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Role Neoadjuvant Chemotherapy In Ca Cervix Dr Umesh V

Role neoadjuvant chemotherapy in ca cervix

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NACT IN CARCINOMA CERVIX

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Page 1: Role   neoadjuvant   chemotherapy  in  ca   cervix

Role Neoadjuvant Chemotherapy In Ca Cervix

Dr Umesh V

Page 2: Role   neoadjuvant   chemotherapy  in  ca   cervix

RationaleThe rationales for the use of neoadjuvant chemotherapy (NACT) are several.

Tumor-size reduction may facilitate subsequent local therapy, whether radiotherapy or surgery. This reduction can transform inoperable tumors into radically resectable ones.

Also, NACT has been suggested to increase radiosensitivity and decrease the hypoxic cell fraction.

Moreover, NACT, treats themicrometastatic disease, preventing a significant proportion of relapses.

Finally, response to NACT has been identified as an important prognostic factor in several studies

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Stage IB and II ANeoadjuvant chemotherapy has usually included cisplatin and bleomycin plus one or two other drugs.

The results of uncontrolled studies cannot easily be compared with the results with more traditional treatments because the series are small and often have short follow-up and the criteria for patient selection are not always clear.

Some or all of the patients in each of these series underwent postoperative pelvic irradiation.

Sardi et al. compared radical hysterectomy followed by postoperative radiotherapy with chemotherapy followed by hysterectomy and irradiation; they observed similar outcomes with the two treatments for patients who had tumors smaller than 4 cm in diameter, but they reported a significantly better projected 4-year disease-free survival with neoadjuvant chemotherapy for patients who had larger tumors.

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In 2001, the GOG completed a similar trial; patients who underwent hysterectomy in their trial were treated with postoperative irradiation if they had high-risk features. The results of the GOG study are pending.

Chang et al. 124 patients with bulky stage IB or IIA cervical cancer were randomly assigned to treatment with either chemotherapy followed by radical hysterectomy and radiotherapy or radical radiotherapy alone (without chemotherapy); the authors found no significant differences in disease-free or overall survival between the two treatment groups

Benedetti-Panici et al suggested that among patients with bulky IB & IIA disease, women who received neoadjuvant chemotherapy followed by surgery had a better outcome than women treated with radiotherapy alone; however, because the dose of radiation used in this trial was low and because radiotherapy was frequently protracted and administered without chemotherapy, the results are difficult to relate to current treatment standards.

Ultimately, the cost and morbidity of this triple-modality treatment may only be justified if it proves to be more effective than treatment with the current standard of concurrent chemotherapy and radiotherapy.

Studies comparing these approaches have not yet been reported.

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Stages IIB, III, IV ASeven prospective randomized trials were conducted comparing radiotherapy alone with neoadjuvant chemotherapy followed by radiotherapy

Unfortunately, of these seven trials, five demonstrated no benefit from neoadjuvant therapy, and two demonstrated a significantly better survival rate with radiotherapy alone.

None of these trials compared neoadjuvant chemotherapy followed by radiotherapy with concurrent chemoradiation.

Page 7: Role   neoadjuvant   chemotherapy  in  ca   cervix

Results of Prospective Randomized Trials that Compared Neoadjuvant Chemotherapy Followed by Radiotherapy with Radiotherapy Alone in Patients with Locally Advanced Cervical Cancer

SURVIVAL RATESStudy Year Pati

entsStages Drugs CT +

RT (%)

RT Alone (%)

P End Point

Kumar et al. 1994 184 IIB-IVA BIP 38 43 0.5 OS @32m

Tattersall et al. 1992 71 IIB-IVA PVB 44 40 NS OS @48m

Chauvergne et al.

1990 107 IIIB MtxCVP 47 50 NS OS @48m

Tattersall et al 1995 260 IIB-IVA EpP 50 69 0.02 OS @36m

Sundr et al 1996 94 IIIB-IVA PF 34 37 0.9 OS @48m

Leborgne et al 1997 96 IB2-IVA BOP 38 45 0.4 DFS@ 60m

Souhami et al. 1991 107 IIIB BOMP 23 39 0.02 OS @ 60m

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In summary, despite the high rate of response of locally advanced cervical cancers to neoadjuvant chemotherapy, randomized studies have demonstrated little or no improvement in outcome with the addition of neoadjuvant chemotherapy to radical radiotherapy

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Stage IVBSingle-Agent Chemotherapy

Cisplatin has been studied in a variety of doses and schedules in the management of recurrent or metastatic cervix cancer and is considered the most active agent against the malignancy

Although a number of other agents (e.g., ifosfamide, carboplatin, irinotecan, and paclitaxel) have also exhibited a modest level of biologic activity (response rates of 10% to 20%),the clinical utility of these drugs in patients who have not responded to cisplatin or who have experienced recurrence or progression after chemoradiation is uncertain.

Page 10: Role   neoadjuvant   chemotherapy  in  ca   cervix

Combination Chemotherapy

The results of two phase III randomized trials, published in 2004 and 2005, have provided the first solid evidence that combination chemotherapy can improve both progression-free survival (cisplatin plus paclitaxel vs. single-agent cisplatin, cisplatin plus topotecan vs. single-agent cisplatin) and overall survival (cisplatin plus topotecan) when it is administered as treatment for recurrent or metastatic carcinoma of the cervix.

In the cisplatin-topotecan trial, the combination regimen (cisplatin 50 mg/m2 day 1 and topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks) was associated with a median overall survival of 9.4 months, compared with 6.5 months (P = .17) for single-agent cisplatin.

An ongoing GOG phase 3 trial is directly comparing several platinum-based combination chemotherapy regimens in this clinical setting.

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ConclusionsNACT is feasible and produces impressive responses in cervical carcinoma, as has been demonstrated by several phase II and phase III trials.

Unfortunately, the results of an individual patient data meta-analysis did not support the administration of NACT before radiotherapy alone.

On the other hand, the same meta-analysis suggested that NACT followed by surgeryimproves overall survival compared with nonstandard radiotherapy.

However, the inferiority of the control arm (radiotherapy alone) compared with the current standard of care of chemoradiotherapy precluded the adoption of NACT before surgery as the standard of care.

An ongoing trial by the EORTC Gynecologic Group has been designed to compare NACT followed by surgery to standard chemoradiotherapy, and the final results are eagerly awaited.

In the meantime, NACT should still be considered investigational.

Several trials have shown that patients achieving a pathological complete response to NACT do experience a significant improvement in rates of overall survival.

Based on this observation, new drugs and regimens must be explored in order to increase the rate of pathological complete response.