Neoadjuvant therapy: an emerging concept in oncology.

Abstract: Neoadjuvant therapy, an adjunctive therapy given before the main therapy, has become an integral part of modern multidisciplinary cancer management. Organized by the primary organ involved by cancer, this review summarizes the outcomes of neoadjuvant therapy for common malignant solid tumors, based on large, randomized, controlled trials. In locally advanced rectal, laryngeal, and breast cancer, neoadjuvant therapy enables organ preservation; however, it does not improve overall survival when compared with definitive treatment followed by adjuvant therapy. In locally advanced bladder and cervical cancer, patients who undergo neoadjuvant therapy before radical surgery appear to have better survival than those receiving definitive therapy alone; however, it is unclear if the neoadjuvant approach will be superior to definitive therapy followed by adjuvant therapy. To date, the survival benefits of neoadjuvant therapy for resectable non-small cell lung, esophageal, gastric, and prostate cancer remains under investigation.

Key Words: malignancy, neoadjuvant therapy, organ preservation, preoperative therapy

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Neoadjuvant therapy, an adjunctive therapy given before a definitive treatment, is an essential component of modern multidisciplinary cancer therapy. Although neoadjuvant or induction therapy does not contribute the most to the treatment outcome, it may improve the result substantially. For example, neoadjuvant therapy allows patients with large breast cancer to undergo breast-conserving surgery. It enables patients with locally advanced laryngeal cancer to have their vocal function preserved. Many patients with rectal cancer can avoid permanent colostomy after undergoing this approach. In addition, in certain cancers, neoadjuvant therapy may improve long-term survival. Recent years have seen an increase in the popularity of this treatment technique. The number of clinical trials on this topic published from 2000 to 2003 exceeded the number published during the entire previous decade.

This review summarizes the outcomes of neoadjuvant therapy for common malignant solid tumors. Since many patients rely on non-oncologists for guidance and support during cancer treatment, understanding the rationale and benefit of neoadjuvant therapy may aid primary care physicians in providing support and encouragement to their patients, ultimately improving care and treatment outcomes. The effect of neoadjuvant therapy can be delineated by comparing it with main therapy alone, or in some cancers, with main therapy plus adjuvant therapy, an adjunctive therapy given after the main treatment modality. This review, organized by organ of primary cancer, puts emphasis on long-term survival and organ preservation based on large phase III randomized, controlled trials.

Neoadjuvant therapy has its downside. Many neoadjuvant therapy regimens are cumbersome, requiring a highly motivated patient. For instance, one neoadjuvant therapy regimen for rectal cancer calls for weekly 2-hour infusional chemotherapy for 6 weeks, followed by a pause of 2 weeks. (1) The regimen goes on with daily 5-day intravenous chemotherapy at the beginning of daily 5-week radiation therapy, and another 5-day chemotherapy during the last week of radiation. There is a mandatory pause of up to 8 weeks before surgery, the definitive therapy, to allow maximal tumor shrinkage. The duration of neoadjuvant therapy in this regimen adds up to about 6 months. Unlike an immediate removal of the tumor, prolonged neoadjuvant therapy for resectable cancer can be physically, socially, and emotionally difficult for patients, especially those with gynecologic malignancy. (2) In addition, ineffective neoadjuvant therapy simply means a delay of the definitive treatment and an increase in treatment-related toxicities.

Rectal Cancer

The extensiveness of radical surgery, the main treatment modality for rectal cancer, is an important impetus for neoadjuvant therapy trials. Locally advanced, large, or lower rectal cancer usually necessitates an abdominoperineal resection (APR). APR will result in permanent colostomy and loss of anal function. In addition, after APR, patients whose pathologic findings indicate malignant invasion of rectal subserosa will need adjuvant chemotherapy and radiation to reduce the risk of cancer recurrence. (3) Improved staging techniques, including the use of endoscopic ultrasonography, make it possible to preoperatively identify the patients who will need adjuvant therapy after surgery. In this group of patients who would ultimately need more therapy after surgery, administering adjunctive therapy before surgery appears an attractive option to avoid APR and to improve long-term survival.

