra et al and Zhong et al studied the role of induction chemotherapy prior to surgery.
PARADIGM Trial studied the role of induction chemotherapy followed by concurrent chemo-radiotherapy (CCRT) versus concurrent chemotherapy alone. The study included 145 patients, unresectable Stage III/IV HNSCC or candidates for organ preservation.
Patients were randomized into two arms, the first arm patients received 3 cycles of TPF followed by CCRT, while patients in second arm received upfront CCRT. With a median follow-up of 49 months, survival results were good in both groups and no significant difference was observed in overall survival between induction chemotherapy followed by CCRT (73%) versus CCRT alone (77%).
Similar to PARADIGM Trial, the DeCIDE Trial studied the role of induction chemotherapy followed by concurrent chemo-radiotherapy (CCRT) versus concurrent chemotherapy alone. 285 patients of N2/3 head and neck squamous cell carcinoma or candidates for organ preservation were included in the DeCIDE Trial.
Patients were randomized into two arms, the first arm patients received 2 cycles of TPF followed by CCRT, while patients in the second arm received upfront CCRT.
DeCIDE Trial observed significantly higher toxicities in the induction chemotherapy followed by CCRT arm. The trial concluded that induction chemotherapy did not translate into improved overall survival compared with CRT alone and induction chemo cannot be recommended routinely in patients with N2 or N3 locally advanced head and neck squamous cell carcinoma.
The TTCC Trial included 439 stage III/IV locally advanced head and neck squamous cell carcinoma patients. Patients were randomized into three arms. Patients in Group I received induction chemo with TPF followed by CCRT, Group II received induction chemo with PF followed by CCRT and Group III received upfront CCRT.
At a median follow-up of 23 months, induction chemotherapy failed to show any advantage over CCRT alone in patients with unresectable locally advanced head and neck squamous cell carcinoma.
|Progression-free survival||Time to treatment failure||Overall survival||Grade 3/4 toxicity|
The RTOG 91-11 trial (explained above) observed an increased risk of serious toxicity with induction chemotherapy better locoregional control and high rates of larynx preservation achievable with CCRT. The overall conclusion was induction chemotherapy followed by CCRT was inferior to CCRT alone for laryngeal preservation and locoregional control.
A meta-analysis by Budach et al on induction chemotherapy followed by CCRT versus CCRT alone in locally advanced head and neck cancers included trials and 1022 patients. They concluded that additional induction TPF before CCRT does not improve overall survival and progression-free survival in locally advanced HNSCC compared to definite CCRT.
The MACH-NC Meta-Analysis of chemotherapy in head and neck cancers included 100 randomized trials, 19,248 patients having resectable or unresectable disease. They concluded that with longer follow-up, CCRT is superior compared to induction chemotherapy followed by RT in HNSCC and the addition of induction chemotherapy did not increase overall survival.
The role of primary chemotherapy in resectable oral cavity squamous cell cancer was studied by Licitra et al (explained before). Though they observed no significant difference in locoregional recurrence, distant metastasis, 2nd primary or 5-year overall survival, need for a destructive surgery (like mandibulectomy) was less in patients who received NACT prior to surgery. Also, patients who have shown a good clinical response after NACT had a better 5-year overall survival than those with poor response to NACT.
Another similar study by Zhong et al regarding role induction chemotherapy prior to surgery observed that patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those who received upfront surgery. But there were no significant differences in overall 5-year survival rates.
As of today, the current evidence (category 3) support induction chemotherapy only in locally advanced head and neck squamous cell carcinomas. Evidence shows that NACT may have a role in organ preservation.
Metaanalysis has proven that TPF drug regimen is better than PF drug regimen, but the optimum number of cycles needed is still not clear.
Hopefully, more randomized phase 3 trials in future may demonstrate the benefit of the NACT approach in head and neck cancers.
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