Neoadjuvant therapy indeed can help avoid APR in many patients with large or lower rectal tumors. (1,4) Anal sphincter-sparing surgery such as low-anterior resection is feasible in patients judged preoperatively to require APR--after tumor shrinkage from neoadjuvant therapy. Preoperative radiation or combined chemoradiation may offer an up to 75% chance of sphincter-preserving surgery at 6 to 8 weeks after completion of radiation (4); however, long-term survival of patients undergoing neoadjuvant therapy remains similar to those receiving surgery followed by adjuvant therapy. (1)

Nevertheless, when compared with surgery alone, neoadjuvant therapy followed by surgery may improve overall survival. In a large prospective trial published in 1997, the Swedish investigators, using a 5-day course of radiation and a 1-week pause followed by surgery, demonstrated an increase in 5-year survival of patients with resectable rectal cancer from 48% to 58%. (5) However, a subsequent study from the Dutch Colorectal Cancer Group, using the same neoadjuvant radiation, did not indicate a survival advantage of neoadjuvant therapy, although cancer recurrence rate significantly decreased. (6) In this study, every patient also received a total mesorectal excision, a technique known to reduce cancer recurrence. In a meta-analysis of randomized, controlled trials on this topic, patients with resectable rectal cancer treated with neoadjuvant radiotherapy had significantly improved overall and cancer-specific survival compared with surgery alone, but the magnitude of the benefit was small. (7)

Head and Neck Cancer

Surgery, a key treatment for resectable head and neck cancers, frequently results in disfigurement and loss of organ function. Although plastic reconstruction may restore cosmetic appearance, patients with advanced laryngeal or hypopharyngeal cancer will permanently lose their voice after total laryngectomy. Experiences indicate that head and neck tumors respond to chemotherapy and radiation. In fact, many patients who undergo surgery require adjuvant radiation and/or chemotherapy for residual or recurrent disease. The use of chemotherapy and radiation before surgery has been attempted to preserve the larynx and to improve long-term survival.

Laryngeal preservation is possible after neoadjuvant therapy for patients with laryngeal or hypopharyngeal cancer who need total laryngectomy. (8-10) In the late 1980s, the Veterans Affairs Cooperative Laryngeal Cancer Study Group randomly assigned patients with resectable glottic or supraglottic cancer to two treatment arms. (8) One arm received neoadjuvant chemotherapy followed by radiation. If poor response to chemotherapy occurred, patients would proceed to surgery. The other arm received immediate total laryngectomy. Although there was no overall survival difference between the two arms, 64% of patients in the neoadjuvant arm had a functional larynx at 2 years as compared with none in the other arm. In resectable cancer of the piriform sinus or aryepiglottic fold, the same technique also allowed 35% of patients to have functional larynx at 5 years. (9) Recently, however, the use of concurrent chemoradiation has shown a better result when compared with chemotherapy followed by radiation. Concurrent treatment, though associated with greater toxicities, results in 88% of patients with a functional larynx at 2 years as compared with 74% in those receiving treatment in a sequential fashion. (10)

Survival benefit of neoadjuvant therapy for resectable head and neck cancers, however, remains controversial. Many studies comparing neoadjuvant therapy followed by surgery with surgery alone in various sites of head and neck cancer have shown no improvement in long-term survival. (11-13) A few trials, particularly in patients with cancer of the oropharynx or oral cavity, reported a modest improvement in survival outcome with neoadjuvant approach. (14-16)

Breast Cancer

Neoadjuvant chemotherapy plays an important role in breast conservation. Breast conserving surgery, lumpectomy, followed by radiation, gives equivalent results to mastectomy for women with operable invasive breast cancer. (17) Lumpectomy, however, is difficult to perform if the tumor is large. In this situation, neoadjuvant chemotherapy may help reduce the tumor size, enable lumpectomy, and avert mastectomy. (18-20) In a large trial conducted by the National Surgical Breast and Bowel Project, patients with primary operable breast cancer were randomly assigned to surgery with neoadjuvant or adjuvant chemotherapy. (20) Although there was no survival difference between the two arms, 12% more lumpectomies, instead of mastectomy, were performed in the neoadjuvant arm due to tumor shrinkage. The benefit was most pronounced in tumors larger than 5 cm. In addition, the degree of tumor response to neoadjuvant chemotherapy can be used as a long-term prognostic indicator for the individual patient.

Currently, there are many neoadjuvant chemotherapy regimens for breast cancer. Women who have hormone receptor-positive tumor may be eligible for neoadjuvant hormonal treatment. (21,22) Patients who do not respond to one neoadjuvant regimen may respond to others and ultimately become candidates for breast conservation. (23) No neoadjuvant regimen improves overall survival however, when compared with the adjuvant approach. Although longer and more intensive chemotherapy regimens produce greater response rate, none has so far been shown to improve overall survival over the adjuvant approach. (24-26) It is important to note that breast conservation after neoadjuvant therapy may be associated with a higher incidence of local recurrences when compared with mastectomy. (27)

Bladder Cancer 

Patients with bladder cancer, whose tumor grows deep and invades the muscle layer, are at high risk of cancer recurrence after radical cystectomy, the standard treatment, and more than half of the patients who have malignant invasion of perivesicular tissue will have recurrence. (28) Therefore, patients with these unfavorable pathologic findings including those with lymph node metastasis are typically offered adjuvant chemotherapy. Unfortunately, many patients cannot tolerate or become ineligible for chemotherapy after going through radical surgery, leading to the use of preoperative chemotherapy in this group of patients with locally advanced disease. (29)

Neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy improves survival among patients with locally advanced bladder cancer when compared with surgery alone. (30) The median survival among patients receiving surgery alone is 46 months, as compared with 77 months among those receiving neoadjuvant therapy. Nevertheless, it remains unclear if neoadjuvant therapy followed by surgery is better than surgery followed by adjuvant therapy. In an effort to clarify this uncertainty, Millikan et al (29) studied the sequence of chemotherapy in patients with locally advanced bladder cancer. They found that treatment with two cycles of preoperative chemotherapy, followed by three cycles after surgery, produced the same overall survival as 5 cycles after surgery.

Another treatment option for patients with locally advanced bladder cancer is bladder preservation by chemoradiation. (31-33) Salvage surgery is provided only if residual cancer remains. Long-term survival from this approach is not superior to immediate surgery. Although approximately 70% of patients will have their bladder preserved, the preserved bladder may malfunction and frequent cystoscopic surveillance is necessary. Additional neoadjuvant chemotherapy before chemoradiation for bladder preservation does not increase the rate of bladder preservation. (32-34)

Non-small Cell Lung Cancer 

Neoadjuvant therapy for locally advanced non-small cell lung cancer has evolved rapidly near the turn of the century. Historically, radiation used to be the only treatment for unresectable non-small cell lung cancer. In 1990, Dillman et al (35) introduced the use of neoadjuvant cisplatin-based chemotherapy before radiation with better survival, and other chemotherapy regimens used in this fashion also yielded comparable results. (36-38) Nevertheless, adding adjuvant chemotherapy after radiation provided no additional benefit. (39,40) Subsequently, the use of neoadjuvant chemotherapy followed by radiation waned, when concurrent chemoradiation had been found to produce better survival outcome. (41) Today, concurrent chemoradiation is the standard of care for patients with unresectable non-small cell lung cancer who have good performance status.

In certain situations, concurrent chemoradiation has transformed its role from a definitive treatment into a neoadjuvant treatment before radical resection. Concurrent chemoradiation may render some unresectable non-small cell lung cancers resectable. Although no data from randomized, controlled trials are available, it is evident that patients with superior sulcus tumor or pancoast tumor, after undergoing neoadjuvant radiation with or without concurrent chemotherapy, may become eligible for complete resection and achieve prolonged disease-free survival. (42)

For patients with resectable but locally advanced non-small cell lung cancer, outcome of treatment with surgery alone is poor. Several small, randomized studies suggest that neoadjuvant chemotherapy before surgery improves overall survival when compared with surgery alone. (43-45) One such study, for instance, using 3 cycles of chemotherapy followed by surgery, demonstrated an increase in median survival from 8 months in the surgery-alone arm to 26 months in the neoadjuvant arm. (43) Subsequent larger studies, however, produced conflicting results. (46,47) Other investigators have experimented with concurrent chemoradiation followed by surgery in comparison with chemoradiation alone. (48) Preliminary data indicate that patients who respond well to chemoradiation may benefit from subsequent surgery, although long-term follow-up is still necessary.

Recently, Arriagada et al (49) have demonstrated a survival benefit of postoperative chemotherapy for resectable nonsmall cell lung cancer. To date, however, no large, randomized trials between neoadjuvant and adjuvant therapy is available, leaving the role of neoadjuvant therapy in resectable non-small cell lung cancer inconclusive.

Cervical Cancer

Neoadjuvant therapy has a therapeutic role for patients with bulky, locally advanced cervical cancer. Preoperative chemotherapy can induce tumor shrinkage and render radical excision possible in a high percentage of cases. In a large, prospective study, Italian investigators randomly assigned patients with locally advanced cervical cancer to receive neoadjuvant chemotherapy followed by surgery or to undergo a standard treatment with definitive radiation. (50) At 5 years, there was a 10% to 15% survival advantage observed among patients who received neoadjuvant therapy and surgery. Patients with tumor a size less than 4 cm, however, did not appear to benefit from this approach, since the tumors were generally amenable to radical resection at presentation.

Another effective treatment for locally advanced cervical cancer is definitive concurrent chemoradiation. Some gynecologists also choose to perform extrafascial or nonradical hysterectomy after chemoradiation. Because chemoradiation contributes the most to the treatment outcome, in this situation, surgery may be considered an adjuvant therapy. Weekly infusions of cisplatin during radiation, followed by hysterectomy, reduce the risk of disease recurrence and death in women with bulky, locally advanced cervical cancers when compared with radiation alone followed by hysterectomy. (51)

Esophageal and Gastric Cancer 

The value of neoadjuvant therapy before esophagectomy, which is the definitive treatment for esophageal cancer, remains controversial. Two promising neoadjuvant modalities exist, chemoradiation or chemotherapy alone.

In 1996, Walsh et al (52) published a randomized study of treatment with neoadjuvant chemoradiation followed by surgery or immediate surgery. The study included patients with resectable adenocarcinoma of the middle or distal esophagus. Treatment with neoadjuvant chemoradiation followed by surgery was associated with a significantly longer median survival: 16 months compared with 11 months among patients who underwent immediate surgery. However, a subsequent large study of neoadjuvant chemoradiation for patients with resectable squamous cell carcinoma of the esophagus did not confirm this benefit, showing a median survival of approximately 19 months in both arms. (53) Another study including both the patients with squamous cell carcinoma and patients with adenocarcinoma also demonstrated no survival benefit from neoadjuvant chemoradiation when compared with immediate surgery. (54)

The benefit of neoadjuvant chemotherapy without radiation in esophageal cancer is also debatable. (55-58) Chemotherapy alone without radiation potentially reduces toxicity, particularly dysphagia. Some investigators have given chemotherapy both before and after esophagectomy. In a 1998 publication, Kelsen et al (59) found no advantage of intensive treatment comprising neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy over surgery alone. A meta-analysis of randomized, controlled trials on this topic also suggested no survival benefit of neoadjuvant chemotherapy. (60) Recently, however, investigators from the Medical Research Council Esophageal Cancer Working Group (58) demonstrated in a large study that preoperative chemotherapy before surgery significantly increased median survival from approximately 13 months in the surgery-alone arm to 17 months in the neoadjuvant arm.

For gastric cancer, preoperative therapy remains investigational. Neoadjuvant chemotherapy typically yields a low response rate, and no large trial to date has demonstrated a clear benefit on patient's survival or resectability rate of the cancer. (61-63) However, neoadjuvant radiation followed by surgery may improve survival in some patients with cancer of the cardia of the stomach when compared with surgery alone. (63) Currently, surgery followed by adjuvant chemoradiation remains the standard of care in high-risk patients with cancer of the stomach or gastroesophageal junction. (64) This adjuvant approach has been demonstrated in a large phase III, randomized trial to help improve patient's survival when compared with surgery alone. (65)

Prostate Cancer

Prostate cancer is hormone sensitive, and a strong rationale exists for neoadjuvant hormonal therapy. However, none of the trials using androgen deprivation therapy (ADT) to facilitate surgery for locally advanced tumor shows a long-term survival benefit when compared with immediate surgery. Nevertheless, neoadjuvant ADT, typically a 3-month medical castration before prostatectomy, can decrease the incidence of positive surgical margins by 40% to 60%. (66-69) Neoadjuvant chemotherapy with estramustine also produces comparable outcome. (70) Longer duration of neoadjuvant therapy produces greater effect. (71,72) Unfortunately, in most of these studies, long-term follow-up, if available, indicates no decrement in cancer recurrence when compared with surgery alone.

Neoadjuvant ADT before definitive radiation, another principal treatment modality for locally advanced prostate cancer, has also been widely investigated. This treatment may help decrease cancer recurrence when compared with radiation alone, especially among patients with locally advanced disease. (73,74) For example, Shipley et al (74) randomly assigned patients with locally advanced disease to receive neoadjuvant plus concurrent ADT during radiation or radiation followed by adjuvant ADT. After a median follow-up of 9 years, 45% of patients in the neoadjuvant arm had cancer recurrence requiring treatment, as opposed to 63% in the adjuvant arm. However, no overall survival benefit was observed. Because of the long natural history of prostate cancer and the excellent efficacy of hormone therapy when cancer recurs, prolonged follow-up of these studies is necessary to observe the survival benefit of neoadjuvant hormonal treatment.

Conclusion

The role of neoadjuvant therapy has been defined through numerous randomized, controlled trials published during the past few decades. Neoadjuvant regimens, however, continue to evolve rapidly. Typically, one effective neoadjuvant modality leads to the investigation of combined approaches, either sequentially or concurrently. This review, providing a brief overview of some important benefits obtained from neoadjuvant therapy, does not put emphasis on the details of, and variations in, treatment regimens and their associated toxicities. Because separate cancers originating from the same organ can behave differently, and because different treatment regimens, despite being given in a similar neoadjuvant fashion, can produce dramatically different results, it is important that treatment be tailored for each patient, preferably through the collaboration of multidisciplinary specialists.

In summary, neoadjuvant therapy can help preserve organs in certain patients with laryngeal, breast, and rectal cancers (Table). The survival benefit of neoadjuvant therapy is less clear, although it may improve long-term survival in selected patients with rectal, lung, bladder, or cervical cancers.

Table. Selected benefits of neoadjuvant therapy as supported by large
randomized controlled trials

Primary cancer site;               Type of neoadjuvant
stage                              therapy

Rectum; operable                   Chemoradiation followed by surgery
                                   Radiation followed by surgery
Larynx and hypopharynx;            Chemotherapy followed by
  operable, locally advanced         radiation (with salvage surgery)
Breast; operable                   Chemotherapy followed by surgery
Bladder; operable, locally         Chemotherapy followed by surgery
  advanced
Non-small cell lung;               Chemotherapy followed by surgery
  operable, locally advanced
Cervix; locally advanced           Chemotherapy followed by surgery
Esophagus; operable                Chemotherapy followed by surgery
Prostate; locally advanced         Hormone therapy followed by radiation

Primary cancer site;             Compared
stage                            treatment          Benefit

Rectum; operable              Surgery followed by   Anal sphincter
                                adjuvant              preservation
                                chemoradiation
                              Surgery               Survival (a)
Larynx and hypopharynx;       Surgery followed by   Laryngeal
  operable, locally advanced    adjuvant radiation    preservation
Breast; operable              Surgery followed by   Breast conservation
                                adjuvant              (in patients with
                                chemotherapy          large tumors)
Bladder; operable, locally    Surgery               Survival
  advanced
Non-small cell lung;          Surgery               Survival (a)
  operable, locally advanced
Cervix; locally advanced      Radiation             Survival (in stage
                                                      IB2 to IIB)
Esophagus; operable           Surgery               Survival (a)
Prostate; locally advanced    Radiation             Cancer recurrence
                                                      (if Gleason score
                                                      2-6)

Primary cancer site;
stage                         References

Rectum; operable               1, 4
                               5
Larynx and hypopharynx;        8, 9
  operable, locally advanced
Breast; operable              20
Bladder; operable, locally    30
  advanced
Non-small cell lung;          43-45
  operable, locally advanced
Cervix; locally advanced      50
Esophagus; operable           52
Prostate; locally advanced    74

(a) At least one large randomized trial does not demonstrate this
benefit.

Accepted August 9, 2004.

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RELATED ARTICLE: Key Points

* In locally advanced resectable rectal, laryngeal, and breast cancer, neoadjuvant therapy enables organ preservation, but it does not improve overall survival.

* In locally advanced bladder and cervical cancer, patients who undergo neoadjuvant therapy before radical surgery appear to have better survival than those receiving definitive therapy alone.

* The survival benefits of neoadjuvant therapy for resectable non-small cell lung, esophageal, gastric, and prostate cancer remains under investigation.

Tawee Tanvetyanon, MD, Joseph I. Clark, MD, Steve C. Campbell, MD, PHD, and Simon S. Lo

From the Division of Hematology/Oncology, Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL; the Department of Urology, Loyola University Chicago Stritch School of Medicine and Edward Hines Jr. Veterans Administration Hospital, Hines, IL; and the Department of Radiation Oncology, Indiana University Medical Center, Indianapolis, IN.

Reprint requests to Dr. Tawee Tanvetyanon, Cardinal Bernardin Cancer Center, 2160 South First Avenue, Maywood, IL 60153. E-mail: [e-mail]